人干扰素-β在生菜中的表达、鉴定和生物活性研究
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摘要
随着分子生物学和遗传转化技术的发展,利用转基因植物生产人或动物基因工程药物蛋白已成为植物基因工程的一个新兴研究领域。与目前的细菌、酵母及哺乳动物细胞等传统药物蛋白生产系统相比,用转基因植物生产基因工程药物蛋白具有其独特的优势:成本低,可以以农业化的规模生产昂贵的生化药物;完整的真核细胞表达系统,使表达产物具有较好的生物活性;安全性好,无外源性病原污染;口服植物疫苗能诱导粘膜免疫反应,生产简便、成本低廉,不需要冷藏和低温运输。但植物表达存在表达量低、下游分离纯化困难等严重问题,因此寻找新的转基因植物受体,开发新的植物表达系统,成为植物生物反应器研究的重点。
本研究以叶用生菜(Lactuca sativa L.sp)为试验材料,探讨优化生菜农杆菌真空渗透瞬时转化方法和稳定转化组织培养体系,采用瞬时转化方法将四种不同的干扰素-β基因转入生菜中,研究生菜瞬时表达干扰素-β的水平和生物活性,获得结果如下:
1.对生菜的瞬时表达方法进行了系统优化,建立了适宜生菜高效瞬时表达的转化体系(200μmol/L乙酰丁香酮、0.8OD600菌液密度、真空处理30min、共培养6d)。以条件A1B1C1D1(0μmol/L乙酰丁香酮、0.4OD600菌液密度、真空处理10min、共培养2d)为对照,应用结果表明:优势组合的GUS表达水平为21.39nmol? mg-1? min-1 MU,比对照(1.31 nmol? mg-1? min-1 MU)提高16.3倍。结果表明该生菜瞬时表达体系可有效的提高外源基因的表达。
2.糖蛋白药物干扰素-β在生菜叶片中成功表达为27kDa的蛋白,推测为带有植物特有糖基化形式的糖蛋白;抗病毒活性表明,该干扰素-β能抑制水泡性口膜炎病毒对人羊膜Wish细胞的攻击,这也是首次对农杆菌真空渗透瞬时表达来源的生化药物进行生物活性检测的报道。由于基因定点突变使第17位半胱氨酸改为丝氨酸(Cys-Ser),去除了Cys17对正常二硫键(Cys31和Cys141)的影响,使干扰素β的空间结构更稳定,因此,突变型的干扰素表达量和活性高于原始型干扰素。四种干扰素-β(IFN,无信号肽的干扰素-β;sIFN,有信号肽的干扰素-β;mIFN,无信号肽突变型的干扰素-β;smIFN,有信号肽突变型的干扰素-β)表达产物的活性分别为:3.1×104IU/mL,5.8×104IU/mL,6.3×104IU/mL,9.8×104IU/mL;表达量也依次升高。表明:Cys17向Ser17的改变及信号肽的添加有利于干扰素-β表达量和活性的提高,可以利用农杆菌介导的瞬时表达方法快速、大量、廉价的生产人源细胞因子、疫苗等生化药物。
3.为探讨干扰素-β在植物中的糖基化形式,构建含有糖基酶PNGase F的植物双元表达载体pBI121-F,将含有pBI121-F的农杆菌GV3101与含有pBI121-smIFN的农杆菌GV3101混合后,真空渗透转化生菜叶片,以期利用PNGase F的酰胺内切酶作用将干扰素-β的糖链切除,但通过Western检测,没有发现干扰素-β分子量的变化,可能是由于干扰素-β的表达量较低,不能检测到PNGase F的作用,也可能是由于植物糖基化结构中含有较多的α-1,3-岩藻糖,α-1,3-岩藻糖的位阻影响了PNGase F的酶切作用。
4.以三种不同基因型生菜(日本生菜,美国大叶速生,泰国生菜)的两种外植体(10d龄的子叶和真叶)为材料,建立了适合多种基因型生菜组织培养和植株再生体系:MS培养基添加0.1 mg/L NAA和0.1-0.5mg/L 6-BA,为不同基因型生菜的最适不定芽诱导培养基;基因型不同,所要求的激素浓度配比也不同:日本生菜的高效不定芽诱导激素配比为0.1mg/L 6-BA和0.1mg/L NAA,美国大叶速生为0.3mg/L 6-BA and 0.1mg/L NAA,泰国生菜为0.5mg/L 6-BA和0.1mg/L NAA;真叶的不定芽分化率显著高于子叶的分化率。最适的生根培养基为添加0.1mg/L NAA的MS;生菜不定芽诱导生根较易,基因型和外植体类型对生根的影响较小;基因转化中卡那霉素的适宜筛选浓度为50mg/L。生菜为强自花授粉作物,转入基因不容易丢失;生菜叶片可直接生食。该体系的建立有利于生菜的基因转化,对利用生菜稳定表达基因工程类药物奠定试验基础。
5.采用重叠延伸PCR的方法构建了与GUS基因融合的IFN基因片段,以期利用GUS的高表达带动HuIFN-β的表达。
With the development of plant molecular biology and genetic engineering, plant-based expression system have emerged as a new promising force in the large-scale biopharmaceutical protein production for preventation or therapy. For some products, transgenic plants offer many potential advantages over traditional systems based on microbial or animal cells, or transgenic animals. A major advantage is the comparatively low cost of large-scale production. Plants also have the ability to process post-translational modifications, a low risk of contamination by organisms pathogenic, oncogenic DNA sequences, and endotoxins to humans and animal. Furthermore, plants or plant products which are edible provide the additional unique opportunity of serving as vehicles for oral delivery of the vaccine. However, several challenges remain to be met in terms of increasing yields, improving glycoprotein authenticity, removing processing bottlenecks and addressing biosafety and acceptability issues, as well as industry inertia. So finding new plant-expression host and exploiting new plant expression systems are the focus of plant-base expression study.
Using Leaf lettuce(Lactuca sativa L.sp) as plant material, Agrobacterium vacuum infiltration transient expression system and tissue culture system were discussed and optimized. Employed the optimized transient expression system, expression vectors containing four IFN genes were transferred to lettuce leaves. Western blot and antivirus detection were employed to analyze these four genes expression and bioactivity. The main results were as follows:
1. Established a high efficient transient expression system in lettuce. Intact lettuce leaves infiltrated with 200μM acetosyringone and 0.8 OD600 bacterial suspensions under vacuum for 30 minutes, then co-cultured at 24℃for 6 ds had the highest transient expression level. Used A1B1C1D1(0μmol/L acetosyringone, 0.4OD600 bacterial suspensions, vacuum for 10min, vacuum for 30 minutes 2d) as control,the optimized system produced a maximum GUS protein of 2.5% TSP with 21.39nmol?mg-1?min-1 MU activity, which was nineteen times of the control (1.31 nmol?mg-1?min-1 MU). The result indicated that the established transient expression system can significantly enhance transgenic gene expression.
2. HuIFN-beta was successfully expressed as a 27kDaa glycoproein with plant special glycosylation in lettuce leaves. Antivirus bioactivity detection confirmed that the HuIFN-beta achieved by agrobacterium infiltration could inhibit VSV cytopathic effect in human amnionic (WISH) cells. By site-specific mutagenesis with serine (Ser) substitute cysteine (Cys) at the 17th in human interferon-beta gene, the influence of Cys17 on the normal bisulfur bond of Cys31 and Cys141 was elimating, and the space structure of interferon-beta became more stable. So the mutant interferon-beta had higher expression level. Antivirus bioactivities of four interferon-beta types (IFN,interferon-beta without signal peptide; sIFN, interferon-beta with signal peptide;mIFN,interferon-beta with mutant; smIFN, interferon- beta with signal peptide and mutant) were 3.1×104IU/mL, 5.8×104IU/mL, 6.3×104IU/ML, and 9.8×104IU/mL respectively. To our knowledge, it is the first detailed orthogonal optimizing study of Agrobacterium mediated transient expression and the first report on the production of the biologically active therapeutic proteins produced by Agrobacterium mediated transient expression in lettuce. In summary, transient expression by Agrobacterium vacuum infiltration can be adopted as an efficient, inexpensive and small-scaled plant expression system for therapeutic protein production.
3. Constructed plant expression vector pBI121-F containing the gene of PNGase F with the aim to discuss glycosylation of interferon-beta in lettuce. Individual Agrobacterium cultures (GV3101) carrying the 35S: F and the 35S: IFN constructs were mixed together and infiltrated into leaves of lettuce. The result of Western blot indicated that: the molecular weight of IFN is not changed. This maybe because the expression level is too low to detect or moreα-1, 3-Fucose contained in plant glycosylation blocked the process of PNGase F.
4. Cotyledons and leaves of three genotype leaf lettuce (Lactuca sativa L cultivars: Japanese Lettuce, American Grand Rapid, Thailand Lettuce) at 10-day were excised and cultured on MS basal medium supplemented with different combinations of hormones. A high efficient plant regeneration system adaptive to three different genotypes was developed in our study. MS-medium supplemented with 0.1-0.5 mg/L N6-benzylaminopurine (6-BA) in combination with 0.1mg/Lα-naphthaleneacetic acid (NAA) was the most effective to induce adventitious shoot directly. Genotype and explant type all have significant effects on shoot regeneration efficiency in terms of the percentage of explants producing shoots and the number of shoots produced per explant. Different genotype has its own optimal shoot-inducing medium and leaf is more responsive than cotyledons for shooting on the same culture conditions. Regenerated shoots were highly rooted on 1/2MS basal medium just supplemented with 0.1mg/L NAA alone. In addition, we also discovered that 50 mg/L kanamycin is enough for selection in gene transformation for different genotype leaf lettuces. These protocols will facilitate explants regeneration and gene transformation for a range of genotype lettuces.
5. Used overlap extension PCR, constructed a fused gene with GUS and IFN with the aim to increase the expression level of IFN.
本研究以叶用生菜(Lactuca sativa L.sp)为试验材料,探讨优化生菜农杆菌真空渗透瞬时转化方法和稳定转化组织培养体系,采用瞬时转化方法将四种不同的干扰素-β基因转入生菜中,研究生菜瞬时表达干扰素-β的水平和生物活性,获得结果如下:
1.对生菜的瞬时表达方法进行了系统优化,建立了适宜生菜高效瞬时表达的转化体系(200μmol/L乙酰丁香酮、0.8OD600菌液密度、真空处理30min、共培养6d)。以条件A1B1C1D1(0μmol/L乙酰丁香酮、0.4OD600菌液密度、真空处理10min、共培养2d)为对照,应用结果表明:优势组合的GUS表达水平为21.39nmol? mg-1? min-1 MU,比对照(1.31 nmol? mg-1? min-1 MU)提高16.3倍。结果表明该生菜瞬时表达体系可有效的提高外源基因的表达。
2.糖蛋白药物干扰素-β在生菜叶片中成功表达为27kDa的蛋白,推测为带有植物特有糖基化形式的糖蛋白;抗病毒活性表明,该干扰素-β能抑制水泡性口膜炎病毒对人羊膜Wish细胞的攻击,这也是首次对农杆菌真空渗透瞬时表达来源的生化药物进行生物活性检测的报道。由于基因定点突变使第17位半胱氨酸改为丝氨酸(Cys-Ser),去除了Cys17对正常二硫键(Cys31和Cys141)的影响,使干扰素β的空间结构更稳定,因此,突变型的干扰素表达量和活性高于原始型干扰素。四种干扰素-β(IFN,无信号肽的干扰素-β;sIFN,有信号肽的干扰素-β;mIFN,无信号肽突变型的干扰素-β;smIFN,有信号肽突变型的干扰素-β)表达产物的活性分别为:3.1×104IU/mL,5.8×104IU/mL,6.3×104IU/mL,9.8×104IU/mL;表达量也依次升高。表明:Cys17向Ser17的改变及信号肽的添加有利于干扰素-β表达量和活性的提高,可以利用农杆菌介导的瞬时表达方法快速、大量、廉价的生产人源细胞因子、疫苗等生化药物。
3.为探讨干扰素-β在植物中的糖基化形式,构建含有糖基酶PNGase F的植物双元表达载体pBI121-F,将含有pBI121-F的农杆菌GV3101与含有pBI121-smIFN的农杆菌GV3101混合后,真空渗透转化生菜叶片,以期利用PNGase F的酰胺内切酶作用将干扰素-β的糖链切除,但通过Western检测,没有发现干扰素-β分子量的变化,可能是由于干扰素-β的表达量较低,不能检测到PNGase F的作用,也可能是由于植物糖基化结构中含有较多的α-1,3-岩藻糖,α-1,3-岩藻糖的位阻影响了PNGase F的酶切作用。
4.以三种不同基因型生菜(日本生菜,美国大叶速生,泰国生菜)的两种外植体(10d龄的子叶和真叶)为材料,建立了适合多种基因型生菜组织培养和植株再生体系:MS培养基添加0.1 mg/L NAA和0.1-0.5mg/L 6-BA,为不同基因型生菜的最适不定芽诱导培养基;基因型不同,所要求的激素浓度配比也不同:日本生菜的高效不定芽诱导激素配比为0.1mg/L 6-BA和0.1mg/L NAA,美国大叶速生为0.3mg/L 6-BA and 0.1mg/L NAA,泰国生菜为0.5mg/L 6-BA和0.1mg/L NAA;真叶的不定芽分化率显著高于子叶的分化率。最适的生根培养基为添加0.1mg/L NAA的MS;生菜不定芽诱导生根较易,基因型和外植体类型对生根的影响较小;基因转化中卡那霉素的适宜筛选浓度为50mg/L。生菜为强自花授粉作物,转入基因不容易丢失;生菜叶片可直接生食。该体系的建立有利于生菜的基因转化,对利用生菜稳定表达基因工程类药物奠定试验基础。
5.采用重叠延伸PCR的方法构建了与GUS基因融合的IFN基因片段,以期利用GUS的高表达带动HuIFN-β的表达。
With the development of plant molecular biology and genetic engineering, plant-based expression system have emerged as a new promising force in the large-scale biopharmaceutical protein production for preventation or therapy. For some products, transgenic plants offer many potential advantages over traditional systems based on microbial or animal cells, or transgenic animals. A major advantage is the comparatively low cost of large-scale production. Plants also have the ability to process post-translational modifications, a low risk of contamination by organisms pathogenic, oncogenic DNA sequences, and endotoxins to humans and animal. Furthermore, plants or plant products which are edible provide the additional unique opportunity of serving as vehicles for oral delivery of the vaccine. However, several challenges remain to be met in terms of increasing yields, improving glycoprotein authenticity, removing processing bottlenecks and addressing biosafety and acceptability issues, as well as industry inertia. So finding new plant-expression host and exploiting new plant expression systems are the focus of plant-base expression study.
Using Leaf lettuce(Lactuca sativa L.sp) as plant material, Agrobacterium vacuum infiltration transient expression system and tissue culture system were discussed and optimized. Employed the optimized transient expression system, expression vectors containing four IFN genes were transferred to lettuce leaves. Western blot and antivirus detection were employed to analyze these four genes expression and bioactivity. The main results were as follows:
1. Established a high efficient transient expression system in lettuce. Intact lettuce leaves infiltrated with 200μM acetosyringone and 0.8 OD600 bacterial suspensions under vacuum for 30 minutes, then co-cultured at 24℃for 6 ds had the highest transient expression level. Used A1B1C1D1(0μmol/L acetosyringone, 0.4OD600 bacterial suspensions, vacuum for 10min, vacuum for 30 minutes 2d) as control,the optimized system produced a maximum GUS protein of 2.5% TSP with 21.39nmol?mg-1?min-1 MU activity, which was nineteen times of the control (1.31 nmol?mg-1?min-1 MU). The result indicated that the established transient expression system can significantly enhance transgenic gene expression.
2. HuIFN-beta was successfully expressed as a 27kDaa glycoproein with plant special glycosylation in lettuce leaves. Antivirus bioactivity detection confirmed that the HuIFN-beta achieved by agrobacterium infiltration could inhibit VSV cytopathic effect in human amnionic (WISH) cells. By site-specific mutagenesis with serine (Ser) substitute cysteine (Cys) at the 17th in human interferon-beta gene, the influence of Cys17 on the normal bisulfur bond of Cys31 and Cys141 was elimating, and the space structure of interferon-beta became more stable. So the mutant interferon-beta had higher expression level. Antivirus bioactivities of four interferon-beta types (IFN,interferon-beta without signal peptide; sIFN, interferon-beta with signal peptide;mIFN,interferon-beta with mutant; smIFN, interferon- beta with signal peptide and mutant) were 3.1×104IU/mL, 5.8×104IU/mL, 6.3×104IU/ML, and 9.8×104IU/mL respectively. To our knowledge, it is the first detailed orthogonal optimizing study of Agrobacterium mediated transient expression and the first report on the production of the biologically active therapeutic proteins produced by Agrobacterium mediated transient expression in lettuce. In summary, transient expression by Agrobacterium vacuum infiltration can be adopted as an efficient, inexpensive and small-scaled plant expression system for therapeutic protein production.
3. Constructed plant expression vector pBI121-F containing the gene of PNGase F with the aim to discuss glycosylation of interferon-beta in lettuce. Individual Agrobacterium cultures (GV3101) carrying the 35S: F and the 35S: IFN constructs were mixed together and infiltrated into leaves of lettuce. The result of Western blot indicated that: the molecular weight of IFN is not changed. This maybe because the expression level is too low to detect or moreα-1, 3-Fucose contained in plant glycosylation blocked the process of PNGase F.
