Functional characterization of the selective pan-allele anti-SIRPα antibody ADU-1805 that blocks the SIRPα–CD47 innate immune checkpoint
| Autor: | Gilbert van den Tillaart, Sander M.J. van Duijnhoven, David Lutje Hulsik, Erik Voets, Andrea van Elsas, Peter van Zandvoort, Paul Vink, Inge Reinieren-Beeren, Maurice Habraken, Joost Kreijtz, Lilian Driessen, Hans van Eenennaam, Wout Janssen, Marc Parade, Sanne Spijkers, Joost Rens |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Neutrophils medicine.medical_treatment Cancer immunotherapy Mice Antineoplastic Agents Immunological 0302 clinical medicine Neoplasms Immunology and Allergy Medicine Receptors Immunologic CD47 biology lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Flow Cytometry Mixed lymphocyte reaction Cytokine Oncology 030220 oncology & carcinogenesis Myeloid cells Monoclonal Molecular Medicine Female Antibody Research Article Trogocytosis Immunology CD47 Antigen lcsh:RC254-282 Models Biological Immunomodulation 03 medical and health sciences Phagocytosis Cell Line Tumor SIRPα Biomarkers Tumor Animals Humans Innate immune checkpoint Pharmacology Innate immune system Dose-Response Relationship Drug business.industry Macrophages Antibody-Dependent Cell Cytotoxicity Antigens Differentiation Immunity Innate Disease Models Animal 030104 developmental biology biology.protein Cancer research business |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-15 (2019) |
| ISSN: | 2051-1426 |
| DOI: | 10.1186/s40425-019-0772-0 |
| Popis: | Background Accumulating preclinical data indicate that targeting the SIRPα/CD47 axis alone or in combination with existing targeted therapies or immune checkpoint inhibitors enhances tumor rejection. Although several CD47-targeting agents are currently in phase I clinical trials and demonstrate activity in combination therapy, high and frequent dosing was required and safety signals (acute anemia, thrombocytopenia) were recorded frequently as adverse events. Based on the restricted expression pattern of SIRPα we hypothesized that antibodies targeting SIRPα might avoid some of the concerns noted for CD47-targeting agents. Methods SIRPα-targeting antibodies were generated and characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. Functional activity was established in vitro using human macrophages or neutrophils co-cultured with human Burkitt’s lymphoma cell lines. The effect of SIRPα versus CD47 targeting on human T-cell activation was studied using an allogeneic mixed lymphocyte reaction and a Staphylococcus enterotoxin B-induced T-cell proliferation assay. Potential safety concerns of the selected SIRPα-targeting antibody were addressed in vitro using a hemagglutination assay and a whole blood cytokine release assay, and in vivo in a single-dose toxicity study in cynomolgus monkeys. Results The humanized monoclonal IgG2 antibody ADU-1805 binds to all known human SIRPα alleles, showing minimal binding to SIRPβ1, while cross-reacting with SIRPγ, and potently blocking the interaction of SIRPα with CD47. Reduced FcγR binding proved critical to retaining its function towards phagocyte activation. In vitro characterization demonstrated that ADU-1805 promotes macrophage phagocytosis, with similar potency to anti-CD47 antibodies, and enhances neutrophil trogocytosis. Unlike CD47-targeting agents, ADU-1805 does not interfere with T-cell activation and is not expected to require frequent and extensive dosing due to the restricted expression of SIRPα to cells of the myeloid lineage. ADU-1805 is cross-reactive to cynomolgus monkey SIRPα and upon single-dose intravenous administration in these non-human primates (NHPs) did not show any signs of anemia, thrombocytopenia or other toxicities. Conclusions Blocking the SIRPα-CD47 interaction via SIRPα, while similarly efficacious in vitro, differentiates ADU-1805 from CD47-targeting agents with respect to safety and absence of inhibition of T-cell activation. The data presented herein support further advancement of ADU-1805 towards clinical development. |
| Databáze: | OpenAIRE |
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