TCRγδ-Ig融合蛋白抗人卵巢癌活性的研究及功能性抗人TCRγδ抗体及单链抗体的制备和鉴定
|
摘要
二十余年来,肿瘤的抗体靶向治疗发展迅速。曲妥珠单克隆抗体(Trastuzumab)和利妥昔单克隆抗体(Rituximab)分别被用于靶向性治疗乳腺癌转移和非何杰金式淋巴瘤；并取得了良好的临床治疗效果。肿瘤靶向治疗的关键在于发现肿瘤特异性抗原。然而,已获鉴定的肿瘤特异性抗原数量较少,这大大限制了应用抗体进行肿瘤靶向治疗的发展。
除了抗体,肿瘤浸润性T细胞表面的T细胞受体(T cell receptor, TCR)也能特异地识别肿瘤抗原,这使之成为肿瘤靶向治疗的理想候选者。据报道,应用TCRαβ进行肿瘤靶向治疗的研究已取得了初步的进展。TCRγ9δ2在TCR缺失的JRT3-T3.5细胞中表达,能够赋予后者识别和杀伤肿瘤细胞的能力,表明TCRγ9δ2在γ9δ2T细胞对肿瘤细胞的杀伤中起着关键性作用。对肿瘤细胞的特异识别使TCRγ9δ2可能像抗体一样应用于肿瘤的靶向治疗。更重要的是,与TCRαβ相比,TCRγδ的抗原识别不受主要组织相容性复合物(Major histocompability complex, MHC)限制,其抗原识别谱可能更广。因此,TCRγδ应用于肿瘤靶向治疗可能也具有一定优势。
本课题组致力于研究TCRγ9δ2在肿瘤靶向治疗中的作用。在前期工作中,本组在人卵巢上皮癌浸润性T淋巴细胞中获得了一个优势TCRδ2链互补决定区3(complementary determining region3, CDR3)序列,将其命名为OT3。实验证明,TCRγ9δ2(OT3)是卵巢癌反应性的特异性TCR。用OT3取代抗体重链CDR3区,构建的CDR3δ(OT3)移植性抗体,保留了其与多种肿瘤细胞的结合特性,但亲和力较弱。为了获得既具有对肿瘤抗原的高亲合特性,又具有抗体生物学功能的融合蛋白,我们将TCRγ9δ2(OT3)的完整胞外段或可变区分别与人IgGl重链恒定区连接起来,构建了三种TCRγδ-Ig融合蛋白,即TCRγ9δ2(OT3)-Fc, TCRVδ2(OT3)-Fc和TCRVδ2(OT3)H/Vγ9Lλ。体外结合实验的结果表明,三种融合蛋白中,TCRγ9δ2(OT3)-Fc与卵巢癌细胞系和组织的结合能力最强。
因此,本研究的第一部分工作,主要研究了TCRγ9δ2(OT3)-Fc的肿瘤结合能力和体内外抗卵巢癌效应。我们发现,除了卵巢癌,TCRγ9δ2(OT3)-Fc在体外能结合其他多种肿瘤细胞系,提示其可能具有广谱肿瘤靶向性;体外杀伤实验结果显示,TCRγ9δ2(OT3)-Fc的加入可以明显增强人外周血单个核细胞(Peripheral blood mononuclear cells, PBMCs)对卵巢癌细胞系SKOV3和ES-2细胞的杀伤作用,并具有剂量依赖的特性。体内实验结果显示,在人卵巢癌移植瘤裸鼠模型中,与PBS对照组相比,TCRγ9δ2(OT3)-Fc能够有效抑制肿瘤生长,并延长荷瘤裸鼠的生存期。这些数据表明,TCRγ9δ2(OT3)-Fc融合蛋白保留了TCRγδ的抗原识别特性,同时也兼具抗体Fc段介导的效应功能,将其应用于卵巢癌的靶向治疗是可行的。而且,由于TCRγ9δ2(OT3)-Fc能结合多种肿瘤细胞系,具有潜在的广谱肿瘤靶向性,有望扩大肿瘤靶向治疗的应用范围。
本研究的第二部分工作,主要是功能性抗人TCRγδ抗体的研究,以期用其扩增γδT细胞,应用于肿瘤的过继免疫治疗。在肿瘤免疫中,γδ T细胞对肿瘤抗原的识别不具MHC限制性,能分泌大量干扰素-γ(Interferon-γ, IFN-γ),且能杀伤多种肿瘤细胞系,从而具有用于肿瘤过继免疫治疗的潜能。由于γδ T细胞仅占外周血T细胞的1～10%,获取足够数量且有相应生物学功能的γδ T细胞,成为制约其应用于过继免疫治疗的瓶颈。目前获得用于过继免疫治疗的γδ T细胞的方法有两种,一种是磷酸抗原刺激增殖,如4-羟基-3-甲基-2-已烯基-4-焦磷酸(HMBPP),另一种是固相化抗体体外扩增；两种方法均需联合白细胞介素-2(Interleukin-2, IL-2)。本课题组重点研究固相化抗体体外扩增的γδ T细胞的过继免疫治疗。但是由于目前使用的抗TCRγδ单克隆抗体是鼠源的,有产生人抗鼠抗体(human anti-mouse antibody, HAMA)反应的潜在危险,因而在临床治疗上受到一定限制。因此,本文第二部分的工作,旨在构建稳定分泌抗人TCRγδ单克隆抗体的杂交瘤细胞株,并在此基础上,构建人源化的抗人TCRγδ抗体或单链抗体(single chain variable fragment, ScFv)。通过对人源化抗体或单链抗体的生物学功能进行分析,以验证其能否替代鼠源亲本抗体,用于制备过继免疫治疗的γδT细胞制剂。
首先,我们以TCRγ9δ2(OT3)-Fc为免疫原免疫BALB/c小鼠,用常规杂交瘤技术获得能稳定分泌抗人TCRγδ抗体的杂交瘤细胞株。并用固相化抗体体外扩增的方法,筛选到分泌能体外扩增γδT细胞的单抗的杂交瘤细胞株--G5-4。
其后,通过RT-PCR法,从杂交瘤细胞株G5-4的cDNA中分别扩增获得抗体的轻重链的可变区基因；并分别构建了嵌合抗体的表达质粒G5-4-pAc-κ-CH3和单链抗体的表达质粒G5-4ScFv-pET22b(+)。嵌合抗体和单链抗体分别在在昆虫杆状病毒表达系统和大肠杆菌TransB(DE3)中得到成功表达。
最后,重点对单链抗体G5-4ScFv的生物学功能进行了分析。结果表明,单链抗体G5-4ScFv能与TCRγδ特异结合；固相化G5-4ScFv能刺激人PBMC中γδT细胞增殖,2周时其纯度可达90%；扩增得到的γδT细胞能有效杀伤肿瘤细胞系,如Daudi细胞；并在刺激时能有效分泌干扰素-γ(INIFN-γ)和TGF-α。提示,本实验成功构建并表达了具有生物学活性的抗人TCRγδ单链抗体G5-4ScFv,为进一步研究其用于制备肿瘤过继免疫治疗的细胞制剂奠定了基础。
综上所述,本文的研究有以下成果：
1.我们构建并表达了具有较高亲和力的TCRγ9δ2(OT3)-Fc融合蛋白,该蛋白兼具TCRγδ的抗原识别特性和抗体的效应功能。
2. TCRγ9δ2(OT3)-Fc在体内外均表现出抗卵巢癌的功能,提示有应用于卵巢癌靶向治疗的前景。
3.由于TCRγ9δ2(OT3)-Fc的潜在广谱肿瘤识别特性,因此,它具有应用于多种肿瘤靶向治疗的可能性。
4.成功构建了稳定分泌抗人TCRγδ单克隆抗体的杂交瘤细胞株。
5.构建并表达了人源化的抗人TCRγδ抗体或单链抗体。
6.单链抗体G5-4ScFv能与人TCRγδ特异结合,固相化后能有效刺激人PBMC中γδT细胞增殖,有望替代鼠源抗体用于制备过继免疫治疗的γδT细胞制剂。
Antibody (Ab)-based tumor-targeting immunotherapy has been rapidly developed during the last few decades. Trastuzumab and rituximab, two monoclonal antibodies used for the treatment of metastatic breast cancer and non-Hodgkin's lymphoma, respectively, have showed great clinical success. The identification of tumor-specific antigens is crucial for Ab-based tumor-targeting immunotherapy. However, only a limited number of tumor-specific antigens have been discovered so far, which greatly limits the use of Ab-based therapies in clinic.
The ability of T cell receptors (TCRs) on tumor infiltrating lymphocytes (TILs) to specifically recognize tumor cells makes TCRs as ideal candidates for tumor-targeting applications. Several studies have attempted to develop novel TCRαβ-based antitumor strategies. The introduction of TCRy982into TCR-deficient JRT3-T3.5cells could enable the cells to possess the ability of tumor cell recognition and cytotoxicity, indicating the crucial role of TCRγ9δ2for y982T cells in fighting against tumors. The ability of specific recognition of tumor cells makes TCRγ9δ2available for tumor targeting therapies like Abs. Compared with TCRαβ, TCRγδ recognizes broader spectrum of tumor antigens, due to its human major histocompatibility complex (MHC)-independent manner. This may be a great advantage for the application of TCRγδ in tumor-targeting therapies.
Our research focused on the study of application of TCRγδ in tumor-targeting therapies. We previously identified a complementarity determining region (CDR)3gene sequence, named OT3, in82chain from TILs in human ovarian epithelial carcinoma. TCRγ9δ2(OT3), containing the specific CDR3δ(OT3), was demonstrated to be a ovarian carcinoma specific TCR. A CDR38(OT3)-grafted Ab was constructed by grafting OT3 instead of the CDR3in the heavy chain of human IgG1. The CDR3δ(OT3)-grafted Ab showed specific binding activities to multiple tumor cell lines, but the affinities were low. To obtain an Ab-like TCRγδ-Ig fusion protein with high affinity, we constructed three TCRγδ-Ig fusion proteins by fusing the complete extracellular domains or V regions of TCRγ9δ2(OT3) to the constant domains of human IgG1. We analyzed the tumor-binding abilities of three TCRγδ-Ig fusion proteins and found TCRγ9δ2(OT3)-Fc possessing the best binding ability to tumor cell lines and tissues.
In the first part of this study, we evaluated the antitumor effect of TCRy982(OT3)-Fc both in vitro and in vivo. The results showed that TCRγ9δ2(OT3)-Fc could bind to multiple tumor cell lines, including carcinoma of the ovary, cervix, lung, kidney and stomach. TCRγ9δ2(OT3)-Fc fusion protein mediated cytolysis by antibody-dependent cellular cytotoxicity (ADCC) in a dose dependent manner in vitro. TCRy982(OT3)-Fc fusion protein could also significantly inhibit tumor growth in vivo and provide a protection for the survival of animals in human ovarian cancer xenograft model. These data taken together demonstrate the feasibility of TCRγ9δ2(OT3)-Fc application for ovarian tumor-targeting therapy. TCRy982(OT3)-Fc fusion protein behaved as Abs but possessed the ability of TCRγδ to recognize antigens. Moreover, due to its broad spectrum of tumor recognition, TCRy982(OT3)-Fc has the potential to expand the range of tumors available for targeting therapies.
In the second part of work, we mainly focused on the preparation and characterization of functional antibodies being able to amplify human γδT cells in vitro for adoptive immunotherapy. Based on their particular properties such as abundant interferon (IF)-γ secretion, potent cytotoxicity, and MHC-independent recognition of a broad spectrum of tumors, human γδT cells have been demonstrated as an attractive candidate for cancer immunotherapy. Unfortunately, γδT cells is a minor subset of T cells, constituting approximately1～0%of total T cells in human peripheral blood. Currently, there are mainly two methods to obtain y8T cells for adoptive cell therapy. One is to expand γδT cells by phosphoantigens such as bromohydrin pyrophosphate and1-hydroxy-2-methyl-2-(E)-butenyl4-diphosphate (HMBPP). Another is to expand y8T cells by immobilized anti-pan-TCRγδ Ab. Both methods require the participation of interleukin (IL)-2. In our laboratory, our research mainly focuses on Ab-expanded γδT cells in adoptive cellular therapy. Due to the human anti-mouse antibody (HAMA) response, the use of mouse-derived monoclonal antibody (mAb) in clinic treatments is limited. Therefore, in the second part of work, we proposed to develop a hybridoma cell line which could secrete a mAb against human TCRγδ. Thus, a humanized Ab and a single chain variable fragment (ScFv) were constructed and expressed. Biological function of the humanized Ab or ScFv was analyzed to detect whether they could substitute the mouse-derived Ab to expand human y8T cells.
First, the BALB/c mice were immunized with TCRγ9δ2(OT3)-Fc. Hybridomas secreted the mAbs against human TCRγδ were selected by using traditional hybridoma methods. The Abs with the ability to expand y8T cells were identified.
Subsequently, the genes of the antibody heavy (VH) and light chains (VL) were amplified by RT-PCR from the hybridoma cell line G5-4. Recombinant plasmids G5-4-pAc-K-CH3for the chimeric Ab and pET22b(+)-G5-4ScFv for ScFv were constructed. Then, the chimeric Abs were successfully expressed through baculovirus expression vector system in the sf9cells while the anti-hTCRγδ-ScFv (G5-4ScFv) was expressed in E.coli TransB (DE3).
Finally, we focused on the biological function analysis of the G5-4ScFv. The results showed that G5-4ScFv could bind to γδ T cells and greatly inhibit the binding of a pan-TCRγδ antibody to y8T cells. The purity of y8T cells expanded by G5-4ScFv stimulation attained up to90%after culture for2weeks. The expanded γδT cells exhibited the abilities of IFN-y and TNF-a secretion and strong cytotoxicity against Daudi cells. Together, these results suggest that anti-hTCRγδ-ScFv with biological function has been successfully constructed and expressed in prokaryotic expression system, which provides the basis for further studying on its potential application in tumor immunotherapy.
In summary, in the present study we have made several major discoveries as follows:
1. We successfully constructed a TCRγ9δ2(OT3)-Fc fusion protein with both antigen-recognition properties of TCRγδ and effector functions like antibody.
2. TCRy982(OT3)-Fc exhibited anti-tumor effects both in vitro and in vivo, indicating the feasibility of TCRy982(OT3)-Fc application for ovarian tumor targeting therapy.
3. Due to its broad spectrum of tumor recognition, TCRγ9δ2(OT3)-Fc has the potential to expand the range of tumors available for targeting therapies.
4. We have developed a hybridoma cell line, G5-4, which can secrete the mAb with the ability to expand human γδT cells.
5. We constructed and expressed the chimeric Ab or ScFv of G5-4.
6. G5-4ScFv possessed the properties to specifically bind to human TCRγδ and to efficiently expand γδT cells, indicating that it could substitute the mouse antibody to expand human γδT cells for adoptive immunotherapy.
