Molecular mechanisms of antibody-mediated immunotherapies

抗体介导的免疫疗法的分子机制

• 批准号: 10684073
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 44.75万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684073
• 关键词: Advanced Malignant Neoplasm; Antibodies; Antibody Therapy; Biology; Clinical; Clinical Trials; Engineering; Funding; Generations; Goals; Immune response; Immunotherapeutic agent; Immunotherapy; Knowledge; Malignant Neoplasms; Mediating; Memory; Methods; Molecular; Monoclonal Antibodies; Pathway interactions; Pre-Clinical Model; Recurrence; Research; Testing; Therapeutic; Therapeutic Effect; Tumor Antibodies; Work; cancer therapy; cancer vaccination; immunoregulation; improved; long term memory; neoplasm immunotherapy; response; therapy development; tumor; tumor microenvironment

ABSTRACT Our studies over the past two decades have focused on clarifying the mechanisms by which anti-tumor immunotherapies elicit their therapeutic effects. As a result of our studies, the importance of Fc-FcγR mediated effector pathways for the elimination of tumors has been elucidated, resulting in the optimization of these interactions in second-generation anti-tumor immunotherapeutics with improved clinical activity. One of the therapies developed as part of our previously funded NCI studies is now being tested across three clinical trials with early evidence of promising activity. While strategies improving antibody-based therapeutics through Fc engineering have resulted in more effective anti-tumor antibodies (Abs) with significantly improved survival, the long-term goal of immunotherapy is to develop therapeutic strategies that will elicit memory responses and effectively eliminate recurrences, resulting in improvements in overall survival. This current proposal aims to mechanistically investigate general strategies to accomplish this goal by focusing on 1) inducing tumor vaccination using anti-tumor monoclonal Abs (mAbs), 2) define the mechanisms by which agonistic and antagonistic immunomodulatory mAbs enhance anti-tumor vaccination, and 3) explore how the tumor microenvironment may be manipulated to improve these immunotherapeutic strategies. Our preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-FcγR interactions are integrated into these Abs. Manipulating both the cellular effector responses and the tumor microenvironment through the use of Fc-optimized immunomodulatory Abs can further augment these pathways and result in long-term memory responses.

摘要

项目成果

Site-Selective Chemoenzymatic Modification on the Core Fucose of an Antibody Enhances Its Fcγ Receptor Affinity and ADCC Activity.

对抗体核心岩藻糖进行位点选择性化学酶修饰可增强其 Fcγ 受体亲和力和 ADCC 活性。

• DOI: 10.1021/jacs.1c03174
• 发表时间: 2021-05-26
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Li C;Chong G;Zong G;Knorr DA;Bournazos S;Aytenfisu AH;Henry GK;Ravetch JV;MacKerell AD Jr;Wang LX
• 通讯作者: Wang LX

Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect.

• DOI: 10.1016/j.cell.2015.04.016
• 发表时间: 2015-05-21
• 期刊: Cell
• 影响因子: 64.5
• 作者: DiLillo DJ;Ravetch JV
• 通讯作者: Ravetch JV

Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement.

• DOI: 10.1016/j.ccell.2016.05.001
• 发表时间: 2016-06-13
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Dahan R;Barnhart BC;Li F;Yamniuk AP;Korman AJ;Ravetch JV
• 通讯作者: Ravetch JV

Immunotherapy and Hyperprogression: Unwanted Outcomes, Unclear Mechanism.

• DOI: 10.1158/1078-0432.ccr-18-3144
• 发表时间: 2019-02-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Knorr DA;Ravetch JV
• 通讯作者: Ravetch JV