Abstract CT143: Resolved hematological toxicities associated with anti-CD47 agents using a bispecific design involving an optimized anti-CD47 arm: A clinical proof of concept study

Abstract Anti-CD47 agents, including anti-CD47 antibodies and signal regulatory protein alpha (SIRPα)/Fc fusion proteins, have been seen to be associated with hematological toxicities/adverse events (AEs) in multiple clinic trials. These AEs are believed to be driven by the expression of CD47 on red blood cells (RBCs), platelets and neutrophils, which are rapidly cleared by monocytes/macrophages activated by the CD47-targeting agent. Here we show, using spevatamig (PT886), a novel IgG1-based bispecific antibody targeting claudin 18.2 (CLDN18.2) and CD47 with an optimized anti-CD47 arm that has higher binding to CD47 on cancer cells than that on human RBCs, that hematological AEs can be significantly reduced. Moreover, combination therapy with chemotherapy and/or immune-checkpoint inhibitors such as pembrolizumab can be well tolerated, with hematological AEs not exceeding standard of care (SOC) alone. As of September 24, 2025, 95 patients have been treated with spevatamig monotherapy (N=31) and combination therapies (N=64) in the USA. There have been no Grade ≥ 3 hematological events in monotherapy dosing up to 9 mg/kg Q2W, with no neutropenia or CRS observed. Grade 1/2 anemia was observed in 32% (10/31) of patients, and Grade 1/2 thrombocytopenia was observed in 19% (6/31) of patients, with no trend suggesting dose dependency. When spevatamig was combined with chemotherapy, anemia, thrombocytopenia and neutropenia were predominantly Grade 1/2; all Grade ≥ 3 events recovered with the exception of one patient with Grade 3 anemia at the end of study. Observed cytopenias did not exceed rates anticipated with backbone chemotherapy. In spevatamig + pembrolizumab combination therapy (N=14), hematological AEs were similar to spevatamig monotherapy, with no neutropenia, only 1 patient experiencing Grade 1 thrombocytopenia, and anemia predominantly Grade 1/2. Overall, observed hematological AEs have been well tolerated despite occurring in the backdrop of underlying disease and known AEs of chemotherapy. These clinical data are consistent with preclinical studies in dose range-finding studies in non-human primates. Our findings demonstrate that by adopting a bispecific design with one optimized anti-CD47 arm, CD47 can be safely targeted, enabling the opportunity to assess clinical efficacy of the molecule for patients with advanced malignancies. Citation Format: Harshabad Singh, Michael J. Overman, Alexander I. Spira, Jason T. Henry, Dani Castillo, Nataliya Uboha, Naomi Fei, Nicholas DeVito, Diana Hanna, Michael J. Chisamore, Grace H. McGregor, Hui Zou, Minghan Wang, Satya (Nanu) Das, Rita Laeufle, Anwaar Saeed. Resolved hematological toxicities associated with anti-CD47 agents using a bispecific design involving an optimized anti-CD47 arm: A clinical proof of concept study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT143.