20 PF-08634404 (SSGJ-707), a Tetravalent PD-1/VEGF Bispecific Antibody for the Treatment of Renal Cell Carcinoma (NCT07227415)

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Abstract Background Renal cell carcinoma (RCC) is characterized by an immunogenic tumor microenvironment and frequent activation of angiogenic pathways. Therefore, combining immune checkpoint blockade with VEGF pathway inhibition is a rational therapeutic approach. PF‑08634404 is an investigational anti–PD‑1 and anti‑VEGF bispecific antibody that effectively binds both targets. PF‑08634404 uses a tetravalent (2 + 2) structure that enables binding cooperativity between PD-1 and VEGF-A, increasing the avidity for and functional inhibition of PD-1 and resulting in enhanced target engagement. This enhancement differentiates PF‑08634404 from combinations of separate PD‑1 and VEGF inhibitors. PF‑08634404 has shown promising clinical activity in patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC), with no dose-limiting toxicities observed up to 45 mg/kg Q3W, highlighting the wide therapeutic margin. Here, we present preclinical data demonstrating high-affinity binding to and functional inhibition of both PD‑1 and VEGF‑A by PF‑08634404, including evidence of VEGF‑mediated cooperative binding. Methods Assays include: 1) flow cytometry to measure binding affinity on PD-1–expressing cells; 2) size exclusion chromatography to measure PF-08634404/VEGF-A multimerization; 3) flow cytometry using pH dye to assess internalization of cell surface PD-1/PF-08634404 complexes; 4) reporter cell assay to determine PD-1 signal blockade; 5) surface plasmon resonance (SPR) to measure affinity for soluble VEGF-A; and 6) in vitro proliferation assays to examine inhibition of VEGF-induced proliferation. Results PF‑08634404 binds PD‑1 and VEGF‑A with sub‑nanomolar affinity and can engage both targets simultaneously. Its affinity for soluble VEGF‑A is approximately 30-fold and 60-fold higher than that of ivonescimab and bevacizumab, respectively, resulting in deeper and more potent VEGF inhibition in vitro. Consistent with the bispecific mechanism, PF‑08634404 multimerizes in the presence of VEGF‑A, increasing avidity for PD‑1 (>100-fold), promoting rapid internalization of PD‑1, and enhancing functional PD‑1 inhibition (>10-fold). Conclusions Collectively, these encouraging preclinical data that define the core mechanistic features of PF‑08634404, the preliminary safety and antitumor activity, and the importance of targeting PD-(L)1 and VEGF support the investigation of PF‑08634404 in pivotal trials across multiple tumor types, including RCC. A phase 1b/2 study (Symbiotic-GU-08) in patients with newly diagnosed advanced or metastatic RCC is being conducted to evaluate the efficacy and safety of PF‑08634404, either as monotherapy or in combination with ipilimumab (anti–CTLA‑4) or axitinib (VEGF tyrosine kinase inhibitor) (NCT07227415). Symbiotic-GU-08 enables a novel “tripartite” approach to frontline treatment of RCC through combination therapy. PD‑1 blockade in combination with ipilimumab-mediated CTLA‑4 inhibition produces complementary immune activation. Adding PF‑08634404’s VEGF neutralization to a PD‑1/CTLA‑4 backbone would be expected to further enhance the immune response by reducing VEGF-driven immunosuppression and abnormal vasculature and by improving T‑cell infiltration and function. PF‑08634404 in combination with axitinib, a potent VEGFR1–3 tyrosine kinase inhibitor, creates dual VEGF-pathway blockade on top of PD‑1 inhibition. This strategy could more thoroughly shut down tumor angiogenesis, in addition to leveraging the immunomodulatory effects of axitinib that may further complement PD‑1 blockade. PF‑08634404 has demonstrated clinical proof of concept in other cancers. Together, these data provide a strong scientific rationale to evaluate PF‑08634404, alone or in combination regimens, in alignment with established effective RCC treatment paradigms. Previously presented in part at the 2026 AACR Annual Meeting.