除了抗体,肿瘤浸润性T细胞表面的T细胞受体(T cell receptor, TCR)也能特异地识别肿瘤抗原,这使之成为肿瘤靶向治疗的理想候选者。据报道,应用TCRαβ进行肿瘤靶向治疗的研究已取得了初步的进展。TCRγ9δ2在TCR缺失的JRT3-T3.5细胞中表达,能够赋予后者识别和杀伤肿瘤细胞的能力,表明TCRγ9δ2在γ9δ2T细胞对肿瘤细胞的杀伤中起着关键性作用。对肿瘤细胞的特异识别使TCRγ9δ2可能像抗体一样应用于肿瘤的靶向治疗。更重要的是,与TCRαβ相比,TCRγδ的抗原识别不受主要组织相容性复合物(Major histocompability complex, MHC)限制,其抗原识别谱可能更广。因此,TCRγδ应用于肿瘤靶向治疗可能也具有一定优势。
本课题组致力于研究TCRγ9δ2在肿瘤靶向治疗中的作用。在前期工作中,本组在人卵巢上皮癌浸润性T淋巴细胞中获得了一个优势TCRδ2链互补决定区3(complementary determining region3, CDR3)序列,将其命名为OT3。实验证明,TCRγ9δ2(OT3)是卵巢癌反应性的特异性TCR。用OT3取代抗体重链CDR3区,构建的CDR3δ(OT3)移植性抗体,保留了其与多种肿瘤细胞的结合特性,但亲和力较弱。为了获得既具有对肿瘤抗原的高亲合特性,又具有抗体生物学功能的融合蛋白,我们将TCRγ9δ2(OT3)的完整胞外段或可变区分别与人IgGl重链恒定区连接起来,构建了三种TCRγδ-Ig融合蛋白,即TCRγ9δ2(OT3)-Fc, TCRVδ2(OT3)-Fc和TCRVδ2(OT3)H/Vγ9Lλ。体外结合实验的结果表明,三种融合蛋白中,TCRγ9δ2(OT3)-Fc与卵巢癌细胞系和组织的结合能力最强。
因此,本研究的第一部分工作,主要研究了TCRγ9δ2(OT3)-Fc的肿瘤结合能力和体内外抗卵巢癌效应。我们发现,除了卵巢癌,TCRγ9δ2(OT3)-Fc在体外能结合其他多种肿瘤细胞系,提示其可能具有广谱肿瘤靶向性;体外杀伤实验结果显示,TCRγ9δ2(OT3)-Fc的加入可以明显增强人外周血单个核细胞(Peripheral blood mononuclear cells, PBMCs)对卵巢癌细胞系SKOV3和ES-2细胞的杀伤作用,并具有剂量依赖的特性。体内实验结果显示,在人卵巢癌移植瘤裸鼠模型中,与PBS对照组相比,TCRγ9δ2(OT3)-Fc能够有效抑制肿瘤生长,并延长荷瘤裸鼠的生存期。这些数据表明,TCRγ9δ2(OT3)-Fc融合蛋白保留了TCRγδ的抗原识别特性,同时也兼具抗体Fc段介导的效应功能,将其应用于卵巢癌的靶向治疗是可行的。而且,由于TCRγ9δ2(OT3)-Fc能结合多种肿瘤细胞系,具有潜在的广谱肿瘤靶向性,有望扩大肿瘤靶向治疗的应用范围。
本研究的第二部分工作,主要是功能性抗人TCRγδ抗体的研究,以期用其扩增γδT细胞,应用于肿瘤的过继免疫治疗。在肿瘤免疫中,γδ T细胞对肿瘤抗原的识别不具MHC限制性,能分泌大量干扰素-γ(Interferon-γ, IFN-γ),且能杀伤多种肿瘤细胞系,从而具有用于肿瘤过继免疫治疗的潜能。由于γδ T细胞仅占外周血T细胞的1～10%,获取足够数量且有相应生物学功能的γδ T细胞,成为制约其应用于过继免疫治疗的瓶颈。目前获得用于过继免疫治疗的γδ T细胞的方法有两种,一种是磷酸抗原刺激增殖,如4-羟基-3-甲基-2-已烯基-4-焦磷酸(HMBPP),另一种是固相化抗体体外扩增；两种方法均需联合白细胞介素-2(Interleukin-2, IL-2)。本课题组重点研究固相化抗体体外扩增的γδ T细胞的过继免疫治疗。但是由于目前使用的抗TCRγδ单克隆抗体是鼠源的,有产生人抗鼠抗体(human anti-mouse antibody, HAMA)反应的潜在危险,因而在临床治疗上受到一定限制。因此,本文第二部分的工作,旨在构建稳定分泌抗人TCRγδ单克隆抗体的杂交瘤细胞株,并在此基础上,构建人源化的抗人TCRγδ抗体或单链抗体(single chain variable fragment, ScFv)。通过对人源化抗体或单链抗体的生物学功能进行分析,以验证其能否替代鼠源亲本抗体,用于制备过继免疫治疗的γδT细胞制剂。
首先,我们以TCRγ9δ2(OT3)-Fc为免疫原免疫BALB/c小鼠,用常规杂交瘤技术获得能稳定分泌抗人TCRγδ抗体的杂交瘤细胞株。并用固相化抗体体外扩增的方法,筛选到分泌能体外扩增γδT细胞的单抗的杂交瘤细胞株--G5-4。
其后,通过RT-PCR法,从杂交瘤细胞株G5-4的cDNA中分别扩增获得抗体的轻重链的可变区基因；并分别构建了嵌合抗体的表达质粒G5-4-pAc-κ-CH3和单链抗体的表达质粒G5-4ScFv-pET22b(+)。嵌合抗体和单链抗体分别在在昆虫杆状病毒表达系统和大肠杆菌TransB(DE3)中得到成功表达。
最后,重点对单链抗体G5-4ScFv的生物学功能进行了分析。结果表明,单链抗体G5-4ScFv能与TCRγδ特异结合；固相化G5-4ScFv能刺激人PBMC中γδT细胞增殖,2周时其纯度可达90%；扩增得到的γδT细胞能有效杀伤肿瘤细胞系,如Daudi细胞；并在刺激时能有效分泌干扰素-γ(INIFN-γ)和TGF-α。提示,本实验成功构建并表达了具有生物学活性的抗人TCRγδ单链抗体G5-4ScFv,为进一步研究其用于制备肿瘤过继免疫治疗的细胞制剂奠定了基础。
综上所述,本文的研究有以下成果：
1.我们构建并表达了具有较高亲和力的TCRγ9δ2(OT3)-Fc融合蛋白,该蛋白兼具TCRγδ的抗原识别特性和抗体的效应功能。
2. TCRγ9δ2(OT3)-Fc在体内外均表现出抗卵巢癌的功能,提示有应用于卵巢癌靶向治疗的前景。
3.由于TCRγ9δ2(OT3)-Fc的潜在广谱肿瘤识别特性,因此,它具有应用于多种肿瘤靶向治疗的可能性。
4.成功构建了稳定分泌抗人TCRγδ单克隆抗体的杂交瘤细胞株。
5.构建并表达了人源化的抗人TCRγδ抗体或单链抗体。
6.单链抗体G5-4ScFv能与人TCRγδ特异结合,固相化后能有效刺激人PBMC中γδT细胞增殖,有望替代鼠源抗体用于制备过继免疫治疗的γδT细胞制剂。
Antibody (Ab)-based tumor-targeting immunotherapy has been rapidly developed during the last few decades. Trastuzumab and rituximab, two monoclonal antibodies used for the treatment of metastatic breast cancer and non-Hodgkin's lymphoma, respectively, have showed great clinical success. The identification of tumor-specific antigens is crucial for Ab-based tumor-targeting immunotherapy. However, only a limited number of tumor-specific antigens have been discovered so far, which greatly limits the use of Ab-based therapies in clinic.
The ability of T cell receptors (TCRs) on tumor infiltrating lymphocytes (TILs) to specifically recognize tumor cells makes TCRs as ideal candidates for tumor-targeting applications. Several studies have attempted to develop novel TCRαβ-based antitumor strategies. The introduction of TCRy982into TCR-deficient JRT3-T3.5cells could enable the cells to possess the ability of tumor cell recognition and cytotoxicity, indicating the crucial role of TCRγ9δ2for y982T cells in fighting against tumors. The ability of specific recognition of tumor cells makes TCRγ9δ2available for tumor targeting therapies like Abs. Compared with TCRαβ, TCRγδ recognizes broader spectrum of tumor antigens, due to its human major histocompatibility complex (MHC)-independent manner. This may be a great advantage for the application of TCRγδ in tumor-targeting therapies.
Our research focused on the study of application of TCRγδ in tumor-targeting therapies. We previously identified a complementarity determining region (CDR)3gene sequence, named OT3, in82chain from TILs in human ovarian epithelial carcinoma. TCRγ9δ2(OT3), containing the specific CDR3δ(OT3), was demonstrated to be a ovarian carcinoma specific TCR. A CDR38(OT3)-grafted Ab was constructed by grafting OT3 instead of the CDR3in the heavy chain of human IgG1. The CDR3δ(OT3)-grafted Ab showed specific binding activities to multiple tumor cell lines, but the affinities were low. To obtain an Ab-like TCRγδ-Ig fusion protein with high affinity, we constructed three TCRγδ-Ig fusion proteins by fusing the complete extracellular domains or V regions of TCRγ9δ2(OT3) to the constant domains of human IgG1. We analyzed the tumor-binding abilities of three TCRγδ-Ig fusion proteins and found TCRγ9δ2(OT3)-Fc possessing the best binding ability to tumor cell lines and tissues.
In the first part of this study, we evaluated the antitumor effect of TCRy982(OT3)-Fc both in vitro and in vivo. The results showed that TCRγ9δ2(OT3)-Fc could bind to multiple tumor cell lines, including carcinoma of the ovary, cervix, lung, kidney and stomach. TCRγ9δ2(OT3)-Fc fusion protein mediated cytolysis by antibody-dependent cellular cytotoxicity (ADCC) in a dose dependent manner in vitro. TCRy982(OT3)-Fc fusion protein could also significantly inhibit tumor growth in vivo and provide a protection for the survival of animals in human ovarian cancer xenograft model. These data taken together demonstrate the feasibility of TCRγ9δ2(OT3)-Fc application for ovarian tumor-targeting therapy. TCRy982(OT3)-Fc fusion protein behaved as Abs but possessed the ability of TCRγδ to recognize antigens. Moreover, due to its broad spectrum of tumor recognition, TCRy982(OT3)-Fc has the potential to expand the range of tumors available for targeting therapies.
In the second part of work, we mainly focused on the preparation and characterization of functional antibodies being able to amplify human γδT cells in vitro for adoptive immunotherapy. Based on their particular properties such as abundant interferon (IF)-γ secretion, potent cytotoxicity, and MHC-independent recognition of a broad spectrum of tumors, human γδT cells have been demonstrated as an attractive candidate for cancer immunotherapy. Unfortunately, γδT cells is a minor subset of T cells, constituting approximately1～0%of total T cells in human peripheral blood. Currently, there are mainly two methods to obtain y8T cells for adoptive cell therapy. One is to expand γδT cells by phosphoantigens such as bromohydrin pyrophosphate and1-hydroxy-2-methyl-2-(E)-butenyl4-diphosphate (HMBPP). Another is to expand y8T cells by immobilized anti-pan-TCRγδ Ab. Both methods require the participation of interleukin (IL)-2. In our laboratory, our research mainly focuses on Ab-expanded γδT cells in adoptive cellular therapy. Due to the human anti-mouse antibody (HAMA) response, the use of mouse-derived monoclonal antibody (mAb) in clinic treatments is limited. Therefore, in the second part of work, we proposed to develop a hybridoma cell line which could secrete a mAb against human TCRγδ. Thus, a humanized Ab and a single chain variable fragment (ScFv) were constructed and expressed. Biological function of the humanized Ab or ScFv was analyzed to detect whether they could substitute the mouse-derived Ab to expand human y8T cells.
First, the BALB/c mice were immunized with TCRγ9δ2(OT3)-Fc. Hybridomas secreted the mAbs against human TCRγδ were selected by using traditional hybridoma methods. The Abs with the ability to expand y8T cells were identified.
Subsequently, the genes of the antibody heavy (VH) and light chains (VL) were amplified by RT-PCR from the hybridoma cell line G5-4. Recombinant plasmids G5-4-pAc-K-CH3for the chimeric Ab and pET22b(+)-G5-4ScFv for ScFv were constructed. Then, the chimeric Abs were successfully expressed through baculovirus expression vector system in the sf9cells while the anti-hTCRγδ-ScFv (G5-4ScFv) was expressed in E.coli TransB (DE3).
Finally, we focused on the biological function analysis of the G5-4ScFv. The results showed that G5-4ScFv could bind to γδ T cells and greatly inhibit the binding of a pan-TCRγδ antibody to y8T cells. The purity of y8T cells expanded by G5-4ScFv stimulation attained up to90%after culture for2weeks. The expanded γδT cells exhibited the abilities of IFN-y and TNF-a secretion and strong cytotoxicity against Daudi cells. Together, these results suggest that anti-hTCRγδ-ScFv with biological function has been successfully constructed and expressed in prokaryotic expression system, which provides the basis for further studying on its potential application in tumor immunotherapy.
In summary, in the present study we have made several major discoveries as follows:
1. We successfully constructed a TCRγ9δ2(OT3)-Fc fusion protein with both antigen-recognition properties of TCRγδ and effector functions like antibody.
2. TCRy982(OT3)-Fc exhibited anti-tumor effects both in vitro and in vivo, indicating the feasibility of TCRy982(OT3)-Fc application for ovarian tumor targeting therapy.
3. Due to its broad spectrum of tumor recognition, TCRγ9δ2(OT3)-Fc has the potential to expand the range of tumors available for targeting therapies.
4. We have developed a hybridoma cell line, G5-4, which can secrete the mAb with the ability to expand human γδT cells.
5. We constructed and expressed the chimeric Ab or ScFv of G5-4.
6. G5-4ScFv possessed the properties to specifically bind to human TCRγδ and to efficiently expand γδT cells, indicating that it could substitute the mouse antibody to expand human γδT cells for adoptive immunotherapy.
引文
1. Weiner, L. M., R. Surana, and S. Wang.2010. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10:317-327.
2. Vogel, C. L., M. A. Cobleigh, D. Tripathy, J. C. Gutheil, L. N. Harris, L. Fehrenbacher, D. J. Slamon, M. Murphy, W. F. Novotny, M. Burchmore, S. Shak, and S. J. Stewart.2001. First-line Herceptin monotherapy in metastatic breast cancer. Oncology 61 Suppl 2:37-42.
