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Background Immunotherapies targeting programmed cell death protein-1 (PD-1) and its ligand (PD-L1) are standard treatments in an ever-growing list of indications. However, limited patient response rates have driven the development of next-generation therapies such as those that pair PD-1/PD-L1 inhibitors with anti-angiogenic agents (anti-VEGF-A antibodies or tyrosine kinase inhibitors, TKIs). These types of combinations are established first-line treatments in non-small cell lung cancer, cervical cancer, advanced renal cell carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The simultaneous targeting of VEGF-A and PD-1 in a single molecule could conceivably reduce the complexity of combination treatment regimens by potentially concentrating PD-1 blockade at VEGF-rich, immunosuppressed tumor sites. It may also offer improved safety over VEGF TKI-containing combination regimens. To achieve this, Compass Therapeutics is developing a novel, bispecific, tetravalent antibody that concurrently targets VEGF-A and PD-1. CTX-10726 incorporates an anti-VEGF-A IgG1 with Fc-silencing LALA mutations fused to anti-PD-1 single-chain variable fragments (scFvs) via a flexible linker.Methods Binding of CTX-10726 to PD-1 (human, mouse, and cynomolgus macaque) and FcγRs was assessed by biolayer interferometry (BLI) using purified proteins and by flow cytometry (FACS) in primary and target-expressing cell lines. Immunomodulatory functions in vitro were measured by interferon-gamma (IFN-γ) release in a two-way mixed lymphocyte reaction (MLR) and in vitro cytotoxicity assays with activated PBMCs. In vivo anti-tumor efficacy was tested in PBMC-humanized xenograft models or in double hPD-1/hPD-L1 transgenic mice implanted with tumor cells and treated with CTX-10726 or control antibodies. Models were selected to assess the relative contribution of the VEGF and PD-1 targeting arms.Results CTX-10726 showed high-affinity binding to both human and cynomolgus monkey VEGF-A and PD-1, with no significant binding to murine PD-1, thus justifying the use of non-human primates to evaluate its toxicity. CTX-10726 effectively blocked VEGF-A/VEGFR2 and PD-1/PD-L1 interactions in a dose-dependent manner and showed reduced engagement with Fcγ receptors, limiting off-target immune activation. Functionally, it significantly enhanced IFN-γ production in MLRs and tumor cell killing by activated PBMCs. In vivo, CTX-10726 outperformed benchmark biosimilar anti-VEGF or PD-1 antibodies in controlling tumor growth across multiple xenograft and syngeneic models.Conclusions CTX-10726 is a potent bispecific antibody that simultaneously inhibits tumor angiogenesis and PD-1-mediated immune suppression and eliminates tumors in preclinical mouse models. CTX-10726 is currently undergoing IND-enabling studies to determine the optimal starting dose for first-in-human trials.