ALX006, a PD-1/VEGF bispecific antibody with best-in-class potential demonstrates superior antitumor activity and favorable PK in preclinical models

Background: PD-1 and VEGF are frequently co-expressed in the tumor microenvironment. PD-1 blockade reverses tumor-induced immunosuppression, while VEGF inhibition normalizes tumor vasculature and modulates immune cell infiltration. Clinical data from bispecific antibodies, such as Ivonescimab, particularly in advanced non-small cell lung cancer, support the synergistic potential of anti-PD-1 and anti-VEGF therapies to enhance efficacy and reduce systemic toxicity. Here we developed a novel PD-1/VEGF bispecific antibody ALX006 with thoroughly preclinical characterization. Methods: Binding affinities of ALX006 to PD-1 and VEGF were quantified by surface plasmon resonance (SPR). PD-1/PD-L1 pathway blockade was assessed using a luciferase reporter assay. T-cell reactivation was evaluated by mixed lymphocyte reaction assays. Antitumor activity was tested in A375 cell-derived xenograft (CDX) model in PBMC humanized mice and MC38 syngeneic model in human PD-1/PD-L1/VEGF transgenic mice. Biophysical liabilities and developability were profiled. Pharmacokinetics (PK) were evaluated in Sprague-Dawley rats and cynomolgus macaques. Results: ALX006 is a 2+2 symmetric IgG1 (Fc-null) bispecific antibody that binds to both targets with high affinity. In the presence of VEGF, ALX006 significantly enhanced PD-1 cell binding and PD-1/PD-L1 signal blockade. ALX006 also increased IL-2 and IFN-gamma secretion in a dose-dependent manner in mixed lymphocyte reaction. In addition, ALX006 potently suppressed VEGF-induced endothelial cell proliferation. Importantly, superior antitumor efficacy was observed in the A375 CDX model compared with Ivonescimab and two other clinical-stage bispecifics. Consistent activity was also observed in the MC38 syngeneic tumor model in transgenic mice. ALX006 exhibited favorable biophysical properties and overall developability, with an improved PK profile compared with Ivonescimab. Conclusions: ALX006, a PD-1/VEGF bispecific antibody with best-in-class potential, demonstrates superior antitumor activity and favorable PK in preclinical models, supporting its potential as a therapeutic candidate for immuno-oncology applications.