3. Hainsworth, J. D., S. Litchy, H. A. Burris,3rd, D. C. Scullin, Jr., S. W. Corso, D. A. Yardley, L. Morrissey, and F. A. Greco.2002. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol 20:4261-4267.
4. Linley, A. J., M. Ahmad, and R. C. Rees.2011. Tumour-associated antigens: considerations for their use in tumour immunotherapy. Int J Hematol 93:263-273.
5. Reichert, J. M.2011. Antibody-based therapeutics to watch in 2011. MAbs 3:76-99.
6. McKee, M. D., A. Fichera, and M. I. Nishimura.2007. T cell immunotherapy. Front Biosci 12:919-932.
7. Weber, J., M. Atkins, P. Hwu, L. Radvanyi, M. Sznol, and C. Yee.2011. White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. Clin Cancer Res 17:1664-1673.
8. Morgan, R. A., M. E. Dudley, J. R. Wunderlich, M. S. Hughes, J. C. Yang, R. M. Sherry, R. E. Royal, S. L. Topalian, U. S. Kammula, N. P. Restifo, Z. Zheng, A. Nahvi, C. R. de Vries, L. J. Rogers-Freezer, S. A. Mavroukakis, and S. A. Rosenberg.2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126-129.
9. Ochi, T., H. Fujiwara, and M. Yasukawa.2010. Application of adoptive T-cell therapy using tumor antigen-specific T-cell receptor gene transfer for the treatment of human leukemia. JBiomed Biotechnol 2010:521248.
10. Peng, L., J. Kjaergaard, G. E. Plautz, M. Awad, J. A. Drazba, S. Shu, and P. A. Cohen.2002. Tumor-induced L-selectinhigh suppressor T cells mediate potent effector T cell blockade and cause failure of otherwise curative adoptive immunotherapy. J Immunol 169:4811-4821.
11. Dudley, M. E., J. R. Wunderlich, T. E. Shelton, J. Even, and S. A. Rosenberg. 2003. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. JImmunother 26:332-342.
12. Molloy, P. E., A. K. Sewell, and B. K. Jakobsen.2005. Soluble T cell receptors: novel immunotherapies. Curr Opin Pharmacol 5:438-443.
13. Liddy, N., G. Bossi, K. J. Adams, A. Lissina, T. M. Mahon, N. J. Hassan, J. Gavarret, F. C. Bianchi, N. J. Pumphrey, K. Ladell, E. Gostick, A. K. Sewell, N. M. Lissin, N. E. Harwood, P. E. Molloy, Y. Li, B. J. Cameron, M. Sami, E. E. Baston, P. T. Todorov, S. J. Paston, R. E. Dennis, J. V. Harper, S. M. Dunn, R. Ashfield, A. Johnson, Y. McGrath, G. Plesa, C. H. June, M. Kalos, D. A. Price, A. Vuidepot, D. D. Williams, D. H. Sutton, and B. K. Jakobsen.2012. Monoclonal TCR-redirected tumor cell killing. Nat Med 6:doi:10.1038.
14. Epel, M., J. D. Ellenhorn, D. J. Diamond, and Y. Reiter.2002. A functional recombinant single-chain T cell receptor fragment capable of selectively targeting antigen-presenting cells. Cancer Immunol Immunother 51:565-573.
15. Card, K. F., S. A. Price-Schiavi, B. Liu, E. Thomson, E. Nieves, H. Belmont, J. Builes, J. A. Jiao, J. Hernandez, J. Weidanz, L. Sherman, J. L. Francis, A. Amirkhosravi, and H. C. Wong.2004. A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. Cancer Immunol Immunother 53:345-357.
16. Belmont, H. J., S. Price-Schiavi, B. Liu, K. F. Card, H. I. Lee, K. P. Han, J. Wen, S. Tang, X. Zhu, J. Merrill, P. A. Chavillaz, J. L. Wong, P. R. Rhode, and H. C. Wong.2006. Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein. Clin Immunol 121:29-39.
17. Wen, J., X. Zhu, B. Liu, L. You, L. Kong, H. I. Lee, K. P. Han, J. L. Wong, P. R. Rhode, and H. C. Wong.2008. Targeting activity of a TCR/IL-2 fusion protein against established tumors. Cancer Immunol Immunother 57:1781-1794.
18. Mosquera, L. A., K. F. Card, S. A. Price-Schiavi, H. J. Belmont, B. Liu, J. Builes, X. Zhu, P. A. Chavaillaz, H. I. Lee, J. A. Jiao, J. L. Francis, A. Amirkhosravi, R. L. Wong, and H. C. Wong.2005. In vitro and in vivo characterization of a novel antibody-like single-chain TCR human IgG 1 fusion protein. J Immunol 174:4381-4388.
19. Allison, T. J., C. C. Winter, J. J. Fournie, M. Bonneville, and D. N. Garboczi. 2001. Structure of a human gammadelta T-cell antigen receptor. Nature 411:820-824.
20. Morita, C. T., E. M. Beckman, J. F. Bukowski, Y. Tanaka, H. Band, B. R. Bloom, D. E. Golan, and M. B. Brenner.1995. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells. Immunity 3:495-507.
21. Sicard, H., S. Ingoure, B. Luciani, C. Serraz, J. J. Fournie, M. Bonneville, J. Tiollier, and F. Romagne.2005. In vivo immunomanipulation of V gamma 9V delta 2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model. J Immunol 175:5471-5480.
22. Kunzmann, V., and M. Wilhelm.2005. Anti-lymphoma effect of gammadelta T cells. Leuk Lymphoma 46:671-680.
23. Kobayashi, H., Y. Tanaka, J. Yagi, N. Minato, and K. Tanabe.2011. Phase I/II study of adoptive transfer of gammadelta T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma. Cancer Immunol Immunother 60:1075-1084.
24. Lang, J. M., M. R. Kaikobad, M. Wallace, M. J. Staab, D. L. Horvath, G. Wilding, G. Liu, J. C. Eickhoff, D. G. McNeel, and M. Malkovsky.2011. Pilot trial of interleukin-2 and zoledronic acid to augment gammadelta T cells as treatment for patients with refractory renal cell carcinoma. Cancer Immunol Immunother 60:1447-1460.
25. Nicol, A. J., H. Tokuyama, S. R. Mattarollo, T. Hagi, K. Suzuki, K. Yokokawa, and M. Nieda.2011. Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours. Br J Cancer 105:778-786.
26. Xu, C., H. Zhang, H. Hu, H. He, Z. Wang, Y. Xu, H. Chen, W. Cao, S. Zhang, L. Cui, D. Ba, and W. He.2007. Gammadelta T cells recognize tumor cells via CDR3delta region. Mol Immunol 44:302-310.
27. Wang, Z., T. Zhang, H. Hu, H. Zhang, Z. Yang, L. Cui, and W. He.2008. Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody. Cancer Lett 272:242-252.
28. Wang, H., Z. Fang, and C. T. Morita.2010. Vgamma2Vdelta2 T Cell Receptor recognition of prenyl pyrophosphates is dependent on all CDRs. J Immunol 184:6209-6222.
29. Kabelitz, D.2011. gammadelta T-cells:cross-talk between innate and adaptive immunity. Cell Mol Life Sci 68:2331-2333.
30. Hayday, A. C.2000. [gamma][delta] cells:a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975-1026.
31. Cao, W, and W. He.2005. The recognition pattern of gammadelta T cells. Front Biosci 10:2676-2700.
32. Kreslavsky, T., and H. von Boehmer.2010. gammadeltaTCR ligands and lineage commitment. Semin Immunol 22:214-221.
33. Kabelitz, D., D. Wesch, and W. He.2007. Perspectives of gammadelta T cells in tumor immunology. Cancer Res 67:5-8.
34. Dokouhaki, P., M. Han, B. Joe, M. Li, M. R. Johnston, M. S. Tsao, and L. Zhang.2010. Adoptive immunotherapy of cancer using ex vivo expanded human gammadelta T cells:A new approach. Cancer Lett 297:126-136.
35. Zhou, J., N. Kang, L. Cui, D. Ba, and W. He.2012.2012. Anti-gammadelta TCR antibody-expanded gammadelta T cells:a better choice for the adoptive immunotherapy of lymphoid malignancies Cell Mol Immunol 9:34-44.
36. Bonneville, M., and E. Scotet.2006. Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol 18:539-546.
37. Caccamo, N., S. Meraviglia, G. Cicero, G. Gulotta, F. Moschella, A. Cordova, E. Gulotta, A. Salerno, and F. Dieli.2008. Aminobisphosphonates as new weapons for gammadelta T Cell-based immunotherapy of cancer. Curr Med Chem 15:1147-1153.
38. Kunzmann, V., E. Bauer, J. Feurle, F. Weissinger, H. P. Tony, and M. Wilhelm. 2000. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 96:384-392.
39. Siegers, G. M., H. Dhamko, X. H. Wang, A. M. Mathieson, Y. Kosaka, T. C. Felizardo, J. A. Medin, S. Tohda, J. Schueler, P. Fisch, and A. Keating.2011. Human Vdeltal gammadelta T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells. Cytotherapy 13:753-764.
40. Ismail, A. S., K. M. Severson, S. Vaishnava, C. L. Behrendt, X. Yu, J. L. Benjamin, K. A. Ruhn, B. Hou, A. L. DeFranco, F. Yarovinsky, and L. V. Hooper.2011. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci USA 108:8743-8748.
41. Tagawa, T., H. Nishimura, T. Yajima, H. Hara, K. Kishihara, G. Matsuzaki, I. Yoshino, Y. Maehara, and Y. Yoshikai.2004. Vdeltal+gammadelta T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice. J Immunol 173:5156-5164.
42. Maeurer, M. J., D. Martin, W. Walter, K. Liu, L. Zitvogel, K. Halusczcak, H. Rabinowich, R. Duquesnoy, W. Storkus, and M. T. Lotze.1996. Human intestinal Vdeltal+lymphocytes recognize tumor cells of epithelial origin. J Exp Med 183:1681-1696.
43. Goto, M., K. Kuribayashi, Y. Umemori, Y. Ohe, K. Asanuma, M. Tanaka, D. Kobayashi, and N. Watanabe.2010. High prevalence of human anti-mouse antibodies in the serum of colorectal cancer patients. Anticancer Res 30:4353-4356.
44. Cavalier, E., A. Carlisi, J. P. Chapelle, P. Orfanos, M. Uzan, V. Falque, P. Delanaye, and M. Hachicha.2009. Human anti-mouse antibodies interferences in Elecsys PTH assay after OKT3 treatment. Transplantation 87:451-452.
45. Xi, X., Y. Guo, H. Chen, C. Xu, H. Zhang, H. Hu, L. Cui, D. Ba, and W. He. 2009. Antigen specificity of gammadelta T cells depends primarily on the flanking sequences of CDR3delta. JBiol Chem 284:27449-27455.
46. Liu, X., E. A. Peralta, J. D. Ellenhom, and D. J. Diamond.2000. Targeting of human p53-overexpressing tumor cells by an HLA A*0201-restricted murine T-cell receptor expressed in Jurkat T cells. Cancer Res 60:693-701.
47. Bukowski, J. F., C. T. Morita, Y. Tanaka, B. R. Bloom, M. B. Brenner, and H. Band.1995. V gamma 2V delta 2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer. J Immunol 154:998-1006.
48. Johnson, L. A., B. Heemskerk, D. J. Powell, Jr., C. J. Cohen, R. A. Morgan, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg.2006. Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 177:6548-6559.
49. Boulter, J. M., and B. K. Jakobsen.2005. Stable, soluble, high-affinity, engineered T cell receptors:novel antibody-like proteins for specific targeting of peptide antigens. Clin Exp Immunol 142:454-460.
50. Verma, B., F. A. Neethling, S. Caseltine, G. Fabrizio, S. Largo, J. A. Duty, P. Tabaczewski, and J. A. Weidanz. 2010. TCR mimic monoclonal antibody targets a specific peptide/HLA class I complex and significantly impedes tumor growth in vivo using breast cancer models. J Immunol 184:2156-2165.
51. Norell, H., M. Carlsten, T. Ohlum, K. J. Malmberg, G. Masucci, K. Schedvins, W. Altermann, D. Handke, D. Atkins, B. Seliger, and R. Kiessling. 2006. Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity. Cancer Res 66:6387-6394.
52. Reiman, J. M., M. Kmieciak, M. H. Manjili, and K. L. Knutson. 2007. Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol 17:275-287.
53. Morita, C. T., Y. Tanaka, B. R. Bloom, and M. B. Brenner. 1996. Direct presentation of non-peptide prenyl pyrophosphate antigens to human gamma delta T cells. Res Immunol 147:347-353.
54.Siberil, S., C. A. Dutertre, W. H. Fridman, and J. L. Teillaud. 2007. FcgammaR: The key to optimize therapeutic antibodies? Crit Rev Oncol Hematol 62:26-33.
55.Weiner, G. J. 2010. Rituximab: mechanism of action. Semin Hematol 47:115-123.
56.Hubert, P., A. Heitzmann, S. Viel, A. Nicolas, X. Sastre-Garau, P. Oppezzo, O. Pritsch, E. Osinaga, and S. Amigorena. 2011. Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy. Cancer Res 71:5134-5143.
57.Weiner, L. M, R. Surana, and S. Wang. 2011. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10:317-327.
58.Cartron, G, L. Dacheux, G. Salles, P. Solal-Celigny, P. Bardos, P. Colombat, and H. Watier. 2002. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754-758.
59.Villamor, N., E. Montserrat, and D. Colomer. 2003. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol 30:424-433.
60.Tanaka, Y., C. T. Morita, Y. Tanaka, E. Nieves, M. B. Brenner, and B. R. Bloom. 1995. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375:155-158.
61.Vantourout, P., J. Mookerjee-Basu, C. Rolland, F. Pont, H. Martin, C. Davrinche, L. O. Martinez, B. Perret, X. Collet, C. Perigaud, S. Peyrottes, and E. Champagne. 2009. Specific requirements for Vgamma9Vdelta2 T cell stimulation by a natural adenylated phosphoantigen. J Immunol 183:3848-3857.
62.Gober, H. J., M. Kistowska, L. Angman, P. Jeno, L. Mori, and G. De Libero. 2003. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163-168.
63.Constant, P., F. Davodeau, M. A. Peyrat, Y. Poquet, G. Puzo, M. Bonneville, and J. J. Fournie. 1994. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264:267-270.
64. Scotet, E., L. O. Martinez, E. Grant, R. Barbaras, P. Jeno, M. Guiraud, B. Monsarrat, X. Saulquin, S. Maillet, J. P. Esteve, F. Lopez, B. Perret, X. Collet, M. Bonneville, and E. Champagne.2005. Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71-80.
65. Mookerjee-Basu, J., P. Vantourout, L. O. Martinez, B. Perret, X. Collet, C Perigaud, S. Peyrottes, and E. Champagne.2010. F1-adenosine triphosphatase displays properties characteristic of an antigen presentation molecule for Vgamma9Vdelta2 T cells. J Immunol 184:6920-6928.
