Abstract 6061: Dual PD-L1 blockade and VEGF-A neutralization with the bispecific antibody BNT327/PM8002 shows potent antitumor activity in preclinical models
Authors: Xiaoniu Miao, Yifeng Xu, Shaogang Peng, Weifeng Huang, Junying Chen, Maren Köhne, Andrea Imle, Alexander Muik, Özlem Türeci, Ugur Sahin, Andy Tsun, Yi Luo
Journal: Cancer Research (2025)

Abstract The combined blockade of the PD-1/PD-L1 checkpoint and VEGF-A driven angiogenesis has been shown to reduce immune suppression in the tumor microenvironment, to enhance antitumor immune responses, and exhibit improved antitumor activity compared to each individual treatment. BNT327 (also known as PM8002) is an investigational bispecific antibody (bsAb) composed of a bivalent Fc-silenced anti-VEGF-A IgG1 antibody fused at its C-terminus to two humanized anti-PD-L1 single-domain VHH antibodies. By simultaneously targeting PD-L1 and VEGF-A, BNT327 is designed to combine the two complementary functions of amplifying pre-existing immune responses and anti-angiogenesis. Here, we report preclinical studies characterizing the functional activity of BNT327 in vitro and antitumor activity in vivo. BNT327 bound with high affinity (i.e., nanomolar or subnanomolar KD) to recombinant human PD-L1 and VEGF-A, as shown by biolayer interferometry. In cell-based bioluminescent reporter assays, BNT327 inhibited PD-L1/PD-1 signaling and VEGF-A/VEGFR2 signaling with subnanomolar EC50 values. In mixed lymphocyte reaction assays using human PBMCs and allogeneic monocyte-derived dendritic cells, BNT327 and the parental anti-PD-L1 VHH dose-dependently increased IL-2 and IFN-γ secretion. Furthermore, BNT327 dose-dependently enhanced CD8+ T-cell mediated tumor-cell killing in an antigen-specific cytotoxicity assay in vitro, with the effects being comparable to those of PD-L1 blockade by atezolizumab. In vivo, a BNT327 surrogate bsAb targeting human PD-L1 and mouse VEGF-A exhibited dose-dependent antitumor activity in human PD-L1 knock-in mice bearing syngeneic human PD-L1-expressing CT26 tumors. Tumor growth inhibition was superior to individual treatments with PD-L1 blockade (parental anti-PD-L1 or atezolizumab) or with anti-VEGF-A. Furthermore, BNT327 showed antitumor activity in several xenograft models, including A375 melanoma cells, NCI-H1975 lung carcinoma cells, LoVo colon carcinoma cells, and MDA-MB-231 breast carcinoma cells. Antitumor activity was dose-dependent where tested, and superior to single PD-1 (pembrolizumab) or PD-L1 (atezolizumab) checkpoint inhibitor treatment. In conclusion, BNT327 inhibits PD-1/PD-L1 signaling and VEGF-A/VEGFR2 signaling in vitro and shows potent antitumor activity in vivo both in syngeneic and xenograft models. The safety and efficacy of BNT327 as a monotherapy or in combination is being investigated in multiple clinical trials in patients with solid tumors, including Phase II and Phase III trials investigating the combination with chemotherapeutic agents in triple-negative breast cancer and lung cancer. Citation Format: Xiaoniu Miao, Yifeng Xu, Shaogang Peng, Weifeng Huang, Junying Chen, Maren Köhne, Andrea Imle, Alexander Muik, Özlem Türeci, Ugur Sahin, Andy Tsun, Yi Luo. Dual PD-L1 blockade and VEGF-A neutralization with the bispecific antibody BNT327/PM8002 shows potent antitumor activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6061.