Fc-enhanced CD40 agonist antibodies for immune modulation of the tumor microenvironment

Fc 增强的 CD40 激动剂抗体用于肿瘤微环境的免疫调节

• 批准号: 10470292
• 负责人: David A. Knorr
• 金额: $ 21.2万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470292
• 关键词: Address; Advisory Committees; Affect; Agonist; Anti-CD40; Antibodies; Antibody Therapy; Antigen Presentation; Antigen-Presenting Cells; BCG Live; Bacillus Calmette-Guerin Therapy; Binding; Bladder Neoplasm; Blocking Antibodies; CD40 Ligand; CD8-Positive T-Lymphocytes; Cancer Model; Career Mobility; Cells; Clinic; Clinical; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development Plans; Disease; Engineering; Ensure; Family; Fc Receptor; Fc domain; Foundations; Funding; Future; Gases; Generations; Goals; Human; IgG Receptors; Immune; Immune system; Immunity; Immunocompetent; Immunology; Immunotherapeutic agent; Immunotherapy; International; Knowledge; Laboratories; Lead; Ligands; Ligation; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical Oncology; Mentors; Modeling; Mus; Necrosis; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Physicians; Play; Pre-Clinical Model; Principal Investigator; Proteins; Recombinant Antibody; Research; Research Project Grants; Role; Route; Scientist; Site; Specimen; Strategic Planning; Surface; T cell response; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Tissues; Toxic effect; Training; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; Universities; Vaccines; Work; anti-PD1 antibodies; anti-PD1 therapy; antigen-specific T cells; base; cancer care; cancer immunotherapy; career development; clinical candidate; clinical investigation; crosslink; defined contribution; design; effector T cell; efficacy evaluation; exhaust; experience; human tissue; humanized mouse; immune checkpoint blockade; immunoregulation; improved; improved outcome; in situ vaccination; in vivo; instructor; interest; intravesical; member; mouse model; novel; programmed cell death protein 1; rational design; receptor; recruit; response; success; systemic toxicity; targeted agent; targeted treatment; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract Candidate: The PI, an Instructor in Clinical Investigation at the Rockefeller University, has developed a 5-year career development plan building upon his scientific background in immunology and clinical training in medical oncology. His mentor, Dr. Jeffrey Ravetch, is an internationally recognized expert in Fc receptors. The PI has strategically planned to address the necessary training and mentoring required for his successful career transition to independence through select coursework and a robust mentoring plan. An advisory committee composed of leaders in the field will not only ensure that the PI’s research project progresses as planned, but also is recognized by promotion and leads to independent research funding. This exciting research project is also sufficiently different from that of his mentor’s in order to avoid competition or overlap. Research plan: The recent success of immunotherapy has re-invigorated an interest in harnessing a patient’s own immune system against cancer. While therapies blocking PD-1 have improved the overall survival of patients with bladder cancer, a number of patients don’t derive clinical benefit. My studies have focused on optimizing immune stimulating agents targeting CD40. CD40 plays a key role in the activation of antigen presenting cells (APCs) and the generation of tumor specific T cells. Agonistic anti-CD40 antibodies have been proposed as an efficient approach to promote the maturation of APCs in patients; however, they were toxic with little activity. A likely explanation for this limited activity was provided by our prior studies demonstrating an absolute requirement for the antibody Fc to bind to the inhibitory Fc receptor, FcRIIB. Using this knowledge, we Fc-engineered lead clinical candidate, 2141-V11, which had superior anti-tumor efficacy. Additionally, using an in situ vaccination approach we demonstrated potent anti-tumor activity without evidence of toxicity. We are now investigating the role CD40 in the tumor microenvironment (TME) and how it can be targeted for the treatment of bladder cancer. This is because current immunotherapy in the form of intravesical Bacillus Calmette-Guerin (BCG) is not effective for a large proportion of patients affected by this disease. Our preliminary data support a role for CD40 in bladder tumors and reversal of T cell phenotypes thought to be targeted by anti-PD-1 therapies. Thus, CD40 antibodies, alone or in combination with “checkpoint blockade”, could help improve outcomes in patients not responding to intravesical BCG therapy. Building on our groups extensive experience in studying antibody therapies and access to unique tissue specimens, we now aim to test the hypothesis that 2141-V11 will target dendritic cells in the TME to promote successful anti-tumor immunity.

项目总结/摘要 候选人：PI，洛克菲勒大学临床研究讲师，制定了一项为期5年的 职业发展计划建立在他的免疫学科学背景和医学临床培训的基础上 肿瘤学他的导师Jeffrey Ravetch博士是国际公认的Fc受体专家。主要研究者有 战略规划，以解决他成功职业生涯所需的必要培训和指导 通过选择课程和强大的辅导计划过渡到独立。一个咨询委员会 由该领域的领导者组成，不仅将确保PI的研究项目按计划进行， 也是公认的推广和导致独立的研究经费。这个令人兴奋的研究项目是 也足够不同于他的导师的，以避免竞争或重叠。 研究计划：最近免疫疗法的成功再次引起了人们对利用患者的免疫功能的兴趣。 自身免疫系统对抗癌症。虽然阻断PD-1的治疗改善了患者的总生存期， 对于膀胱癌患者来说，许多患者没有获得临床益处。我的研究重点是 优化靶向CD 40的免疫刺激剂。CD 40在抗原活化中起关键作用 在某些实施方案中，肿瘤细胞可以通过呈递细胞（APCs）和肿瘤特异性T细胞的产生来表达。激动性抗CD 40抗体已经被 作为促进患者APC成熟的有效方法提出;然而，它们具有毒性， 小活动。我们先前的研究提供了这种有限活性的可能解释，表明 抗体Fc与抑制性Fc受体Fc γ RIIB结合的绝对要求。利用这些知识，我们 Fc工程化的主要临床候选物2141-V11，其具有上级的抗肿瘤功效。此外，使用 原位接种方法，我们证明了有效的抗肿瘤活性，而没有毒性的证据。我们现在 研究CD 40在肿瘤微环境（TME）中的作用以及如何靶向治疗 膀胱癌这是因为目前膀胱内卡介苗形式的免疫疗法 (BCG)对大部分患有这种疾病的患者无效。我们的初步数据支持 CD 40在膀胱肿瘤中的作用以及被认为是抗PD-1疗法靶向的T细胞表型的逆转。 因此，CD 40抗体，单独或与“检查点阻断”组合，可以帮助改善治疗结果。 膀胱内BCG治疗无效的患者。我们的团队在学习方面积累了丰富的经验， 抗体治疗和获得独特的组织标本，我们现在的目标是测试假设，2141-V11将 靶向TME中的树突状细胞，以促进成功的抗肿瘤免疫。