學術報告 

題   目：New mechanisms for proper bispecific fusion proteins: targeting tumor cells or immune cells 

報告人: Yang-Xin Fu MD., Ph.D.

Endowed Professor, Tsinghua University

時    間: 10月6日（周四）13:00-14:00

地    點: 鄧佑才報告廳（金光101）

主持人: 曾澤賢 研究員

摘 要:

Many bispecific antibodies have been widely tested but most fail in clinical trials. Here we provide two examples to show next generation of bispecific antibodies. Bispecific T-cell engagers (BiTEs) that preferentially target tumor-associated antigens to reengage CD3 signaling mainly control residual leukemia but not effective for solid tumors hampered by short half-life and severe toxicity at therapeutic doses. To address this, we designed a bispecific antibody (BsAb) which simultaneously targets CD3 and immune checkpoint PD-L1. Compared with conventional tumor cell targeting BsAb, PD-L1xCD3 generates superior anti-tumor immune responses in vivo. Mechanistically, blockade of PD-L1 on dendritic cells but not tumor cells rejuvenates pre-existing CD8 T cells in a B7-1/2 dependent manner for a durable antigen specific T cell response. This study raises a novel model of DC-T cell instead of tumor-T cell engagement for better T cell rejuvenation in BsAb therapy.

Blockade of CD47, the “don’t eat me” signal, has limited effects in solid tumors despite its potent anti-tumor effects in hematopoietic malignancies. Taking advantage of the high expression of CTLA-4 on Treg cells and abundant Fc receptor-expressing active phagocytes inside the tumor microenvironment (TME), we designed and tested a heterodimer combining an anti-CTLA-4 antibody, which targets Treg cells, with the CD47 ligand, signal regulatory protein α (SIRPα), to selectively block CD47 on intratumoral Treg cells.  Mechanistically, anti-CTLA-4×SIRPα preferentially depleted ICOShigh immunosuppressive Treg cells in the TME we discovered that CD47 expression on Treg cells limited anti-CTLA-4 mediated depletion and Fc on the heterodimer enhanced depletion., these results demonstrate that simultaneously modulating both “eat me” and “don’t eat me” signals induces Treg cell depletion inside the TME and may be an effective strategy for treating solid tumors.

報告人簡介：

傅陽心教授于1990年獲得美國邁阿密大學醫學微生物學和免疫學博士學位。1994-1998年任華盛頓大學住院醫師，1998-2005年任哥大學助理教授、病理系主治醫師及免疫委員會成員。2005年晉升芝加哥大學終身教授，随後榮獲冠名教授。2015年任德州大學醫學中心病理系冠名教授。2021全職年回清華大學任教，現任清華大學醫學院講席教授。

傅陽心教授在臨床和基礎醫學研究領域都具有重大創新，現已在Science，Nature，Nature Medicine等領域内頂尖學術刊物發表260多篇高水平的學術研究論文，文章被引用次數超過45000餘次，H-index 104，入選高被引科學家，成為少數同時在醫學和基礎科研領域都取得突出成績的醫生和科學家。他在腫瘤免疫學領域内尤其具有很高的聲望和影響力，是藥物、放療和靶向治療對免疫細胞及分子機制研究的開拓者。近年來，他主持開發了新一代雙特異性抗體、融合蛋白、細胞因子前藥和抗體前藥用于腫瘤免疫治療，研究靶向藥物、局部輻射、腫瘤靶向抗體對腫瘤微環境，免疫系統的調控機制，發展免疫協同治療新策略，很多已應用于不同階段的臨床試驗，展現出了極大的應用前景和價值。