4. Cotyledons and leaves of three genotype leaf lettuce (Lactuca sativa L cultivars: Japanese Lettuce, American Grand Rapid, Thailand Lettuce) at 10-day were excised and cultured on MS basal medium supplemented with different combinations of hormones. A high efficient plant regeneration system adaptive to three different genotypes was developed in our study. MS-medium supplemented with 0.1-0.5 mg/L N6-benzylaminopurine (6-BA) in combination with 0.1mg/Lα-naphthaleneacetic acid (NAA) was the most effective to induce adventitious shoot directly. Genotype and explant type all have significant effects on shoot regeneration efficiency in terms of the percentage of explants producing shoots and the number of shoots produced per explant. Different genotype has its own optimal shoot-inducing medium and leaf is more responsive than cotyledons for shooting on the same culture conditions. Regenerated shoots were highly rooted on 1/2MS basal medium just supplemented with 0.1mg/L NAA alone. In addition, we also discovered that 50 mg/L kanamycin is enough for selection in gene transformation for different genotype leaf lettuces. These protocols will facilitate explants regeneration and gene transformation for a range of genotype lettuces.
5. Used overlap extension PCR, constructed a fused gene with GUS and IFN with the aim to increase the expression level of IFN.
引文
1.金伯泉主编. 细胞和分子免疫学.第一版,世界图书出版公司,西安,1995 年,1335-1371
2.刘红莉, 雷霆, 王一理, 司履生. 转基因植物疫苗研究策略. 中国生物工程杂志, 2004, 4:30-33
3. Aalberse R. C., Koshte V. and Clemens J. G.. Cross-reactions between vegetable foods, pollen and bee venom due to IgE antibodies to a ubiquitous carbohydrate determinant. Int. Arch. Allergy Appl. Immunol., 1981, 66:259-260
4. Abe M., Goto T., Kosaka M., Wolfenbarger D., Weiss D. T. and Solomon A.. Differences in kappa to lambda (κ:λ) ratios of serum and urinary free light chains. Clin. Exp. Immunol., 1998, 111:457-462
5. Alconero R.. Regeneration of plants from cell suspensions of Lactuca saligna, Lactuca sativa, and Lactuca serriola. HortScience, 1983,18: 305–307
6. Allen G. C., Spiker S. and Thompson W. F.. Use of matrix attachment regions (MARs) to minimize transgene silencing. Plant Mol. Biol., 2000, 43:361-376
7. Altschul S. F., Madden T. L., Schaffer A. A., Zhang J., Zhang Z., Miller W. and Lipman D. J .. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res., 1997, 25:3389-3402
8. Ampomah-Dwamena C.; Conner A.J. and Fautrier A.G.. Genotypic response of lettuce coty- ledons to regeneration in vitro. Scientia Horticulture, 1997,71: 137-145
9. Arakawa T., Chong D. K. and Langridge W. H.. Efficacy of a food plantbased oral cholera toxin B subunit vaccine. Nat. Biotechnol., 1998, 16:292-297
10. Arakawa T., Chong D. K., Merritt J. L. and Langridge W. H.. Expression of cholera toxin B subunit oligomers in transgenic plants. Transgenic Res., 1997, 6:403-413
11. Arcalis E., Marcel S., Altmann F., Kolarich D., Drakakaki G., Fischer R., Christou P. and Stoger E.. Unexpected deposition patterns of recombinant proteins in post-endoplasmic reticulum compartments of wheat endosperm. Plant Physiol., 2004, 136:3457-3466
12. Artsaenko O., Kettig B., Fiedler U., Conrad U. and During K.. Potato tubers as a bio- factory for recombinant antibodies. Mol. Breed., 1998, 4:313-319
13. Austin S., Bingham E. T., Koegel R. G., Mathews D. E., Shahan M. N., Straub R. J. and Burgess R. R.. An overview of a feasibility study for the production of industrial enzymes in transgenic alfalfa. Annu. NY. Acad. Sci., 1994, 721:235-244
14. Awram P., Gardner R. C., Forster R. L. and Bellamy A. R.. The potemtial of Plant viral vectors and transgenic plants for subunit vaccine production. Adv. Virus. Res., 2002, 58:81-124
15. Azzoni A. R., Kusnadi A. R., Miranda E. A. and Nikolov Z. L.. Recombinant aprotinin produced in transgenic corn seed: extraction and purification studies. Biotechnol. Bioeng., 2002, 80:268-276
16. Bakker H., Bardor M., Molthoff J. W., Gomord V., Elbers I., Stevens L. H., Jordi W., Lommen A., Faye L., Lerouge P. and Bosch D.. Galactose-extended glycans of antibodies produced by transgenic plants. Proc. Natl. Acad. Sci., 2001, 98:2899-2904
17. Bakker H., Florack D., Bosch H. and Rouwendal G.. Optimizing Glycan Processing in Plants. Patent WO 03/078637, 2003
18. Bandyopadhyay P. K., Garrett J. E., Shetty R. P., Keate T., Walker C. S. and Olivera B. M.. Gammaglutamyl carboxylation: an extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates. Proc. Natl. Acad. Sci., 2002, 99:1264-1269
19. Banerjee S., Shang T. Q., Wilson A. M., Moore A. L., Strand S. E., Gordon M. P. and Doty S. L.. Expression of functional mammalian P450 in hairy root cultures. Biotechnol. Bioeng., 2002, 77:462-466
20. Bardor M., Faveeuw C., Fitchette A. C., Gilbert D., Galas L., Trottein F., Faye L. and Lerouge P.. Immunoreactivity in mammals of two typical plant glycoepitopes, core α(1,3)-fucose and core xylose. Glycobiology, 2003, 13:427-434
21. Bardor M., Loutelier-Bourhis C., Paccalet T., Cosette P., Fitchette A. C., Vezina L. P., Trepanier S., Dargis M., Lemieux R., Lange C., Faye L. and Lerouge P.. Monoclonal C5-1 antibody produced in transgenic alfalfa plants exhibits a N-glycosylation that is suitable for glycol-engineering into human-compatible structures. Plant Biotechnol. J., 2003, 1:451-462
22. Barta A., Sommergruber K., Thompson D., Hartmuth K., Matzke M. and Matzke A.. The expression of a nopaline synthase-human growth hormone chimeric gene in transformed tobacco and sunflower callus tissue. Plant. Mol. Biol., 1986, 6:347-357
23. Becker G. W., Tackitt P. M., Bromer W. W., Lefeber D. S. and Riggin R. M.. Isolation and characterization of a sulfoxide and a desamido derivative of biosynthetic human growth hormone. Biotechnol. Appl. Biochem., 1988, 10: 326-337
24. Belanger H., Fleysh N., Cox S., Bartman G., Deka D., Trudel M., Koprowski H. and Yusibov V.. Human respiratory syncytial virus vaccine antigen produced in plants. FASEB J., 2000, 14: 2323-2328
25. Berger M., Shankar V. and Vafai A.. Therapeutic applications of monoclonal antibodies. Am. J. Med. Sci., 2002, 324: 14-30
26. Betthauser J,Forsberg E,Augenstein M,Childs L,Eilertsen K,Enos J,Forsythe T,Golueke P,Jurgella G,Koppang R,Lesmeister T,Mallon K,Mell G,Misica P,Pace M,Pfister-Genskow M,Strelchenko N,Voelker G,Watt S,Thompson S and Bishop M.. Production of cloned pigs from in vitro systems. Nat Biotechnol, 2000, 18: 1055-1059
27. Betts D., Bordignon V., Hill J., Winger Q., Westhusin M., Smith L. and King W.. Repro- gramming of telomerase activity and rebuilding of telomere length in cloned cattle. Proc. Natl. Acad. Sci., 2001, 98:1077-1082
28. Biemelt S., Sonnewald U., Gaimbacher P., Willmitzer L. and Muller M.. Production of human papillomavirus type 16 viral like particles in transgenic plants. J. Virol., 2003, 77:9211-9220
29. Blixt O., Allin K., Pereira L., Datta A. and Paulson JC.. Efficient chemoenzymatic synth- esis of O-linked sialyloligosaccharides. J. Am. Chem. Soc., 2002, 124 :5739-5746
30. Boisson M., Gomord V., Audran C., Berger N., Dubreucq B., Granier F., Lerouge P., Faye L., Caboche M. and Lepiniec L.. Arabidopsis glucosidase I mutants reveal a critical role of N-glycan trimming in seed development. EMBO J., 2001, 20 :1010-1019
31. Boothe J. G., Saponja J. A. and Parmenter D. L.. Molecular farming in plants: oilseed as vehicles for the production of pharmaceutical proteins. Drug Dev. Res., 1997, 42:172-178
32. Borisjuk N.V., Borisjuk L. G., Logendra S., Petersen F., Gleba Y. and Raskin I.. Production of recombinant proteins in plant root exudates. Nat. Biotechnol., 1999, 17:466-469
33. Borth N., Strutzenberger K., Kunert R., Steinfellner W. and Katinger H.. Analysis of changes during subclone development and ageing of human antibody-producing heterohybridoma cells by northern blot and flow cytometry. Biotechnol., 1999, 67: 57-66
34. Bruyns A.M., De Jaeger G., De Neve M., De Wilde C., Van Montagu M. and Depicker A.. Bacterial and plant produced scFv proteins have similar antigen-binding properties. FEBS Lett., 1996, 386:5-10
35. Cabanes-Macheteau M., Fitchette-Laine A. C., Loutelier-Bourhis C., Lange C., Vine N. D., Ma J. K., Lerouge P. and Faye L.. N-Glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology, 1999, 9:365-372
36. Cacia J., Quan C. P., Vasser M., Sliwkowski M. B. and Frenz J.. Protein sorting by high performance liquid chromatography. I. Biomimetic interaction chromatography of recom- binant human deoxyribonuclease I on polyionic stationary phases. J. Chromatogr., 1993, 634:229-239
37. Carrington D. M., Auffret A. and Hanke D. E.. Polypeptide ligation occurs during post- translational modification of concanavalin A. Nature, 1985, 313:64-67
38. Chargelegue D., Obregon P., Drake P. M. W.. Transgenic plants for vaccine production: Expectations and limitations. Trends Plant Sci., 2001, 6:495-496
39. Chargelegue D., Vine N. D., van Dolleweerd C. J., Drake P. M. and Ma J. K.. A murine monoclonal antibody produced in transgenic plants with plant specific glycans is not im- munogenic in mice. Transgenic Res., 2000, 9:187-194
40. Chen T.L., Lin Y.L., Lee Y.L., Yang N.S. and Chan M.T.. Expression of bioactive human interferon-gamma in transgenic rice cell suspension cultures. Transgenic research, 2004,13 (5):499-510
41. Chenu S., Gregoire A., Malykh Y., Visvikis A., Monaco L., Shaw L., Schauer R., Marc A. and Goergen J. L.. Reduction of CMP-N-acetylneuraminic acid hydroxylase activity in engi- neered Chinese hamster ovary cells using an antisense-RNA strategy. Biochim. Biophys. Acta., 2003, 1622:133-144
42. Chong D. K. X. and Langridge W. H. R.. Expression of fulllength bioactive antimicrobial human lactoferrin in potato plants. Transgenic Res., 2000, 9:71-78
43. Chong D.K.X., Roberts W., Arakawa T., Illes K., Bagi G., Slattery C. W. and Langridge W. H.. Expression of the human milk protein β-casein in transgenic potato plants. Transgenic Res., 1997, 6:289-296
44. Christensen A. H. and Quail P. H.. Ubiquitin promoter-based vectors for high level expre- ssion of selectable and/or screenable marker genes in monocotyledonous plants. Transgenic Res., 1996, 5:213-218
45. Coker J. S. and Davies E.. Selection of candidate housekeeping controls in tomato plants using EST data. Bio. Techniques, 2003, 35:740-748
46. Commandeur U., Twyman R. M. and Fischer R.. The biosafety of molecular farming in plants. Ag. Bio. Tech. Net., 2003, 5:110
47. Conrad U. and Fiedler U.. Compartment specific accumulation of recombinant immuno- globulins in plant cells: an essential tool for antibody production and immunomodulation of physiological functions and pathogen activity. Plant Mol. Biol., 1998, 38:101-109
48. Conrad U., Fiedler U., Artsaenko O. and Phillips J.. High-level and stable accumulation of single-chain Fv antibodies in plant storage organs. J. Plant Physiol., 1998, 152:708-711
49. Cramer C. L., Weissenborn D. L., Oishi K. K., Grabau E. A., Bennett S., Ponce E., Grabo- wski G. A. and Radin D. N.. Bioproduction of human enzymes in transgenic tobacco. Ann. NY. Acad., 1996, 792:62-71
50. Cramer C.L., Boothe J. G. and Oishi K. K.. Transgenic plants for therapeutic proteins: linking upstream and downstream strategies. Curr. Top. Microbiol. Immunol., 1999, 240:95-118
51. Crofcheck C., Loiselle M., Weekly J., Maiti I., Pattanaik S., Bummer P. M. and Jayt M.. Histidine-tagged protein recovery from tobacco extract by foam fractionation. Biotechnol. Prog., 2003, 19:680-682
52. Curtis, W.R.. Quantitative transient protein expression in plant tissue culture, U.S. Patent 6,740,526, 2004
53. Dai Z.Y., Hooker B. S., Anderson D.B. and Thomas S. R.. Improved plant-based produ- ction of E1 endoglucanase using potato: expression optimization and tissue targeting. Mol. Breed, 2000, 6:277-285
54. Dalsgaard K., Uttenthal A., Jones T. D., Xu F., Merryweather A., Hamilton W. D., Lange- veld J. P., Boshuizen R. S., Kamstrup S., Lomonossoff G. P., Porta C., Vela C., Casal J. I., Meloen R. H. and Rodgers P. B.. Plant-derived vaccine protects target animals against a viral disease. Nat. Biotechnol., 1997, 15:248-252
55. Damell J E , Kerr IM and Stark GR.. JakSTAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994,264: 1415-1421
56. Daniell H. and Dhingra A.. Multigene engineering: dawn of an exciting new era in biotechnology. Curr. Opin. Biotechnol., 2002, 13:136-141
57. Daniell H., Khan M. S. and Allison L.. Milestones in chloroplast genetic engineering: an environmentally friendly era in biotechnology. Trends Plant Sci., 2002, 7:84-91
58. Daniell H., Lee S. B., Panchal T. and Wiebe P. O.. Expression of the native cholera B toxin subunit gene and assembly as functional oligomers in transgenic tobacco chloroplasts. J. Mol. Biol., 2001, 311:1001-1009
59. Daniell H., Streatfield S. J. and Wycoff K.. Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci., 2001, 6:219-226
60. De Cosa B., Moar W., Lee S-B., Miller M. and Daniell H.. Overexpression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nat. Biotechnol. 2001, 19:71-74
61. De Jaeger G., Scheffer S., Jacobs A., Zambre M., Zobell O., Goossens A., Depicker A. and Angenon G.. Boosting heterologous protein production in transgenic dicotyledonous seeds using Phaseolus vulgaris regulatory sequences. Nat. Biotechnol., 2002, 20:1265-1268
62. De Jaeger G., Buys E., Eeckhout D., De Wilde C., Jacobs A., Kapila J., Angenon G., Van Montagu M., Gerats T. and Depicker A.. High-level accumulation of single-chain variable fragments in the cytosol of transgenic Petunia hybrida. Eur. J. Biochem., 1999, (259):426-434
63. De Neve M., De Loose M., Jacobs A., van Houdt H., Kaluza B., Weidle U., Van Montagu M. and Depicker A.. Assembly of an antibody fragment in N. tabacum and Arabidopsis. Transgenic Res., 1993, 2:227-237
64. De Wilde C., de Neve M., de Rycke R., Bruyns A.M., De Jaeger G., Van Montagu M., Depicker A. and Engler G.. Intact antigen-binding MAK33 antibody and Fab fragment accumulate in intercellular spaces of A. thaliana. Plant Sci., 1996, 114:233-241
65. De Wilde C., Peeters K., Jacobs A., Peck I. and Depicker A.. Expression of antibodies and Fab fragments in transgenic potato plants: a case study for bulk production in crop plants. Mol. Breed., 2002, 9:271-282
66. De Wilde C., Van Houdt H., de Buck S., Angenon G., de Jaeger G. and Depicker A.. Plants as bioreactors for protein production: avoiding the problem of transgene silencing. Plant Mol. Biol. 2000, 43:347-359
67. Deblaere R., Bytebier B., Greve D.H., Deboeck F., Schell J., Montagu V.M.and Leemans J.. Efficient octopine Ti plasmid-derived vectors for Agrobacterium-mediated gene transfer to plants. Nucleic Acids Res., 1985,13: 777-788
68. Denbow D.M., Grabau E. A., Lacy G. H., Kornegay E.T., Russell D. R. and Umbeck P. F.. Soybeans transformed with fungal phytase gene improve phosphorus availability for broilers. Poult. Sci., 1998, 77:878-881
69. DeZoeten G. A., Penswick J. R., Horisberger M. A., Ahl P., Schultze M. and Hohn T.. The expression, localization, and effect of a human interferon in plants. Virology, 1989, 172: 213-222
70. Dieryck W., Gruber V., Baudino S., Lenee P., Pagnier J., Merot B. and Poyart C.. Expre- ssion of recombinant human hemoglobin in plants. Transfus. Clin. Biol., 1995, 2:441-447
71. Dieryck W., Pagnier J., Poyart G., Marden M.C., Gruber V., Bournat P., Baudino S. and Merot B.. Human haemoglobin from transgenic tobacco. Nature, 1997, 386:29-30
72. Doerschug M.R. and Miller C.O.. Chemical control of adventitious organ formation in Lactuca sativa explants. American Journal of Botany, 1967,54: 410–413
73. Doran P. M.. Foreign protein production in plant tissue cultures. Curr. Opin. Biotechnol., 2000, 11:199-204
74. Drake P. M. W., Chargelegue D. M., Vine N. D., Van Dolleweerd C. J., Obregon P. and Ma J. K.C.. Rhizosecretion of a monoclonal antibody protein complex from transgenic tobacco roots. Plant Mol. Biol., 2003, 52:233-241
75.Edelbaum O., Ilan N., Grafi G., Sher N., Stram Y., Novick D., Tal N., Sela I. and Rubinstein M.. Purification and characterization of two antivirally active proteins from tobacco by monoclonal antibodies to human beta-interferon. Proc. Natl. Acad. Sci., 1990, 87: 588-592.
