Evaluation of novel cytotoxic compounds for immunoconjugates

用于免疫缀合物的新型细胞毒性化合物的评价

基本信息

批准号：
7273791
负责人：
STANLEY C BELL
金额：
$ 15.51万
依托单位：
ONCONOVA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-21 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7273791
关键词：
90Y Acids Address Adverse effects Affect Affinity Alkalies Amino Acids, Peptides, and Proteins Antibiotics Antibodies Antigen Targeting Antineoplastic Agents Apoptosis B-Cell Lymphomas Benchmarking Binding Biological Biological Assay Biological Models Biotin Blood Circulation Cancer Patient Cancer cell line Cell Cycle Cell Cycle Progression Cells Chemical Structure Chemicals Chemistry Class Cleaved cell Clinical Research Clinical Trials Collection Cytotoxic agent Cytotoxin Data Development Discrimination Dose Dose-Limiting Drug resistance ERBB2 gene Ensure Evaluation Exhibits Extravasation Fc Receptor Future Geldanamycin Half-Life Hospitals Hybridomas I131 isotope Immunoconjugates In Vitro Inhibitory Concentration 50 Ionizing radiation Legal patent Libraries Link Literature Magic Malignant - descriptor Maps Mediating Medical Melanocytic nevus Methodology Modality Mole the mammal Molecular Weight Monoclonal Antibodies Multi-Drug Resistance Multidrug Resistance Gene Multiple Myeloma Mus Normal Cell Normal tissue morphology Numbers Parents Patients Penetration Pharmaceutical Preparations Phase I Clinical Trials Phosphotransferases Physiological Plasma Prodrugs Production Property Radioisotopes Radiolabeled Range Roche brand of trastuzumab Serum Specificity Structure-Activity Relationship Sulfhydryl Compounds Sulfones Surface Surface Antigens System Technology Testing Therapeutic Therapeutic Index Toxic effect Tumor Antigens Variant Vitamins Work antibody conjugate anticancer treatment base cancer cell cancer therapy cancer type cell killing cell type chemical property chemotherapy cytotoxic cytotoxicity design disulfide bond drug efficacy experience functional group hydroxyl group immunogenicity improved in vivo in vivo Model inhibitor/antagonist interest killings malignant breast neoplasm model development mouse model neoplastic cell new technology novel pre-clinical programs protein aggregation radiotracer receptor binding research clinical testing selective expression small molecule success tumor tumor growth uptake water solubility

90Y Acids Address Adverse effects Affect Affinity Alkalies Amino Acids, Peptides, and Proteins Antibiotics Antibodies Antigen Targeting Antineoplastic Agents Apoptosis B-Cell Lymphomas Benchmarking Binding Biological Biological Assay Biological Models Biotin Blood Circulation Cancer Patient Cancer cell line Cell Cycle Cell Cycle Progression Cells Chemical Structure Chemicals Chemistry Class Cleaved cell Clinical Research Clinical Trials Collection Cytotoxic agent Cytotoxin Data Development Discrimination Dose Dose-Limiting Drug resistance ERBB2 gene Ensure Evaluation Exhibits Extravasation Fc Receptor Future Geldanamycin Half-Life Hospitals Hybridomas I131 isotope Immunoconjugates In Vitro Inhibitory Concentration 50 Ionizing radiation Legal patent Libraries Link Literature Magic Malignant - descriptor Maps Mediating Medical Melanocytic nevus Methodology Modality Mole the mammal Molecular Weight Monoclonal Antibodies Multi-Drug Resistance Multidrug Resistance Gene Multiple Myeloma Mus Normal Cell Normal tissue morphology Numbers Parents Patients Penetration Pharmaceutical Preparations Phase I Clinical Trials Phosphotransferases Physiological Plasma Prodrugs Production Property Radioisotopes Radiolabeled Range Roche brand of trastuzumab Serum Specificity Structure-Activity Relationship Sulfhydryl Compounds Sulfones Surface Surface Antigens System Technology Testing Therapeutic Therapeutic Index Toxic effect Tumor Antigens Variant Vitamins Work antibody conjugate anticancer treatment base cancer cell cancer therapy cancer type cell killing cell type chemical property chemotherapy cytotoxic cytotoxicity design disulfide bond drug efficacy experience functional group hydroxyl group immunogenicity improved in vivo in vivo Model inhibitor/antagonist interest killings malignant breast neoplasm model development mouse model neoplastic cell new technology novel pre-clinical programs protein aggregation radiotracer receptor binding research clinical testing selective expression small molecule success tumor tumor growth uptake water solubility

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项目摘要

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.

描述（由申请人提供）：单克隆抗体的出色商业和医学成功导致探索了这种治疗方式的变化。一种特别适合抗癌治疗的方法涉及抗体 - 药物缀合物（ADC）或免疫缀合物，并且在过去二十年中取得了有限的成功。单克隆抗体（mAb）与高效细胞毒素的肿瘤特异性选择性的结合使ADC的发现和发展成为非常合乎逻辑且值得的追求。但是，尽管与创建有用的共轭物有关的许多问题已经通过创造性化学解决了，但仍然存在仅基于ADC中的活性药物的成功障碍。我们在这里提供了新型的化合物，理想情况下可能适合免疫偶联物有效载荷。有几个mAb可用，这些mAb被定向靶向抗原在恶性细胞表面有选择性表达或过度表达，并已知将其内部化为癌细胞。这些mAB为使用我们的抗癌化合物的ADC提供了绝佳的机会。两个特别感兴趣的例子是赫赛汀（R）（用于治疗HER2（+）乳腺癌）和抗CD138 mAb B-B4（对多发性骨髓瘤的潜在mAb治疗）的商业单元。 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.我们已经开发了使用血清稳定的自动化连接器将这些分子结合给mAb的策略，这些连接器旨在释放细胞内细胞毒性有效载荷。在01500和013100上使用化合物的关键优势是：它们对广泛的癌细胞类型具有很高的有效（低纳摩尔），具有相对较高的治疗指数，不是多药耐药性（MDR）基因的底物，并且是在多千里尺度上生产的基因。与描述Herceptin（R） - 甘甲胺和基于Maytansinoid的Immunoconjugate B-B4-DM1相比，我们建议评估Herceptin和抗CD138 MAB的新型免疫偶联物和抗CD138 MAB。该计划的关键目的是在临床试验中识别一个或多个高度有效的ADC，以供将来评估。另一个目的是创建可以应用于增加良好mAB供应的启用技术，并可能对大量抗癌应用有用。随着改善的抗癌治疗，与高效有毒剂相互关联的抗体 - 药物结合物（ADC）正在迅速获得接受。人性化抗体可用于越来越多的肿瘤表面抗原，为癌症治疗提供了“魔力”。可以与肿瘤特异性抗体有关的新型高效合成分子的新型高效合成分子的发展将为癌症患者提供增强的治疗选择。