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: 10249062
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10249062
• 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; antibody test; 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; 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.

项目摘要/摘要 候选人：PI是洛克菲勒大学临床调查的讲师，已经开发了5年 职业发展计划基于他的免疫学和医学临床培训的科学背景 肿瘤学。他的导师杰弗里·拉维奇（Jeffrey Ravetch）博士是FC受体的国际知名专家。 Pi具有 战略性计划解决其成功职业所需的必要培训和心理 通过精选课程和强大的心理计划过渡到独立性。咨询委员会 由该领域的领导者组成的不仅会确保PI的研究项目按计划进行，而且还可以确保 也可以通过晋升来认可，并导致独立的研究资金。这个令人兴奋的研究项目是 也与他的心理差异很大，以避免竞争或重叠。 研究计划：免疫疗法的最新成功重新激发了人们对利用患者的兴趣 自己针对癌症的免疫系统。虽然阻止PD-1的疗法提高了 膀胱癌患者，许多患者没有获得临床益处。我的研究重点是 优化靶向CD40的免疫刺激剂。 CD40在抗原激活中起关键作用 呈现细胞（APC）和特异性T细胞的产生。激动抗CD40抗体已经 提议作为促进患者APC成熟的有效方法；但是，它们有毒 很少的活动。我们先前的研究证明了这项有限活动的可能解释 绝对要求抗体FC与抑制性FC受体FCRIIB结合。使用这些知识，我们 FC工程铅临床候选者，2141-V11，具有较高的抗肿瘤有效性。另外，使用 原位疫苗接种方法我们证明了没有毒性证据的有效抗肿瘤活性。我们现在 研究肿瘤微环境（TME）中CD40的作用以及如何针对治疗 膀胱癌。这是因为目前的免疫疗法以静脉片状状态杆菌的形式 （BCG）对于受此疾病影响的大部分患者无效。我们的初步数据支持 CD40在膀胱肿瘤中的作用和T细胞表型的逆转，被认为是抗PD-1疗法针对的。 这是单独或与“检查点封锁”组合的CD40抗体，可以帮助改善结果 对静脉内BCG治疗的患者不反应。基于我们的团体学习丰富的学习经验 抗体疗法并获得独特的组织标本，我们现在旨在测试2141-V11将会的假设 靶向TME中的树突状细胞，以促进成功的抗肿瘤免疫。