以Ⅳ型胶原酶为靶点的单抗导向药物的抗肿瘤作用以及建立Ⅳ型胶原酶抑制剂筛选模型的研究
摘要
近几年来，基质金属蛋白酶因在肿瘤的生长、转移和血管生成等多个环节中发挥着重要作用而成为肿瘤治疗研究中引人注目的新靶点。研究表明，MMPs的组织特异性抑制剂TIMPs或合成的小分子MMP抑制剂(MMPIs)可以抑制肿瘤的生长和转移。Ⅳ型胶原酶作为MMPs家族中的重要成员之一，可以通过降解Ⅳ型胶原等胶原底物破坏基底膜和细胞外基质的完整性，从而有利于肿瘤的生长、转移和血管生成。一般来说，在肿瘤细胞及其邻近的间质组织中，Ⅳ型胶原酶的表达和活化显著增加，并且这种增加与肿瘤的恶性表型呈正相关。以其为分子靶点，发展的多种小分子Ⅳ型胶原酶抑制剂在恶性肿瘤的治疗中显示出确切的疗效，部分化合物进入了临床研究阶段。我室制备的小鼠抗Ⅳ型胶原酶单抗3D6可以与Ⅳ型胶原酶特异性结合并中和该酶的活性，以其为基础构建的单抗导向药物在小鼠实验肿瘤模型中显示出很好的疗效。本研究进一步构建了单抗3D6及其小型化片段与高效抗肿瘤抗生素力达霉素的免疫偶联物，并对其体内外抗肿瘤作用进行了研究。另外，我们利用单抗3D6与Ⅳ型胶原酶的结合特性，以竞争性抑制为基础，建立了Ⅳ型胶原酶抑制剂的筛选模型，并利用该模型进行了Ⅳ型胶原酶抑制剂的筛选。研究内容主要包括以下几个部分。
一、抗Ⅳ型胶原酶单抗3D6与力达霉素偶联物的制备及其抗肿瘤作用
单抗3D6可以与Ⅳ型胶原酶特异性结合，以其为载体与抗肿瘤抗生素平阳霉素构建的偶联物在肿瘤生长和转移的动物实验模型中显示出比游离药物更好的治疗作用，以SPDP作为偶联剂制备的3D6-LDM偶联物对小鼠移植性肝癌(H22)的初步研究亦显示出一定的疗效。最近，放射免疫偶联物Zevalin获得FDA的批准上市，给鼠源性单抗用于肿瘤治疗带来了希望。我们以巯基引入试剂2-IT和异型双功能偶联剂MBS作为交联剂，制备了以1：1分子比的偶联产物为主的单抗3D6与高效抗肿瘤抗生素力达霉素的偶联物，该偶联物保留了单抗3D6与Ⅳ型胶原酶和Ⅳ型胶原酶表达较高的H22肿瘤细胞的结合能力，并在体外MTT实验中显示出比游离力达霉素更强的细胞毒作用。采用体外细胞毒性实验中与游离力达霉素作用相当的剂量，在第1
Matrix metalloproteinases (MMPs) has been viewed as a promising target in tumor therapy in recent years due to their key role in tumor growth, angiogenesis, invasion and metastasis. MMP inhibitors, including both the natural tissues MMPs inhibitors (TIMPs) and synthetic low molecular MMPs inhibitors showed the potency of inhibiting tumor growth and metastsis. Type Ⅳ collagenase is an important member of MMPs family which can destroy the integrity of basement membrane and extracellular matrix through the degrading of Type Ⅳ collagen, thus facilitate the process of tumor invasion and metastasis. Also, the expression and secretion of Type Ⅳ collagenase is highly elevated in tumor cells and adjacent interstitial tissue, especially in malignancy with high potential of invasion and metastasis. Studies using Type Ⅳ collagenase as a molecular target have achieved a lot in tumor therapy especially in the control of tumor metastasis. Based on this, the study of using Type Ⅳ collagenase inhibitors to control its activity and the study of using anti-Type Ⅳ collagenase monoclonal antibody as a vector to realize targeting antitumor drugs to the tumor site are two prospective methods for malignancy therapy. And the latter may have dual effects due to the antibody neutralization of enzyme activity and the specific cell-killing effect of antitumor drugs. In this study we developed research on both of the two methods mentioned above. The studies focus on the below fields.
