The CD47/SIRPα axis is a critical checkpoint in the innate immune system, and CD47 is recognized as a prominent target for cancer treatment. While the clinical potential of CD47 blockade is evident, significant safety concerns have emerged. One major challenge is that CD47 is also expressed on healthy cells such as red blood cells (RBCs) and platelets. As a result, the first generation of therapies often caused serious side effects, including anemia and thrombocytopenia, which limited their therapeutic utility. EpCAM is a well-established tumor marker that is highly expressed in many epithelial cancers, such as colorectal, gastric, ovarian and lung cancers. We previously introduced VP1186 (also known as VBI-003), a novel CD47xEpCAM bispecific antibody that cross-reacts with both human and cynomolgus monkey antigens with comparable affinities. VP1186 selectively targets cancer cells with high EpCAM expression while sparing healthy cells. This tumor selectivity allows VP1186 to retain its Fc region with full effector function, acting as a potent "eat me" signal to the immune system. Consequently, VP1186 effectively activates macrophages and natural killer (NK) cells within the tumor microenvironment, enhancing the immune system's ability to eliminate cancer cells (Journal for ImmunoTherapy of Cancer 2021;9:doi:10.1136/jitc-2021-SITC2021.274), (Cancer Res 2023;83(7_Supplement):1870). To further evaluate the safety profile of VP1186, we conducted a GLP-compliant repeat-dose toxicity study in cynomolgus monkeys. The bispecific antibody was administered intravenously at three dose levels as a 30-minute infusion once weekly for five consecutive weeks (Days 1, 8, 15, 22, and 29). The study also assessed the reversibility, progression, or delayed onset of any observed effects following 1-week and 4-week post-dosing periods. All animals were older than 3 years, with body weights ranging from 2.3 to 3.6 kg at the start of dosing. The results showed no clinically significant changes in clinical pathology endpoints, including hematology, clinical chemistry and coagulation, in VP1186-treated animals at doses up to 60 mg/kg/dose. Notably, RBC and platelet counts remained within the normal range across all dose levels, and hemoglobin concentrations stayed above the transfusion threshold throughout the study. No significant changes were observed in pancreatic enzymes, including lipase and amylase. Minimal effects on T cells were observed based on immunophenotyping (IPT) results. Transient but fully reversible changes in B cell and NK cell counts were noted. Pharmacokinetic (PK) analysis confirmed good drug exposure. These findings, combined with the potent anti-tumor activity of VP1186, support its further clinical evaluation as a potential treatment for CD47- and EpCAM-expressing cancers, particularly small cell lung cancer, gastric cancer, ovarian cancer and colorectal cancer. Xiaocheng Chen, Xinhua Wang, Oi Kwan Wong, Leonard Post, Laurie Tatalick. Preclinical safety evaluation of VP1186, a CD47xEpCAM bispecific antibody [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 6086.
