Lead Optimization and Evaluation of Anti-SN38 Payload Binding Selectivity Enhancers

抗 SN38 有效负载结合选择性增强剂的先导优化和评估

• 批准号: 10325518
• 负责人: Larry C Wienkers
• 金额: $ 16.8万
• 依托单位: ABCEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325518
• 关键词: Adverse event; Affinity; Albumins; Antibodies; Antibody-drug conjugates; Antineoplastic Agents; Binding; Blood Circulation; Buffaloes; Bystander Effect; Camptothecin; Cell membrane; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Development; Diffuse; Diffusion; Dose; Drug Kinetics; Engineering; Enhancers; Evaluation; Extracellular Fluid; FDA approved; Failure; Funding; Gemtuzumab Ozogamicin; Half-Life; Human; Hydrolysis; Immunoglobulin Fragments; Immunoglobulin G; In Vitro; Investigation; Lead; Left; Legal patent; Life Extension; Malignant Neoplasms; Membrane Proteins; Methods; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; New York; Patients; Phase; Plasma; Prognosis; Safety; Site; Small Business Innovation Research Grant; Sum; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxin; Trastuzumab; Tumor Antigens; Universities; Work; Xenograft procedure; anti-cancer; base; cancer cell; cancer therapy; clinical application; commercialization; cytotoxicity; design; dosage; experimental study; extracellular; human cancer mouse model; improved; in vivo; lead optimization; malignant breast neoplasm; mortality; nanobodies; novel; pre-clinical; premature; prevent; pyrrolobenzodiazepine; receptor mediated endocytosis; research clinical testing; safety assessment; targeted delivery; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor eradication; tumor specificity; uptake

Cancer is a major cause of morbidity and mortality in the US, with 1.8 million cases and 600 thousand cancer deaths projected for 2020. Substantial progress in cancer treatment has been made in the past two decades, largely through the development of highly targeted therapies, including development of antibody-drug conjugates (ADCs). ADCs employ monoclonal antibodies with specificity for tumor-associated antigens to increase the efficiency and selectivity of the delivery of anti-cancer toxins (i.e., payloads) to cancer cells. Although this approach has proven to be successful, with 8 anti-cancer ADCs approved for use in the US (brentuximab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, and sacituzumab govitecan), ADC therapies are often associated with substantial off-target toxicity, narrow therapeutic windows, and high failure rates in clinical testing. Consideration of the FDA-approved ADCs shows that these agents often allow a modest extension in average survival time, but they very rarely cure a patient from their cancer. The development of adverse events prevents the administration of ADC at dosages that are necessary to achieve tumor eradication. This project pursues a new strategy to increase the tumor-selectivity of antibody-directed delivery of anti-cancer drugs. In our approach, payload-binding antibody fragments, termed payload-binding selectivity enhancers (PBSE), are co-administered with ADCs to decrease the exposure of healthy tissues to payload agents, thereby reducing the development of off-target toxicity, increasing the tolerable dose of ADCs, and increasing ADC efficacy. The strategy is based on the recognition that off-site ADC toxicity is primarily attributed to the released (“free”) payload molecule, and also on the hypothesis that PBSE may be employed to prevent cellular entry of free payload molecules in non-targeted cells (by preventing diffusion across plasma membranes) without altering entry of ADCs into targeted cells (which proceeds via receptor mediated endocytosis). Work on this project focuses on lead optimization for newly developed anti-SN38 PBSE, which are expected to increase the safety and efficacy of SN38 ADC, including sacituzumab govitecan. The project will develop optimized derivatives of our lead anti-SN38 PBSE, evaluate the PBSE constructs for plasma, tissue, and tumor disposition, and conduct assessments of safety and efficacy in mice bearing human breast cancer xenografts. In sum, work proposed in this Phase 1 project will enable the identification of an optimized lead anti-SN38 PBSE, which will then advance through IND-enabling preclinical investigations.

癌症是美国发病率和死亡率的主要原因，有180万病例和60万癌症患者