854 Amplification & redirection of endogenous IL-15 activity with a bispecific antibody

Background Cytokines have the potential to reinvigorate the immune response against tumors and address shortcomings of checkpoint inhibition. We are developing a novel therapeutic modality using bispecific antibodies we refer to as Amplify•R. These antibodies engage endogenous cytokines in vivo and enhance their persistence, whilst regulating and redirecting the therapeutic effect to target cells of interest. We hypothesize this modality will overcome limitations associated with traditional approaches attempting to use recombinant cytokine or their muteins.Methods A panel of bispecific antibodies were designed to co-engage the T and NK cell stimulating cytokine, IL-15, and the immune checkpoint, PD-1. They were expressed and evaluated for activity in IL-15 and PD-1 reporter cell-based assays. Primary human peripheral blood mononuclear cells (PBMC) were used to test the ability of bispecific antibodies to stimulate IL-15 dependent STAT5 phosphorylation in T and NK cells and for their ability to induce proliferation of T cell subsets. For in vivo studies, C57BL/6 mice humanized for PD-1 were implanted with the MC38 colorectal cancer cell line, humanized for PD-L1. Antibody was administered subcutaneously in the presence or absence of recombinant human IL-15 administered interperitoneally, and tumor growth was monitored.Results In reporter cell-based assays, the bispecific antibodies were able to mediate IL-15 signaling in a controlled manner and were capable of inducing PD-1 signal blockade. Using PBMC, the bispecific antibodies were able to selectively stimulate pSTAT5 activity in PD-1+ T cells versus NK cells in a dose-dependent manner. This activity also correlated with increased proliferation of CD8+ effector memory T cells in in vitro cultures of PBMC. These in vitro results demonstrate redirection of IL-15 activity towards PD-1 expressing T cells, and away from NK cells. In in vivo studies we observed significantly more control of tumor growth with the bispecific antibodies in the presence of IL-15 relative to pembrolizumab alone or in combination with IL-15. Furthermore, upon treatment of animals expressing endogenous levels of IL-15 we observed in vivo expansion of cell subsets expressing the IL-15 receptor complex.Conclusions We show that the Amplify•R modality of endogenous cytokine engagement and redirection may be a viable approach in clinic, capable of overcoming limitations encountered with traditional cytokine treatment.

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