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Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo.

ABSTRACT:

Background and purpose

Interleukin-15 (IL-15) is important in the activation and proliferation of lymphocytic cell populations and is implicated in inflammatory disease. We report the characterization of a novel monoclonal antibody DISC0280 which is specific for human IL-15.

Experimental approach

DISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor ? (IL-15R?) and by its ability to alter IL-15 mediated proliferation of a range of cell lines (cytotoxic T lymphocyte line-2, M-07e, KIT225). A pharmacodynamic model injecting male C57/BL6 mice with IL-15 or IL-15/IL-15R?, with or without DISC0280, and assessing changes in lymphocytic cell populations and serum cytokines was utilized.

Key results

DISC0280 inhibited the binding of IL-15 to IL-15R? and also potently inhibits IL-15 dependent proliferation of cells expressing IL-15R?, shared interleukin 2/ interleukin 15 receptor ? chain (IL-15R?) and common gamma chain (?(c) ). DISC0280 also inhibited the IL-15 dependent proliferation of M-07e cells that only express IL-15R?/?(c) subunits. Human IL-15 injected into mice caused an increase in NK1.1(+) and CD3(+) cells in the spleen and peripheral blood and these effects were unexpectedly potentiated by giving DISC0280 with human IL-15. This increase in cells caused by DISC0280/IL-15 co-administration was greater than that observed when IL-15 was administered complexed with soluble IL-15R?.

Conclusions and implications

The ability of DISC0280 to bind to the IL-15R?-binding site on IL-15 allows trans-presentation of IL-15 by DISC0280 in vivo, similar to the trans-presentation by soluble IL-15R?. DISC0280 may be therefore suitable as a clinical substitute for IL-15.

SUBMITTER: Finch DK

PROVIDER: S-EPMC3031067 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Publications

Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo.

Finch D K DK Midha A A Buchanan C L CL Cochrane D D Craggs R I RI Cruwys S S Grahames C C Kolbeck R R Lowe D C DC Maltby J J Pattison D V DV Vousden K A KA Ward A A Sleeman M A MA Mallinder P R PR

British journal of pharmacology 20110101 2

<h4>Background and purpose</h4>Interleukin-15 (IL-15) is important in the activation and proliferation of lymphocytic cell populations and is implicated in inflammatory disease. We report the characterization of a novel monoclonal antibody DISC0280 which is specific for human IL-15.<h4>Experimental approach</h4>DISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor α (IL-15Rα) and by its ability to alter IL-15 mediated proliferation of a range of cell lines (cytotoxic ...[more]

PMID: 20942844

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Project description:BackgroundImmunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8+ T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8+ T and NK cell function. Most reported preclinical studies administered N-803 intraperitoneally not subcutaneously, the current clinical route of administration. N-803 is now being evaluated clinically in combination with PD-1/PD-L1 inhibitors. However, the mechanism of action has not been fully elucidated. Here, we examined the anti-tumor efficacy and immunomodulatory effects of combining N-803 with an anti-PD-L1 antibody in preclinical models of solid carcinomas refractory to anti-PD-L1 or N-803.MethodsSubcutaneous N-803 and an anti-PD-L1 monoclonal antibody were administered as monotherapy or in combination to 4T1 triple negative breast and MC38-CEA colon tumor-bearing mice. Anti-tumor efficacy was evaluated, and a comprehensive analysis of the immune-mediated effects of each therapy was performed on the primary tumor, lung as a site of metastasis, and spleen.ResultsWe demonstrate that N-803 treatment increased PD-L1 expression on immune cells in vivo, supporting the combination of N-803 and anti-PD-L1. N-803 plus anti-PD-L1 was well-tolerated, reduced 4T1 lung metastasis and MC38-CEA tumor burden, and increased survival as compared to N-803 and anti-PD-L1 monotherapies. Efficacy of the combination therapy was dependent on both CD8+ T and NK cells and was associated with increased numbers of these activated immune cells in the lung and spleen. Most alterations to NK and CD8+ T cell phenotype and number were driven by N-803. However, the addition of anti-PD-L1 to N-803 significantly enhanced CD8+ T cell effector function versus N-803 and anti-PD-L1 monotherapies, as indicated by increased Granzyme B and IFNγ production, at the site of metastasis and in the periphery. Increased CD8+ T cell effector function correlated with higher serum IFNγ levels, without related toxicities, and enhanced anti-tumor efficacy of the N-803 plus anti-PD-L1 combination versus either monotherapy.ConclusionsWe provide novel insight into the mechanism of action of N-803 plus anti-PD-L1 combination and offer preclinical proof of concept supporting clinical use of N-803 in combination with checkpoint inhibitors, including for patients non- and/or minimally responsive to either monotherapy.

Dataset Information

Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo.

Similar Datasets

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