2022.10.06 New mechanisms for proper bispecific fusion proteins: targeting tumor cells or immune cells

2022-10-05 18:29:22



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

报告人:  Yang-Xin Fu MD., Ph.D.

Endowed Professor, Tsinghua University



主持人: 曾泽贤 研究员


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.



傅阳心教授在临床和基础医学研究领域都具有重大创新,现已在ScienceNatureNature Medicine等领域内顶尖学术刊物发表260多篇高水平的学术研究论文,文章被引用次数超过45000余次,H-index 104,入选高被引科学家,成为少数同时在医学和基础科研领域都取得突出成绩的医生和科学家。他在肿瘤免疫学领域内尤其具有很高的声望和影响力,是药物、放疗和靶向治疗对免疫细胞及分子机制研究的开拓者。近年来,他主持开发了新一代双特异性抗体、融合蛋白、细胞因子前药和抗体前药用于肿瘤免疫治疗,研究靶向药物、局部辐射、肿瘤靶向抗体对肿瘤微环境,免疫系统的调控机制,发展免疫协同治疗新策略,很多已应用于不同阶段的临床试验,展现出了极大的应用前景和价值。