Molecular mechanisms of antibody-mediated immunotherapies

抗体介导的免疫疗法的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在过去的二十年中，我们的研究重点是阐明抗肿瘤的机制免疫疗法引起其治疗作用。由于我们的研究，FC-FCγR介导的重要性已经阐明了消除肿瘤的效应途径，从而优化了这些肿瘤第二代抗肿瘤免疫疗法的相互作用与临床活性的改善。中的一个作为我们先前资助的NCI研究的一部分而开发的疗法现在正在三个临床试验中进行测试早期证据表明活动活动。同时通过FC改善基于抗体的治疗的策略工程导致了更有效的抗肿瘤抗体（ABS），并显着提高了生存率，免疫疗法的长期目标是制定将引起记忆反应和的理论策略有效消除回报，从而改善了总体生存。目前的提议旨在通过专注于1）诱导肿瘤来研究一般策略以实现这一目标的一般策略使用抗肿瘤单克隆ABS（mAb）的疫苗接种，2）定义了激动和激动的机制拮抗性免疫调节mABS增强抗肿瘤疫苗接种，3）探索肿瘤如何可以操纵微环境以改善这些免疫治疗策略。我们的初步结果已经表明，抗肿瘤ABS会在适当的FC-FCγR时引起长期的细胞记忆反应相互作用被整合到这些ABS中。操纵细胞效应子的反应和肿瘤微环境通过使用FC优化的免疫调节性ABS可以进一步增加这些途径和导致长期记忆响应。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Knorr DA;Ravetch JV
通讯作者：
Ravetch JV