66. Kong, Y., W. Cao, X. Xi, C. Ma, L. Cui, and W. He.2009. The NKG2D ligand ULBP4 binds to TCRgamma9/delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D. Blood 114:310-317.
67. Chen, H., X. He, Z. Wang, D. Wu, H. Zhang, C. Xu, H. He, L. Cui, D. Ba, and W. He.2008. Identification of human T cell receptor gammadelta-recognized epitopes/proteins via CDR3delta peptide-based immunobiochemical strategy. J Biol Chem 283:12528-12537.
68. Chalupny, N. J., C. L. Sutherland, W. A. Lawrence, A. Rein-Weston, and D. Cosman.2003. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305:129-135.
69. Conejo-Garcia, J. R., F. Benencia, M. C. Courreges, E. Khang, L. Zhang, A. Mohamed-Hadley, J. M. Vinocur, R. J. Buckanovich, C. B. Thompson, B. Levine, and G. Coukos.2003. Letal, A tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells. Cancer Biol Ther 2:446-451.
70. Pecorari, F., A. C. Tissot, and A. Pluckthun.1999. Folding, heterodimeric association and specific peptide recognition of a murine alphabeta T-cell receptor expressed in Escherichia coli. J Mol Biol 285:1831-1843.
71. Willcox, B. E., G. F. Gao, J. R. Wyer, C. A. O'Callaghan, J. M. Boulter, E. Y. Jones, P. A. van der Merwe, J. I. Bell, and B. K. Jakobsen.1999. Production of soluble alphabeta T-cell receptor heterodimers suitable for biophysical analysis of ligand binding. Protein Sci 8:2418-2423.
72. Boulter, J. M., M. Glick, P. T. Todorov, E. Baston, M. Sami, P. Rizkallah, and B. K. Jakobsen.2003. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng 16:707-711.
73. Lunde, E., G. A. Loset, B. Bogen, and I. Sandlie.2010. Stabilizing mutations increase secretion of functional soluble TCR-Ig fusion proteins. BMC Biotechnol 10:61-72.
74. Rudnick, S. I., and G. P. Adams.2009. Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 24:155-161.
75. Graff, C. P., and K. D. Wittrup.2003. Theoretical analysis of antibody targeting of tumor spheroids:importance of dosage for penetration, and affinity for retention. Cancer Res 63:1288-1296.
76. Jiang, X. R., A. Song, S. Bergelson, T. Arroll, B. Parekh, K. May, S. Chung, R. Strouse, A. Mire-Sluis, and M. Schenerman.2011. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov 10:101-111.
77. Starr, T. K., S. C. Jameson, and K. A. Hogquist.2003. Positive and negative selection of T cells. Annu Rev Immunol 21:139-176.
78. Holler, P. D., P. O. Holman, E. V. Shusta, S. O'Herrin, K. D. Wittrup, and D. M. Kranz.2000. In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc Natl Acad Sci USA 97:5387-5392.
79. Weber, K. S., D. L. Donermeyer, P. M. Allen, and D. M. Kranz.2005. Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci USA 102:19033-19038.
80. Alli, R., Z. M. Zhang, P. Nguyen, J. J. Zheng, and T. L. Geiger.2011. Rational design of T cell receptors with enhanced sensitivity for antigen. PLoS One 6:e18027.
81. Chlewicki, L. K., P. D. Holler, B. C. Monti, M. R. Clutter, and D. M. Kranz. 2005. High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. JMol Biol 346:223-239.
82. Presta, L. G.2008. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol 20:460-470.
83. Liu, X. Y., L. M. Pop, and E. S. Vitetta.2008. Engineering therapeutic monoclonal antibodies. Immunol Rev 222:9-27.
84. Stavenhagen, J. B., S. Gorlatov, N. Tuaillon, C. T. Rankin, H. Li, S. Burke, L. Huang, S. Vijh, S. Johnson, E. Bonvini, and S. Koenig.2007. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res 67:8882-8890.
85. Lazar, G. A., W. Dang, S. Karki, O. Vafa, J. S. Peng, L. Hyun, C. Chan, H. S. Chung, A. Eivazi, S. C. Yoder, J. Vielmetter, D. F. Carmichael, R. J. Hayes, and B. I. Dahiyat.2006. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 103:4005-4010.
86. Shields, R. L., J. Lai, R. Keck, L. Y. O'Connell, K. Hong, Y. G. Meng, S. H. Weikert, and L. G. Presta.2002. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem 277:26733-26740.
87. Shinkawa, T., K. Nakamura, N. Yamane, E. Shoji-Hosaka, Y. Kanda, M. Sakurada, K. Uchida, H. Anazawa, M. Satoh, M. Yamasaki, N. Hanai, and K. Shitara.2003. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278:3466-3473.
88. Kobayashi, H., Y. Tanaka, J. Yagi, Y. Osaka, H. Nakazawa, T. Uchiyama, N. Minato, and H. Toma.2007. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma:a pilot study. Cancer Immunol Immunother 56:469-476.
89. Dieli, F., D. Vermijlen, F. Fulfaro, N. Caccamo, S. Meraviglia, G. Cicero, A. Roberts, S. Buccheri, M. D'Asaro, N. Gebbia, A. Salerno, M. Eberl, and A. C. Hayday.2007. Targeting human{gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450-7457.
90. Correia, D. V, M. Fogli, K. Hudspeth, M. G. da Silva, D. Mavilio, and B. Silva-Santos.2011. Differentiation of human peripheral blood Vdeltal+T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118:992-1001.
91. Zhou, J., N. Kang, L. Cui, D. Ba, and W. He.2012. Anti-gammadelta TCR antibody-expanded gammadelta T cells:a better choice for the adoptive immunotherapy of lymphoid malignancies. Cell Mol Immunol 9:34-44.
92. Klee, G. G.2000. Human anti-mouse antibodies. Arch Pathol Lab Med 124:921-923.
93. Scott, A. M., J. D. Wolchok, and L. J. Old.2012. Antibody therapy of cancer. Nat Rev Cancer 12:278-287.
94. Shojaei, S., M. Gardaneh, and A. Rahimi Shamabadi.2012. Target points in trastuzumab resistance. Int J Breast Cancer 2012:761917.
95. Morrison, S. L.2002. Cloning, expression, and modification of antibody V regions. Curr Protoc Immunol Chapter 2:Unit 212.
96. Almagro, J. C., and J. Fransson.2008. Humanization of antibodies. Front Biosci 13:1619-1633.
97. Ill, C. R., J. N. Gonzales, E. K. Houtz, J. R. Ludwig, E. D. Melcher, J. E. Hale, R. Pourmand, V. M. Keivens, L. Myers, K. Beidler, P. Stuart, S. Cheng, and R. Radhakrishnan.1997. Design and construction of a hybrid immunoglobulin domain with properties of both heavy and light chain variable regions. Protein Eng 10:949-957.
98. Kugler, M., C. Stein, M. Schwenkert, D. Saul, L. Vockentanz, T. Huber, S. K. Wetzel, O. Scholz, A. Pluckthun, A. Honegger, and G. H. Fey.2009. Stabilization and humanization of a single-chain Fv antibody fragment specific for human lymphocyte antigen CD 19 by designed point mutations and CDR-grafting onto a human framework. Protein Eng Des Sel 22:135-147.
99. Kashmiri, S. V., R. De Pascalis, N. R. Gonzales, and J. Schlom.2005. SDR grafting--a new approach to antibody humanization. Methods 36:25-34.
100. Kim, K. S., H. J. Kim, B. W. Han, P. K. Myung, and H. J. Hong.2010. Construction of a humanized antibody to hepatitis B surface antigen by specificity-determining residues (SDR)-grafting and de-immunization. Biochem Biophys Res Commun 396:231-237.
101. Gonzales, N. R., R. De Pascalis, J. Schlom, and S. V. Kashmiri.2005. Minimizing the immunogenicity of antibodies for clinical application. Tumour Biol 26:31-43.
102. Ahmad, Z. A., S. K. Yeap, A. M. Ali, W. Y. Ho, N. B. Alitheen, and M. Hamid. 2012.2012. scFv antibody:principles and clinical application. Clin Dev Immunol 2012:980250.
103. Yuasa, N., H. Ogawa, T. Koizumi, K. Tsukamoto, A. Matsumoto-Takasaki, H. Asanuma, H. Nakada, and Y. Fujita-Yamaguchi.2012. Construction and expression of anti-Tn-antigen-specific single-chain antibody genes from hybridoma producing MLS 128 monoclonal antibody. J Biochem 151:371-381.
104. Ahmad, Z. A., S. K. Yeap, A. M. Ali, W. Y. Ho, N. B. Alitheen, and M. Hamid. 2012. scFv antibody:principles and clinical application. Clin Dev Immunol 2012:980250.
105. Sun, W., J. Xie, H. Lin, S. Mi, Z. Li, F. Hua, and Z. Hu.2012. A combined strategy improves the solubility of aggregation-prone single-chain variable fragment antibodies. Protein Expr Purif 83:21-29.
1. Robbins, J. B., R. Schneerson, and S. C. Szu.1996. Specific Acquired Immunity.
2. Grupp, S. A., and C. H. June.2011. Adoptive cellular therapy. Curr Top Microbiol Immunol 344:149-172.
3. Ochi, T., H. Fujiwara, and M. Yasukawa.2010. Application of adoptive T-cell therapy using tumor antigen-specific T-cell receptor gene transfer for the treatment of human leukemia. J Biomed Biotechnol 2010:521248.
4. Johnson, L. A., B. Heemskerk, D. J. Powell, Jr., C. J. Cohen, R. A. Morgan, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg.2006. Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 177:6548-6559.
5. Pardoll, D. M., B. J. Fowlkes, J. A. Bluestone, A. Kruisbeek, W. L. Maloy, J. E. Coligan, and R. H. Schwartz.1987. Differential expression of two distinct T-cell receptors during thymocyte development. Nature 326:79-81.
6. Kreslavsky, T., and H. von Boehmer.2010. gammadeltaTCR ligands and lineage commitment. Semin Immunol 22:214-221.
7. Masuda, K., K. Kakugawa, T. Nakayama, N. Minato, Y. Katsura, and H. Kawamoto.2007. T cell lineage determination precedes the initiation of TCR beta gene rearrangement. J Immunol 179:3699-3706.
8. Lu, C. L., G. D. Li, W. P. Liu, J. Guo, F. Y. Li, D. Y. Liao, and W. Y. Zhang. 2004. [Detection of TCR-gamma chain gene rearrangement in malignant histiocytosis].Zhongh.ua Xue Ye Xue Za Zhi 25:220-222.
9. Joachims, M. L., J. L. Chain, S. W. Hooker, C. J. Knott-Craig, and L. F. Thompson.2006. Human alpha beta and gamma delta thymocyte development: TCR gene rearrangements, intracellular TCR beta expression, and gamma delta developmental potential--differences between men and mice. J Immunol 176:1543-1552.
10. Wilbert, O. M., J. Weber-Arden, D. Kabelitz, and B. Arden.1997. TCR-delta gene rearrangement and selection during fetal thymocyte development. J Immunol 159:3338-3346.
11. Xiong, N., L. Zhang, C. Kang, and D. H. Raulet.2008. Gene placement and competition control T cell receptor gamma variable region gene rearrangement. J Exp Med 205:929-938.
12.Marrack, P., M. McDuffie, W. Born, M. Blackman, C. Hannum, and J. Kappler. 1987. The T cell receptor: its repertoire and role in thymocyte development. Adv Exp Med Biol 213:1-12.
13.Abul k. Abbas, A. H. L., Shiv Pillai. 2012. Cellular and molecular immunology, 7th edition. Med Sci Sports Exerc 44:983.
14.Nakano, K., T. Ishiguro, H. Konishi, M. Tanaka, M. Sugimoto, I. Sugo, T. Igawa, H. Tsunoda, Y. Kinoshita, K. Habu, T. Orita, M. Tsuchiya, K. Hattori, and H. Yamada-Okabe. 2010. Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. Anticancer Drugs 21:907-916.
15.Davis, M. M., J. J. Boniface, Z. Reich, D. Lyons, J. Hampl, B. Arden, and Y. Chien. 1998. Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol 16:523-544.
16.Davis, S. J., S. Ikemizu, E. J. Evans, L. Fugger, T. R. Bakker, and P. A. van der Merwe. 2003. The nature of molecular recognition by T cells. Nat Immunol 4:217-224.
17.Sun, J., and P. B. Kavathas. 1997. Comparison of the roles of CD8 alpha alpha and CD8 alpha beta in interaction with MHC class I. J Immunol 159:6077-6082.
18.Metz, D. P., D. L. Farber, R. Konig, and K. Bottomly. 1997. Regulation of memory CD4 T cell adhesion by CD4-MHC class II interaction. J Immunol 159:2567-2573.
19.Tanaka, Y, C. T. Morita, Y. Tanaka, E. Nieves, M. B. Brenner, and B. R. Bloom. 1995. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375:155-158.
20.Vantourout, P., J. Mookerjee-Basu, C. Rolland, F. Pont, H. Martin, C. Davrinche, L. O. Martinez, B. Perret, X. Collet, C. Perigaud, S. Peyrottes, and E. Champagne. 2009. Specific requirements for Vgamma9Vdelta2 T cell stimulation by a natural adenylated phosphoantigen. J Immunol 183:3848-3857.
21.Gober, H. J., M. Kistowska, L. Angman, P. Jeno, L. Mori, and G. De Libero. 2003. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163-168.
22.Constant, P., F. Davodeau, M. A. Peyrat, Y. Poquet, G. Puzo, M. Bonneville, and J. J. Fournie. 1994. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264:267-270.
23.Wang, H., Z. Fang, and C. T. Morita. 2010. Vgamma2Vdelta2 T Cell Receptor recognition of prenyl pyrophosphates is dependent on all CDRs. J Immunol 184:6209-6222.
24.Scotet, E., L. O. Martinez, E. Grant, R. Barbaras, P. Jeno, M. Guiraud, B. Monsarrat, X. Saulquin, S. Maillet, J. P. Esteve, F. Lopez, B. Perret, X. Collet, M. Bonneville, and E. Champagne. 2005. Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71-80.
25. Mookerjee-Basu, J., P. Vantourout, L. O. Martinez, B. Perret, X. Collet, C. Perigaud, S. Peyrottes, and E. Champagne.2010. F1-adenosine triphosphatase displays properties characteristic of an antigen presentation molecule for Vgamma9Vdelta2 T cells. J Immunol 184:6920-6928.
26. Kong, Y., W. Cao, X. Xi, C. Ma, L. Cui, and W. He.2009. The NKG2D ligand ULBP4 binds to TCRgamma9/delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D. Blood 114:310-317.