76. Eeckhout D., Fiers E., Sienaert R., Snoeck V., Depicker A. and De Jaeger G.. Isolation and characterization of recombinant antibody fragments against CDC2a from Arabidopsis thaliana. Eur. J. Biochem., 2000, 267:6775-6783.
77. Elbers I. J., Stoopen G. M., Bakker H., Stevens L. H., Bardor M., Molthoff J. W., Jordi W. J., Bosch D. and Lommen A.. Influence of growth conditions and developmental stage on N-glycan heterogeneity of transgenic immunoglobulin G and endogenous proteins in tobacco leaves. Plant Physiol., 2001, 126:1314-1322
78. Elliott S., Lorenzini T., Asher S., Aoki K., Brankow D., Buck L., Busse L., Chang D., Fuller J., Grant J., Hernday N., Hokum M., Hu S., Knudten A., Levin N., Komorowski R., Martin F., Navarro R., Osslund T., Rogers G., Roger, N., Trail G. and Egrie J.. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat. Biotechnol., 2003, 21:414-421
79. Ellstrand N. C.. Going to “great lengths” to prevent the escape of genes that produce specialty chemicals. Plant Physiol., 2003, 132:1770-1774
80. Evangelista R. L., Kusnadi, A.R., Howard J. A. and Nikolov Z. L.. Process and economic evaluation of the extraction and purification of recombinant β-glucuronidase from transgenic corn. Biotechnol. Prog., 1998, 14: 607-614
81. Farran I., Sanchez-Serrano J. J., Medina J. F., Prieto J. and Mingo-Castel A. M.. Targeted expression of human serum albumin to potato tubers. Transgenic Res., 2002, 11:337-346
82. Faye L. and Chrispeels M. J.. Transport and processing of the glycosylated precursor of concanavalin A in jack-bean. Planta, 1987, 170:217-224
83. Faye L. and Chrispeels M.J.. Common antigenic determinants in the glycoproteins of plants, molluscs and insects. Glycoconj. J., 1988, 5:245-256
84. Faye L., Gomord V., Fitchette-Laine A. C. and Chrispeels M. J.. Affinity purification of antibodies specific for Asn-linked glycans containing alpha 1→3? fucose or beta 1 →2? xylose. Anal. Biochem., 1993, 209:104-108
85. Fiedler U. and Conrad U.. High-level production and long-term storage of engineered antibodies in transgenic tobacco seeds. Bio.Technol. 1995, 13:1090-1093
86. Fiedler U., Phillips J., Artsaenko O. and Conrad U.. Optimization of scFv antibody production in transgenic plants. Immunotechnology, 1997, 3:205:216
87. Fischer R. and Emans N.. Molecular farming of pharmaceutical proteins. Transgen Res., 2000, 9:279-299
88. Fischer R., Drossard J., Emans N., Commandeur U. and Hellwig S.. Towards molecular farming in the future: Pichia pastoris-based production of single-chain antibody fragments. Biotechnol. Appl. Biochem., 1999, 30:117-120
89. Fischer R., Emans N., Schuster F., Hellwig S. and Drossard J.. Towards molecular farming in the future: using plant cell suspension cultures as bioreactors. Biotechnol. Appl. Biochem., 1999, 30: 109-112
90. Fischer R., Hoffmann K., Schillberg A. and Emans N.. Antibody production by molecular farming in plants. J. Biol. Regul. Hemeost. Agents, 2000, 14:83-92
91. Fischer R., Liao Y. C. and Drossard J.. Affinity-purification of a TMV-specific recombi- nant full-size antibody from a transgenic tobacco suspension culture. J. Immunol. Methods, 1999, 226:1-10
92. Fischer R., Stoger E., Schillberg S., Christou P. and Twyman R. M.. Plant-based production of biopharmaceuticals. Curr. Opin. Plant. Biol., 2004, 7:152-158
93. Fischer R., Vaquero-Martin C., Sack M., Drossard J., Emans N. and Commandeur U.. Towards molecular farming in the future: transient protein expression in plants. Biotechnol. Appl. Biochem., 1999, 30:113-116
94. Fischer R. and Emans N.. Molecular farming of pharmaceutical proteins. Transgenic Res., 2000,9: 279-299
95. Fitchette-Laine A.C., Gomord V., Chekkafi A. and Faye L..Distribution of xylosylation and fucosylation in the plant Golgi apparatus. Plant J., 1994, 5:673-682
96. Fooks A. R.. Development of oral vaccines for human use. Curr. Opin. Mol. Ther., 2000, 2:80-86
97. Fotisch K., Altmann F., Haustein D. and Vieths S.. Involvement of carbohydrate epitopes in the IgE response of celery-allergic patients. Int. Arch. Allergy. Immunol., 1999, 120:30-42
98. Fraley R. T., Rogers S. G., Horsch R. B., Sander P. R., Flick J. S., Adams S. P., Bittner M. L., Brand L. A., Fink J. S., Galluppi G. R. Goldberg S. B., Hoffmann N. L. and Woo S. C.. Expression of bacterial genes in plant cells. Proc. Natl. Acad. Sci., 1983, 80:4803- 4807
99. Francesco S. M., Manuela R. and Alessandra B.. Vaccine antigen production in transgentic plants: strategies, gene constructs and perspectives. Vaccine, 2003, 21:803-805
100. Frigerio L., Vine N.D., Pedrazzini E., Hein M. B., Wang F., Ma J. K. and Vitale A.. Assembly, secretion, and vacuolar delivery of a hybrid immunoglobulin in plants. Plant Physiol., 2000, 123:1483-1494
101. Fu X.D., Duc L. T., Fontana S., Bong B. B., Tinjuangjun P., Sudhakar D., Twyman R. M., Christou P. and Kohli A.. Linear transgene constructs lacking vector backbone sequences generate low copy number transgenic plants with simple integration patterns. Transgenic Res., 2000, 9:11-19
102. Garcia-Casado G., Sanchez-Monge R., Chrispeels M. J., Armentia A., Salcedo G. and Gomez L.. Role of complex asparagine-linked glycans in the allergenicity of plant glycol- proteins. Glycobiology, 1996, 4:471-477
103. Gasdaska J. R., Spencer D. and Dickey L.. Advantages of therapeutic protein production in the aquatic plant Lemna. Bioprocess J., 2003,2:49-56
104. Geetha K. B., Lending C. R., Lopes M. A., Wallace J. C. and Larkins B.A.. opaque-2 modifiers increase γ-zein synthesis and alter its spatial distribution in maize endosperm. Plant Cell, 1991, 3:1207-1219
105. Giddings G., Allison G., Brooks D. and Carter A.. Transgenic plants as factories for biopharmaceuticals. Nat. Biotechnol. 2000, 18:1151-1155
106. Giddings G.. Transgenic plants as protein factories. Curr. Opin. Biotechnol. 2001, 12:450-454
107. Gil F., Brun A., Wigdorovitz A., Catala R., Martinez-Torrecuadrada J. L., Casal I., Salinas J., Borca M. V. and Escribano J. M.. High yield expression of a viral peptide vaccine in transgenic plants. FEBS Lett. 2001, 488:13-27
108. Gleba Y., Marillonnet S. and Klimyuk V.. Engineering viral expression vectors for plants: the ‘full virus’ and the ‘deconstructed virus’ strategies. Curr. Opin. Plant Biol., 2004, 7:182-188
109. Gleba Y., Klimyuk V. and Marillonnet S.. Magnifection-a new platform for expressing recombinant vaccines in plants. Vaccine, 2005, 23: 2042–2048
110. Goddjin O. J. M. and Pen J.. Plants as bioreactors. Trends Biotechnol., 1995, 13: 379-387
111. Goldstein D. A. and Thomas J. A.. Biopharmaceuticals derived from genetically modified plants. Q.J.M., 2004, 97:705-716
112. Gomord V. and Faye L.. Posttranslational modification of therapeutic proteins in plants. Current. Opin. Plant Biol., 2004, 7:171-181
113. Gomord V., Chamberlain P., Jefferis R. and Faye L.. Biopharmaceutical production in plants: problems, solutions and opportunities. Trends Biotechnol., 2005, 23:559-565
114. Gomord V., Denmat L. A., Fitchette-Laine A. C., Satiat-Jeunemaitre B., Hawes C. and Faye L.. The C-terminal HDEL sequence is sufficient for retention of secretory proteins in the endoplasmic reticulum (ER) but promotes vacuolar targeting of proteins that escape the ER. Plant J. 1997, 11:313-325
115. Gomord V., Sourrouille C., Fitchette A. C., Bardor M., Pagny S., Lerouge P. and Faye L.. Production and glycosylation of plant-made pharmaceuticals: the antibodies as a challenge. Plant Biotechnol. J., 2004, 2:83-100
116. Gomord V., Wee E. and Faye L.. Protein retention and localization in the endoplasmic reticulum and the golgi apparatus. Biochimie., 1999, 81:607-618
117. Gruber V., Berna P. P., Arnaud T., Bournat P., Clement C., Mison D., Olagnier B., Philippe L., Theisen M., Baudino S., Benicourt C., Cudrey C., Blo?s C., Duchateau N., Dufour S., Gueguen C., Jacquet S., Ollivo C., Poncetta C., Zorn N., Ludevid D., Van Dorsselaer A., Verger R., Doherty A., Merot B. and Danzin C.. Large-scale production of a therapeutic protein in transgenic tobacco plants: effects of subcellular targeting on quality of a recombinant dog gastric lipase. Mol. Breed., 2001, 7:329-340
118. Gura T.. Therapeutic antibodies: magic bullets hit the target. Nature, 2002, 417:584-586
119. Gutierrez-Ortega A., Sandoval-Montes C., Olivera-Flores T.D., Santos-Argumedo L. and Gomez-Lim M. A.. Expression of functional interleukin-12 from mouse in transgenic tomato plant. Transgenic Research, 2005,14 (6):877-885
120. Gutterman JU. Cytokine therapeutics. lessons from interferonα.Proc Natl Acad Sci,1994 ,91:1198-1205
121. Hamamoto H., Sugiyama Y., Nakagawa N., Hashida E., Matsunaga Y., Takemoto S., Watanabe Y. and Okada Y.. A new tobacco mosaic virus vector and its use for the systematic production of angiotensin-I-converting enzyme inhibitor in transgenic tobacco and tomato. Biotechnology, 1993, 11:930-932
122. Haq T. A., Mason H. S., Clements J. D. and Arntzen C. J.. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science, 1995, 268:714-716
123. Hendy S., Chen Z. C., Barker H., Santa Cruz S., Chapman S., Torrance L., Cockburn W. and Whitelam G. C.. Rapid production of single-chain Fv fragments in plants using a potato virus X episomal vector. J. Immunol. Methods, 1999, 231:137-146
124. Hens J. R., Amstutz M. D., Schanbacher F. L. and Mather I. H.. Introduction of the human growth hormone gene into the guinea pig mammary gland by in vivo transfection promotes sustained expression of human growth hormone in the milk throughout lactation. Biochim. Biophys. Acta. 2000, 1523:161-171
125. Hiatt A., Cafferkey R. and Bowdish K.. Production of antibodies in transgenic plants. Nature, 1989, 342:76-78
126. Hiatt A., Schillberg S., Emans N. and Fischer R.. Antibody molecular farming in plants and plant cells. Phytochem. Rev., 2002, 1:45-54
127. Hockney R. C..Recent developments in heterologous protein production in Escherichia coli . Trends in Biotech , 1994 , 12 (11): 456-463
128. Hood E. E. and Jilka J. M.. Plant-based production of xenogenic proteins. Curr. Opin. Biotechnol., 1999, 10:382-386
129. Hood E. E., Kusnadi A., Nikolov Z. and Howard J. A.. Molecular farming of industrial proteins from transgenic maize. Adv. Exp. Med. Biol., 1999, 464:127-147
130. Hood E. E., Woodard S. L. and Horn M. E.. Monoclonal antibody manufacturing in transgenic plants-myths and realities. Curr. Opin. Biotechnol., 2002, 13: 630-635
131. Horsch R., Fry J. E. , Hoffman N., Eicholtz D., Rogers S. and Fraley R.. A simple and general method for transferring genes into plants. Science, 1985, 227:1229-1231
132. Horvath H., Huang J., Wong O., Kohl E., Okita T., Kannangara L. G. and Von Wettstein D.. The production of recombinant proteins in transgenic barley grains. Proc. Natl. Acad. Sci., 2000, 97:1914-1919
133. Houdebine L. M.. Antibody manufacture in transgenic animals and comparisons with other systems. Curr. Opin. Biotechnol., 2002, 13:625-629
134. Huang Z., Dry I., Webster D., Strugnell R. and Wesselingh S.. Plant-derived measles virus hemagglutinin protein induces neutralizing antibodies in mice. Vaccine, 2001, 19:2163-2171
135. Hudson P. J.. Recombinant antibody fragments. Curr. Opin. Biotechnol., 1998, 9:395-402
136. Humphreys D. P. and Glover D. J.. Therapeutic antibody production technologies: molecules, applications, expression, and purification. Curr. Opin. Drug Discover. Dev., 2001, 4:172-185
137. Hunter D.C. and Burritt D.J.. Improved adventitious shoot production from cotyledon explant of lettuce (Lactuca sativa L.). Scientia Horticulturae, 2002, 95: 269-276
138. Hyeon-Jin S., Min-Long C., Biao M. and Hiroshi E.. Functional expression of the taste-modifying protein miraculin in transgenic lettuce. FEBS Letters, 2006, 580: 620-626
139. Isaacs A. and Lindenmann J.. Virus interference. I. The interferon. Proc. R. Soc. Lond. B. Biol. Sci., 1957,147: 258–267
140. James E.A., Wang C. and Wang Z.. Production and characterization of biologically active human GM-CSf secreted by genetically modified plant cells. Protein Expr. Purif., 2000, 19:131-138
141. Jeanna M., Pipe M.D., Tony T-S., Wen M.D., Elly M-J. and Xenakis M.D.. Interferon therapy in primary care. Primary Care Update for OB/GYNS. , 2001,8: 163-169
142. Jefferson R.A., Kavanagh T.A. and Eenan M.W.. GUS fusion: beta-glucuranidase as a sensitive and versatile gene fusion marker in higher plants. Embo. J., 1987,6: 3901-3907
143. Jobling S.A., Jarman C., Teh M. M., Holmberg N., Blake C. and Verhoeyen M. E.. Immunomodulation of enzyme function in plants by single domain antibody fragments. Nat. Biotechnol., 2003, 21:77-80
144. Joh. L. D., Wroblewski T., Ewing N.N. and vander Gheynst J.S.. High-level transient expression of recombinant protein in lettuce. Biotechnology and Bioengineering, 2005, 91(7): 861-871
145. Julian K C.M., Pascal M.W.D and Paul C.. The production of recombinant pharmaceutical proteins in plants. Nature Review Genetics , 2003,4: 794-805
146. Kagawa T ,Morizane T , Saito H.. A pilot study of long term weekly interferon-β administration for chronic hepatitis B. Am. J. Gastroenterol, 1993,88:212-216
147. Kanno T., Naito S. and Shimamoto K.. Post-transcriptional gene silencing in cultured rice cells. Plant Cell Physiol., 2000, 41:321-326
148. Kapila J., De Rycke R., Van Montagu M. and Angenon G.. An agrobacterium-mediated transient gene expression system for intact leaves. Plant Sci., 1997, 122:101-108
149. Kapusta J., Modelska A., Figlerowicz M., Pniewski T., Letellier M., Lisowa O., Yusibov V., Koprowski H., Plucienniczak A. and Legocki A. B.. A plant-derived edible vaccine against hepatitis B virus. FASEB J., 1999, 13:1796-1799
150. Kathuria S., Sriraman R., Nath R., Sack M., Pal R., Artsaenko O., Talwar G. P., Fischer R. and Finnern R.. Efficacy of plant-produced recombinant antibodies against HCG. Hum Reprod, 2002, 17:2054-2061
151.Kawaguchi R. and Bailey-Serres J.. Regulation of translational initiation in plants. Curr. Opin. Plant Biol., 2002, 5:460-465
152. Kay E., Vogel T. M., Bertolla F., Nalin R. and Simonet P.. In situ transfer of antibiotic resistance genes from transgenic (transplastomic) tobacco plants to bacteria. Appl. Environ. Microbiol., 2002, 68:3345–3351
153. Khoudi H., Laberge S., Ferullo JM., Bazin R., Darveau A., Castonguay Y., Allard G., Lemieux R. and Vezina L. P.. Production of a diagnostic monoclonal antibody in perennial alfalfa plants. Biotechnol. Bioeng., 1999, 64:135-143
154. Kim K. Y., Kwon S. Y., Lee H. S., Hur Y., Bang J. W and Kwak S. S.. A novel oxidative stress-inducible peroxidase promoter from sweet potato: molecular cloning and characterization in transgenic tobacco plants and cultured cells. Plant. Mol. Biol., 2003, 51:831-838
155. Ko K., Tekoah Y., Rudd P. M., Harvey D. J., Dwek R. A., Spitsin S., Hanlon C. A., Rupprecht C., Dietzschold B., Golovkin M. and Koprowski H.. Function and glycosylation of plant-derived antiviral monoclonal antibody. Proc. Natl. Acad. Sci. USA, 2003, 100:8013 -8018
