用于全面评估T细胞接合器的集成临床前平台

T-cell engagers (TCEs) are bispecific antibodies designed to bind both CD3 on T cells and a tumor-associated antigen (TAA) on cancer cells, representing a promising class of immunotherapies. Given their complex mechanisms of action, physiologically relevant preclinical models are essential for accurately evaluating the efficacy and safety profiles of TCE candidates. We developed a panel of medium- to high-throughput in vitro assays to screen TCEs based on target binding, T-cell activation, and tumor cell killing capabilities. Lead candidates were further assessed using in vivo efficacy studies in both xenograft and syngeneic models. In xenograft studies, we utilized NCG mice and NCG-MHC-dKO mice-the latter generated by deleting murine MHC class I and II genes in the NCG background-to reduce graft-versus-host disease (GvHD) after human PBMC engraftment and extend the experimental observation period. AMG509 (targeting STEAP1), AMG757 (targeting DLL3), and IBI-389 (targeting CLDN18.2) were evaluated in models of prostate cancer, small-cell lung cancer, and patient-derived xenografts (PDX), respectively. For syngeneic studies, we used BALB/c-hCD3EDG mice, in which endogenous Cd3e, Cd3d, and Cd3g genes were replaced with human versions. These mice were engrafted with A20-hCD20 lymphoma cells to test a CD3/CD20 bispecific antibody. Both AMG509 and AMG757 significantly suppressed tumor growth in PBMC-humanized NCG and NCG-MHC-dKO models, with no major adverse effects on animal health. The efficacy of AMG509 varied across prostate cancer cell lines with different levels of STEAP1 expression. In NCI-H69 tumor-bearing mice treated with AMG757, the degree of tumor response correlated with the extent of human immune cell reconstitution observed three weeks post-treatment. IBI-389 exhibited marked tumor growth inhibition in two gastric cancer PDX models and one pancreatic cancer PDX model. In the BALB/c-hCD3EDG syngeneic model, administration of the CD3/CD20 bispecific antibody led to 81.5% tumor growth inhibition after 18 days. GemPharmatech's integrated strategy-combining in vitro screening with a range of in vivo models such as NCG, NCG-MHC-dKO, and CD3-humanized mice-enables rapid, scalable, and translationally relevant assessment of T-cell engager candidates. This comprehensive platform supports robust and efficient immuno-oncology drug discovery and development.