一种新型多模态PD-L1xVEGF-ADC HX116可能成为泛实体瘤的新型强效候选治疗药物

PD-L1 is an immune-checkpoint frequently over-expressed in many tumor cells as compared to normal tissues, while VEGF is an angiogenesis growth factor widely present within solid tumor microenvironment (TME). Therefore, both are also considered “tumor-associated antigen (TAA)” targetable by ADC modality, in addition to being druggable by mAbs against PD-L1-mAb (ICI) or VEGF that both are standard cancer treatments. Furthermore, multi-modal bispecific antibody (BsAb) simultaneously against PD-L1xVEGF has recently demonstrated impressive therapeutic benefit against different cancers in clinics, superior to single modal treatments or their combo treatments. It is therefore reasonable to hypothesize that a PD-L1xVEGF BsAb-ADC, HX116, with additional modalities of TOPO-I inhibitor, could become an even more powerful next-generation treatment of cancers than the naked BsAb. We thus tested HX116 for its anti-tumor activity in preclinical settings, in parallel to naked antibodies of HX116-and those against VEGF and PD-L1, respectively, so enabling assessing the roles of each modality of HX116. First, although the naked HX116 BsAb specifically binds to several PD-L1 + tumor cells with high affinity, it exhibited poor internalization in PD-L1 + cells. As a result, HX116 showed poor cytotoxicity in these cells as compared to SGN-PDL1V, a PD-L1-MMAE-ADC that is internalized efficiently. In contrast, HX116 demonstrated as robust cytotoxicity as much as, if not more, as SGN-PDL1V in these two PD-L1 + 3D-tumor organoids in vitro , contrasting to the very poor cytotoxicity induction seen in the 2D-cell culture. It also showed robust anti-tumor activity in multiple PD-L1 + human tumor xenograft models in vivo , including the ones with poor in vitro cytoxicity induction, and also superior to the naked BsAb, confirming the contributions of the additive ADC modality. Secondly, the parallel VEGF-mAb and naked HX116 BsAb in the same xenografts also demonstrated equal and robust tumor responses, suggesting the contribution of anti-angiogenesis modality. Thirdly, the pharmacology evaluation in human PBMC humanized xenograft model is currently ongoing, its superior activity over naked HX116 BsAb and PD-L1mAb would confirm its ICI contribution to the anti-tumor activity. Considering that the clinical dose for the similar PD-L1xVEGF BsAb needs to be high as 20~30 mg/kg to fully deploy their immune-checkpoint and anti-angiogenesis modalities in human, we have specifically selected a payload with moderate-potency as well as an optimal DAR value that will be tolerated in such high clinical doses. The high safety and tolerability of HX116 will also be confirmed in NHP model. If all are confirmed, HX116 would become a powerful new candidate for future cancer treatment. Reference: A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology. PLoS One, 2023. 18(1): p. e0279821.