27. Chen, H., X. He, Z. Wang, D. Wu, H. Zhang, C. Xu, H. He, L. Cui, D. Ba, and W. He.2008. Identification of human T cell receptor gammadelta-recognized epitopes/proteins via CDR3 delta peptide-based immunobiochemical strategy. J Biol Chem 283:12528-12537.
28. Chalupny, N. J., C. L. Sutherland, W. A. Lawrence, A. Rein-Weston, and D. Cosman.2003. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305:129-135.
29. Conejo-Garcia, J. R., F. Benencia, M. C. Courreges, E. Khang, L. Zhang, A. Mohamed-Hadley, J. M. Vinocur, R. J. Buckanovich, C. B. Thompson, B. Levine, and G. Coukos.2003. Letal, A tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells. Cancer Biol Ther 2:446-451.
30. Brichard, V. G., and D. Lejeune.2008. Cancer immunotherapy targeting tumour-specific antigens:towards a new therapy for minimal residual disease. Expert Opin Biol Ther 8:951-968.
31. Linley, A. J., M. Ahmad, and R. C. Rees.2011. Tumour-associated antigens: considerations for their use in tumour immunotherapy. Int J Hematol 93:263-273.
32. Reichert, J. M.2011. Antibody-based therapeutics to watch in 2011. MAbs 3:76-99.
33. Sensi, M., S. Salvi, C. Castelli, C. Maccalli, A. Mazzocchi, R. Mortarini, G. Nicolini, M. Herlyn, G. Parmiani, and A. Anichini.1993. T cell receptor (TCR) structure of autologous melanoma-reactive cytotoxic T lymphocyte (CTL) clones:tumor-infiltrating lymphocytes overexpress in vivo the TCR beta chain sequence used by an HLA-A2-restricted and melanocyte-lineage-specific CTL clone. JExp Med 178:1231-1246.
34. Sensi, M., and G. Parmiani.1995. Analysis of TCR usage in human tumors:a new tool for assessing tumor-specific immune responses. Immunol Today 16:588-595.
35. Starr, T. K., S. C. Jameson, and K. A. Hogquist.2003. Positive and negative selection of T cells. Annu Rev Immunol 21:139-176.
36. Weber, K. S., D. L. Donermeyer, P. M. Allen, and D. M. Kranz.2005. Class Ⅱ-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci U S A 102:19033-19038.
37. Alli, R., Z. M. Zhang, P. Nguyen, J. J. Zheng, and T. L. Geiger.2011. Rational design of T cell receptors with enhanced sensitivity for antigen. PLoS One 6:e 18027.
38. Chlewicki, L. K., P. D. Holler, B. C. Monti, M. R. Clutter, and D. M. Kranz. 2005. High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. J Mol Biol 346:223-239.
39. Moran, A. E., and K. A. Hogquist.2012. T-cell receptor affinity in thymic development. Immunology 135:261-267.
40. Holler, P. D., P. O. Holman, E. V. Shusta, S. O'Herrin, K. D. Wittrup, and D. M. Kranz.2000. In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc Natl Acad Sci USA 97:5387-5392.
41. Zhao, Y., A. D. Bennett, Z. Zheng, Q. J. Wang, P. F. Robbins, L. Y. Yu, Y. Li, P. E. Molloy, S. M. Dunn, B. K. Jakobsen, S. A. Rosenberg, and R. A. Morgan. 2007. High-affinity TCRs generated by phage display provide CD4+T cells with the ability to recognize and kill tumor cell lines. J Immunol 179:5845-5854.
42. Boulter, J. M., M. Glick, P. T. Todorov, E. Baston, M. Sami, P. Rizkallah, and B. K. Jakobsen.2003. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng 16:707-711.
43. Boulter, J. M., and B. K. Jakobsen.2005. Stable, soluble, high-affinity, engineered T cell receptors:novel antibody-like proteins for specific targeting of peptide antigens. Clin Exp Immunol 142:454-460.
44. Kuball, J., B. Hauptrock, V. Malina, E. Antunes, R. H. Voss, M. Wolfl, R. Strong, M. Theobald, and P. D. Greenberg.2009. Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain. J Exp Med 206:463-475.
45. Daniels, M. A., K. A. Hogquist, and S. C. Jameson.2002. Sweet'n'sour:the impact of differential glycosylation on T cell responses. Nat Immunol 3:903-910.
46. Yee, C., J. A. Thompson, D. Byrd, S. R. Riddell, P. Roche, E. Celis, and P. D. Greenberg.2002. Adoptive T cell therapy using antigen-specific CD8+T cell clones for the treatment of patients with metastatic melanoma:in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168-16173.
47. Besser, M. J., R. Shapira-Frommer, A. J. Treves, D. Zippel, O. Itzhaki, L. Hershkovitz, D. Levy, A. Kubi, E. Hovav, N. Chermoshniuk, B. Shalmon, I. Hardan, R. Catane, G. Markel, S. Apter, A. Ben-Nun, I. Kuchuk, A. Shimoni, A. Nagler, and J. Schachter.2010. Clinical responses in a phase Ⅱ study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16:2646-2655.
48. Rubinstein, M. P., A. N. Kadima, M. L. Salem, C. L. Nguyen, W. E. Gillanders, M. I. Nishimura, and D. J. Cole.2003. Transfer of TCR genes into mature T cells is accompanied by the maintenance of parental T cell avidity. J Immunol 170:1209-1217.
49. Renkvist, N., C. Castelli, P. F. Robbins, and G. Parmiani.2001. A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother 50:3-15.
50. Circosta, P., L. Granziero, A. Follenzi, E. Vigna, S. Stella, A. Vallario, A. R. Elia, L. Gammaitoni, K. Vitaggio, F. Orso, M. Geuna, D. Sangiolo, M. Todorovic, C. Giachino, and A. Cignetti.2009. T cell receptor (TCR) gene transfer with lentiviral vectors allows efficient redirection of tumor specificity in naive and memory T cells without prior stimulation of endogenous TCR. Hum Gene Ther 20:1576-1588.
51. Xue, S., R. Gillmore, A. Downs, A. Tsallios, A. Holler, L. Gao, V. Wong, E. Morris, and H. J. Stauss.2005. Exploiting T cell receptor genes for cancer immunotherapy. Clin Exp Immunol 139:167-172.
52. Weber, E., W. F. Anderson, and N. Kasahara.2001. Recent advances in retrovirus vector-mediated gene therapy:teaching an old vector new tricks. Curr Opin Mol Ther 3:439-453.
53. Chen, Z., M. Ahonen, H. Hamalainen, J. M. Bergelson, V. M. Kahari, and R. Lahesmaa.2002. High-efficiency gene transfer to primary T lymphocytes by recombinant adenovirus vectors. J Immunol Methods 260:79-89.
54. Frecha, C., C. Levy, F. L. Cosset, and E. Verhoeyen.2010. Advances in the field of lentivector-based transduction of T and B lymphocytes for gene therapy. Mol Ther 18:1748-1757.
55. Joseph, A., J. H. Zheng, A. Follenzi, T. Dilorenzo, K. Sango, J. Hyman, K. Chen, A. Piechocka-Trocha, C. Brander, E. Hooijberg, D. A. Vignali, B. D. Walker, and H. Goldstein.2008. Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. J Virol 82:3078-3089.
56. Tsuji, T., M. Yasukawa, J. Matsuzaki, T. Ohkuri, K. Chamoto, D. Wakita, T. Azuma, H. Niiya, H. Miyoshi, K. Kuzushima, Y. Oka, H. Sugiyama, H. Ikeda, and T. Nishimura.2005. Generation of tumor-specific, HLA class Ⅰ-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 106:470-476.
57. Hofmann, C., S. Hofflin, A. Huckelhoven, S. Bergmann, E. Harrer, G. Schuler, J. Dorrie, N. Schaft, and T. Harrer.2011. Human T cells expressing two additional receptors (TETARs) specific for HIV-1 recognize both epitopes. Blood 18:5174-5177.
58. Zhao, Y., Z. Zheng, C. J. Cohen, L. Gattinoni, D. C. Palmer, N. P. Restifo, S. A. Rosenberg, and R. A. Morgan.2006. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol Ther 13:151-159.
59. Morgan, R. A., M. E. Dudley, J. R. Wunderlich, M. S. Hughes, J. C. Yang, R. M. Sherry, R. E. Royal, S. L. Topalian, U. S. Kammula, N. P. Restifo, Z. Zheng, A. Nahvi, C. R. de Vries, L. J. Rogers-Freezer, S. A. Mavroukakis, and S. A. Rosenberg.2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126-129.
60. Zhao, Y., Z. Zheng, P. F. Robbins, H. T. Khong, S. A. Rosenberg, and R. A. Morgan.2005. Primary human lymphocytes transduced with NY-ESO-1 antigen-specific TCR genes recognize and kill diverse human tumor cell lines. J Immunol 174:4415-4423.
61. Cohen, C. J., Z. Zheng, R. Bray, Y. Zhao, L. A. Sherman, S. A. Rosenberg, and R. A. Morgan.2005. Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR. J Immunol 175:5799-5808.
62. Santomasso, B. D., W. K. Roberts, A. Thomas, T. Williams, N. E. Blachere, M. E. Dudley, A. N. Houghton, J. B. Posner, and R. B. Darnell.2007. A T-cell receptor associated with naturally occurring human tumor immunity. Proc Natl Acad Sci U S A 104:19073-19078.
63. Weiner, L. M., R. Surana, and S. Wang.2010. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10:317-327.
64. Epel, M., J. D. Ellenhorn, D. J. Diamond, and Y. Reiter.2002. A functional recombinant single-chain T cell receptor fragment capable of selectively targeting antigen-presenting cells. Cancer Immunol Immunother 51:565-573.
65. Card, K. F., S. A. Price-Schiavi, B. Liu, E. Thomson, E. Nieves, H. Belmont, J. Builes, J. A. Jiao, J. Hernandez, J. Weidanz, L. Sherman, J. L. Francis, A. Amirkhosravi, and H. C. Wong.2004. A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. Cancer Immunol Immunother 53:345-357.
66. Willcox, B. E., G. F. Gao, J. R. Wyer, C. A. O'Callaghan, J. M. Boulter, E. Y Jones, P. A. van der Merwe, J. I. Bell, and B. K. Jakobsen.1999. Production of soluble alphabeta T-cell receptor heterodimers suitable for biophysical analysis of ligand binding. Protein Sci 8:2418-2423.
67. Lunde, E., G. A. Loset, B. Bogen, and I. Sandlie.2010. Stabilizing mutations increase secretion of functional soluble TCR-Ig fusion proteins. BMC Biotechnol 10:61-72.
68. Rudnick, S. I., and G. P. Adams.2009. Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 24:155-161.
69. Graff, C. P., and K. D. Wittrup.2003. Theoretical analysis of antibody targeting of tumor spheroids:importance of dosage for penetration, and affinity for retention. Cancer Res 63:1288-1296.
70. Jiang, X. R., A. Song, S. Bergelson, T. Arroll, B. Parekh, K. May, S. Chung, R. Strouse, A. Mire-Sluis, and M. Schenerman.2011. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov 10:101-111.
71. van der Merwe, P. A., and S. J. Davis.2003. Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 21:659-684.
72. Laugel, B., J. M. Boulter, N. Lissin, A. Vuidepot, Y. Li, E. Gostick, L. E. Crotty, D. C. Douek, J. Hemelaar, D. A. Price, B. K. Jakobsen, and A. K. Sewell.2005. Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition. JBiol Chem 280:1882-1892.
73. Subbramanian, R. A., C. Moriya, K. L. Martin, F. W. Peyerl, A. Hasegawa, A. Naoi, H. Chhay, P. Autissier, D. A. Gorgone, M. A. Lifton, K. Kuus-Reichel, J. E. Schmitz, N. L. Letvin, and M. J. Kuroda.2004. Engineered T-cell receptor tetramers bind MHC-peptide complexes with high affinity. Nat Biotechnol 22:1429-1434.
74. McGregor, D. P., P. E. Molloy, C. Cunningham, and W. J. Harris.1994. Spontaneous assembly of bivalent single chain antibody fragments in Escherichia coli. Mol Immunol 31:219-226.
75. Molloy, P. E., A. K. Sewell, and B. K. Jakobsen.2005. Soluble T cell receptors: novel immunotherapies. Curr Opin Pharmacol 5:438-443.
76. Belmont, H. J., S. Price-Schiavi, B. Liu, K. F. Card, H. I. Lee, K. P. Han, J. Wen, S. Tang, X. Zhu, J. Merrill, P. A. Chavillaz, J. L. Wong, P. R. Rhode, and H. C. Wong.2006. Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein. Clin Immunol 121:29-39.
77. Wen, J., X. Zhu, B. Liu, L. You, L. Kong, H. I. Lee, K. P. Han, J. L. Wong, P. R. Rhode, and H. C. Wong.2008. Targeting activity of a TCR/IL-2 fusion protein against established tumors. Cancer Immunol Immunother 57:1781-1794.
78. Mosquera, L. A., K. F. Card, S. A. Price-Schiavi, H. J. Belmont, B. Liu, J. Builes, X. Zhu, P. A. Chavaillaz, H. I. Lee, J. A. Jiao, J. L. Francis, A. Amirkhosravi, R. L. Wong, and H. C. Wong.2005. In vitro and in vivo characterization of a novel antibody-like single-chain TCR human IgG 1 fusion protein. J Immunol 174:4381-4388.
79. Halin, C., V. Gafner, M. E. Villani, L. Borsi, A. Berndt, H. Kosmehl, L. Zardi, and D. Neri.2003. Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor alpha. Cancer Res 63:3202-3210.
80. Dela Cruz, J. S., T. H. Huang, M. L. Penichet, and S. L. Morrison.2004. Antibody-cytokine fusion proteins:innovative weapons in the war against cancer. Clin Exp Med 4:57-64.
81. Norell, H., M. Carlsten, T. Ohlum, K. J. Malmberg, G. Masucci, K. Schedvins, W. Altermann, D. Handke, D. Atkins, B. Seliger, and R. Kiessling.2006. Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity. Cancer Res 66:6387-6394.
82. Reiman, J. M., M. Kmieciak, M. H. Manjili, and K. L. Knutson.2007. Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol 17:275-287.
83. Morita, C. T., Y. Tanaka, B. R. Bloom, and M. B. Brenner.1996. Direct presentation of non-peptide prenyl pyrophosphate antigens to human gamma delta T cells. Res Immunol 147:347-353.
84. Cao, W, and W. He.2005. The recognition pattern of gammadelta T cells. Front Biosci 10:2676-2700.
2. Vogel, C. L., M. A. Cobleigh, D. Tripathy, J. C. Gutheil, L. N. Harris, L. Fehrenbacher, D. J. Slamon, M. Murphy, W. F. Novotny, M. Burchmore, S. Shak, and S. J. Stewart.2001. First-line Herceptin monotherapy in metastatic breast cancer. Oncology 61 Suppl 2:37-42.