1. The preparation of immunoconjugate composed of lidamycin and monoclonal antibody 3D6 and the evaluation of its antitumor effects
Murine monoclonal antibody 3D6 can bind to Type Ⅳ collagenase specifically. The immunoconjugate composed of mAb 3D6 and pingyangmycin have shown some striking results in tumor therapy. Lidamycin (LDM, also named as C1027), conjugated with mAb 3D6 also exhibited preliminary results. Recently, the approval of a new immunoconjugate consisting of radionuclides Yttrium-90 and an intact murine anti-CD20 antibody by FDA
一、抗Ⅳ型胶原酶单抗3D6与力达霉素偶联物的制备及其抗肿瘤作用
单抗3D6可以与Ⅳ型胶原酶特异性结合，以其为载体与抗肿瘤抗生素平阳霉素构建的偶联物在肿瘤生长和转移的动物实验模型中显示出比游离药物更好的治疗作用，以SPDP作为偶联剂制备的3D6-LDM偶联物对小鼠移植性肝癌(H22)的初步研究亦显示出一定的疗效。最近，放射免疫偶联物Zevalin获得FDA的批准上市，给鼠源性单抗用于肿瘤治疗带来了希望。我们以巯基引入试剂2-IT和异型双功能偶联剂MBS作为交联剂，制备了以1：1分子比的偶联产物为主的单抗3D6与高效抗肿瘤抗生素力达霉素的偶联物，该偶联物保留了单抗3D6与Ⅳ型胶原酶和Ⅳ型胶原酶表达较高的H22肿瘤细胞的结合能力，并在体外MTT实验中显示出比游离力达霉素更强的细胞毒作用。采用体外细胞毒性实验中与游离力达霉素作用相当的剂量，在第1
Matrix metalloproteinases (MMPs) has been viewed as a promising target in tumor therapy in recent years due to their key role in tumor growth, angiogenesis, invasion and metastasis. MMP inhibitors, including both the natural tissues MMPs inhibitors (TIMPs) and synthetic low molecular MMPs inhibitors showed the potency of inhibiting tumor growth and metastsis. Type Ⅳ collagenase is an important member of MMPs family which can destroy the integrity of basement membrane and extracellular matrix through the degrading of Type Ⅳ collagen, thus facilitate the process of tumor invasion and metastasis. Also, the expression and secretion of Type Ⅳ collagenase is highly elevated in tumor cells and adjacent interstitial tissue, especially in malignancy with high potential of invasion and metastasis. Studies using Type Ⅳ collagenase as a molecular target have achieved a lot in tumor therapy especially in the control of tumor metastasis. Based on this, the study of using Type Ⅳ collagenase inhibitors to control its activity and the study of using anti-Type Ⅳ collagenase monoclonal antibody as a vector to realize targeting antitumor drugs to the tumor site are two prospective methods for malignancy therapy. And the latter may have dual effects due to the antibody neutralization of enzyme activity and the specific cell-killing effect of antitumor drugs. In this study we developed research on both of the two methods mentioned above. The studies focus on the below fields.
1. The preparation of immunoconjugate composed of lidamycin and monoclonal antibody 3D6 and the evaluation of its antitumor effects
Murine monoclonal antibody 3D6 can bind to Type Ⅳ collagenase specifically. The immunoconjugate composed of mAb 3D6 and pingyangmycin have shown some striking results in tumor therapy. Lidamycin (LDM, also named as C1027), conjugated with mAb 3D6 also exhibited preliminary results. Recently, the approval of a new immunoconjugate consisting of radionuclides Yttrium-90 and an intact murine anti-CD20 antibody by FDA
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