PD-1, a critical immune checkpoint receptor on T cells, is frequently exploited by tumors to evade immune surveillance. While PD-1 inhibitors have revolutionized cancer therapy by reactivating exhausted T cells, treatment responses remain limited for many patients. The immunosuppressive tumor microenvironment (TME), along with resistance mechanisms, continues to pose significant barriers to treatment efficacy (Jiang, Li, and Zhu, 2015) (Chen and Mellman, 2017).

VEGF, a key pro-angiogenic and immunosuppressive factor, contributes to tumor growth and immune evasion through multiple mechanisms:

• Stimulating angiogenesis to enhance nutrient and oxygen delivery to tumors

• Increasing vascular permeability to promote tumor cell invasion and metastasis

• Supporting tumor cell survival and proliferation through VEGF receptor signaling

• Inhibiting T cell function to weaken antitumor immune responses

• Promoting the accumulation of Tregs and MDSCs to suppress immune activity

• Suppressing dendritic cell maturation and antigen presentation

Anti-VEGF therapies (Hegde, Wallin, and Mancao, 2018) counteract these effects. When combined with PD-1 blockade, this dual approach has shown synergistic benefits, enhancing T cell infiltration and restoring antitumor immunity—a true "1+1>2" outcome (Zhong et al., 2025). 

In September 2024, Summit Therapeutics and Akeso Biopharma announced encouraging Phase III HARMONi-2 trial results for AK112 (ivonescimab), a PD-1/VEGF bispecific antibody. In PD-L1–positive, treatment-naïve non-small cell lung cancer (NSCLC) patients, AK112 reduced the risk of disease progression by 49% compared to Keytruda® (pembrolizumab)—highlighting the strong clinical potential of dual PD-1 and VEGF pathway inhibition in cancer immunotherapy.

Another strong player, BNT327 (PM8002) from BioNTech / Biotheus, has shown promising results in clinical trials as well. In a Phase Ib/II study involving patients with locally advanced or metastatic triple-negative breast cancer (TNBC), BNT327 combined with nab-paclitaxel achieved a median progression-free survival of 13.3 months and an objective response rate of 73.8%, regardless of PD-L1 status.

To support the preclinical development of VEGF-targeted bispecifics and combination therapies, Biocytogen offers a robust portfolio of dual- and multi-targeted humanized mouse models for the immune checkpoint and VEGF pathways. These models enable preclinical efficacy and safety evaluations, generating high-quality data to accelerate clinical translation.

In vivo evaluation of an anti-human VEGFA antibody (bevacizumab) demonstrates its efficacy in inhibiting tumor growth and angiogenesis in B-hVEGFA mice

(A) Anti-human VEGFA antibody bevacizumab inhibited tumor growth in B-hVEGFA mice implanted with B-hVEGFA MC38 colon cancer cells. Treatment began when tumors reached ~100 mm³. (B) Body weight changes during treatment. (C) CD31⁺ area in tumor tissue. Bevacizumab reduced tumor growth and vascularization, validating B-hVEGFA mice as a preclinical model for anti-VEGFA therapy. Mean ± SEM.

In vivo evaluation of the anti-human VEGFR2 antibody (Ramucirumab) demonstrates its efficacy in suppressing tumor growth and angiogenesis in B-hVEGFR2 mice

(A) In-house Ramucirumab inhibited MC38 tumor growth in B-hVEGFR2 mice subcutaneously implanted with MC38 cells. Treatment began at ~100 mm³ tumor volume per schedule in panel A. (B) Body weight during treatment. (C) CD31⁺ area in tumor tissue. Ramucirumab (in house) reduced tumor growth and vascularization, supporting B-hVEGFR2 mice as a preclinical model for anti-human VEGFR2 therapy. Mean ± SEM.

In vivo evaluation of an anti-PD-1/VEGFA bispecific antibody demonstrates its efficacy in inhibiting tumor growth in B-hPD-1/hPD-L1/hVEGFA mice

(A) B-hVEGFA MC38 cells were implanted into B-hPD-1/hPD-L1/hVEGFA mice. When tumors reached ~70–90 mm³, mice received intraperitoneal injections of an in-house anti-PD-1/VEGFA bispecific antibody (ivonescimab analog), which significantly reduced tumor growth. (B) Body weight changes during treatment.

Contact us today to explore how Biocytogen’s humanized PD1/VEGF models can advance your drug development pipeline!

Reference

Jiang, Y., Y. Li, and B. Zhu. "T-cell exhaustion in the tumor microenvironment." Cell death & disease 6.6 (2015): e1792-e1792.

Chen, Daniel S., and Ira Mellman. "Elements of cancer immunity and the cancer–immune set point." Nature 541.7637 (2017): 321-330.

Hegde, Priti S., Jeffrey J. Wallin, and Christoph Mancao. "Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics." Seminars in cancer biology. Vol. 52. Academic Press, 2018.
Zhong, Tingting, et al. "Design of a fragment crystallizable-engineered tetravalent bispecific antibody targeting programmed cell death-1 and vascular endothelial growth factor with cooperative biological effects." iScience 28.3 (2025).