3. Hainsworth, J. D., S. Litchy, H. A. Burris,3rd, D. C. Scullin, Jr., S. W. Corso, D. A. Yardley, L. Morrissey, and F. A. Greco.2002. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol 20:4261-4267.
4. Linley, A. J., M. Ahmad, and R. C. Rees.2011. Tumour-associated antigens: considerations for their use in tumour immunotherapy. Int J Hematol 93:263-273.
5. Reichert, J. M.2011. Antibody-based therapeutics to watch in 2011. MAbs 3:76-99.
6. McKee, M. D., A. Fichera, and M. I. Nishimura.2007. T cell immunotherapy. Front Biosci 12:919-932.
7. Weber, J., M. Atkins, P. Hwu, L. Radvanyi, M. Sznol, and C. Yee.2011. White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. Clin Cancer Res 17:1664-1673.
8. Morgan, R. A., M. E. Dudley, J. R. Wunderlich, M. S. Hughes, J. C. Yang, R. M. Sherry, R. E. Royal, S. L. Topalian, U. S. Kammula, N. P. Restifo, Z. Zheng, A. Nahvi, C. R. de Vries, L. J. Rogers-Freezer, S. A. Mavroukakis, and S. A. Rosenberg.2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126-129.
9. Ochi, T., H. Fujiwara, and M. Yasukawa.2010. Application of adoptive T-cell therapy using tumor antigen-specific T-cell receptor gene transfer for the treatment of human leukemia. JBiomed Biotechnol 2010:521248.
10. Peng, L., J. Kjaergaard, G. E. Plautz, M. Awad, J. A. Drazba, S. Shu, and P. A. Cohen.2002. Tumor-induced L-selectinhigh suppressor T cells mediate potent effector T cell blockade and cause failure of otherwise curative adoptive immunotherapy. J Immunol 169:4811-4821.
11. Dudley, M. E., J. R. Wunderlich, T. E. Shelton, J. Even, and S. A. Rosenberg. 2003. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. JImmunother 26:332-342.
12. Molloy, P. E., A. K. Sewell, and B. K. Jakobsen.2005. Soluble T cell receptors: novel immunotherapies. Curr Opin Pharmacol 5:438-443.
13. Liddy, N., G. Bossi, K. J. Adams, A. Lissina, T. M. Mahon, N. J. Hassan, J. Gavarret, F. C. Bianchi, N. J. Pumphrey, K. Ladell, E. Gostick, A. K. Sewell, N. M. Lissin, N. E. Harwood, P. E. Molloy, Y. Li, B. J. Cameron, M. Sami, E. E. Baston, P. T. Todorov, S. J. Paston, R. E. Dennis, J. V. Harper, S. M. Dunn, R. Ashfield, A. Johnson, Y. McGrath, G. Plesa, C. H. June, M. Kalos, D. A. Price, A. Vuidepot, D. D. Williams, D. H. Sutton, and B. K. Jakobsen.2012. Monoclonal TCR-redirected tumor cell killing. Nat Med 6:doi:10.1038.
14. Epel, M., J. D. Ellenhorn, D. J. Diamond, and Y. Reiter.2002. A functional recombinant single-chain T cell receptor fragment capable of selectively targeting antigen-presenting cells. Cancer Immunol Immunother 51:565-573.
15. Card, K. F., S. A. Price-Schiavi, B. Liu, E. Thomson, E. Nieves, H. Belmont, J. Builes, J. A. Jiao, J. Hernandez, J. Weidanz, L. Sherman, J. L. Francis, A. Amirkhosravi, and H. C. Wong.2004. A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. Cancer Immunol Immunother 53:345-357.
16. Belmont, H. J., S. Price-Schiavi, B. Liu, K. F. Card, H. I. Lee, K. P. Han, J. Wen, S. Tang, X. Zhu, J. Merrill, P. A. Chavillaz, J. L. Wong, P. R. Rhode, and H. C. Wong.2006. Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein. Clin Immunol 121:29-39.
17. Wen, J., X. Zhu, B. Liu, L. You, L. Kong, H. I. Lee, K. P. Han, J. L. Wong, P. R. Rhode, and H. C. Wong.2008. Targeting activity of a TCR/IL-2 fusion protein against established tumors. Cancer Immunol Immunother 57:1781-1794.
18. Mosquera, L. A., K. F. Card, S. A. Price-Schiavi, H. J. Belmont, B. Liu, J. Builes, X. Zhu, P. A. Chavaillaz, H. I. Lee, J. A. Jiao, J. L. Francis, A. Amirkhosravi, R. L. Wong, and H. C. Wong.2005. In vitro and in vivo characterization of a novel antibody-like single-chain TCR human IgG 1 fusion protein. J Immunol 174:4381-4388.
19. Allison, T. J., C. C. Winter, J. J. Fournie, M. Bonneville, and D. N. Garboczi. 2001. Structure of a human gammadelta T-cell antigen receptor. Nature 411:820-824.
20. Morita, C. T., E. M. Beckman, J. F. Bukowski, Y. Tanaka, H. Band, B. R. Bloom, D. E. Golan, and M. B. Brenner.1995. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells. Immunity 3:495-507.
21. Sicard, H., S. Ingoure, B. Luciani, C. Serraz, J. J. Fournie, M. Bonneville, J. Tiollier, and F. Romagne.2005. In vivo immunomanipulation of V gamma 9V delta 2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model. J Immunol 175:5471-5480.
22. Kunzmann, V., and M. Wilhelm.2005. Anti-lymphoma effect of gammadelta T cells. Leuk Lymphoma 46:671-680.
23. Kobayashi, H., Y. Tanaka, J. Yagi, N. Minato, and K. Tanabe.2011. Phase I/II study of adoptive transfer of gammadelta T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma. Cancer Immunol Immunother 60:1075-1084.
24. Lang, J. M., M. R. Kaikobad, M. Wallace, M. J. Staab, D. L. Horvath, G. Wilding, G. Liu, J. C. Eickhoff, D. G. McNeel, and M. Malkovsky.2011. Pilot trial of interleukin-2 and zoledronic acid to augment gammadelta T cells as treatment for patients with refractory renal cell carcinoma. Cancer Immunol Immunother 60:1447-1460.
25. Nicol, A. J., H. Tokuyama, S. R. Mattarollo, T. Hagi, K. Suzuki, K. Yokokawa, and M. Nieda.2011. Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours. Br J Cancer 105:778-786.
26. Xu, C., H. Zhang, H. Hu, H. He, Z. Wang, Y. Xu, H. Chen, W. Cao, S. Zhang, L. Cui, D. Ba, and W. He.2007. Gammadelta T cells recognize tumor cells via CDR3delta region. Mol Immunol 44:302-310.
27. Wang, Z., T. Zhang, H. Hu, H. Zhang, Z. Yang, L. Cui, and W. He.2008. Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody. Cancer Lett 272:242-252.
28. Wang, H., Z. Fang, and C. T. Morita.2010. Vgamma2Vdelta2 T Cell Receptor recognition of prenyl pyrophosphates is dependent on all CDRs. J Immunol 184:6209-6222.
29. Kabelitz, D.2011. gammadelta T-cells:cross-talk between innate and adaptive immunity. Cell Mol Life Sci 68:2331-2333.
30. Hayday, A. C.2000. [gamma][delta] cells:a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975-1026.
31. Cao, W, and W. He.2005. The recognition pattern of gammadelta T cells. Front Biosci 10:2676-2700.
32. Kreslavsky, T., and H. von Boehmer.2010. gammadeltaTCR ligands and lineage commitment. Semin Immunol 22:214-221.
33. Kabelitz, D., D. Wesch, and W. He.2007. Perspectives of gammadelta T cells in tumor immunology. Cancer Res 67:5-8.
34. Dokouhaki, P., M. Han, B. Joe, M. Li, M. R. Johnston, M. S. Tsao, and L. Zhang.2010. Adoptive immunotherapy of cancer using ex vivo expanded human gammadelta T cells:A new approach. Cancer Lett 297:126-136.
35. Zhou, J., N. Kang, L. Cui, D. Ba, and W. He.2012.2012. Anti-gammadelta TCR antibody-expanded gammadelta T cells:a better choice for the adoptive immunotherapy of lymphoid malignancies Cell Mol Immunol 9:34-44.
36. Bonneville, M., and E. Scotet.2006. Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol 18:539-546.
37. Caccamo, N., S. Meraviglia, G. Cicero, G. Gulotta, F. Moschella, A. Cordova, E. Gulotta, A. Salerno, and F. Dieli.2008. Aminobisphosphonates as new weapons for gammadelta T Cell-based immunotherapy of cancer. Curr Med Chem 15:1147-1153.
38. Kunzmann, V., E. Bauer, J. Feurle, F. Weissinger, H. P. Tony, and M. Wilhelm. 2000. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 96:384-392.
39. Siegers, G. M., H. Dhamko, X. H. Wang, A. M. Mathieson, Y. Kosaka, T. C. Felizardo, J. A. Medin, S. Tohda, J. Schueler, P. Fisch, and A. Keating.2011. Human Vdeltal gammadelta T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells. Cytotherapy 13:753-764.
40. Ismail, A. S., K. M. Severson, S. Vaishnava, C. L. Behrendt, X. Yu, J. L. Benjamin, K. A. Ruhn, B. Hou, A. L. DeFranco, F. Yarovinsky, and L. V. Hooper.2011. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci USA 108:8743-8748.
41. Tagawa, T., H. Nishimura, T. Yajima, H. Hara, K. Kishihara, G. Matsuzaki, I. Yoshino, Y. Maehara, and Y. Yoshikai.2004. Vdeltal+gammadelta T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice. J Immunol 173:5156-5164.
42. Maeurer, M. J., D. Martin, W. Walter, K. Liu, L. Zitvogel, K. Halusczcak, H. Rabinowich, R. Duquesnoy, W. Storkus, and M. T. Lotze.1996. Human intestinal Vdeltal+lymphocytes recognize tumor cells of epithelial origin. J Exp Med 183:1681-1696.
43. Goto, M., K. Kuribayashi, Y. Umemori, Y. Ohe, K. Asanuma, M. Tanaka, D. Kobayashi, and N. Watanabe.2010. High prevalence of human anti-mouse antibodies in the serum of colorectal cancer patients. Anticancer Res 30:4353-4356.
44. Cavalier, E., A. Carlisi, J. P. Chapelle, P. Orfanos, M. Uzan, V. Falque, P. Delanaye, and M. Hachicha.2009. Human anti-mouse antibodies interferences in Elecsys PTH assay after OKT3 treatment. Transplantation 87:451-452.
45. Xi, X., Y. Guo, H. Chen, C. Xu, H. Zhang, H. Hu, L. Cui, D. Ba, and W. He. 2009. Antigen specificity of gammadelta T cells depends primarily on the flanking sequences of CDR3delta. JBiol Chem 284:27449-27455.
46. Liu, X., E. A. Peralta, J. D. Ellenhom, and D. J. Diamond.2000. Targeting of human p53-overexpressing tumor cells by an HLA A*0201-restricted murine T-cell receptor expressed in Jurkat T cells. Cancer Res 60:693-701.
47. Bukowski, J. F., C. T. Morita, Y. Tanaka, B. R. Bloom, M. B. Brenner, and H. Band.1995. V gamma 2V delta 2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer. J Immunol 154:998-1006.
48. Johnson, L. A., B. Heemskerk, D. J. Powell, Jr., C. J. Cohen, R. A. Morgan, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg.2006. Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 177:6548-6559.
49. Boulter, J. M., and B. K. Jakobsen.2005. Stable, soluble, high-affinity, engineered T cell receptors:novel antibody-like proteins for specific targeting of peptide antigens. Clin Exp Immunol 142:454-460.
50. Verma, B., F. A. Neethling, S. Caseltine, G. Fabrizio, S. Largo, J. A. Duty, P. Tabaczewski, and J. A. Weidanz. 2010. TCR mimic monoclonal antibody targets a specific peptide/HLA class I complex and significantly impedes tumor growth in vivo using breast cancer models. J Immunol 184:2156-2165.
51. Norell, H., M. Carlsten, T. Ohlum, K. J. Malmberg, G. Masucci, K. Schedvins, W. Altermann, D. Handke, D. Atkins, B. Seliger, and R. Kiessling. 2006. Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity. Cancer Res 66:6387-6394.
52. Reiman, J. M., M. Kmieciak, M. H. Manjili, and K. L. Knutson. 2007. Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol 17:275-287.
53. Morita, C. T., Y. Tanaka, B. R. Bloom, and M. B. Brenner. 1996. Direct presentation of non-peptide prenyl pyrophosphate antigens to human gamma delta T cells. Res Immunol 147:347-353.
54.Siberil, S., C. A. Dutertre, W. H. Fridman, and J. L. Teillaud. 2007. FcgammaR: The key to optimize therapeutic antibodies? Crit Rev Oncol Hematol 62:26-33.
55.Weiner, G. J. 2010. Rituximab: mechanism of action. Semin Hematol 47:115-123.
56.Hubert, P., A. Heitzmann, S. Viel, A. Nicolas, X. Sastre-Garau, P. Oppezzo, O. Pritsch, E. Osinaga, and S. Amigorena. 2011. Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy. Cancer Res 71:5134-5143.
57.Weiner, L. M, R. Surana, and S. Wang. 2011. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10:317-327.
58.Cartron, G, L. Dacheux, G. Salles, P. Solal-Celigny, P. Bardos, P. Colombat, and H. Watier. 2002. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754-758.
59.Villamor, N., E. Montserrat, and D. Colomer. 2003. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol 30:424-433.
60.Tanaka, Y., C. T. Morita, Y. Tanaka, E. Nieves, M. B. Brenner, and B. R. Bloom. 1995. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375:155-158.
61.Vantourout, P., J. Mookerjee-Basu, C. Rolland, F. Pont, H. Martin, C. Davrinche, L. O. Martinez, B. Perret, X. Collet, C. Perigaud, S. Peyrottes, and E. Champagne. 2009. Specific requirements for Vgamma9Vdelta2 T cell stimulation by a natural adenylated phosphoantigen. J Immunol 183:3848-3857.
62.Gober, H. J., M. Kistowska, L. Angman, P. Jeno, L. Mori, and G. De Libero. 2003. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163-168.
63.Constant, P., F. Davodeau, M. A. Peyrat, Y. Poquet, G. Puzo, M. Bonneville, and J. J. Fournie. 1994. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264:267-270.
64. Scotet, E., L. O. Martinez, E. Grant, R. Barbaras, P. Jeno, M. Guiraud, B. Monsarrat, X. Saulquin, S. Maillet, J. P. Esteve, F. Lopez, B. Perret, X. Collet, M. Bonneville, and E. Champagne.2005. Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71-80.
