Abstract LB137: Bispecific antibody-based redirection of endogenous IL-15 to PD-1 positive cells enhances antitumor activity over checkpoint inhibition alone

Abstract Cytokines have the potential to reinvigorate the immune response against tumors, address shortcomings of checkpoint inhibition and expand the reach of immunotherapy. Yet, development efforts with recombinant cytokines, their engineered muteins and fusion molecules have encountered challenges. We are developing a novel therapeutic modality using bispecific antibodies we refer to as Amplify•R. These antibodies engage the naturally present endogenous cytokines in vivo, enhance persistence of the bound cytokine, while regulating and redirecting its therapeutic effect to target cells of interest. We hypothesize that this modality will overcome limitations such as systemic toxicity, increased immunogenicity, and manufacturing challenges often associated with traditional recombinant cytokine treatment approaches. As a proof of concept, we have designed a panel of bispecific antibodies capable of co-engaging the T and NK cell stimulating cytokine, IL-15, and the immune checkpoint, PD-1. The bispecific antibodies can bind IL-15 and selectively present it to its cognate receptor on PD-1+ cells. In reporter cell-based assays, the panel of antibodies were able to mediate IL-15 signaling in a controlled manner. Further, these bispecific antibodies were as efficient at PD-1 signal blockade as a clinical benchmark. The ability of the bispecific antibodies to stimulate IL-15 dependent STAT5 phosphorylation in human peripheral blood mononuclear cells (PBMC) was tested. In a dose-dependent manner, the bispecific antibodies were able to selectively stimulate pSTAT5 activity in PD-1+ T cells versus NK cells, whereas IL-15 alone stimulated greater pSTAT5 activity in NK cells compared to T cells. The ability of the bispecific antibodies to induce cell proliferation was determined by culturing PBMC in the presence of antibodies complexed with IL-15. After 4 days of culture, a dose dependent expression of Ki67 was detected in CD8+ T cells cultured with bispecific antibodies while they failed to stimulate Ki67 expression in NK cells. These in vitro results demonstrate redirection of IL-15 activity towards PD-1 expressing T cells, and away from NK cells. We have further explored the Amplify•R antibody effect in vivo. Using C57BL/6 mice engineered with human PD1, engrafted with the MC38 colorectal cancer cell line humanized for PD-L1, we observed significantly more efficient control of tumor growth with the bispecific antibodies in the presence of IL-15 relative to pembrolizumab alone or in combination with IL-15. In addition, upon repeated dosing, CD8+ T cells were preferentially expanded over CD4+ and NK cells in the Amplify•R antibody treated animals. In summary, 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. Citation Format: Surjit Dixit, Mark Fogg, Stacey Tom-Yew, Harsh Pratap, Vivian Li, Abhishek Mukhopadhyay, Jason Baardsnes, Yuneivy Cepero Donates, David de Graaf. Bispecific antibody-based redirection of endogenous IL-15 to PD-1 positive cells enhances antitumor activity over checkpoint inhibition alone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB137.

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