PF-08634404（SSGJ-707）——一种用于癌症治疗的四价PD-1 x VEGF双特异性抗体的表征与功能评价

PF-08634404 (formerly known as SSGJ-707) is an investigational anti-PD-1 and anti-VEGF bispecific antibody designed to simultaneously inhibit PD-1-mediated T cell dysfunction and VEGF-A-mediated tumor angiogenesis and immune suppression in the tumor microenvironment. PF-08634404 is a tetravalent 2+2 bispecific leveraging Common Light Chain Linear Fab x2 (CLF 2 ) technology with an IgG4 backbone. The PD-1 and VEGF-A binding arms of PF-08634404 are unique among the PD-1 x VEGF bispecific class. PF-08634404 has demonstrated promising clinical activity in NSCLC and CRC in clinical trials conducted in China. Here we present preclinical data demonstrating binding to and functional inhibition of PD-1 and VEGF-A by PF-08634404 in vitro. PF-08634404 displays nanomolar binding affinities for PD-1 and VEGF-A and can bind both targets simultaneously. The functional inhibition of VEGF by PF-08634404 is increased (~7.5-fold) compared to relevant benchmarks, and the inhibition of PD-1 is equivalent or superior to relevant benchmarks. Consistent with this class of bispecific molecules, PF-08634400 multimerizes in the presence of dimeric VEGF-A, increasing the avidity for PD-1 (>100-fold), driving rapid internalization of PD-1 on T cells, and improving the functional inhibition of PD-1 (>10-fold). Collectively, these data characterize core features of the bispecific mechanism and support the ongoing clinical investigation of PF-08634404 proof of concept and pivotal trials in multiple disease settings/tumor types.