65. Mookerjee-Basu, J., P. Vantourout, L. O. Martinez, B. Perret, X. Collet, C Perigaud, S. Peyrottes, and E. Champagne.2010. F1-adenosine triphosphatase displays properties characteristic of an antigen presentation molecule for Vgamma9Vdelta2 T cells. J Immunol 184:6920-6928.
66. Kong, Y., W. Cao, X. Xi, C. Ma, L. Cui, and W. He.2009. The NKG2D ligand ULBP4 binds to TCRgamma9/delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D. Blood 114:310-317.
67. Chen, H., X. He, Z. Wang, D. Wu, H. Zhang, C. Xu, H. He, L. Cui, D. Ba, and W. He.2008. Identification of human T cell receptor gammadelta-recognized epitopes/proteins via CDR3delta peptide-based immunobiochemical strategy. J Biol Chem 283:12528-12537.
68. Chalupny, N. J., C. L. Sutherland, W. A. Lawrence, A. Rein-Weston, and D. Cosman.2003. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305:129-135.
69. Conejo-Garcia, J. R., F. Benencia, M. C. Courreges, E. Khang, L. Zhang, A. Mohamed-Hadley, J. M. Vinocur, R. J. Buckanovich, C. B. Thompson, B. Levine, and G. Coukos.2003. Letal, A tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells. Cancer Biol Ther 2:446-451.
70. Pecorari, F., A. C. Tissot, and A. Pluckthun.1999. Folding, heterodimeric association and specific peptide recognition of a murine alphabeta T-cell receptor expressed in Escherichia coli. J Mol Biol 285:1831-1843.
71. Willcox, B. E., G. F. Gao, J. R. Wyer, C. A. O'Callaghan, J. M. Boulter, E. Y. Jones, P. A. van der Merwe, J. I. Bell, and B. K. Jakobsen.1999. Production of soluble alphabeta T-cell receptor heterodimers suitable for biophysical analysis of ligand binding. Protein Sci 8:2418-2423.
72. Boulter, J. M., M. Glick, P. T. Todorov, E. Baston, M. Sami, P. Rizkallah, and B. K. Jakobsen.2003. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng 16:707-711.
73. Lunde, E., G. A. Loset, B. Bogen, and I. Sandlie.2010. Stabilizing mutations increase secretion of functional soluble TCR-Ig fusion proteins. BMC Biotechnol 10:61-72.
74. Rudnick, S. I., and G. P. Adams.2009. Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 24:155-161.
75. Graff, C. P., and K. D. Wittrup.2003. Theoretical analysis of antibody targeting of tumor spheroids:importance of dosage for penetration, and affinity for retention. Cancer Res 63:1288-1296.
76. Jiang, X. R., A. Song, S. Bergelson, T. Arroll, B. Parekh, K. May, S. Chung, R. Strouse, A. Mire-Sluis, and M. Schenerman.2011. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov 10:101-111.
77. Starr, T. K., S. C. Jameson, and K. A. Hogquist.2003. Positive and negative selection of T cells. Annu Rev Immunol 21:139-176.
78. Holler, P. D., P. O. Holman, E. V. Shusta, S. O'Herrin, K. D. Wittrup, and D. M. Kranz.2000. In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc Natl Acad Sci USA 97:5387-5392.
79. Weber, K. S., D. L. Donermeyer, P. M. Allen, and D. M. Kranz.2005. Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci USA 102:19033-19038.
80. Alli, R., Z. M. Zhang, P. Nguyen, J. J. Zheng, and T. L. Geiger.2011. Rational design of T cell receptors with enhanced sensitivity for antigen. PLoS One 6:e18027.
81. Chlewicki, L. K., P. D. Holler, B. C. Monti, M. R. Clutter, and D. M. Kranz. 2005. High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. JMol Biol 346:223-239.
82. Presta, L. G.2008. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol 20:460-470.
83. Liu, X. Y., L. M. Pop, and E. S. Vitetta.2008. Engineering therapeutic monoclonal antibodies. Immunol Rev 222:9-27.
84. Stavenhagen, J. B., S. Gorlatov, N. Tuaillon, C. T. Rankin, H. Li, S. Burke, L. Huang, S. Vijh, S. Johnson, E. Bonvini, and S. Koenig.2007. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res 67:8882-8890.
85. Lazar, G. A., W. Dang, S. Karki, O. Vafa, J. S. Peng, L. Hyun, C. Chan, H. S. Chung, A. Eivazi, S. C. Yoder, J. Vielmetter, D. F. Carmichael, R. J. Hayes, and B. I. Dahiyat.2006. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 103:4005-4010.
86. Shields, R. L., J. Lai, R. Keck, L. Y. O'Connell, K. Hong, Y. G. Meng, S. H. Weikert, and L. G. Presta.2002. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem 277:26733-26740.
87. Shinkawa, T., K. Nakamura, N. Yamane, E. Shoji-Hosaka, Y. Kanda, M. Sakurada, K. Uchida, H. Anazawa, M. Satoh, M. Yamasaki, N. Hanai, and K. Shitara.2003. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278:3466-3473.
88. Kobayashi, H., Y. Tanaka, J. Yagi, Y. Osaka, H. Nakazawa, T. Uchiyama, N. Minato, and H. Toma.2007. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma:a pilot study. Cancer Immunol Immunother 56:469-476.
89. Dieli, F., D. Vermijlen, F. Fulfaro, N. Caccamo, S. Meraviglia, G. Cicero, A. Roberts, S. Buccheri, M. D'Asaro, N. Gebbia, A. Salerno, M. Eberl, and A. C. Hayday.2007. Targeting human{gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450-7457.
90. Correia, D. V, M. Fogli, K. Hudspeth, M. G. da Silva, D. Mavilio, and B. Silva-Santos.2011. Differentiation of human peripheral blood Vdeltal+T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118:992-1001.
91. Zhou, J., N. Kang, L. Cui, D. Ba, and W. He.2012. Anti-gammadelta TCR antibody-expanded gammadelta T cells:a better choice for the adoptive immunotherapy of lymphoid malignancies. Cell Mol Immunol 9:34-44.
92. Klee, G. G.2000. Human anti-mouse antibodies. Arch Pathol Lab Med 124:921-923.
93. Scott, A. M., J. D. Wolchok, and L. J. Old.2012. Antibody therapy of cancer. Nat Rev Cancer 12:278-287.
94. Shojaei, S., M. Gardaneh, and A. Rahimi Shamabadi.2012. Target points in trastuzumab resistance. Int J Breast Cancer 2012:761917.
95. Morrison, S. L.2002. Cloning, expression, and modification of antibody V regions. Curr Protoc Immunol Chapter 2:Unit 212.
96. Almagro, J. C., and J. Fransson.2008. Humanization of antibodies. Front Biosci 13:1619-1633.
97. Ill, C. R., J. N. Gonzales, E. K. Houtz, J. R. Ludwig, E. D. Melcher, J. E. Hale, R. Pourmand, V. M. Keivens, L. Myers, K. Beidler, P. Stuart, S. Cheng, and R. Radhakrishnan.1997. Design and construction of a hybrid immunoglobulin domain with properties of both heavy and light chain variable regions. Protein Eng 10:949-957.
98. Kugler, M., C. Stein, M. Schwenkert, D. Saul, L. Vockentanz, T. Huber, S. K. Wetzel, O. Scholz, A. Pluckthun, A. Honegger, and G. H. Fey.2009. Stabilization and humanization of a single-chain Fv antibody fragment specific for human lymphocyte antigen CD 19 by designed point mutations and CDR-grafting onto a human framework. Protein Eng Des Sel 22:135-147.
99. Kashmiri, S. V., R. De Pascalis, N. R. Gonzales, and J. Schlom.2005. SDR grafting--a new approach to antibody humanization. Methods 36:25-34.
100. Kim, K. S., H. J. Kim, B. W. Han, P. K. Myung, and H. J. Hong.2010. Construction of a humanized antibody to hepatitis B surface antigen by specificity-determining residues (SDR)-grafting and de-immunization. Biochem Biophys Res Commun 396:231-237.
101. Gonzales, N. R., R. De Pascalis, J. Schlom, and S. V. Kashmiri.2005. Minimizing the immunogenicity of antibodies for clinical application. Tumour Biol 26:31-43.
102. Ahmad, Z. A., S. K. Yeap, A. M. Ali, W. Y. Ho, N. B. Alitheen, and M. Hamid. 2012.2012. scFv antibody:principles and clinical application. Clin Dev Immunol 2012:980250.
103. Yuasa, N., H. Ogawa, T. Koizumi, K. Tsukamoto, A. Matsumoto-Takasaki, H. Asanuma, H. Nakada, and Y. Fujita-Yamaguchi.2012. Construction and expression of anti-Tn-antigen-specific single-chain antibody genes from hybridoma producing MLS 128 monoclonal antibody. J Biochem 151:371-381.
104. Ahmad, Z. A., S. K. Yeap, A. M. Ali, W. Y. Ho, N. B. Alitheen, and M. Hamid. 2012. scFv antibody:principles and clinical application. Clin Dev Immunol 2012:980250.
105. Sun, W., J. Xie, H. Lin, S. Mi, Z. Li, F. Hua, and Z. Hu.2012. A combined strategy improves the solubility of aggregation-prone single-chain variable fragment antibodies. Protein Expr Purif 83:21-29.
1. Robbins, J. B., R. Schneerson, and S. C. Szu.1996. Specific Acquired Immunity.
2. Grupp, S. A., and C. H. June.2011. Adoptive cellular therapy. Curr Top Microbiol Immunol 344:149-172.
3. Ochi, T., H. Fujiwara, and M. Yasukawa.2010. Application of adoptive T-cell therapy using tumor antigen-specific T-cell receptor gene transfer for the treatment of human leukemia. J Biomed Biotechnol 2010:521248.
4. Johnson, L. A., B. Heemskerk, D. J. Powell, Jr., C. J. Cohen, R. A. Morgan, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg.2006. Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 177:6548-6559.
5. Pardoll, D. M., B. J. Fowlkes, J. A. Bluestone, A. Kruisbeek, W. L. Maloy, J. E. Coligan, and R. H. Schwartz.1987. Differential expression of two distinct T-cell receptors during thymocyte development. Nature 326:79-81.
6. Kreslavsky, T., and H. von Boehmer.2010. gammadeltaTCR ligands and lineage commitment. Semin Immunol 22:214-221.
7. Masuda, K., K. Kakugawa, T. Nakayama, N. Minato, Y. Katsura, and H. Kawamoto.2007. T cell lineage determination precedes the initiation of TCR beta gene rearrangement. J Immunol 179:3699-3706.
8. Lu, C. L., G. D. Li, W. P. Liu, J. Guo, F. Y. Li, D. Y. Liao, and W. Y. Zhang. 2004. [Detection of TCR-gamma chain gene rearrangement in malignant histiocytosis].Zhongh.ua Xue Ye Xue Za Zhi 25:220-222.
9. Joachims, M. L., J. L. Chain, S. W. Hooker, C. J. Knott-Craig, and L. F. Thompson.2006. Human alpha beta and gamma delta thymocyte development: TCR gene rearrangements, intracellular TCR beta expression, and gamma delta developmental potential--differences between men and mice. J Immunol 176:1543-1552.
10. Wilbert, O. M., J. Weber-Arden, D. Kabelitz, and B. Arden.1997. TCR-delta gene rearrangement and selection during fetal thymocyte development. J Immunol 159:3338-3346.
11. Xiong, N., L. Zhang, C. Kang, and D. H. Raulet.2008. Gene placement and competition control T cell receptor gamma variable region gene rearrangement. J Exp Med 205:929-938.
12.Marrack, P., M. McDuffie, W. Born, M. Blackman, C. Hannum, and J. Kappler. 1987. The T cell receptor: its repertoire and role in thymocyte development. Adv Exp Med Biol 213:1-12.
13.Abul k. Abbas, A. H. L., Shiv Pillai. 2012. Cellular and molecular immunology, 7th edition. Med Sci Sports Exerc 44:983.
14.Nakano, K., T. Ishiguro, H. Konishi, M. Tanaka, M. Sugimoto, I. Sugo, T. Igawa, H. Tsunoda, Y. Kinoshita, K. Habu, T. Orita, M. Tsuchiya, K. Hattori, and H. Yamada-Okabe. 2010. Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. Anticancer Drugs 21:907-916.
15.Davis, M. M., J. J. Boniface, Z. Reich, D. Lyons, J. Hampl, B. Arden, and Y. Chien. 1998. Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol 16:523-544.
16.Davis, S. J., S. Ikemizu, E. J. Evans, L. Fugger, T. R. Bakker, and P. A. van der Merwe. 2003. The nature of molecular recognition by T cells. Nat Immunol 4:217-224.
17.Sun, J., and P. B. Kavathas. 1997. Comparison of the roles of CD8 alpha alpha and CD8 alpha beta in interaction with MHC class I. J Immunol 159:6077-6082.
18.Metz, D. P., D. L. Farber, R. Konig, and K. Bottomly. 1997. Regulation of memory CD4 T cell adhesion by CD4-MHC class II interaction. J Immunol 159:2567-2573.
19.Tanaka, Y, C. T. Morita, Y. Tanaka, E. Nieves, M. B. Brenner, and B. R. Bloom. 1995. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375:155-158.
20.Vantourout, P., J. Mookerjee-Basu, C. Rolland, F. Pont, H. Martin, C. Davrinche, L. O. Martinez, B. Perret, X. Collet, C. Perigaud, S. Peyrottes, and E. Champagne. 2009. Specific requirements for Vgamma9Vdelta2 T cell stimulation by a natural adenylated phosphoantigen. J Immunol 183:3848-3857.
21.Gober, H. J., M. Kistowska, L. Angman, P. Jeno, L. Mori, and G. De Libero. 2003. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163-168.
22.Constant, P., F. Davodeau, M. A. Peyrat, Y. Poquet, G. Puzo, M. Bonneville, and J. J. Fournie. 1994. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264:267-270.
23.Wang, H., Z. Fang, and C. T. Morita. 2010. Vgamma2Vdelta2 T Cell Receptor recognition of prenyl pyrophosphates is dependent on all CDRs. J Immunol 184:6209-6222.
24.Scotet, E., L. O. Martinez, E. Grant, R. Barbaras, P. Jeno, M. Guiraud, B. Monsarrat, X. Saulquin, S. Maillet, J. P. Esteve, F. Lopez, B. Perret, X. Collet, M. Bonneville, and E. Champagne. 2005. Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71-80.
25. Mookerjee-Basu, J., P. Vantourout, L. O. Martinez, B. Perret, X. Collet, C. Perigaud, S. Peyrottes, and E. Champagne.2010. F1-adenosine triphosphatase displays properties characteristic of an antigen presentation molecule for Vgamma9Vdelta2 T cells. J Immunol 184:6920-6928.