156. Kohli A., Twyman R. M., Abranches R., Wegel E., Stoger E. and Christou P.. Transgene integration, organization and interaction in plants. Plant Mol. Biol., 2003, 52:247-258
157. Komarnytsky S., Borisjuk N. V., Borisjuk L. G., Alam M. Z. and Raskin I.. Production of recombinant proteins in tobacco guttation fluid. Plant Physiol., 2000, 124:927-933
158. Koprowski H. and Yusibov V.. The green revolution: plants as heterologous expression vectors. Vaccine, 2001, 19:2735-2741
159. Koziel M. G., Carozzi N. B. and Desai N.. Optimizing expression of transgenes with an emphasis on post-transcriptional events. Plant Mol. Biol., 1996, 32:393-405
160. Kumar G. N., Houtz R. L. and Knowles N. R.. Age induced protein modifications and increased proteolysis in potato seed-tubers. Plant Physiol., 1999, 119:89-100
161. Kusnadi A., Nikolov R., Zivko L. and Howard J. A.. Production of recombinant proteins in transgenic plants: practical considerations. Biotechnol. Bioeng., 1997, 56:473-484
162. Kusnadi A.R., Evangelista R. L., Hood E. E., Howard J. A. and Nikolov Z. L.. Process of transgenic corn seed and its effect on the recovery of recombinant β-glucuronidase. Biotechnol. Bioeng., 1998, 60: 44-52
163. Kwon T. H., Kim Y. S., Lee J. H. and Yang M. S.. Production and secretion of biologically active human granulocytemacrophage colony stimulating factor in transgenic tomato suspension cultures. Biotechnol. Lett., 2003, 25:1571-1574
164. Lamphear B. J., Streatfield S. J., Jilka J. A., Brooks C. A., Barker D. K., Turner D. D., Delaney D. E., Garcia M., Wiggins B., Woodard S. L., Hood E. E., Tizard I. R., Lawhorn B. and Howard J. A.. Delivery of subunit vaccines in maize seed. J. Control Release, 2002, 85:169-180
165. Langford M.P., Weigent D.A., Stanton F.J. and Baron S.. Virus plaque-reduction assay for interferon: microplaque and regular macroplaque reduction assays. Methods Enzymol., 1981, 78:339-346
166. Larkins B. A., Bracker C. E. and Tsai C.Y.. Storage protein synthesis in maize: isolation of zein-synthesizing polyribosomes. Plant Physiol, 1976, 57:740-745
167. Larrick J. W. and Thomas D. W.. Producing proteins in transgenic plants and animals. Curr. Opin. Biotechnol., 2001, 12:411-418
168. Larrick J. W., Yu L., Chen J., Jaiswal S. and Wycoff K.. Production of antibodies in transgenic plants. Res. Immunol., 1998, 149:603-608
169. Lauterslager T. G, Florack D. E, van der Wal T. J., Molthoff J. W., Langeveld J. P., Bosch D., Boersma W. J. and Hilgers L. A.. Oral immunization of naive and primed animals with transgenic potato tuber expressing LT2B.Vaccine, 2001, 19:2749-2755
170. Law R. D. and Suttle J. C.. Changes in histone H3 and H4 multiacetylation during natural and forced dormancy break in potato tubers. Physiol. Plant, 2004, 120:642-649
171. Law R. D. and Suttle J. C.. Transient decreases in methylation at 5′-CCGG-3′ sequences in potato (Solanum tuberosum L.) meristem DNA during progression of tubers through dormancy precede the resumption of sprout growth. Plant Mol. Biol., 2003, 51:437-447
172. Law R. D., Russell D. A., Thompson L. C., Schroeder S. C., Middle C. M., Tremaine M. T., Jury T. P., Delannay X. and Slater S. C.. Biochemical limitations to high-level expression of humanized monoclonal antibodies in transgenic maize seed endosperm. Biochim. Biophys. Acta., 2006, 1760:1434-1444
173. Lee D. and Natesan E.. Evaluating genetic containment strategies for transgenic plants. Trends Biotechnol., 2006, 24:109-114
174. Leelavathi S. and Reddy V. S.. Chloroplast expression of His-tagged GUS fusions: a general strategy to overproduce and purify foreign proteins using transplastomic plants as bioreactors. Mol. Breed, 2003, 11:49-58
175. Leelavathi S., Gupta N., Maiti S., Ghosh A. and Reddy V. S.. Overproduction of an alkali- and thermostable xylanase in tobacco chloroplasts and efficient recovery of the enzyme. Mol. Breed., 2003,11:59-67
176. Leonard R., Costa G., Darrambide E., Lhernould S., Fleurat- Lessard P., Carlue M., Gomord V., Faye L. and Maftah A.. The presence of Lewis a epitopes in Arabidopsis thaliana glycoconjugates depends on an active alpha-4-fucosyltransferase gene. Glycobiology, 2002, 12:299-306
177. Lerouge P., Cabanes-Macheteau M., Rayon C., Fischette-Laine A. C., Gomord V. and Faye L.. N-glycoprotein biosynthesis in plants: recent developments and future trends. Plant Mol. Biol., 1998, 38:31-48
178. Lin L.S. , Yamamoto R and Drummond R.J.. Purification of recombinant interferon-β expressed in Escherichia coli. Methods in Enzymology, 1986 ,119 :183-193
179. Lindsay S, Mulroy R and Semeniuk D..Expression of secreted human α-fetoprotein in transgenic animals. Patent Number WO040693A2. Issued July 13, 2000
180. Lisowska K. and Wysokinska H.. In vitro propagation of Catalpa ovata G. Don. Plant Cell Tissue Organ Cult., 2000, 60:171-176
181. Ludwig D. L., Witte L., Hicklin D. J., Prewett M., Bassi R., Burtrum D., Pereira D. S., Jimenez X., Fox F., Saxena B., Zhou Q., Ma Y., Kang X., Patel D., Barry M., Kussie P., Zhu Z., Russell D. A., Petersen W. L., Jury T. P., Gaitan-Gaitan F., Moran D. L., Delannay X., Storrs B. S., Tou J., Zupec M. E., Gustafson K. S., McIntyre J., Tarnowski S. J. and Bohlen P.. Conservation of receptor antagonist antitumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed. Hum. Antib., 2004, 13:81-90
182. Lynn W.. Interferon-beta-la approved for replapsing multiple sclerosis. Med. Sci. Bull, 1996,18: 456-468
183. Ma J. K. C., Drake P. M. W. and Christou P.. The production of recombinant pharmaceutical proteins in plants. Nature Rev. Genet., 2003, 4:794-805
184. Ma J. K., Hikmat B. Y., Wycoff K., Vine N. D., Chargelegue D., Yu L., Hein M. B. and Lehner T.. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat. Med., 1998,4:601-606
185. Ma J.K., Hiatt A., Hein M., Vine N. D., Wang F., Stabila P., Van Dolleweerd C., Mostov K. and Lehner T.. Generation and assembly of secretory antibodies in plants. Science, 1995, 268:716-719
186. Mallory A. C., Ely L., Smith T. H., Marathe R., Anandalakshmi R., Fagard M., Vaucheret H., Pruss G., Bowman L. and Vance V. B.. HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal. Plant Cell, 2001, 13:571-583
187. Manjunath S. and Sachs M. M.. Molecular characterization and promoter analysis of the maize cytosolic glyceraldehyde 3-phosphate dehydrogenase gene family and its expression during anoxia. Plant Mol. Biol., 1997, 33:97-112
188. Mark D.F, Lu S.D. and Creasey A.A.. Site specific mutagenesis of human fibroblast interferon gene. Proc. Natl. Acad. Sci., 1984 ,81 :5662-5666
189. Mason H. S. and Arntzen C. J.. Transgenic plants as vaccine production systems. Trends Biotechnol., 1995, 13:388-392
190. Mason H. S., Haq T. A., Clements J. D. and Arntzen C. J.. Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine, 1998, 16:1336-1343
191. Mason H. S., Lam D. M.and Arntzen C. J.. Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci., 1992, 89:11745-11749
192. Mason H.S., Warzecha H., Mor T. and Arntzen C. J.. Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends Mol. Med., 2002, 8:324-329
193. Matsumoto S., Ikura K., Ueda M. and Sasaki R.. Characterization of a human glycoprotein (erythropoietin) produced in cultured tobacco cells. Plant Mol. Biol., 1995, 27:1163-1172
194. Matsuoka K. and Nakamura K:. Propeptide of a precursor to a plant vacuolar protein required for vacuolar targeting. Proc. Natl. Acad. Sci., 1991, 88:834-838
195. Mayfield S. P., Franklin S. E. and Lerner R. A.. Expression and assembly of a fully active antibody in algae. Proc. Natl. Acad. Sci., 2003, 100:438-442
196. McCormick A. A., Kumagai M. H., Hanley K., Turpen T. H., Hakim I., Grill L. K., Tuse D., Levy S. and Levy R.. Rapid production of specific vaccines for lymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc. Natl. Acad. Sci., 1999, 96:703-708
197. McCormick, F., Trahey, M., Innis, M., Dieckmann, B. and Ringold, G.. Inducible expression of amplified human beta interferon genes in CHO cells. Mol. Cell Biol., 1984,4: 166-172
198. Merle C., Perret S., Lacour T., Jonval V., Hudaverdian S., Garrone R., Ruggiero F. and Theisen M.. Hydroxylated human homotrimeric collagen I in Agrobacterium tumefaciens mediated transient expression and in transgenic tobacco plant. FEBS Lett., 2002, 515:114-118
199. Michelmore R.W.; Marsh E.; Seely S. and Landry B.. Transformation of lettuce (Lactuca sativa) mediated by Agrobacterium tumefaciens. Plant Cell Reports, 1987,6: 439-442
200. Millan A.F-S., Mingo-Castel A., Miller M. and Daniell H.. A chloroplast transgenic approach to hyperexpress and purify human serum albumin, a protein highly susceptible to proteolytic degradation. Plant Biotechnol., 2003, 1:77-79
201. Min C., Xian-wei L., Zhan-kun W., Jing S., Qing-sheng Q. and Georger-Peng W.. Modication of plant N-glycans processing:the future of producing therapeutic protein by transgenic plants. Medicinal Research Reviews, 2004, 25: 343-360
202. Mokrzycki-Issartel N., Bouchonb B., Farrera S., Berlanda P., Laparraa H., Madel- montb J.C. and Theisena M.A..Transient tobacco expression system coupled to MALDI- TOF- MS allows validation of the impact of diferential targeting on structure and activity of a recombinant therapeutic glycoprotein produced in plants. FEBS Letters, 2003, 552: 170-176
203. Morassutti C., De Amicis F., Skerlavaj B., Zanetti M and Marchetti S..Production of a recombinant antimicrobial peptide in transgenic plants using a modified VMA intein expression system. FEBS Lett., 2002, 519:141-146
204.Moschera J.A.,Woehle D. and Tsai K.P.. Purification of Recombinant human fibroblast interferon produced in Escherichia coli. Methods in Enzymology, 1986 ,119 :177-183
205. Murray C., Sutherland P. W., Phung M. M., Lester M. T., Marshall R. K. and Christeller J. T.. Expression of biotin-binding protein, avidin and streptavidin, in plant tissues using plant vacuolar targeting sequences. Transgenic Res., 2002, 11:199-214
206. Navazio L., Baldan B., Mariani P., Gerwig G. J. and Vliegenthart J. F.. Primary structure of the N-linked carbohydrate chains of Calreticulin from spinach leaves. Glycoconj. J., 1996, 13:977-983
207. Nebenfuhr A., Gallagher L. A., Dunahay T. G., Frohlick J. A., Mazurkiewicz A. M., Meehl J. B. and Staehelin L. A.. Stop and gomovements of plant Golgi stacks are mediated by the actomyosin system. Plant Physiol., 1999, 121:1127-1142
208. Negouk V., Eisner G., Lee H., Han K., Taylor D. and Wong H.C.. Highly efficient transient expression of functional recombinant antibody in lettuce. Plant Science, 2005, 169: 433-438
209 Nolke G., Fischer R. and Schillberg S.. Production of therapeutic antibodies in plants. Expert Opin. Biol. Ther., 2003 3:1153-1162
210. Page A. and Angell S.. Transient expression of reporter proteins can alter plant gene expression. Plant Science, 2002,163: 431-437
211. Pagny S., Bouissonnie F., Sarkar M., Follet-Gueye M. L., Driouich A., Schachter H., Faye L. and Gomord V.. Structural requirements for Arabidopsis beta 1,2-xylosyl- transferase activity and targeting to the Golgi. Plant J., 2003, 33:189-203
212. Pagny S., Cabanes-Macheteau M., Gillikin J. W., Leborgne-Castel N., Lerouge P., Boston R. S., Faye L. and Gomord V.. Protein recycling from the Golgi apparatus to the endoplasmic reticulum in plants and its minor contribution to calreticulin retention. Plant Cell., 2000, 12:739-756
213. Pagny S., Denmat-Ouisse L. A., Gomord V. and Faye L.. Fusion with HDEL protects cell wall invertase from early degradation when N-glycosylation is inhibited. Plant Cell Physiol., 2003, 44:173-182
214. Parmenter D. L., Boothe J. G., van Rooijen G. J., Yeung E. C. and Moloney M. M.. Production of biologically active hirudin in plant seeds using oleosin partitioning. Plant Mol. Biol., 1995, 29:1167-1180
215. Paty D.W. and .Li D.K.B.. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology, 1993,43: 662-667
216. Peeters K., De Wilde C. and Depicker A.. Highly efficient targeting and accumulation of a Fab fragment within the secretory pathway and apoplast of A. thaliana. Eur. J. Biochem., 2001, 268:4251-4260
217. Pileggi M.; Pereira A.A.M.; Silva J.S.S.; Pileggi A.V. and Verma D.P.S.. An Improved Method for Transformation of Lettuce by Agrobacterium tumefaciens with a Gene that Confers Freezing Resistance. Braz. arch. biol. Technol., 2001,44:191-196
218. Pueyo J. J., Chrispeels M. J. and Herman E. M.. Degradation of transport-competent destabilized phaseolin with a signal for retention in the endoplasmic reticulum occurs in the vacuole. Planta, 1995, 196:586-596
219. Ramirez N., Ayala M., Orenzo D., Palenzuela D., Herrera L., Doreste V., Perez M., Gavilond J.V. and Oramas P.. Expression of a single-chain Fv antibody fragment specific for the hepatitis B surface antigen in transgenic tobacco plants. Transgenic Res., 2002, 11:61-64
220. Ramirez N., Rodriguez M., Ayala M., Cremata J., Perez M., Martinez A., Linares M., Hevia Y., Paez R., Valdes R., Gavilondo J. V. and Selman-Housein G.. Expression and characterization of an anti-hepatitis B surface antigen glycosylated mouse antibody in transgenic tobacco plants, and its use in the immunopurification of its target antigen. Biotechnol Appl. Biochem., 2003, 38:223-230
221. Richter L. and Kipp P. B.. Transgenic plants as edible vaccines. Curr. Topics Microbiol. Immunol., 1999, 240:159-176
222. Richter L., Thanavala Y., Arntzen C. J. and Mason H. S.. Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nat. Biotechnol., 2000, 18:1167- 1171
223. Rourke E.C., Drummond R.J. and Creasey A.A.. Binding of 1-5I-labeled recombinant beta interferon ( IFN-beta Ser 17) to human cells. Mol. Cell Biol., 1984,4:2745-2749
224. Ruf S., Hermann M., Berger I. J., Carrer H. and Bock R.. Stable genetic transformation of tomato plastids and expression of a foreign protein in fruit. Nat. Biotechnol., 2001, 19:870- 875
225. Ruggiero F., Exposito J. Y., Bournat P., Gruber V., Perret S., Comte J., Olagnier B., Garrone R. and Theisen M.. Triple helix assembly and processing of human collagen produced in transgenic tobacco plants. FEBS Lett., 2000, 469:132-136
226. Russell D. A. and Fromm M. E.. Tissue-specific expression in transgenic maize of four endosperm promoters from maize and rice. Transgenic Res., 1997, 6:157-168
227. Russell D. A. and Sachs M. M.. Differential expression and sequence analysis of the maize glyceraldehyde-3-phosphate dehydrogenase gene family. Plant Cell, 1989,1: 793-803
228. Russell D. A.. Feasibility of antibody production in plants for human therapeutic use. Curr. Top. Microbiol. Immunol., 1999, 240:119-138
229. Sala F., Manuela R. M., Barbante A., Basso B., Walmsley A. M. and Castiglione S.. Vaccine antigen production in transgenic plants: strategies, gene constructs and perspectives. Vaccine, 2003,21:803-808.
