PD-1 X VEGF
OVERVIEW
- Programmed death protein 1 (PD-1) is a type 1 cell surface receptor expressed by activated CD4+ and CD8+ T cells, natural killer (NK) T cells, and antigen-presenting cells (APCs).1,2 The PD-1 receptor has two ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2), which are mainly expressed on APCs. Receptor/ligand interactions maintain immune homeostasis by reducing T-cell priming and inhibiting effector T-cell proliferation and function while increasing immunosuppressive regulatory T cell (Treg) function.1,3,4
- Vascular endothelial growth factor (VEGF) is a family of secreted glycoproteins required for blood vessel growth and development. VEGF binds VEGF tyrosine kinase receptors expressed on endothelial cells leading to dimerization and autophosphorylation. Signaling through PLCγ, PI3K, and RAS pathways lead to endothelial cell survival, proliferation, permeability, and migration.5
IMPLICATIONS IN CANCER
- Appropriation of the PD-L1/PD-1 pathway can be one mechanism by which the tumor evades immunosurveillance.7
Chronic exposure to tumor antigen steadily increases the expression level of PD-1 and the persistent expression of PD-1 on T cells induces T-cell exhaustion and loss of effector functions, such as proliferation, cytotoxicity, and survival.1
In non-cell small lung cancer, PD-1/PD-L1-inhibiting therapies show more benefit in smokers versus non-smokers; however, evidence suggests that the higher ORR is likely due to the higher tumor mutational burden (TMB) associated with the smoking population.8
Up to 60% of patients across different tumor types display primary resistance to anti-PD-1/PD-L1 agents. To overcome resistance, many ongoing clinical trials are evaluating combination strategies with other immunotherapies, targeted agents, chemotherapy and radiotherapy.9
Activation of PLCγ, PI3K, and RAS pathways by VEGF promote endothelial cell survival, proliferation, permeability, and migration, ultimately leading to angiogenesis.9
VEGF activation leads to immunomodulation of the tumor microenvironment (TME) through stimulation and recruitment of regulatory T cells (Tregs) and differentiation of tumor associated macrophages (TAMs).10
- PD1 x VEGF bsAbs allow for immune checkpoint inhibition while simultaneously inhibiting tumor‑driven angiogenesis.6
- Ohaegbulam KC, et al. Trends Mol Med. 2015;21(1):24-33.
- Gao J, et al. Trends Immunol. 2013;34(2):90-98.
- Freeman GJ, et al. J Exp Med. 2000;192(7):1027-1034.
- Latchman Y, et al. Nat Immunol. 2001;2(3):261-268.
- Nieves BJ, et al. Biofactors. 2009 Jul-Aug;35(4):332-7.
- AbbVie and RemeGen Announce Exclusive Licensing Agreement to Develop A Novel Bispecific Antibody for Advanced Solid Tumors - Jan 12, 2026.
- Hanahan D, Weinberg RA. Cell. 2011;144(5):646-674.
- Califano R, et al. Future Oncol. 2018;14(23):2415–2431.
- Oliva M, et al. Annals of Oncology. 2019;30:57–67.
- Zhao Y, et al. . Int J Biol Sci. 2022 May 29;18(9):3845-3858.
