HX009，一种新型双特异性抗体 (BsAb)，同时靶向 PD1 和 CD47，证明在临床前模型中具有强大的抗淋巴瘤活性。
HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models.
发表日期：2023 Apr 03
作者：
Hang Ke, Faming Zhang, Jingjing Wang, Lingxin Xiong, Xiaoyu An, Xiaolong Tu, Cen Chen, Yueying Wang, Binchen Mao, Sheng Guo, Cunxiang Ju, Xiangfei He, Ruilin Sun, Lei Zhang, Owen A O'Connor, Qi-Xiang Li
来源：
GENES & DEVELOPMENT
摘要：
PD1/PD-L1和CD47阻遏剂已经证明在大多数非霍奇金淋巴瘤亚型中只具有有限活性，除了NK/T细胞淋巴瘤。临床上，抗CD47剂的血液毒性被认为是它们局限性的原因。在这里我们描述了一种首创、合理设计的双特异性抗体（BsAb）HX009，它靶向PD1和CD47，但CD47结合被削弱，通过PD1相互作用选择性地瞄准肿瘤微环境，从而有可能减少毒性。体外表征确认：（1）受体结合/配体阻遏，降低CD47亲和力；（2）通过报告检测方法检测功能性PD1/CD47阻遏；（3）在经过葡萄球菌热毒素B预处理的PBMC和混合淋巴细胞反应中T细胞激活。体内模型证明在Raji-B和Karpass-229-T移植淋巴瘤中具有抗肿瘤活性。在人源化小鼠同基因A20B淋巴瘤（huCD47-A20）HuGEMM模型中，该模型具有四重knock-in hPD1xhPD-L1xhCD47xhSIRPα基因和完整的自主免疫系统，HX008靶向PD1和SIRPα-Fc靶向CD47的每种靶向生物贡献了一定的效果，HX009的双重靶向进一步增强了效果。最后，在淋巴瘤源性异种移植物系列中，免疫检查点PD-L1/L2和CD47的表达似乎是共调节的，HX009在CD47上调节的情况下可能更有效。我们的数据支持HX009在治疗非霍奇金淋巴瘤方面的进一步临床开发。 ©2023. 作者。
Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009's further clinical development for treating NHLs.© 2023. The Author(s).