230. Samyn-Petit B., WajdaDubos J. P., Chirat F., Coddeville B., Demaizieres G., Farrer S., Slomianny M. C., Theisen M. and Delannoy P.. Comparative analysis of the site-specific N-glycosylation of human lactoferrin produced in maize and tobacco plants. Eur. J. Biochem., 2003, 270:3235-3242
231. Schenk P. M., Sagi L., Remans T., Dietzgen R.G., Bernard M. J., Graham M. W. and Manners J.M.. A promoter from sugarcane bacilliform badnavirus drives transgene expression in banana and other monocot and dicot plants. Plant Mol. Biol., 1999, 39:1221-1230
232. Schillberg S., Fischer R. and Emans N.. Molecular farming of recombinant antibodies in plants. Cell Mol. Life Sci., 2003, 60:433-445
233. Schillberg S., Twyman R. M. and Fischer R.. Opportunities for recombinant antigen and antibody expression in transgenic plants-technology assessment. Vaccine, 2005, 23:1764-1769
234. Schillberg, S., Zimmermann S., Voss A. and Fischer R.. Apoplastic and cytosolic expression of fullsize antibodies and antibody fragments in Nicotiana tabacum. Transgenic Res., 1999, 8:255-263
235. Schlatter S., Stansfield S. H., Dinnis D.M., Racher A.J., Birch J. R. and James D.C.. On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells. Biotechnol. Prog., 2005, 21:122-133
236. Schouten A., Roosien J., De Boe J. M., Wilmink A., Rosso M. N., Bosch D., Stiekema W. J., Gommers F. J., Bakker J. and Schots A.. Improving scFv antibody expression levels in the plant cytosol. FEBS Lett., 1997, 415:235-241
237. Schouten A., Roosien J., Van Engelen F. A., De Jong G. A., Borst-Vrenssen A. W., Zilverentant J. F., Bosch D., Stiekema W. J., Gommers F. J., Schots A. and Bakker J.. The C-terminal KDEL sequence increases the expression level of a single chain antibody designed to be targeted to both the cytosol and the secretory pathway in transgenic tobacco. Plant Mol. Biol., 1996, 30:781-793
238. Seon J. H., Szarka S. and Moloney M. M.. A unique strategy for recovering recombinant proteins from molecular farming: affinity capture on engineered oilbodies. J. Plant Biotechnol., 2002, 4:95-101
239. Sharma N., Kim T.G., Yang M.S.. Production and secretion of human interleukin-18 in transgenic tobacco cell suspension culture. BioTechnology and Bioprocess engineering, 2006, 11 2,154-159
240. Shekhter I.,Beiko V.P. and Bulenkov M.T.. Obtaining human recombinant ( Serine217) beta-interferon by the method of oligonucleotide directed mutagenesis and its expression in Escherichia coli. Antibiot Khimioter, 1991,36 :25-28
241. Shin Y. J., Hong S. Y., Kwon T. H., Jang Y. S. and Yang M. S.. High level of expression of recombinant human granulocytemacrophage colony stimulating factor in transgenic rice cell suspension culture. Biotechnol. Bioeng., 2003, 82:778-783
242. Sijmons P. C., Dekker B. M. M., Schrammeijer B., Verwoerd T. C., van den Elzen P. J. M. and Hoekema A.. Production of correctly processed human serum albumin in transgenic plants. Biotechnology, 1990, 8:217-221
243. Smith M. D. and Glick B. R.. The production of antibodies in plants. Biotechnol. Adv., 2000, 18:85-89
244. Smith M. L., Mason H. S. and Shuler M. L.. Hepatitis B surface antigen (HBsAg) expression in plant cell culture kinetics of antigen accumulation in batch culture and its intracellular form. Biotechnol. Bioeng., 2002, 80:812-822
245. Sojikul P., Buehner N. and Mason H. S.. A plant signal peptide hepatitis B surface antigen fusion protein with enhanced stability and immunogenicity expressed in plant cells. Proc. Natl. Acad. Sci., 2003, 100:2209-2214
246. Staub J. M., Garcia B., Graves J., Hajdukiewicz P. T., Hunter P., Nehra N., Paradkar V., Schlittler M., Carroll J. A., Spatola L., Ward D., Ye G. and Russell D.A.. High yieldproduction of a human therapeutic protein in tobacco chloroplasts. Nat. Biotechnol., 2000, 18:333-338
247. Stewart W.E., 1979. The interferon system II. Springer, Vienna, Austria.
248. Stoger E., Sack M., Fischer R. and Christou P.. Plantibodies: applications, advantages and bottlenecks. Curr. Opin. Biotechnol., 2002, 13:161-166
249. Stoger E., Sack M., Perrin Y., Vaquero C., Torres E., Twyman R. M., Christou P. and Fischer R.. Practical considerations for pharmaceutical antibody production in different crop systems. Mol. Breed., 2002, 9:149-158
250. Stoger E., Vaquero C., Torres E., Sack M., Nicholson L., Drossard J., Williams S., Keen D., Perrin Y., Christou P. and Fischer R.. Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol. Biol., 2000, 42:583-590
251. Streatfield S. J., Jilka J. M., Hood E. E., Turner D. D., Baily M. R., Mayor J. M., Woodard S. L., Beifuss K. K., Horn M. E., Delaney D. E., Tizard I. R. and Howard J. A.. Plant-based vaccines: unique advantages. Vaccine, 2001, 19:2742-2748
252. Suzuki H , Nichigaki K and Gunji A.. Toray IFN Research Group :Treatment of chronic non -A, non-B hepatitis with human interferon-β, a randomized controlled trial with different durations. Kan Tan Sui, 1994 , 23:1065-1079
253. Thanavala Y., Wang Y-F., Lyons P., Mason H. S. and Arntzen C.. Immunogenicity of transgenic plant-derived hepatitis B surface antigen. Proc. Natl. Acad. Sci., 1995, 92:3358-3361
254. Torres E., Vaquero C., Nicholson L., Sack M., Stoger E., Drossard J., Christou P., Fischer R. and Perrin Y.. Rice cell culture as an alternative production system for functional diagnostic and therapeutic antibodies. Transgenic Res., 1999, 8:441-449
255.Towbin H., Staehelin T. and Gordon J.. Electrophoretic transfer from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci., 1979,76:4350-4354
256. Twyman R. M., Stoger E., Schillberg S., Christou P. and Fischer R.. Molecular farming in plants: host systems and expression technology. Trends Biotechnol., 2003, 21:570-578
257.Vain P., Finer K. R., Engler D. E., Pratt R. C. and Finer J.J.. Intron-mediated enhancement of gene expression in maize (Zea mays L.) and bluegrass (Poa pratensis L.). Plant Cell Rep., 1996, 15:489-494
258. Vaquero C., Sack M., Chandler J., Drossard J., Schuster F., Monecke M., Schillberg S. and Fischer R.. Transient expression of a tumor-specific single chain fragment and a chimeric antibody in tobacco leaves. Proc. Natl. Acad. Sci.,1999, 96:11128-11133
259. Vaquero C., Sack M., Schuster F., Finnern R., Drossard J., Schumann D., Reimann A. and Fischer R.. A carcinoembryonic antigen specific diabody produced in tobacco. FASEB J., 2002, 16:408-410
260. Vaucheret H. and Fagard M.. Transcriptional gene silencing in plants: targets, inducers and regulators. Trends Genet., 2001, 17:29-35
261. Vietor R., Loutelier-Bourhis C., Fitchette A. C., Margerie P., Gonneau M., Faye L. and Lerouge P.. Protein N-glycosylation is similar in the moss Physcomitrella patens and in higher plants. Planta, 2003, 218:269-275
262.Webb D.T.; Torres L.D. and Fobert P. Interactions of growth regulators, explant age, and culture environment controlling organogenesis from lettuce cotyledons in vitro. Canadian Journal of Botany, 1984,62: 586–590
263. Witcher D. R., Hood E. E., Peterson D., Bailey M., Bond D., Kusnadi A., Evangelista R., Nikolov Z., Wooge C., Mehigh R., Kappel W., Register J. and Howard J.A.. Commercial production of β-glucuronidase (GUS): a model system for the production of proteins in plants. Mol. Breed, 1998, 4: 301-312
264.Wroblewski T., Tomczakt A. and Michelmore R.. Optimization of Agrobacterium- mediated transient assays of gene expression in lettuce, tomato and Arobidopsis. Plant Biotechnology Journal, 2005, 3: 259-273
265. Yang D., Guo F., Liu B., Huang N. and Watkins S. C.. Expression and localization of human lysozyme in the endosperm of transgenic rice. Planta, 2003, 216:597-603
266. Yu J. and Langridge W.. Expression of rotavirus capsid protein VP6 in transgenic potato and its oral immunogenicity in mice. Transgenic Res., 2003, 12:163-169
267. Yuan, Q., Hu W., Pestka J. J., He S.Y. and Hart P.. Expression of a functional antizearal- enone single-chain Fv antibody in transgenic Arabidopsis plants. Appl. Env. Microb., 2000, 66:3499-3505
268. Zeitlin L., Olmsted S. S., Moench T. R., Co M. S., Martinell B. J., Paradkar V. M., Russell D. R., Queen C., Cone R. A. and Whaley K. J.. A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat. Biotechnol., 1998, 16:1361-1664
269. Zhong G. Y., Peterson D. J., Delaney D., Bailey M., Witcher D. R., Register J. C., Bond D., Li C. P., Marshall L., Kulisek E., Ritland D., Meyer T., Hood E. E. and Howard J.. Commercial production of aprotinin in transgenic maize seeds. Mol. Breed., 1999, 5:345-356
270. Ziegler M.T., Thomas S. R. and Danna K. J.. Accumulation of a thermostable endo-1,4-β-D-glucanase in the apoplast of Arabidopsis thaliana leaves. Mol. Breed., 2000, 6: 37-46
271. Zuo X.F., Zhang X.Y., Shan L., Xiao C.Y., He D.X. and Ru B.G. Expression of human intestinal trefoil factor (hITF) gene in lettuce. Acta Botanica Sinica, 2001,43:1047-1051
2.刘红莉, 雷霆, 王一理, 司履生. 转基因植物疫苗研究策略. 中国生物工程杂志, 2004, 4:30-33
3. Aalberse R. C., Koshte V. and Clemens J. G.. Cross-reactions between vegetable foods, pollen and bee venom due to IgE antibodies to a ubiquitous carbohydrate determinant. Int. Arch. Allergy Appl. Immunol., 1981, 66:259-260
4. Abe M., Goto T., Kosaka M., Wolfenbarger D., Weiss D. T. and Solomon A.. Differences in kappa to lambda (κ:λ) ratios of serum and urinary free light chains. Clin. Exp. Immunol., 1998, 111:457-462
5. Alconero R.. Regeneration of plants from cell suspensions of Lactuca saligna, Lactuca sativa, and Lactuca serriola. HortScience, 1983,18: 305–307
6. Allen G. C., Spiker S. and Thompson W. F.. Use of matrix attachment regions (MARs) to minimize transgene silencing. Plant Mol. Biol., 2000, 43:361-376
7. Altschul S. F., Madden T. L., Schaffer A. A., Zhang J., Zhang Z., Miller W. and Lipman D. J .. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res., 1997, 25:3389-3402
8. Ampomah-Dwamena C.; Conner A.J. and Fautrier A.G.. Genotypic response of lettuce coty- ledons to regeneration in vitro. Scientia Horticulture, 1997,71: 137-145
9. Arakawa T., Chong D. K. and Langridge W. H.. Efficacy of a food plantbased oral cholera toxin B subunit vaccine. Nat. Biotechnol., 1998, 16:292-297
10. Arakawa T., Chong D. K., Merritt J. L. and Langridge W. H.. Expression of cholera toxin B subunit oligomers in transgenic plants. Transgenic Res., 1997, 6:403-413
11. Arcalis E., Marcel S., Altmann F., Kolarich D., Drakakaki G., Fischer R., Christou P. and Stoger E.. Unexpected deposition patterns of recombinant proteins in post-endoplasmic reticulum compartments of wheat endosperm. Plant Physiol., 2004, 136:3457-3466
12. Artsaenko O., Kettig B., Fiedler U., Conrad U. and During K.. Potato tubers as a bio- factory for recombinant antibodies. Mol. Breed., 1998, 4:313-319
13. Austin S., Bingham E. T., Koegel R. G., Mathews D. E., Shahan M. N., Straub R. J. and Burgess R. R.. An overview of a feasibility study for the production of industrial enzymes in transgenic alfalfa. Annu. NY. Acad. Sci., 1994, 721:235-244
14. Awram P., Gardner R. C., Forster R. L. and Bellamy A. R.. The potemtial of Plant viral vectors and transgenic plants for subunit vaccine production. Adv. Virus. Res., 2002, 58:81-124
15. Azzoni A. R., Kusnadi A. R., Miranda E. A. and Nikolov Z. L.. Recombinant aprotinin produced in transgenic corn seed: extraction and purification studies. Biotechnol. Bioeng., 2002, 80:268-276
16. Bakker H., Bardor M., Molthoff J. W., Gomord V., Elbers I., Stevens L. H., Jordi W., Lommen A., Faye L., Lerouge P. and Bosch D.. Galactose-extended glycans of antibodies produced by transgenic plants. Proc. Natl. Acad. Sci., 2001, 98:2899-2904
17. Bakker H., Florack D., Bosch H. and Rouwendal G.. Optimizing Glycan Processing in Plants. Patent WO 03/078637, 2003
18. Bandyopadhyay P. K., Garrett J. E., Shetty R. P., Keate T., Walker C. S. and Olivera B. M.. Gammaglutamyl carboxylation: an extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates. Proc. Natl. Acad. Sci., 2002, 99:1264-1269
19. Banerjee S., Shang T. Q., Wilson A. M., Moore A. L., Strand S. E., Gordon M. P. and Doty S. L.. Expression of functional mammalian P450 in hairy root cultures. Biotechnol. Bioeng., 2002, 77:462-466
20. Bardor M., Faveeuw C., Fitchette A. C., Gilbert D., Galas L., Trottein F., Faye L. and Lerouge P.. Immunoreactivity in mammals of two typical plant glycoepitopes, core α(1,3)-fucose and core xylose. Glycobiology, 2003, 13:427-434
21. Bardor M., Loutelier-Bourhis C., Paccalet T., Cosette P., Fitchette A. C., Vezina L. P., Trepanier S., Dargis M., Lemieux R., Lange C., Faye L. and Lerouge P.. Monoclonal C5-1 antibody produced in transgenic alfalfa plants exhibits a N-glycosylation that is suitable for glycol-engineering into human-compatible structures. Plant Biotechnol. J., 2003, 1:451-462
22. Barta A., Sommergruber K., Thompson D., Hartmuth K., Matzke M. and Matzke A.. The expression of a nopaline synthase-human growth hormone chimeric gene in transformed tobacco and sunflower callus tissue. Plant. Mol. Biol., 1986, 6:347-357
23. Becker G. W., Tackitt P. M., Bromer W. W., Lefeber D. S. and Riggin R. M.. Isolation and characterization of a sulfoxide and a desamido derivative of biosynthetic human growth hormone. Biotechnol. Appl. Biochem., 1988, 10: 326-337
24. Belanger H., Fleysh N., Cox S., Bartman G., Deka D., Trudel M., Koprowski H. and Yusibov V.. Human respiratory syncytial virus vaccine antigen produced in plants. FASEB J., 2000, 14: 2323-2328
25. Berger M., Shankar V. and Vafai A.. Therapeutic applications of monoclonal antibodies. Am. J. Med. Sci., 2002, 324: 14-30
26. Betthauser J,Forsberg E,Augenstein M,Childs L,Eilertsen K,Enos J,Forsythe T,Golueke P,Jurgella G,Koppang R,Lesmeister T,Mallon K,Mell G,Misica P,Pace M,Pfister-Genskow M,Strelchenko N,Voelker G,Watt S,Thompson S and Bishop M.. Production of cloned pigs from in vitro systems. Nat Biotechnol, 2000, 18: 1055-1059
27. Betts D., Bordignon V., Hill J., Winger Q., Westhusin M., Smith L. and King W.. Repro- gramming of telomerase activity and rebuilding of telomere length in cloned cattle. Proc. Natl. Acad. Sci., 2001, 98:1077-1082
28. Biemelt S., Sonnewald U., Gaimbacher P., Willmitzer L. and Muller M.. Production of human papillomavirus type 16 viral like particles in transgenic plants. J. Virol., 2003, 77:9211-9220
29. Blixt O., Allin K., Pereira L., Datta A. and Paulson JC.. Efficient chemoenzymatic synth- esis of O-linked sialyloligosaccharides. J. Am. Chem. Soc., 2002, 124 :5739-5746
30. Boisson M., Gomord V., Audran C., Berger N., Dubreucq B., Granier F., Lerouge P., Faye L., Caboche M. and Lepiniec L.. Arabidopsis glucosidase I mutants reveal a critical role of N-glycan trimming in seed development. EMBO J., 2001, 20 :1010-1019
31. Boothe J. G., Saponja J. A. and Parmenter D. L.. Molecular farming in plants: oilseed as vehicles for the production of pharmaceutical proteins. Drug Dev. Res., 1997, 42:172-178
32. Borisjuk N.V., Borisjuk L. G., Logendra S., Petersen F., Gleba Y. and Raskin I.. Production of recombinant proteins in plant root exudates. Nat. Biotechnol., 1999, 17:466-469
33. Borth N., Strutzenberger K., Kunert R., Steinfellner W. and Katinger H.. Analysis of changes during subclone development and ageing of human antibody-producing heterohybridoma cells by northern blot and flow cytometry. Biotechnol., 1999, 67: 57-66
34. Bruyns A.M., De Jaeger G., De Neve M., De Wilde C., Van Montagu M. and Depicker A.. Bacterial and plant produced scFv proteins have similar antigen-binding properties. FEBS Lett., 1996, 386:5-10
