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.

项目摘要/摘要 候选人：PI是洛克菲勒大学临床投资的讲师，已经开发了5年 职业发展计划基于他在免疫学和医学方面的科学背景的基础 Pi具有。 战略性计划解决其成功职业所需的必要培训和指导 通过精选课程和强大的指导计划过渡到独立 由该领域的领导人组成的人将不会确保PI的研究按计划进行评估，但是 晋升也得到了认可，并带来独立的研究资金。 为了避免竞争或重叠，也与导师的合同不同。 研究计划：免疫疗法的休息已重新激发了对利用患者的兴趣 自身对癌症的免疫系统。 膀胱癌的患者没有获得临床益处。 优化靶向CD40的免疫刺激剂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。 作为促进患者APC成熟的有效方法的支撑； 我们先前的研究表明 对吸入性FC受体FCRIIB的抗体FC的绝对需求。 FC工程铅临床候选者，2141-V11，其抗肿瘤功效具有优势 原位疫苗接种方法我们证明了有效的抗肿瘤活性，而我们现在是托克斯城的证据 研究肿瘤微环境（TME）中CD40的作用以及如何针对治疗 膀胱癌。 （BCG）对于受此疾病影响的大部分患者无效。 CD40在膀胱肿瘤中的作用和抗PD-1疗法靶向的T细胞表型的逆转。 因此，CD40抗体，单独或与“检查点封锁”结合使用，可以帮助改善预后 对静脉内BCG疗法的反应不足。 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。

项目成果

COVID-19 vaccine efficacy in patients with chronic lymphocytic leukemia.

• DOI: 10.1038/s41375-021-01270-w
• 发表时间: 2021-09
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Roeker LE;Knorr DA;Thompson MC;Nivar M;Lebowitz S;Peters N;Deonarine I Jr;Momotaj S;Sharan S;Chanlatte V;Hampton B;Butala L;Amato L;Richford A;Lunkenheimer J;Battiato K;Laudati C;Mato AR
• 通讯作者: Mato AR