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SIRP? on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production.

ABSTRACT: The inhibitory immunoreceptor SIRP? is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRP? interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRP? on B1 lymphocytes, a subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRP? signaling (SIRP??CYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective, we investigated the involvement of SIRP? signaling in atherosclerosis development. Bone marrow (SIRP??CYT>LDLR-/-) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRP? as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRP? as a potential therapeutic target in atherosclerosis.

SUBMITTER: Franke K

PROVIDER: S-EPMC7581795 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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SIRPα on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production.

Franke Katka K Pillai Saravanan Y SY Hoogenboezem Mark M Gijbels Marion J J MJJ Matlung Hanke L HL Geissler Judy J Olsman Hugo H Pottgens Chantal C van Gorp Patrick J PJ Ozsvar-Kozma Maria M Saito Yasuyuki Y Matozaki Takashi T Kuijpers Taco W TW Hendriks Rudi W RW Kraal Georg G Binder Christoph J CJ de Winther Menno P J MPJ van den Berg Timo K TK

Frontiers in immunology 20201009

The inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPα<sup>ΔCYT</sup> mice) displayed an enhanced CD11b/CD18 integrin-depe ...[more]

PMID: 33162986

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Project description: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.

Dataset Information

SIRP? on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production.

Publications

SIRPα on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production.

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