35. Cabanes-Macheteau M., Fitchette-Laine A. C., Loutelier-Bourhis C., Lange C., Vine N. D., Ma J. K., Lerouge P. and Faye L.. N-Glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology, 1999, 9:365-372
36. Cacia J., Quan C. P., Vasser M., Sliwkowski M. B. and Frenz J.. Protein sorting by high performance liquid chromatography. I. Biomimetic interaction chromatography of recom- binant human deoxyribonuclease I on polyionic stationary phases. J. Chromatogr., 1993, 634:229-239
37. Carrington D. M., Auffret A. and Hanke D. E.. Polypeptide ligation occurs during post- translational modification of concanavalin A. Nature, 1985, 313:64-67
38. Chargelegue D., Obregon P., Drake P. M. W.. Transgenic plants for vaccine production: Expectations and limitations. Trends Plant Sci., 2001, 6:495-496
39. Chargelegue D., Vine N. D., van Dolleweerd C. J., Drake P. M. and Ma J. K.. A murine monoclonal antibody produced in transgenic plants with plant specific glycans is not im- munogenic in mice. Transgenic Res., 2000, 9:187-194
40. Chen T.L., Lin Y.L., Lee Y.L., Yang N.S. and Chan M.T.. Expression of bioactive human interferon-gamma in transgenic rice cell suspension cultures. Transgenic research, 2004,13 (5):499-510
41. Chenu S., Gregoire A., Malykh Y., Visvikis A., Monaco L., Shaw L., Schauer R., Marc A. and Goergen J. L.. Reduction of CMP-N-acetylneuraminic acid hydroxylase activity in engi- neered Chinese hamster ovary cells using an antisense-RNA strategy. Biochim. Biophys. Acta., 2003, 1622:133-144
42. Chong D. K. X. and Langridge W. H. R.. Expression of fulllength bioactive antimicrobial human lactoferrin in potato plants. Transgenic Res., 2000, 9:71-78
43. Chong D.K.X., Roberts W., Arakawa T., Illes K., Bagi G., Slattery C. W. and Langridge W. H.. Expression of the human milk protein β-casein in transgenic potato plants. Transgenic Res., 1997, 6:289-296
44. Christensen A. H. and Quail P. H.. Ubiquitin promoter-based vectors for high level expre- ssion of selectable and/or screenable marker genes in monocotyledonous plants. Transgenic Res., 1996, 5:213-218
45. Coker J. S. and Davies E.. Selection of candidate housekeeping controls in tomato plants using EST data. Bio. Techniques, 2003, 35:740-748
46. Commandeur U., Twyman R. M. and Fischer R.. The biosafety of molecular farming in plants. Ag. Bio. Tech. Net., 2003, 5:110
47. Conrad U. and Fiedler U.. Compartment specific accumulation of recombinant immuno- globulins in plant cells: an essential tool for antibody production and immunomodulation of physiological functions and pathogen activity. Plant Mol. Biol., 1998, 38:101-109
48. Conrad U., Fiedler U., Artsaenko O. and Phillips J.. High-level and stable accumulation of single-chain Fv antibodies in plant storage organs. J. Plant Physiol., 1998, 152:708-711
49. Cramer C. L., Weissenborn D. L., Oishi K. K., Grabau E. A., Bennett S., Ponce E., Grabo- wski G. A. and Radin D. N.. Bioproduction of human enzymes in transgenic tobacco. Ann. NY. Acad., 1996, 792:62-71
50. Cramer C.L., Boothe J. G. and Oishi K. K.. Transgenic plants for therapeutic proteins: linking upstream and downstream strategies. Curr. Top. Microbiol. Immunol., 1999, 240:95-118
51. Crofcheck C., Loiselle M., Weekly J., Maiti I., Pattanaik S., Bummer P. M. and Jayt M.. Histidine-tagged protein recovery from tobacco extract by foam fractionation. Biotechnol. Prog., 2003, 19:680-682
52. Curtis, W.R.. Quantitative transient protein expression in plant tissue culture, U.S. Patent 6,740,526, 2004
53. Dai Z.Y., Hooker B. S., Anderson D.B. and Thomas S. R.. Improved plant-based produ- ction of E1 endoglucanase using potato: expression optimization and tissue targeting. Mol. Breed, 2000, 6:277-285
54. Dalsgaard K., Uttenthal A., Jones T. D., Xu F., Merryweather A., Hamilton W. D., Lange- veld J. P., Boshuizen R. S., Kamstrup S., Lomonossoff G. P., Porta C., Vela C., Casal J. I., Meloen R. H. and Rodgers P. B.. Plant-derived vaccine protects target animals against a viral disease. Nat. Biotechnol., 1997, 15:248-252
55. Damell J E , Kerr IM and Stark GR.. JakSTAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994,264: 1415-1421
56. Daniell H. and Dhingra A.. Multigene engineering: dawn of an exciting new era in biotechnology. Curr. Opin. Biotechnol., 2002, 13:136-141
57. Daniell H., Khan M. S. and Allison L.. Milestones in chloroplast genetic engineering: an environmentally friendly era in biotechnology. Trends Plant Sci., 2002, 7:84-91
58. Daniell H., Lee S. B., Panchal T. and Wiebe P. O.. Expression of the native cholera B toxin subunit gene and assembly as functional oligomers in transgenic tobacco chloroplasts. J. Mol. Biol., 2001, 311:1001-1009
59. Daniell H., Streatfield S. J. and Wycoff K.. Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci., 2001, 6:219-226
60. De Cosa B., Moar W., Lee S-B., Miller M. and Daniell H.. Overexpression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nat. Biotechnol. 2001, 19:71-74
61. De Jaeger G., Scheffer S., Jacobs A., Zambre M., Zobell O., Goossens A., Depicker A. and Angenon G.. Boosting heterologous protein production in transgenic dicotyledonous seeds using Phaseolus vulgaris regulatory sequences. Nat. Biotechnol., 2002, 20:1265-1268
62. De Jaeger G., Buys E., Eeckhout D., De Wilde C., Jacobs A., Kapila J., Angenon G., Van Montagu M., Gerats T. and Depicker A.. High-level accumulation of single-chain variable fragments in the cytosol of transgenic Petunia hybrida. Eur. J. Biochem., 1999, (259):426-434
63. De Neve M., De Loose M., Jacobs A., van Houdt H., Kaluza B., Weidle U., Van Montagu M. and Depicker A.. Assembly of an antibody fragment in N. tabacum and Arabidopsis. Transgenic Res., 1993, 2:227-237
64. De Wilde C., de Neve M., de Rycke R., Bruyns A.M., De Jaeger G., Van Montagu M., Depicker A. and Engler G.. Intact antigen-binding MAK33 antibody and Fab fragment accumulate in intercellular spaces of A. thaliana. Plant Sci., 1996, 114:233-241
65. De Wilde C., Peeters K., Jacobs A., Peck I. and Depicker A.. Expression of antibodies and Fab fragments in transgenic potato plants: a case study for bulk production in crop plants. Mol. Breed., 2002, 9:271-282
66. De Wilde C., Van Houdt H., de Buck S., Angenon G., de Jaeger G. and Depicker A.. Plants as bioreactors for protein production: avoiding the problem of transgene silencing. Plant Mol. Biol. 2000, 43:347-359
67. Deblaere R., Bytebier B., Greve D.H., Deboeck F., Schell J., Montagu V.M.and Leemans J.. Efficient octopine Ti plasmid-derived vectors for Agrobacterium-mediated gene transfer to plants. Nucleic Acids Res., 1985,13: 777-788
68. Denbow D.M., Grabau E. A., Lacy G. H., Kornegay E.T., Russell D. R. and Umbeck P. F.. Soybeans transformed with fungal phytase gene improve phosphorus availability for broilers. Poult. Sci., 1998, 77:878-881
69. DeZoeten G. A., Penswick J. R., Horisberger M. A., Ahl P., Schultze M. and Hohn T.. The expression, localization, and effect of a human interferon in plants. Virology, 1989, 172: 213-222
70. Dieryck W., Gruber V., Baudino S., Lenee P., Pagnier J., Merot B. and Poyart C.. Expre- ssion of recombinant human hemoglobin in plants. Transfus. Clin. Biol., 1995, 2:441-447
71. Dieryck W., Pagnier J., Poyart G., Marden M.C., Gruber V., Bournat P., Baudino S. and Merot B.. Human haemoglobin from transgenic tobacco. Nature, 1997, 386:29-30
72. Doerschug M.R. and Miller C.O.. Chemical control of adventitious organ formation in Lactuca sativa explants. American Journal of Botany, 1967,54: 410–413
73. Doran P. M.. Foreign protein production in plant tissue cultures. Curr. Opin. Biotechnol., 2000, 11:199-204
74. Drake P. M. W., Chargelegue D. M., Vine N. D., Van Dolleweerd C. J., Obregon P. and Ma J. K.C.. Rhizosecretion of a monoclonal antibody protein complex from transgenic tobacco roots. Plant Mol. Biol., 2003, 52:233-241
75.Edelbaum O., Ilan N., Grafi G., Sher N., Stram Y., Novick D., Tal N., Sela I. and Rubinstein M.. Purification and characterization of two antivirally active proteins from tobacco by monoclonal antibodies to human beta-interferon. Proc. Natl. Acad. Sci., 1990, 87: 588-592.
76. Eeckhout D., Fiers E., Sienaert R., Snoeck V., Depicker A. and De Jaeger G.. Isolation and characterization of recombinant antibody fragments against CDC2a from Arabidopsis thaliana. Eur. J. Biochem., 2000, 267:6775-6783.
77. Elbers I. J., Stoopen G. M., Bakker H., Stevens L. H., Bardor M., Molthoff J. W., Jordi W. J., Bosch D. and Lommen A.. Influence of growth conditions and developmental stage on N-glycan heterogeneity of transgenic immunoglobulin G and endogenous proteins in tobacco leaves. Plant Physiol., 2001, 126:1314-1322
78. Elliott S., Lorenzini T., Asher S., Aoki K., Brankow D., Buck L., Busse L., Chang D., Fuller J., Grant J., Hernday N., Hokum M., Hu S., Knudten A., Levin N., Komorowski R., Martin F., Navarro R., Osslund T., Rogers G., Roger, N., Trail G. and Egrie J.. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat. Biotechnol., 2003, 21:414-421
79. Ellstrand N. C.. Going to “great lengths” to prevent the escape of genes that produce specialty chemicals. Plant Physiol., 2003, 132:1770-1774
80. Evangelista R. L., Kusnadi, A.R., Howard J. A. and Nikolov Z. L.. Process and economic evaluation of the extraction and purification of recombinant β-glucuronidase from transgenic corn. Biotechnol. Prog., 1998, 14: 607-614
81. Farran I., Sanchez-Serrano J. J., Medina J. F., Prieto J. and Mingo-Castel A. M.. Targeted expression of human serum albumin to potato tubers. Transgenic Res., 2002, 11:337-346
82. Faye L. and Chrispeels M. J.. Transport and processing of the glycosylated precursor of concanavalin A in jack-bean. Planta, 1987, 170:217-224
83. Faye L. and Chrispeels M.J.. Common antigenic determinants in the glycoproteins of plants, molluscs and insects. Glycoconj. J., 1988, 5:245-256
84. Faye L., Gomord V., Fitchette-Laine A. C. and Chrispeels M. J.. Affinity purification of antibodies specific for Asn-linked glycans containing alpha 1→3? fucose or beta 1 →2? xylose. Anal. Biochem., 1993, 209:104-108
85. Fiedler U. and Conrad U.. High-level production and long-term storage of engineered antibodies in transgenic tobacco seeds. Bio.Technol. 1995, 13:1090-1093
86. Fiedler U., Phillips J., Artsaenko O. and Conrad U.. Optimization of scFv antibody production in transgenic plants. Immunotechnology, 1997, 3:205:216
87. Fischer R. and Emans N.. Molecular farming of pharmaceutical proteins. Transgen Res., 2000, 9:279-299
88. Fischer R., Drossard J., Emans N., Commandeur U. and Hellwig S.. Towards molecular farming in the future: Pichia pastoris-based production of single-chain antibody fragments. Biotechnol. Appl. Biochem., 1999, 30:117-120
89. Fischer R., Emans N., Schuster F., Hellwig S. and Drossard J.. Towards molecular farming in the future: using plant cell suspension cultures as bioreactors. Biotechnol. Appl. Biochem., 1999, 30: 109-112
90. Fischer R., Hoffmann K., Schillberg A. and Emans N.. Antibody production by molecular farming in plants. J. Biol. Regul. Hemeost. Agents, 2000, 14:83-92
91. Fischer R., Liao Y. C. and Drossard J.. Affinity-purification of a TMV-specific recombi- nant full-size antibody from a transgenic tobacco suspension culture. J. Immunol. Methods, 1999, 226:1-10
92. Fischer R., Stoger E., Schillberg S., Christou P. and Twyman R. M.. Plant-based production of biopharmaceuticals. Curr. Opin. Plant. Biol., 2004, 7:152-158
93. Fischer R., Vaquero-Martin C., Sack M., Drossard J., Emans N. and Commandeur U.. Towards molecular farming in the future: transient protein expression in plants. Biotechnol. Appl. Biochem., 1999, 30:113-116
94. Fischer R. and Emans N.. Molecular farming of pharmaceutical proteins. Transgenic Res., 2000,9: 279-299
95. Fitchette-Laine A.C., Gomord V., Chekkafi A. and Faye L..Distribution of xylosylation and fucosylation in the plant Golgi apparatus. Plant J., 1994, 5:673-682
96. Fooks A. R.. Development of oral vaccines for human use. Curr. Opin. Mol. Ther., 2000, 2:80-86
97. Fotisch K., Altmann F., Haustein D. and Vieths S.. Involvement of carbohydrate epitopes in the IgE response of celery-allergic patients. Int. Arch. Allergy. Immunol., 1999, 120:30-42
98. Fraley R. T., Rogers S. G., Horsch R. B., Sander P. R., Flick J. S., Adams S. P., Bittner M. L., Brand L. A., Fink J. S., Galluppi G. R. Goldberg S. B., Hoffmann N. L. and Woo S. C.. Expression of bacterial genes in plant cells. Proc. Natl. Acad. Sci., 1983, 80:4803- 4807
99. Francesco S. M., Manuela R. and Alessandra B.. Vaccine antigen production in transgentic plants: strategies, gene constructs and perspectives. Vaccine, 2003, 21:803-805
100. Frigerio L., Vine N.D., Pedrazzini E., Hein M. B., Wang F., Ma J. K. and Vitale A.. Assembly, secretion, and vacuolar delivery of a hybrid immunoglobulin in plants. Plant Physiol., 2000, 123:1483-1494
101. Fu X.D., Duc L. T., Fontana S., Bong B. B., Tinjuangjun P., Sudhakar D., Twyman R. M., Christou P. and Kohli A.. Linear transgene constructs lacking vector backbone sequences generate low copy number transgenic plants with simple integration patterns. Transgenic Res., 2000, 9:11-19
102. Garcia-Casado G., Sanchez-Monge R., Chrispeels M. J., Armentia A., Salcedo G. and Gomez L.. Role of complex asparagine-linked glycans in the allergenicity of plant glycol- proteins. Glycobiology, 1996, 4:471-477
103. Gasdaska J. R., Spencer D. and Dickey L.. Advantages of therapeutic protein production in the aquatic plant Lemna. Bioprocess J., 2003,2:49-56
104. Geetha K. B., Lending C. R., Lopes M. A., Wallace J. C. and Larkins B.A.. opaque-2 modifiers increase γ-zein synthesis and alter its spatial distribution in maize endosperm. Plant Cell, 1991, 3:1207-1219
105. Giddings G., Allison G., Brooks D. and Carter A.. Transgenic plants as factories for biopharmaceuticals. Nat. Biotechnol. 2000, 18:1151-1155
106. Giddings G.. Transgenic plants as protein factories. Curr. Opin. Biotechnol. 2001, 12:450-454
107. Gil F., Brun A., Wigdorovitz A., Catala R., Martinez-Torrecuadrada J. L., Casal I., Salinas J., Borca M. V. and Escribano J. M.. High yield expression of a viral peptide vaccine in transgenic plants. FEBS Lett. 2001, 488:13-27
108. Gleba Y., Marillonnet S. and Klimyuk V.. Engineering viral expression vectors for plants: the ‘full virus’ and the ‘deconstructed virus’ strategies. Curr. Opin. Plant Biol., 2004, 7:182-188
109. Gleba Y., Klimyuk V. and Marillonnet S.. Magnifection-a new platform for expressing recombinant vaccines in plants. Vaccine, 2005, 23: 2042–2048
110. Goddjin O. J. M. and Pen J.. Plants as bioreactors. Trends Biotechnol., 1995, 13: 379-387
111. Goldstein D. A. and Thomas J. A.. Biopharmaceuticals derived from genetically modified plants. Q.J.M., 2004, 97:705-716
112. Gomord V. and Faye L.. Posttranslational modification of therapeutic proteins in plants. Current. Opin. Plant Biol., 2004, 7:171-181
113. Gomord V., Chamberlain P., Jefferis R. and Faye L.. Biopharmaceutical production in plants: problems, solutions and opportunities. Trends Biotechnol., 2005, 23:559-565
114. Gomord V., Denmat L. A., Fitchette-Laine A. C., Satiat-Jeunemaitre B., Hawes C. and Faye L.. The C-terminal HDEL sequence is sufficient for retention of secretory proteins in the endoplasmic reticulum (ER) but promotes vacuolar targeting of proteins that escape the ER. Plant J. 1997, 11:313-325
115. Gomord V., Sourrouille C., Fitchette A. C., Bardor M., Pagny S., Lerouge P. and Faye L.. Production and glycosylation of plant-made pharmaceuticals: the antibodies as a challenge. Plant Biotechnol. J., 2004, 2:83-100
