Evaluation of novel cytotoxic compounds for immunoconjugates

描述（由申请人提供）：单克隆抗体的显著商业和医学成功导致了对这种治疗方式的变化的探索。一种特别适用于抗癌治疗的方法涉及抗体-药物偶联物（ADC）或免疫偶联物，并且在过去二十年中取得了有限的成功。单克隆抗体（mAb）的肿瘤特异性选择性与高效细胞毒素的组合使得ADC的发现和开发成为非常合乎逻辑且值得追求的目标。然而，即使已经通过创造性化学解决了与产生有用缀合物相关的许多问题，仍然存在仅基于ADC中活性药物的选择的成功障碍。我们在此提供了可理想地适合作为免疫缀合物有效载荷的新型化合物。有几种mAb可用于靶向恶性细胞表面上选择性表达或过表达的靶抗原，并且已知其内化到癌细胞中。这些mAb为开发采用我们的抗癌化合物的ADC提供了极好的机会。特别感兴趣的两个实例是赫赛汀（r）（用于治疗HER 2（+）乳腺癌的商业mAb）和抗CD 138 mAb，B-B4（用于多发性骨髓瘤的潜在mAb治疗）。作为临床前开发模型，我们将集中精力开发采用两种新型苄基苯乙烯基砜化合物ON 01500和ON 013100的这两种mAb的抗体偶联物。ON 01500和ON 013100是获得专利的高效选择性化合物，其以低纳摩尔IC 50诱导肿瘤细胞凋亡。我们已经开发了使用血清稳定的自降解接头将这些分子与mAb缀合的策略，所述接头被设计用于释放细胞内细胞毒性有效载荷。使用化合物ON 01500和ON 013100的主要优点是：它们对广谱癌细胞类型具有高度效力（低纳摩尔），具有相对高的治疗指数，不是多药耐药（MDR）基因的底物，并且在数千万规模上生产成本低廉。我们建议与描述赫赛汀（r）-格尔德霉素和基于美登木素生物碱的免疫偶联物B-B4-DM 1的文献基准进行比较，评价赫赛汀和抗CD 138 mAb的新型免疫偶联物。该计划的主要目标是鉴定一种或多种高效ADC，用于未来临床试验的评估。另一个目标是创建可应用于增加良好mAb供应并可能用于大量抗癌应用的使能技术。与高效毒性剂共价连接的抗体-药物缀合物（ADC）作为改进的抗癌治疗迅速获得接受。针对越来越多的肿瘤特异性表面抗原的人源化抗体的可用性为癌症治疗提供了“灵丹妙药”。Onconova Therapeutics，Inc.开发新型高效合成分子可以连接到肿瘤特异性抗体的药物将为癌症患者提供增强的治疗选择。

DESCRIPTION (provided by applicant): The remarkable commercial and medical success of monoclonal antibodies has led to the exploration of variations of this therapeutic modality. One approach, which is particularly suited for anticancer therapy, involves Antibody-Drug Conjugates (ADCs), or immunoconjugates, and has experienced limited success in the past two decades. The combination of tumor specific selectivity of monoclonal antibodies (mAbs), with highly potent cytotoxins, makes the discovery and development of ADCs a very logical and worthwhile pursuit. However, even as many problems related to the creation of useful conjugates have been solved via creative chemistry, there still remain barriers to success that are based solely on the selection of the active drug in the ADC. We provide here novel chemical compounds that may be ideally suited as immunoconjugate payloads. Several mAbs are available that are directed to target antigens selectively expressed or over expressed on the surface of malignant cells and are known to be internalized into the cancer cell. These mAbs present excellent opportunities for the development of ADCs employing our anticancer compounds. Two examples of particular interest are Herceptin(r) (a commercial mAb used to treat HER2 (+) breast cancer) and the anti- CD138 mAb, B-B4 (a potential mAb treatment for multiple myeloma). As a preclinical development model, we will focus efforts towards the development of antibody conjugates with these two mAbs employing two novel benzyl styryl sulfone compounds, ON 01500 and ON 013100. ON 01500 and ON 013100 are patented, highly potent and selective compounds which induced apoptosis in tumor cells with low nanomolar IC50. We have developed strategies for the conjugation of these molecules to mAbs using serum stable, self-immolating linkers that are designed for release of intracellular cytotoxic payloads. The key advantages for using compounds ON 01500 and ON 013100 are: they are highly potent (low nanomolar) against a broad spectrum of cancer cell types, have a relatively high therapeutic index, are not substrates for multi-drug resistance (MDR) genes, and are inexpensive to manufacture on multi-kilo scale. We propose to evaluate the novel immunoconjugates of Herceptin and anti-CD138 mAb in comparison to literature benchmarks describing Herceptin(r)-Geldanamycin and the maytansinoid-based immunoconjugate B-B4-DM1. The key objective of this program is to identify one or more highly potent ADCs for future evaluation in clinical trials. Another objective is to create enabling technology that can be applied to the increasing supply of good mAbs and potentially useful for a large number of anticancer applications. Antibody-drug conjugates (ADCs) covalently linked to highly potent toxic agents are rapidly gaining acceptance as improved anticancer treatments. The availability of humanized antibodies to a growing number of tumor specific surface antigens is providing the "magic bullet" for cancer therapy. The development of novel highly potent synthetic molecules from Onconova Therapeutics, Inc. that can be linked to tumor specific antibodies will provide enhanced treatment options for cancer patients.