Potent Monoclonal Antibody Drug Conjugates

BR96-多柔比星（一种识别人类癌症受体的免疫偶联物）的I期和II期临床试验表明，单克隆抗体成分BR96能够安全地将活性多柔比星递送到肿瘤肿块，尽管浓度不是最佳的。我们建议通过新一代优化的肽基连接物构建和测试由强效药物连接到BR96的显著改进的偶联物。所得的结合物在血清中稳定，但在肿瘤细胞溶酶体中不稳定，导致活性药物在靶部位释放。这些药物将分为两类。含有二霉素单元的小凹槽结合物将被连接到DNA烷基化物环丙基吡咯吲哚上，形成一种共价修饰目标癌细胞DNA的结构。第二种药物将是combretastatin A4，一种有效的抗有丝分裂剂，对肿瘤细胞和肿瘤血管都有作用。预期用这些制剂制备的条件稳定的偶联物在生物学相关剂量下是有效的，能够发挥抗肿瘤活性。本研究的目的是合成有效的药物衍生物，将其与BR96和抗CD40抗原的单克隆抗体连接，并评估其体外细胞毒活性的稳定性，以及在人肿瘤移植裸鼠体内的毒性和活性。建议的商业应用：在治疗乳腺癌、肺癌、结肠癌和前列腺癌方面有很大的未满足的临床需求。BR96抗体可识别在这些肿瘤上广泛表达的Lewis-Y抗原。使用BR96抗体向肿瘤输送强效药物可能会产生显著的抗癌活性，同时具有可接受的全身毒性水平。这将是癌症临床治疗的一大进步。

Phase I and II clinical trials with BR96-doxorubicin, an immunoconjugate that recognizes receptors on human carcinomas, have demonstrated that the monoclonal antibody component, BR96, is capable of safely delivering active doxorubicin to tumor masses, albeit at concentrations that are sub-optimal. We propose to construct and test significantly improved conjugates consisting of highly potent drugs attached to BR96 through a new generation of optimized peptide-based linkers. The resulting conjugates should be stable in serum, but labile inside tumor cell lysosomes, leading to the release of active drug at the target site. The drugs will consist of two classes. Minor groove binders containing a distamycin unit will be attached to the DNA alkylator cyclopropylpyrroloindole, forming a construct that will covalently modify the DNA of target cancer cells. The second drug will be combretastatin A4, a potent antimitotic agent that acts both on tumor cells and tumor vasculature. It is expected that conditionally stable conjugates prepared with these agents will be potent and capable of effecting antitumor activities at biologically relevant doses. The aims of the proposed study are to synthesize potent drug derivatives, link them to BR96 and to a ,monoclonal antibody against the CD40 antigen, and evaluate their stability characteristics in vitro cytotoxic activities, and in vivo toxicities and activities in nude mice with human tumor xenografts. PROPOSED COMMERCIAL APPLICATIONS: There is a very large unmet clinical need for treating carcinomas of the breast, lung, colon, and prostate. The BR96 antibody recognizes the Lewis-Y antigen, which is widely expressed on these tumors. Using the BR96 antibody for the delivery of potent drugs to tumors may lead to pronounced anticancer activity with acceptable levels of systemic toxicity. This would constitute a major advancement in the clinical treatment of cancer.