Evaluation of novel cytotoxic compounds for immunoconjugates

描述(由申请人提供)：单抗在商业和医学上的显著成功导致了对这种治疗方式的变异的探索。一种特别适合于抗癌治疗的方法涉及抗体-药物结合物(ADC)，或免疫结合物，在过去20年中取得了有限的成功。肿瘤特异性单抗(MAbs)与高效细胞毒素的结合，使ADCs的发现和发展成为一个非常合理和有价值的追求。然而，尽管许多与创造有用的偶联物相关的问题已经通过创造性的化学方法解决了，但仍然存在仅仅基于ADC中活性药物的选择而取得成功的障碍。我们在这里提供可能非常适合作为免疫偶联有效载荷的新型化合物。有几种单抗是针对肿瘤细胞表面选择性表达或过度表达的靶抗原，并已知内化到癌细胞内。这些单抗为使用我们的抗癌化合物的ADC的开发提供了极好的机会。两个特别令人感兴趣的例子是Herceptin(R)(一种用于治疗HER2(+)乳腺癌的商用单抗)和抗CD138单抗B-B4(一种治疗多发性骨髓瘤的潜在单抗)。作为一个临床前开发模型，我们将致力于开发这两种单抗的抗体结合物，这两种单抗分别使用01500和013100这两种新型的苯基苯乙烯基砜化合物。01500号和013100号是获得专利的、高效的和选择性的化合物，可以诱导低纳米分子IC50的肿瘤细胞凋亡。我们已经开发了使用血清稳定的自焚接头将这些分子连接到单抗上的策略，这些接头是为释放细胞内的细胞毒有效载荷而设计的。在01500和013100上使用化合物的主要优势是：它们对广泛的癌细胞类型具有高度的效力(低纳米分子)，具有相对较高的治疗指数，不是多药耐药基因的底物，并且在几千克规模上制造成本低廉。我们建议评估新的赫赛汀和抗CD138单抗的免疫结合物，并与描述赫赛汀(R)-格尔达那霉素和基于美坦辛的免疫结合物B-B4-DM1的文献基准进行比较。该计划的主要目标是确定一个或多个高效力的ADC，以便在未来的临床试验中进行评估。另一个目标是创造能够应用于越来越多的优质单抗供应的使能技术，并可能对大量抗癌应用有用。抗体-药物结合物(ADC)与高效有毒物质共价连接，作为改进的抗癌治疗方法正迅速被接受。针对越来越多的肿瘤特异性表面抗原的人源化抗体的出现，为癌症治疗提供了“灵丹妙药”。Onconova治疗公司开发的新型高效合成分子可以与肿瘤特异性抗体相联系，这将为癌症患者提供更好的治疗选择。

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.