26. Kong, Y., W. Cao, X. Xi, C. Ma, L. Cui, and W. He.2009. The NKG2D ligand ULBP4 binds to TCRgamma9/delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D. Blood 114:310-317.
27. Chen, H., X. He, Z. Wang, D. Wu, H. Zhang, C. Xu, H. He, L. Cui, D. Ba, and W. He.2008. Identification of human T cell receptor gammadelta-recognized epitopes/proteins via CDR3 delta peptide-based immunobiochemical strategy. J Biol Chem 283:12528-12537.
28. Chalupny, N. J., C. L. Sutherland, W. A. Lawrence, A. Rein-Weston, and D. Cosman.2003. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305:129-135.
29. Conejo-Garcia, J. R., F. Benencia, M. C. Courreges, E. Khang, L. Zhang, A. Mohamed-Hadley, J. M. Vinocur, R. J. Buckanovich, C. B. Thompson, B. Levine, and G. Coukos.2003. Letal, A tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells. Cancer Biol Ther 2:446-451.
30. Brichard, V. G., and D. Lejeune.2008. Cancer immunotherapy targeting tumour-specific antigens:towards a new therapy for minimal residual disease. Expert Opin Biol Ther 8:951-968.
31. Linley, A. J., M. Ahmad, and R. C. Rees.2011. Tumour-associated antigens: considerations for their use in tumour immunotherapy. Int J Hematol 93:263-273.
32. Reichert, J. M.2011. Antibody-based therapeutics to watch in 2011. MAbs 3:76-99.
33. Sensi, M., S. Salvi, C. Castelli, C. Maccalli, A. Mazzocchi, R. Mortarini, G. Nicolini, M. Herlyn, G. Parmiani, and A. Anichini.1993. T cell receptor (TCR) structure of autologous melanoma-reactive cytotoxic T lymphocyte (CTL) clones:tumor-infiltrating lymphocytes overexpress in vivo the TCR beta chain sequence used by an HLA-A2-restricted and melanocyte-lineage-specific CTL clone. JExp Med 178:1231-1246.
34. Sensi, M., and G. Parmiani.1995. Analysis of TCR usage in human tumors:a new tool for assessing tumor-specific immune responses. Immunol Today 16:588-595.
35. Starr, T. K., S. C. Jameson, and K. A. Hogquist.2003. Positive and negative selection of T cells. Annu Rev Immunol 21:139-176.
36. Weber, K. S., D. L. Donermeyer, P. M. Allen, and D. M. Kranz.2005. Class Ⅱ-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci U S A 102:19033-19038.
37. Alli, R., Z. M. Zhang, P. Nguyen, J. J. Zheng, and T. L. Geiger.2011. Rational design of T cell receptors with enhanced sensitivity for antigen. PLoS One 6:e 18027.
38. Chlewicki, L. K., P. D. Holler, B. C. Monti, M. R. Clutter, and D. M. Kranz. 2005. High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. J Mol Biol 346:223-239.
39. Moran, A. E., and K. A. Hogquist.2012. T-cell receptor affinity in thymic development. Immunology 135:261-267.
40. Holler, P. D., P. O. Holman, E. V. Shusta, S. O'Herrin, K. D. Wittrup, and D. M. Kranz.2000. In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc Natl Acad Sci USA 97:5387-5392.
41. Zhao, Y., A. D. Bennett, Z. Zheng, Q. J. Wang, P. F. Robbins, L. Y. Yu, Y. Li, P. E. Molloy, S. M. Dunn, B. K. Jakobsen, S. A. Rosenberg, and R. A. Morgan. 2007. High-affinity TCRs generated by phage display provide CD4+T cells with the ability to recognize and kill tumor cell lines. J Immunol 179:5845-5854.
42. Boulter, J. M., M. Glick, P. T. Todorov, E. Baston, M. Sami, P. Rizkallah, and B. K. Jakobsen.2003. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng 16:707-711.
43. Boulter, J. M., and B. K. Jakobsen.2005. Stable, soluble, high-affinity, engineered T cell receptors:novel antibody-like proteins for specific targeting of peptide antigens. Clin Exp Immunol 142:454-460.
44. Kuball, J., B. Hauptrock, V. Malina, E. Antunes, R. H. Voss, M. Wolfl, R. Strong, M. Theobald, and P. D. Greenberg.2009. Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain. J Exp Med 206:463-475.
45. Daniels, M. A., K. A. Hogquist, and S. C. Jameson.2002. Sweet'n'sour:the impact of differential glycosylation on T cell responses. Nat Immunol 3:903-910.
46. Yee, C., J. A. Thompson, D. Byrd, S. R. Riddell, P. Roche, E. Celis, and P. D. Greenberg.2002. Adoptive T cell therapy using antigen-specific CD8+T cell clones for the treatment of patients with metastatic melanoma:in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168-16173.
47. Besser, M. J., R. Shapira-Frommer, A. J. Treves, D. Zippel, O. Itzhaki, L. Hershkovitz, D. Levy, A. Kubi, E. Hovav, N. Chermoshniuk, B. Shalmon, I. Hardan, R. Catane, G. Markel, S. Apter, A. Ben-Nun, I. Kuchuk, A. Shimoni, A. Nagler, and J. Schachter.2010. Clinical responses in a phase Ⅱ study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16:2646-2655.
48. Rubinstein, M. P., A. N. Kadima, M. L. Salem, C. L. Nguyen, W. E. Gillanders, M. I. Nishimura, and D. J. Cole.2003. Transfer of TCR genes into mature T cells is accompanied by the maintenance of parental T cell avidity. J Immunol 170:1209-1217.
49. Renkvist, N., C. Castelli, P. F. Robbins, and G. Parmiani.2001. A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother 50:3-15.
50. Circosta, P., L. Granziero, A. Follenzi, E. Vigna, S. Stella, A. Vallario, A. R. Elia, L. Gammaitoni, K. Vitaggio, F. Orso, M. Geuna, D. Sangiolo, M. Todorovic, C. Giachino, and A. Cignetti.2009. T cell receptor (TCR) gene transfer with lentiviral vectors allows efficient redirection of tumor specificity in naive and memory T cells without prior stimulation of endogenous TCR. Hum Gene Ther 20:1576-1588.
51. Xue, S., R. Gillmore, A. Downs, A. Tsallios, A. Holler, L. Gao, V. Wong, E. Morris, and H. J. Stauss.2005. Exploiting T cell receptor genes for cancer immunotherapy. Clin Exp Immunol 139:167-172.
52. Weber, E., W. F. Anderson, and N. Kasahara.2001. Recent advances in retrovirus vector-mediated gene therapy:teaching an old vector new tricks. Curr Opin Mol Ther 3:439-453.
53. Chen, Z., M. Ahonen, H. Hamalainen, J. M. Bergelson, V. M. Kahari, and R. Lahesmaa.2002. High-efficiency gene transfer to primary T lymphocytes by recombinant adenovirus vectors. J Immunol Methods 260:79-89.
54. Frecha, C., C. Levy, F. L. Cosset, and E. Verhoeyen.2010. Advances in the field of lentivector-based transduction of T and B lymphocytes for gene therapy. Mol Ther 18:1748-1757.
55. Joseph, A., J. H. Zheng, A. Follenzi, T. Dilorenzo, K. Sango, J. Hyman, K. Chen, A. Piechocka-Trocha, C. Brander, E. Hooijberg, D. A. Vignali, B. D. Walker, and H. Goldstein.2008. Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV-1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. J Virol 82:3078-3089.
56. Tsuji, T., M. Yasukawa, J. Matsuzaki, T. Ohkuri, K. Chamoto, D. Wakita, T. Azuma, H. Niiya, H. Miyoshi, K. Kuzushima, Y. Oka, H. Sugiyama, H. Ikeda, and T. Nishimura.2005. Generation of tumor-specific, HLA class Ⅰ-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 106:470-476.
57. Hofmann, C., S. Hofflin, A. Huckelhoven, S. Bergmann, E. Harrer, G. Schuler, J. Dorrie, N. Schaft, and T. Harrer.2011. Human T cells expressing two additional receptors (TETARs) specific for HIV-1 recognize both epitopes. Blood 18:5174-5177.
58. Zhao, Y., Z. Zheng, C. J. Cohen, L. Gattinoni, D. C. Palmer, N. P. Restifo, S. A. Rosenberg, and R. A. Morgan.2006. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol Ther 13:151-159.
59. Morgan, R. A., M. E. Dudley, J. R. Wunderlich, M. S. Hughes, J. C. Yang, R. M. Sherry, R. E. Royal, S. L. Topalian, U. S. Kammula, N. P. Restifo, Z. Zheng, A. Nahvi, C. R. de Vries, L. J. Rogers-Freezer, S. A. Mavroukakis, and S. A. Rosenberg.2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126-129.
60. Zhao, Y., Z. Zheng, P. F. Robbins, H. T. Khong, S. A. Rosenberg, and R. A. Morgan.2005. Primary human lymphocytes transduced with NY-ESO-1 antigen-specific TCR genes recognize and kill diverse human tumor cell lines. J Immunol 174:4415-4423.
61. Cohen, C. J., Z. Zheng, R. Bray, Y. Zhao, L. A. Sherman, S. A. Rosenberg, and R. A. Morgan.2005. Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR. J Immunol 175:5799-5808.
62. Santomasso, B. D., W. K. Roberts, A. Thomas, T. Williams, N. E. Blachere, M. E. Dudley, A. N. Houghton, J. B. Posner, and R. B. Darnell.2007. A T-cell receptor associated with naturally occurring human tumor immunity. Proc Natl Acad Sci U S A 104:19073-19078.
63. Weiner, L. M., R. Surana, and S. Wang.2010. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10:317-327.
64. Epel, M., J. D. Ellenhorn, D. J. Diamond, and Y. Reiter.2002. A functional recombinant single-chain T cell receptor fragment capable of selectively targeting antigen-presenting cells. Cancer Immunol Immunother 51:565-573.
65. Card, K. F., S. A. Price-Schiavi, B. Liu, E. Thomson, E. Nieves, H. Belmont, J. Builes, J. A. Jiao, J. Hernandez, J. Weidanz, L. Sherman, J. L. Francis, A. Amirkhosravi, and H. C. Wong.2004. A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. Cancer Immunol Immunother 53:345-357.
66. Willcox, B. E., G. F. Gao, J. R. Wyer, C. A. O'Callaghan, J. M. Boulter, E. Y Jones, P. A. van der Merwe, J. I. Bell, and B. K. Jakobsen.1999. Production of soluble alphabeta T-cell receptor heterodimers suitable for biophysical analysis of ligand binding. Protein Sci 8:2418-2423.
67. Lunde, E., G. A. Loset, B. Bogen, and I. Sandlie.2010. Stabilizing mutations increase secretion of functional soluble TCR-Ig fusion proteins. BMC Biotechnol 10:61-72.
68. Rudnick, S. I., and G. P. Adams.2009. Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 24:155-161.
69. Graff, C. P., and K. D. Wittrup.2003. Theoretical analysis of antibody targeting of tumor spheroids:importance of dosage for penetration, and affinity for retention. Cancer Res 63:1288-1296.
70. Jiang, X. R., A. Song, S. Bergelson, T. Arroll, B. Parekh, K. May, S. Chung, R. Strouse, A. Mire-Sluis, and M. Schenerman.2011. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov 10:101-111.
71. van der Merwe, P. A., and S. J. Davis.2003. Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 21:659-684.
72. Laugel, B., J. M. Boulter, N. Lissin, A. Vuidepot, Y. Li, E. Gostick, L. E. Crotty, D. C. Douek, J. Hemelaar, D. A. Price, B. K. Jakobsen, and A. K. Sewell.2005. Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition. JBiol Chem 280:1882-1892.
73. Subbramanian, R. A., C. Moriya, K. L. Martin, F. W. Peyerl, A. Hasegawa, A. Naoi, H. Chhay, P. Autissier, D. A. Gorgone, M. A. Lifton, K. Kuus-Reichel, J. E. Schmitz, N. L. Letvin, and M. J. Kuroda.2004. Engineered T-cell receptor tetramers bind MHC-peptide complexes with high affinity. Nat Biotechnol 22:1429-1434.
74. McGregor, D. P., P. E. Molloy, C. Cunningham, and W. J. Harris.1994. Spontaneous assembly of bivalent single chain antibody fragments in Escherichia coli. Mol Immunol 31:219-226.
75. Molloy, P. E., A. K. Sewell, and B. K. Jakobsen.2005. Soluble T cell receptors: novel immunotherapies. Curr Opin Pharmacol 5:438-443.
76. Belmont, H. J., S. Price-Schiavi, B. Liu, K. F. Card, H. I. Lee, K. P. Han, J. Wen, S. Tang, X. Zhu, J. Merrill, P. A. Chavillaz, J. L. Wong, P. R. Rhode, and H. C. Wong.2006. Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein. Clin Immunol 121:29-39.
77. Wen, J., X. Zhu, B. Liu, L. You, L. Kong, H. I. Lee, K. P. Han, J. L. Wong, P. R. Rhode, and H. C. Wong.2008. Targeting activity of a TCR/IL-2 fusion protein against established tumors. Cancer Immunol Immunother 57:1781-1794.
78. Mosquera, L. A., K. F. Card, S. A. Price-Schiavi, H. J. Belmont, B. Liu, J. Builes, X. Zhu, P. A. Chavaillaz, H. I. Lee, J. A. Jiao, J. L. Francis, A. Amirkhosravi, R. L. Wong, and H. C. Wong.2005. In vitro and in vivo characterization of a novel antibody-like single-chain TCR human IgG 1 fusion protein. J Immunol 174:4381-4388.
79. Halin, C., V. Gafner, M. E. Villani, L. Borsi, A. Berndt, H. Kosmehl, L. Zardi, and D. Neri.2003. Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor alpha. Cancer Res 63:3202-3210.
80. Dela Cruz, J. S., T. H. Huang, M. L. Penichet, and S. L. Morrison.2004. Antibody-cytokine fusion proteins:innovative weapons in the war against cancer. Clin Exp Med 4:57-64.
81. Norell, H., M. Carlsten, T. Ohlum, K. J. Malmberg, G. Masucci, K. Schedvins, W. Altermann, D. Handke, D. Atkins, B. Seliger, and R. Kiessling.2006. Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity. Cancer Res 66:6387-6394.
82. Reiman, J. M., M. Kmieciak, M. H. Manjili, and K. L. Knutson.2007. Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol 17:275-287.
83. Morita, C. T., Y. Tanaka, B. R. Bloom, and M. B. Brenner.1996. Direct presentation of non-peptide prenyl pyrophosphate antigens to human gamma delta T cells. Res Immunol 147:347-353.
84. Cao, W, and W. He.2005. The recognition pattern of gammadelta T cells. Front Biosci 10:2676-2700.