116. Gomord V., Wee E. and Faye L.. Protein retention and localization in the endoplasmic reticulum and the golgi apparatus. Biochimie., 1999, 81:607-618
117. Gruber V., Berna P. P., Arnaud T., Bournat P., Clement C., Mison D., Olagnier B., Philippe L., Theisen M., Baudino S., Benicourt C., Cudrey C., Blo?s C., Duchateau N., Dufour S., Gueguen C., Jacquet S., Ollivo C., Poncetta C., Zorn N., Ludevid D., Van Dorsselaer A., Verger R., Doherty A., Merot B. and Danzin C.. Large-scale production of a therapeutic protein in transgenic tobacco plants: effects of subcellular targeting on quality of a recombinant dog gastric lipase. Mol. Breed., 2001, 7:329-340
118. Gura T.. Therapeutic antibodies: magic bullets hit the target. Nature, 2002, 417:584-586
119. Gutierrez-Ortega A., Sandoval-Montes C., Olivera-Flores T.D., Santos-Argumedo L. and Gomez-Lim M. A.. Expression of functional interleukin-12 from mouse in transgenic tomato plant. Transgenic Research, 2005,14 (6):877-885
120. Gutterman JU. Cytokine therapeutics. lessons from interferonα.Proc Natl Acad Sci,1994 ,91:1198-1205
121. Hamamoto H., Sugiyama Y., Nakagawa N., Hashida E., Matsunaga Y., Takemoto S., Watanabe Y. and Okada Y.. A new tobacco mosaic virus vector and its use for the systematic production of angiotensin-I-converting enzyme inhibitor in transgenic tobacco and tomato. Biotechnology, 1993, 11:930-932
122. Haq T. A., Mason H. S., Clements J. D. and Arntzen C. J.. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science, 1995, 268:714-716
123. Hendy S., Chen Z. C., Barker H., Santa Cruz S., Chapman S., Torrance L., Cockburn W. and Whitelam G. C.. Rapid production of single-chain Fv fragments in plants using a potato virus X episomal vector. J. Immunol. Methods, 1999, 231:137-146
124. Hens J. R., Amstutz M. D., Schanbacher F. L. and Mather I. H.. Introduction of the human growth hormone gene into the guinea pig mammary gland by in vivo transfection promotes sustained expression of human growth hormone in the milk throughout lactation. Biochim. Biophys. Acta. 2000, 1523:161-171
125. Hiatt A., Cafferkey R. and Bowdish K.. Production of antibodies in transgenic plants. Nature, 1989, 342:76-78
126. Hiatt A., Schillberg S., Emans N. and Fischer R.. Antibody molecular farming in plants and plant cells. Phytochem. Rev., 2002, 1:45-54
127. Hockney R. C..Recent developments in heterologous protein production in Escherichia coli . Trends in Biotech , 1994 , 12 (11): 456-463
128. Hood E. E. and Jilka J. M.. Plant-based production of xenogenic proteins. Curr. Opin. Biotechnol., 1999, 10:382-386
129. Hood E. E., Kusnadi A., Nikolov Z. and Howard J. A.. Molecular farming of industrial proteins from transgenic maize. Adv. Exp. Med. Biol., 1999, 464:127-147
130. Hood E. E., Woodard S. L. and Horn M. E.. Monoclonal antibody manufacturing in transgenic plants-myths and realities. Curr. Opin. Biotechnol., 2002, 13: 630-635
131. Horsch R., Fry J. E. , Hoffman N., Eicholtz D., Rogers S. and Fraley R.. A simple and general method for transferring genes into plants. Science, 1985, 227:1229-1231
132. Horvath H., Huang J., Wong O., Kohl E., Okita T., Kannangara L. G. and Von Wettstein D.. The production of recombinant proteins in transgenic barley grains. Proc. Natl. Acad. Sci., 2000, 97:1914-1919
133. Houdebine L. M.. Antibody manufacture in transgenic animals and comparisons with other systems. Curr. Opin. Biotechnol., 2002, 13:625-629
134. Huang Z., Dry I., Webster D., Strugnell R. and Wesselingh S.. Plant-derived measles virus hemagglutinin protein induces neutralizing antibodies in mice. Vaccine, 2001, 19:2163-2171
135. Hudson P. J.. Recombinant antibody fragments. Curr. Opin. Biotechnol., 1998, 9:395-402
136. Humphreys D. P. and Glover D. J.. Therapeutic antibody production technologies: molecules, applications, expression, and purification. Curr. Opin. Drug Discover. Dev., 2001, 4:172-185
137. Hunter D.C. and Burritt D.J.. Improved adventitious shoot production from cotyledon explant of lettuce (Lactuca sativa L.). Scientia Horticulturae, 2002, 95: 269-276
138. Hyeon-Jin S., Min-Long C., Biao M. and Hiroshi E.. Functional expression of the taste-modifying protein miraculin in transgenic lettuce. FEBS Letters, 2006, 580: 620-626
139. Isaacs A. and Lindenmann J.. Virus interference. I. The interferon. Proc. R. Soc. Lond. B. Biol. Sci., 1957,147: 258–267
140. James E.A., Wang C. and Wang Z.. Production and characterization of biologically active human GM-CSf secreted by genetically modified plant cells. Protein Expr. Purif., 2000, 19:131-138
141. Jeanna M., Pipe M.D., Tony T-S., Wen M.D., Elly M-J. and Xenakis M.D.. Interferon therapy in primary care. Primary Care Update for OB/GYNS. , 2001,8: 163-169
142. Jefferson R.A., Kavanagh T.A. and Eenan M.W.. GUS fusion: beta-glucuranidase as a sensitive and versatile gene fusion marker in higher plants. Embo. J., 1987,6: 3901-3907
143. Jobling S.A., Jarman C., Teh M. M., Holmberg N., Blake C. and Verhoeyen M. E.. Immunomodulation of enzyme function in plants by single domain antibody fragments. Nat. Biotechnol., 2003, 21:77-80
144. Joh. L. D., Wroblewski T., Ewing N.N. and vander Gheynst J.S.. High-level transient expression of recombinant protein in lettuce. Biotechnology and Bioengineering, 2005, 91(7): 861-871
145. Julian K C.M., Pascal M.W.D and Paul C.. The production of recombinant pharmaceutical proteins in plants. Nature Review Genetics , 2003,4: 794-805
146. Kagawa T ,Morizane T , Saito H.. A pilot study of long term weekly interferon-β administration for chronic hepatitis B. Am. J. Gastroenterol, 1993,88:212-216
147. Kanno T., Naito S. and Shimamoto K.. Post-transcriptional gene silencing in cultured rice cells. Plant Cell Physiol., 2000, 41:321-326
148. Kapila J., De Rycke R., Van Montagu M. and Angenon G.. An agrobacterium-mediated transient gene expression system for intact leaves. Plant Sci., 1997, 122:101-108
149. Kapusta J., Modelska A., Figlerowicz M., Pniewski T., Letellier M., Lisowa O., Yusibov V., Koprowski H., Plucienniczak A. and Legocki A. B.. A plant-derived edible vaccine against hepatitis B virus. FASEB J., 1999, 13:1796-1799
150. Kathuria S., Sriraman R., Nath R., Sack M., Pal R., Artsaenko O., Talwar G. P., Fischer R. and Finnern R.. Efficacy of plant-produced recombinant antibodies against HCG. Hum Reprod, 2002, 17:2054-2061
151.Kawaguchi R. and Bailey-Serres J.. Regulation of translational initiation in plants. Curr. Opin. Plant Biol., 2002, 5:460-465
152. Kay E., Vogel T. M., Bertolla F., Nalin R. and Simonet P.. In situ transfer of antibiotic resistance genes from transgenic (transplastomic) tobacco plants to bacteria. Appl. Environ. Microbiol., 2002, 68:3345–3351
153. Khoudi H., Laberge S., Ferullo JM., Bazin R., Darveau A., Castonguay Y., Allard G., Lemieux R. and Vezina L. P.. Production of a diagnostic monoclonal antibody in perennial alfalfa plants. Biotechnol. Bioeng., 1999, 64:135-143
154. Kim K. Y., Kwon S. Y., Lee H. S., Hur Y., Bang J. W and Kwak S. S.. A novel oxidative stress-inducible peroxidase promoter from sweet potato: molecular cloning and characterization in transgenic tobacco plants and cultured cells. Plant. Mol. Biol., 2003, 51:831-838
155. Ko K., Tekoah Y., Rudd P. M., Harvey D. J., Dwek R. A., Spitsin S., Hanlon C. A., Rupprecht C., Dietzschold B., Golovkin M. and Koprowski H.. Function and glycosylation of plant-derived antiviral monoclonal antibody. Proc. Natl. Acad. Sci. USA, 2003, 100:8013 -8018
156. Kohli A., Twyman R. M., Abranches R., Wegel E., Stoger E. and Christou P.. Transgene integration, organization and interaction in plants. Plant Mol. Biol., 2003, 52:247-258
157. Komarnytsky S., Borisjuk N. V., Borisjuk L. G., Alam M. Z. and Raskin I.. Production of recombinant proteins in tobacco guttation fluid. Plant Physiol., 2000, 124:927-933
158. Koprowski H. and Yusibov V.. The green revolution: plants as heterologous expression vectors. Vaccine, 2001, 19:2735-2741
159. Koziel M. G., Carozzi N. B. and Desai N.. Optimizing expression of transgenes with an emphasis on post-transcriptional events. Plant Mol. Biol., 1996, 32:393-405
160. Kumar G. N., Houtz R. L. and Knowles N. R.. Age induced protein modifications and increased proteolysis in potato seed-tubers. Plant Physiol., 1999, 119:89-100
161. Kusnadi A., Nikolov R., Zivko L. and Howard J. A.. Production of recombinant proteins in transgenic plants: practical considerations. Biotechnol. Bioeng., 1997, 56:473-484
162. Kusnadi A.R., Evangelista R. L., Hood E. E., Howard J. A. and Nikolov Z. L.. Process of transgenic corn seed and its effect on the recovery of recombinant β-glucuronidase. Biotechnol. Bioeng., 1998, 60: 44-52
163. Kwon T. H., Kim Y. S., Lee J. H. and Yang M. S.. Production and secretion of biologically active human granulocytemacrophage colony stimulating factor in transgenic tomato suspension cultures. Biotechnol. Lett., 2003, 25:1571-1574
164. Lamphear B. J., Streatfield S. J., Jilka J. A., Brooks C. A., Barker D. K., Turner D. D., Delaney D. E., Garcia M., Wiggins B., Woodard S. L., Hood E. E., Tizard I. R., Lawhorn B. and Howard J. A.. Delivery of subunit vaccines in maize seed. J. Control Release, 2002, 85:169-180
165. Langford M.P., Weigent D.A., Stanton F.J. and Baron S.. Virus plaque-reduction assay for interferon: microplaque and regular macroplaque reduction assays. Methods Enzymol., 1981, 78:339-346
166. Larkins B. A., Bracker C. E. and Tsai C.Y.. Storage protein synthesis in maize: isolation of zein-synthesizing polyribosomes. Plant Physiol, 1976, 57:740-745
167. Larrick J. W. and Thomas D. W.. Producing proteins in transgenic plants and animals. Curr. Opin. Biotechnol., 2001, 12:411-418
168. Larrick J. W., Yu L., Chen J., Jaiswal S. and Wycoff K.. Production of antibodies in transgenic plants. Res. Immunol., 1998, 149:603-608
169. Lauterslager T. G, Florack D. E, van der Wal T. J., Molthoff J. W., Langeveld J. P., Bosch D., Boersma W. J. and Hilgers L. A.. Oral immunization of naive and primed animals with transgenic potato tuber expressing LT2B.Vaccine, 2001, 19:2749-2755
170. Law R. D. and Suttle J. C.. Changes in histone H3 and H4 multiacetylation during natural and forced dormancy break in potato tubers. Physiol. Plant, 2004, 120:642-649
171. Law R. D. and Suttle J. C.. Transient decreases in methylation at 5′-CCGG-3′ sequences in potato (Solanum tuberosum L.) meristem DNA during progression of tubers through dormancy precede the resumption of sprout growth. Plant Mol. Biol., 2003, 51:437-447
172. Law R. D., Russell D. A., Thompson L. C., Schroeder S. C., Middle C. M., Tremaine M. T., Jury T. P., Delannay X. and Slater S. C.. Biochemical limitations to high-level expression of humanized monoclonal antibodies in transgenic maize seed endosperm. Biochim. Biophys. Acta., 2006, 1760:1434-1444
173. Lee D. and Natesan E.. Evaluating genetic containment strategies for transgenic plants. Trends Biotechnol., 2006, 24:109-114
174. Leelavathi S. and Reddy V. S.. Chloroplast expression of His-tagged GUS fusions: a general strategy to overproduce and purify foreign proteins using transplastomic plants as bioreactors. Mol. Breed, 2003, 11:49-58
175. Leelavathi S., Gupta N., Maiti S., Ghosh A. and Reddy V. S.. Overproduction of an alkali- and thermostable xylanase in tobacco chloroplasts and efficient recovery of the enzyme. Mol. Breed., 2003,11:59-67
176. Leonard R., Costa G., Darrambide E., Lhernould S., Fleurat- Lessard P., Carlue M., Gomord V., Faye L. and Maftah A.. The presence of Lewis a epitopes in Arabidopsis thaliana glycoconjugates depends on an active alpha-4-fucosyltransferase gene. Glycobiology, 2002, 12:299-306
177. Lerouge P., Cabanes-Macheteau M., Rayon C., Fischette-Laine A. C., Gomord V. and Faye L.. N-glycoprotein biosynthesis in plants: recent developments and future trends. Plant Mol. Biol., 1998, 38:31-48
178. Lin L.S. , Yamamoto R and Drummond R.J.. Purification of recombinant interferon-β expressed in Escherichia coli. Methods in Enzymology, 1986 ,119 :183-193
179. Lindsay S, Mulroy R and Semeniuk D..Expression of secreted human α-fetoprotein in transgenic animals. Patent Number WO040693A2. Issued July 13, 2000
180. Lisowska K. and Wysokinska H.. In vitro propagation of Catalpa ovata G. Don. Plant Cell Tissue Organ Cult., 2000, 60:171-176
181. Ludwig D. L., Witte L., Hicklin D. J., Prewett M., Bassi R., Burtrum D., Pereira D. S., Jimenez X., Fox F., Saxena B., Zhou Q., Ma Y., Kang X., Patel D., Barry M., Kussie P., Zhu Z., Russell D. A., Petersen W. L., Jury T. P., Gaitan-Gaitan F., Moran D. L., Delannay X., Storrs B. S., Tou J., Zupec M. E., Gustafson K. S., McIntyre J., Tarnowski S. J. and Bohlen P.. Conservation of receptor antagonist antitumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed. Hum. Antib., 2004, 13:81-90
182. Lynn W.. Interferon-beta-la approved for replapsing multiple sclerosis. Med. Sci. Bull, 1996,18: 456-468
183. Ma J. K. C., Drake P. M. W. and Christou P.. The production of recombinant pharmaceutical proteins in plants. Nature Rev. Genet., 2003, 4:794-805
184. Ma J. K., Hikmat B. Y., Wycoff K., Vine N. D., Chargelegue D., Yu L., Hein M. B. and Lehner T.. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat. Med., 1998,4:601-606
185. Ma J.K., Hiatt A., Hein M., Vine N. D., Wang F., Stabila P., Van Dolleweerd C., Mostov K. and Lehner T.. Generation and assembly of secretory antibodies in plants. Science, 1995, 268:716-719
186. Mallory A. C., Ely L., Smith T. H., Marathe R., Anandalakshmi R., Fagard M., Vaucheret H., Pruss G., Bowman L. and Vance V. B.. HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal. Plant Cell, 2001, 13:571-583
187. Manjunath S. and Sachs M. M.. Molecular characterization and promoter analysis of the maize cytosolic glyceraldehyde 3-phosphate dehydrogenase gene family and its expression during anoxia. Plant Mol. Biol., 1997, 33:97-112
188. Mark D.F, Lu S.D. and Creasey A.A.. Site specific mutagenesis of human fibroblast interferon gene. Proc. Natl. Acad. Sci., 1984 ,81 :5662-5666
189. Mason H. S. and Arntzen C. J.. Transgenic plants as vaccine production systems. Trends Biotechnol., 1995, 13:388-392
190. Mason H. S., Haq T. A., Clements J. D. and Arntzen C. J.. Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine, 1998, 16:1336-1343
191. Mason H. S., Lam D. M.and Arntzen C. J.. Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci., 1992, 89:11745-11749
192. Mason H.S., Warzecha H., Mor T. and Arntzen C. J.. Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends Mol. Med., 2002, 8:324-329
193. Matsumoto S., Ikura K., Ueda M. and Sasaki R.. Characterization of a human glycoprotein (erythropoietin) produced in cultured tobacco cells. Plant Mol. Biol., 1995, 27:1163-1172
194. Matsuoka K. and Nakamura K:. Propeptide of a precursor to a plant vacuolar protein required for vacuolar targeting. Proc. Natl. Acad. Sci., 1991, 88:834-838
195. Mayfield S. P., Franklin S. E. and Lerner R. A.. Expression and assembly of a fully active antibody in algae. Proc. Natl. Acad. Sci., 2003, 100:438-442
196. McCormick A. A., Kumagai M. H., Hanley K., Turpen T. H., Hakim I., Grill L. K., Tuse D., Levy S. and Levy R.. Rapid production of specific vaccines for lymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc. Natl. Acad. Sci., 1999, 96:703-708
197. McCormick, F., Trahey, M., Innis, M., Dieckmann, B. and Ringold, G.. Inducible expression of amplified human beta interferon genes in CHO cells. Mol. Cell Biol., 1984,4: 166-172
