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FIGURE 3 from Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRPα That Enhances Macrophage-mediated Tumor Phagocytosis When Combined with Opsonizing Antibodies

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posted on 2024-02-22, 15:00 authored by Henry Chan, Christina V. Trout, David Mikolon, Preston Adams, Roberto Guzman, Konstantinos Mavrommatis, Mahan Abbasian, Haralambos Hadjivassiliou, Lawrence Dearth, Brian A. Fox, Pallavur Sivakumar, Ho Cho, Kandasamy Hariharan

Gene expression data from TCGA across four indications (COAD = colon adenocarcinoma, DLBC = diffuse large B-cell lymphoma, HNSC = head and neck cancer, READ = rectal adenocarcinoma) with each point from one patient and expression units shown as the log2(normalized counts+1). The left panel of (A) shows that the absolute level of SIRPα (x-axis) is comparable to and often correlated with CD163 gene expression (y-axis). The right panel of (A) shows that CD163 is a representative marker of myeloid cells as it is highly correlated to CD14 (x-axis), with many other macrophage marker genes showing a similar pattern (not shown). Validation by IHC in tumor samples from CRC, SCCHN, and DLBCL (B), showing overlapping expression of macrophage marker CD163 and SIRPα (data shown are example images from the tumor microarray). Proportion of phagocytic macrophages after exposure to BMS-986351 alone or in combination with cetuximab in samples derived from donors with CRC (C) and SCCHN (D). Immunofluorescence illustrating increased tumor cell phagocytosis with BMS-986351 plus cetuximab compared with cetuximab plus isotype matched control (anti-RSV) or control alone in GP5d (E) and FaDu (F) tumor cells. Arrows indicate phagocytic macrophages. CRC, colorectal cancer; IHC, immunohistochemistry; RSV, respiratory syncytial virus; SCCHN, squamous cell carcinoma of head and neck.

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ARTICLE ABSTRACT

In normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an antiphagocytic signal. Tumor cells hijack this pathway and overexpress CD47 to evade immune destruction. Macrophage antitumor activity can be restored by simultaneously blocking the CD47-SIRPα signaling axis and inducing a prophagocytic signal via tumor-opsonizing antibodies. We identified a novel, fully human mAb (BMS-986351) that binds SIRPα with high affinity. BMS-986351 demonstrated broad binding coverage across SIRPα polymorphisms and potently blocked CD47-SIRPα binding at the CD47 binding site in a dose-dependent manner. In vitro, BMS-986351 increased phagocytic activity against cell lines from solid tumors and hematologic malignancies, and this effect was markedly enhanced when BMS-986351 was combined with the opsonizing antibodies cetuximab and rituximab. A phase I dose-escalation/-expansion study of BMS-986351 for the treatment of advanced solid and hematologic malignancies is underway (NCT03783403). Increasing the phagocytotic capabilities of tumor-associated macrophages by modulating macrophage–tumor cell surface signaling via the CD47-SIRPα axis is a novel strategy. Molecules targeting CD47 have potential but its ubiquitous expression necessitates higher therapeutic doses to overcome potential antigen sink effects. The restricted expression pattern of SIRPα may limit toxicities and lower doses of the SIRPα antibody BMS-986351 may overcome target mediated drug disposition while maintaining the desired pharmacology.