Abstract B077: Discovery and development of a highly differentiated, efficacious, first-in-class anti-SIRPα/β dual antibody with single agent phagocytosis activity

Abstract The SIRPα-CD47 axis has emerged as a critical target in cancer therapy. While CD47-targeting agents have shown clinical promise, their widespread expression raises concerns about hematologic toxicities such as anaemia and thrombocytopenia, limiting their development. This has driven interest in targeting another end of the axis i.e., SIRPα. Additionally, targeting SIRPβ, which is selectively expressed on myeloid cells, through an agonistic approach trigger ITAM-mediated activation signals, promoting cancer cell death. Here, we report the discovery of novel anti-SIRPα/β dual antibody clones generated via a proprietary antibody discovery platform, leveraging a large and diverse human antibody library alongside advanced in vitro and in silico screening methods. These full-length antibodies exhibit high-affinity binding to multiple allelic variants of both SIRPα and SIRPβ in soluble and cell surface forms. They effectively block CD47-SIRPα interactions in biochemical assays and significantly enhance macrophage activation, as evidenced by increased cytokine release. Importantly, these dual antibody clones robustly activate phospho-SLP76, a key downstream effector of SIRPβ signalling, and demonstrate potent single-agent tumor cell phagocytosis by macrophages in vitro, a distinct advantage over other SIRPα antibodies that are currently in clinical development. Unlike many CD47-targeting therapies, our dual antibodies show minimal binding to red blood cells, do not cause hemagglutination, and do not bind SIRPγ on T cells, ensuring selective myeloid targeting without T cell depletion and a favourable safety profile. In a lymphoma tumor model using B-NDG mice expressing human SIRPα, the dual antibody in combination with an opsonizing anti-cancer agent showed more-than-additive antitumor activity. However, the model’s lack of human SIRPβ limits full evaluation of the dual activity of our antibodies. Efficacy correlated with dose-dependent target engagement, effective serum and tumor tissue distribution, and significantly enhanced in vivo phagocytosis relative to a competitor agent, underscoring the superior therapeutic potential of our dual antibodies. Overall, these novel anti-SIRPα/β dual antibodies combine broad pan-allelic SIRPα binding, potent SIRPβ activation, selective immune targeting, and enhanced phagocytosis leading to antitumor efficacy with promising pharmacokinetics and safety. They represent a potentially safer and more effective immunotherapeutic approach for cancer treatment. We are advancing toward non-human primate toxicity studies and aim to complete IND-enabling studies by Q1 next year. Citation Format: Subhra Prakash. Chakrabarty, Sandeep Patil, Sunaina Singh. Rajput, Sandhya Arumugam, Lavanya P, Gayatri Nair, Vaishnavi Shivaji. Khamkar, Gopinath C. H, Kiran Aithal, Girish Daginakatte, Amit Dhudashiya, Mukul Bikash. Maiti, Samiulla DS, R Jagadeesh, Jwala Nagaraj, Vijaya Shankar. Nataraj, Megha Goyal, Sanjeev Giri, Susanta Samajdar, Murali Ramachandra. Discovery and development of a highly differentiated, efficacious, first-in-class anti-SIRPα/β dual antibody with single agent phagocytosis activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B077.