Novel SIRPα Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells
| Autor: | Ronald R. Hiebsch, Daniel S. Pereira, Robyn J Puro, Benjamin J. Capoccia, Gabriela Andrejeva, Isra M. Darwech, Michael J. Donio |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
THP-1 Cells
Phagocytosis T cell T-Lymphocytes Immunology Antigen presentation Population 03 medical and health sciences Jurkat Cells 0302 clinical medicine Antineoplastic Agents Immunological Neoplasms medicine Immunology and Allergy Macrophage Humans Receptors Immunologic education Immunotherapy and Vaccines Tumor microenvironment education.field_of_study Antigen Presentation Innate immune system Chemistry CD47 Macrophages U937 Cells Antigens Differentiation Cell biology Neoplasm Proteins medicine.anatomical_structure 030215 immunology |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 0383-4948 |
| Popis: | The signal regulatory protein α (SIRPα)/CD47 axis has emerged as an important innate immune checkpoint that enables cancer cell escape from macrophage phagocytosis. SIRPα expression is limited to macrophages, dendritic cells, and neutrophils—cells enriched in the tumor microenvironment. In this study, we present novel anti-SIRP Abs, SIRP-1 and SIRP-2, as an approach to targeting the SIRPα/CD47 axis. Both SIRP-1 and SIRP-2 bind human macrophage SIRPα variants 1 and 2, the most common variants in the human population. SIRP-1 and SIRP-2 are differentiated among reported anti-SIRP Abs in that they induce phagocytosis of solid and hematologic tumor cell lines by human monocyte-derived macrophages as single agents. We demonstrate that SIRP-1 and SIRP-2 disrupt SIRPα/CD47 interaction by two distinct mechanisms: SIRP-1 directly blocks SIRPα/CD47 and induces internalization of SIRPα/Ab complexes that reduce macrophage SIRPα surface levels and SIRP-2 acts via disruption of higher-order SIRPα structures on macrophages. Both SIRP-1 and SIRP-2 engage FcγRII, which is required for single-agent phagocytic activity. Although SIRP-1 and SIRP-2 bind SIRPγ with varying affinity, they show no adverse effects on T cell proliferation. Finally, both Abs also enhance phagocytosis when combined with tumor-opsonizing Abs, including a highly differentiated anti-CD47 Ab, AO-176, currently being evaluated in phase 1 clinical trials, NCT03834948 and NCT04445701. SIRP-1 and SIRP-2 are novel, differentiated SIRP Abs that induce in vitro single-agent and combination phagocytosis and show no adverse effects on T cell functionality. These data support their future development, both as single agents and in combination with other anticancer drugs. |
| Databáze: | OpenAIRE |
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