双特异性抗体
癌症治疗
受体
癌症研究
嵌合抗原受体
医学
癌症
免疫疗法
免疫学
内科学
单克隆抗体
抗体
作者
Stanley R. Riddell,Sylvain Simon,Grace Bugos,Rachel Prins,Anusha Rajan,Anandan Palani,Kersten Heyer,Anthony C. Stevens,Longhui Zeng,Kirsten Thompson,Jason P. Price,Mitchell G. Kluesner,Carla A. Jaeger-Ruckstuhl,Tamer B. Shabaneh,James M. Olson,Xiaolei Su
出处
期刊:Research Square - Research Square
日期:2024-04-22
标识
DOI:10.21203/rs.3.rs-4253777/v1
摘要
Abstract The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.
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