198. Merle C., Perret S., Lacour T., Jonval V., Hudaverdian S., Garrone R., Ruggiero F. and Theisen M.. Hydroxylated human homotrimeric collagen I in Agrobacterium tumefaciens mediated transient expression and in transgenic tobacco plant. FEBS Lett., 2002, 515:114-118
199. Michelmore R.W.; Marsh E.; Seely S. and Landry B.. Transformation of lettuce (Lactuca sativa) mediated by Agrobacterium tumefaciens. Plant Cell Reports, 1987,6: 439-442
200. Millan A.F-S., Mingo-Castel A., Miller M. and Daniell H.. A chloroplast transgenic approach to hyperexpress and purify human serum albumin, a protein highly susceptible to proteolytic degradation. Plant Biotechnol., 2003, 1:77-79
201. Min C., Xian-wei L., Zhan-kun W., Jing S., Qing-sheng Q. and Georger-Peng W.. Modication of plant N-glycans processing:the future of producing therapeutic protein by transgenic plants. Medicinal Research Reviews, 2004, 25: 343-360
202. Mokrzycki-Issartel N., Bouchonb B., Farrera S., Berlanda P., Laparraa H., Madel- montb J.C. and Theisena M.A..Transient tobacco expression system coupled to MALDI- TOF- MS allows validation of the impact of diferential targeting on structure and activity of a recombinant therapeutic glycoprotein produced in plants. FEBS Letters, 2003, 552: 170-176
203. Morassutti C., De Amicis F., Skerlavaj B., Zanetti M and Marchetti S..Production of a recombinant antimicrobial peptide in transgenic plants using a modified VMA intein expression system. FEBS Lett., 2002, 519:141-146
204.Moschera J.A.,Woehle D. and Tsai K.P.. Purification of Recombinant human fibroblast interferon produced in Escherichia coli. Methods in Enzymology, 1986 ,119 :177-183
205. Murray C., Sutherland P. W., Phung M. M., Lester M. T., Marshall R. K. and Christeller J. T.. Expression of biotin-binding protein, avidin and streptavidin, in plant tissues using plant vacuolar targeting sequences. Transgenic Res., 2002, 11:199-214
206. Navazio L., Baldan B., Mariani P., Gerwig G. J. and Vliegenthart J. F.. Primary structure of the N-linked carbohydrate chains of Calreticulin from spinach leaves. Glycoconj. J., 1996, 13:977-983
207. Nebenfuhr A., Gallagher L. A., Dunahay T. G., Frohlick J. A., Mazurkiewicz A. M., Meehl J. B. and Staehelin L. A.. Stop and gomovements of plant Golgi stacks are mediated by the actomyosin system. Plant Physiol., 1999, 121:1127-1142
208. Negouk V., Eisner G., Lee H., Han K., Taylor D. and Wong H.C.. Highly efficient transient expression of functional recombinant antibody in lettuce. Plant Science, 2005, 169: 433-438
209 Nolke G., Fischer R. and Schillberg S.. Production of therapeutic antibodies in plants. Expert Opin. Biol. Ther., 2003 3:1153-1162
210. Page A. and Angell S.. Transient expression of reporter proteins can alter plant gene expression. Plant Science, 2002,163: 431-437
211. Pagny S., Bouissonnie F., Sarkar M., Follet-Gueye M. L., Driouich A., Schachter H., Faye L. and Gomord V.. Structural requirements for Arabidopsis beta 1,2-xylosyl- transferase activity and targeting to the Golgi. Plant J., 2003, 33:189-203
212. Pagny S., Cabanes-Macheteau M., Gillikin J. W., Leborgne-Castel N., Lerouge P., Boston R. S., Faye L. and Gomord V.. Protein recycling from the Golgi apparatus to the endoplasmic reticulum in plants and its minor contribution to calreticulin retention. Plant Cell., 2000, 12:739-756
213. Pagny S., Denmat-Ouisse L. A., Gomord V. and Faye L.. Fusion with HDEL protects cell wall invertase from early degradation when N-glycosylation is inhibited. Plant Cell Physiol., 2003, 44:173-182
214. Parmenter D. L., Boothe J. G., van Rooijen G. J., Yeung E. C. and Moloney M. M.. Production of biologically active hirudin in plant seeds using oleosin partitioning. Plant Mol. Biol., 1995, 29:1167-1180
215. Paty D.W. and .Li D.K.B.. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology, 1993,43: 662-667
216. Peeters K., De Wilde C. and Depicker A.. Highly efficient targeting and accumulation of a Fab fragment within the secretory pathway and apoplast of A. thaliana. Eur. J. Biochem., 2001, 268:4251-4260
217. Pileggi M.; Pereira A.A.M.; Silva J.S.S.; Pileggi A.V. and Verma D.P.S.. An Improved Method for Transformation of Lettuce by Agrobacterium tumefaciens with a Gene that Confers Freezing Resistance. Braz. arch. biol. Technol., 2001,44:191-196
218. Pueyo J. J., Chrispeels M. J. and Herman E. M.. Degradation of transport-competent destabilized phaseolin with a signal for retention in the endoplasmic reticulum occurs in the vacuole. Planta, 1995, 196:586-596
219. Ramirez N., Ayala M., Orenzo D., Palenzuela D., Herrera L., Doreste V., Perez M., Gavilond J.V. and Oramas P.. Expression of a single-chain Fv antibody fragment specific for the hepatitis B surface antigen in transgenic tobacco plants. Transgenic Res., 2002, 11:61-64
220. Ramirez N., Rodriguez M., Ayala M., Cremata J., Perez M., Martinez A., Linares M., Hevia Y., Paez R., Valdes R., Gavilondo J. V. and Selman-Housein G.. Expression and characterization of an anti-hepatitis B surface antigen glycosylated mouse antibody in transgenic tobacco plants, and its use in the immunopurification of its target antigen. Biotechnol Appl. Biochem., 2003, 38:223-230
221. Richter L. and Kipp P. B.. Transgenic plants as edible vaccines. Curr. Topics Microbiol. Immunol., 1999, 240:159-176
222. Richter L., Thanavala Y., Arntzen C. J. and Mason H. S.. Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nat. Biotechnol., 2000, 18:1167- 1171
223. Rourke E.C., Drummond R.J. and Creasey A.A.. Binding of 1-5I-labeled recombinant beta interferon ( IFN-beta Ser 17) to human cells. Mol. Cell Biol., 1984,4:2745-2749
224. Ruf S., Hermann M., Berger I. J., Carrer H. and Bock R.. Stable genetic transformation of tomato plastids and expression of a foreign protein in fruit. Nat. Biotechnol., 2001, 19:870- 875
225. Ruggiero F., Exposito J. Y., Bournat P., Gruber V., Perret S., Comte J., Olagnier B., Garrone R. and Theisen M.. Triple helix assembly and processing of human collagen produced in transgenic tobacco plants. FEBS Lett., 2000, 469:132-136
226. Russell D. A. and Fromm M. E.. Tissue-specific expression in transgenic maize of four endosperm promoters from maize and rice. Transgenic Res., 1997, 6:157-168
227. Russell D. A. and Sachs M. M.. Differential expression and sequence analysis of the maize glyceraldehyde-3-phosphate dehydrogenase gene family. Plant Cell, 1989,1: 793-803
228. Russell D. A.. Feasibility of antibody production in plants for human therapeutic use. Curr. Top. Microbiol. Immunol., 1999, 240:119-138
229. Sala F., Manuela R. M., Barbante A., Basso B., Walmsley A. M. and Castiglione S.. Vaccine antigen production in transgenic plants: strategies, gene constructs and perspectives. Vaccine, 2003,21:803-808.
230. Samyn-Petit B., WajdaDubos J. P., Chirat F., Coddeville B., Demaizieres G., Farrer S., Slomianny M. C., Theisen M. and Delannoy P.. Comparative analysis of the site-specific N-glycosylation of human lactoferrin produced in maize and tobacco plants. Eur. J. Biochem., 2003, 270:3235-3242
231. Schenk P. M., Sagi L., Remans T., Dietzgen R.G., Bernard M. J., Graham M. W. and Manners J.M.. A promoter from sugarcane bacilliform badnavirus drives transgene expression in banana and other monocot and dicot plants. Plant Mol. Biol., 1999, 39:1221-1230
232. Schillberg S., Fischer R. and Emans N.. Molecular farming of recombinant antibodies in plants. Cell Mol. Life Sci., 2003, 60:433-445
233. Schillberg S., Twyman R. M. and Fischer R.. Opportunities for recombinant antigen and antibody expression in transgenic plants-technology assessment. Vaccine, 2005, 23:1764-1769
234. Schillberg, S., Zimmermann S., Voss A. and Fischer R.. Apoplastic and cytosolic expression of fullsize antibodies and antibody fragments in Nicotiana tabacum. Transgenic Res., 1999, 8:255-263
235. Schlatter S., Stansfield S. H., Dinnis D.M., Racher A.J., Birch J. R. and James D.C.. On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells. Biotechnol. Prog., 2005, 21:122-133
236. Schouten A., Roosien J., De Boe J. M., Wilmink A., Rosso M. N., Bosch D., Stiekema W. J., Gommers F. J., Bakker J. and Schots A.. Improving scFv antibody expression levels in the plant cytosol. FEBS Lett., 1997, 415:235-241
237. Schouten A., Roosien J., Van Engelen F. A., De Jong G. A., Borst-Vrenssen A. W., Zilverentant J. F., Bosch D., Stiekema W. J., Gommers F. J., Schots A. and Bakker J.. The C-terminal KDEL sequence increases the expression level of a single chain antibody designed to be targeted to both the cytosol and the secretory pathway in transgenic tobacco. Plant Mol. Biol., 1996, 30:781-793
238. Seon J. H., Szarka S. and Moloney M. M.. A unique strategy for recovering recombinant proteins from molecular farming: affinity capture on engineered oilbodies. J. Plant Biotechnol., 2002, 4:95-101
239. Sharma N., Kim T.G., Yang M.S.. Production and secretion of human interleukin-18 in transgenic tobacco cell suspension culture. BioTechnology and Bioprocess engineering, 2006, 11 2,154-159
240. Shekhter I.,Beiko V.P. and Bulenkov M.T.. Obtaining human recombinant ( Serine217) beta-interferon by the method of oligonucleotide directed mutagenesis and its expression in Escherichia coli. Antibiot Khimioter, 1991,36 :25-28
241. Shin Y. J., Hong S. Y., Kwon T. H., Jang Y. S. and Yang M. S.. High level of expression of recombinant human granulocytemacrophage colony stimulating factor in transgenic rice cell suspension culture. Biotechnol. Bioeng., 2003, 82:778-783
242. Sijmons P. C., Dekker B. M. M., Schrammeijer B., Verwoerd T. C., van den Elzen P. J. M. and Hoekema A.. Production of correctly processed human serum albumin in transgenic plants. Biotechnology, 1990, 8:217-221
243. Smith M. D. and Glick B. R.. The production of antibodies in plants. Biotechnol. Adv., 2000, 18:85-89
244. Smith M. L., Mason H. S. and Shuler M. L.. Hepatitis B surface antigen (HBsAg) expression in plant cell culture kinetics of antigen accumulation in batch culture and its intracellular form. Biotechnol. Bioeng., 2002, 80:812-822
245. Sojikul P., Buehner N. and Mason H. S.. A plant signal peptide hepatitis B surface antigen fusion protein with enhanced stability and immunogenicity expressed in plant cells. Proc. Natl. Acad. Sci., 2003, 100:2209-2214
246. Staub J. M., Garcia B., Graves J., Hajdukiewicz P. T., Hunter P., Nehra N., Paradkar V., Schlittler M., Carroll J. A., Spatola L., Ward D., Ye G. and Russell D.A.. High yieldproduction of a human therapeutic protein in tobacco chloroplasts. Nat. Biotechnol., 2000, 18:333-338
247. Stewart W.E., 1979. The interferon system II. Springer, Vienna, Austria.
248. Stoger E., Sack M., Fischer R. and Christou P.. Plantibodies: applications, advantages and bottlenecks. Curr. Opin. Biotechnol., 2002, 13:161-166
249. Stoger E., Sack M., Perrin Y., Vaquero C., Torres E., Twyman R. M., Christou P. and Fischer R.. Practical considerations for pharmaceutical antibody production in different crop systems. Mol. Breed., 2002, 9:149-158
250. Stoger E., Vaquero C., Torres E., Sack M., Nicholson L., Drossard J., Williams S., Keen D., Perrin Y., Christou P. and Fischer R.. Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol. Biol., 2000, 42:583-590
251. Streatfield S. J., Jilka J. M., Hood E. E., Turner D. D., Baily M. R., Mayor J. M., Woodard S. L., Beifuss K. K., Horn M. E., Delaney D. E., Tizard I. R. and Howard J. A.. Plant-based vaccines: unique advantages. Vaccine, 2001, 19:2742-2748
252. Suzuki H , Nichigaki K and Gunji A.. Toray IFN Research Group :Treatment of chronic non -A, non-B hepatitis with human interferon-β, a randomized controlled trial with different durations. Kan Tan Sui, 1994 , 23:1065-1079
253. Thanavala Y., Wang Y-F., Lyons P., Mason H. S. and Arntzen C.. Immunogenicity of transgenic plant-derived hepatitis B surface antigen. Proc. Natl. Acad. Sci., 1995, 92:3358-3361
254. Torres E., Vaquero C., Nicholson L., Sack M., Stoger E., Drossard J., Christou P., Fischer R. and Perrin Y.. Rice cell culture as an alternative production system for functional diagnostic and therapeutic antibodies. Transgenic Res., 1999, 8:441-449
255.Towbin H., Staehelin T. and Gordon J.. Electrophoretic transfer from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci., 1979,76:4350-4354
256. Twyman R. M., Stoger E., Schillberg S., Christou P. and Fischer R.. Molecular farming in plants: host systems and expression technology. Trends Biotechnol., 2003, 21:570-578
257.Vain P., Finer K. R., Engler D. E., Pratt R. C. and Finer J.J.. Intron-mediated enhancement of gene expression in maize (Zea mays L.) and bluegrass (Poa pratensis L.). Plant Cell Rep., 1996, 15:489-494
258. Vaquero C., Sack M., Chandler J., Drossard J., Schuster F., Monecke M., Schillberg S. and Fischer R.. Transient expression of a tumor-specific single chain fragment and a chimeric antibody in tobacco leaves. Proc. Natl. Acad. Sci.,1999, 96:11128-11133
259. Vaquero C., Sack M., Schuster F., Finnern R., Drossard J., Schumann D., Reimann A. and Fischer R.. A carcinoembryonic antigen specific diabody produced in tobacco. FASEB J., 2002, 16:408-410
260. Vaucheret H. and Fagard M.. Transcriptional gene silencing in plants: targets, inducers and regulators. Trends Genet., 2001, 17:29-35
261. Vietor R., Loutelier-Bourhis C., Fitchette A. C., Margerie P., Gonneau M., Faye L. and Lerouge P.. Protein N-glycosylation is similar in the moss Physcomitrella patens and in higher plants. Planta, 2003, 218:269-275
262.Webb D.T.; Torres L.D. and Fobert P. Interactions of growth regulators, explant age, and culture environment controlling organogenesis from lettuce cotyledons in vitro. Canadian Journal of Botany, 1984,62: 586–590
263. Witcher D. R., Hood E. E., Peterson D., Bailey M., Bond D., Kusnadi A., Evangelista R., Nikolov Z., Wooge C., Mehigh R., Kappel W., Register J. and Howard J.A.. Commercial production of β-glucuronidase (GUS): a model system for the production of proteins in plants. Mol. Breed, 1998, 4: 301-312
264.Wroblewski T., Tomczakt A. and Michelmore R.. Optimization of Agrobacterium- mediated transient assays of gene expression in lettuce, tomato and Arobidopsis. Plant Biotechnology Journal, 2005, 3: 259-273
265. Yang D., Guo F., Liu B., Huang N. and Watkins S. C.. Expression and localization of human lysozyme in the endosperm of transgenic rice. Planta, 2003, 216:597-603
266. Yu J. and Langridge W.. Expression of rotavirus capsid protein VP6 in transgenic potato and its oral immunogenicity in mice. Transgenic Res., 2003, 12:163-169
267. Yuan, Q., Hu W., Pestka J. J., He S.Y. and Hart P.. Expression of a functional antizearal- enone single-chain Fv antibody in transgenic Arabidopsis plants. Appl. Env. Microb., 2000, 66:3499-3505
268. Zeitlin L., Olmsted S. S., Moench T. R., Co M. S., Martinell B. J., Paradkar V. M., Russell D. R., Queen C., Cone R. A. and Whaley K. J.. A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat. Biotechnol., 1998, 16:1361-1664
269. Zhong G. Y., Peterson D. J., Delaney D., Bailey M., Witcher D. R., Register J. C., Bond D., Li C. P., Marshall L., Kulisek E., Ritland D., Meyer T., Hood E. E. and Howard J.. Commercial production of aprotinin in transgenic maize seeds. Mol. Breed., 1999, 5:345-356
270. Ziegler M.T., Thomas S. R. and Danna K. J.. Accumulation of a thermostable endo-1,4-β-D-glucanase in the apoplast of Arabidopsis thaliana leaves. Mol. Breed., 2000, 6: 37-46
271. Zuo X.F., Zhang X.Y., Shan L., Xiao C.Y., He D.X. and Ru B.G. Expression of human intestinal trefoil factor (hITF) gene in lettuce. Acta Botanica Sinica, 2001,43:1047-1051