Abstract 4224: BPT-143: a fully synthetic alpha-dead IL-2 with a best-in-class preclinical pharmacodynamic and efficacy profile supporting first-in-human clinical development

Abstract

Abstract High-dose recombinant IL-2 (aldesleukin) is approved for treatment of advanced melanoma and renal cell carcinoma, however, major limitations restrict its therapeutic use. Wild-type IL-2 acts via binding to the medium-affinity IL-2 receptor βγ (IL2Rβγ) expressed in CD8+ T effector cells and NK cells. At the same time, its efficacy is dampened due to strong activation of regulatory T cells (Treg) expressing the high-affinity IL-2 receptor αβγ (IL2Rαβγ). Furthermore, binding to CD25/IL2Rα on endothelial cells and type 2 innate lymphoid cells is thought to be involved in the induction of severe toxicity including vascular leak syndrome (VLS). In addition, aldesleukin exhibits a very short half-life that, combined with its safety risks, requires a burdensome inpatient treatment schedule. We set out to rationally design a variant of human IL-2 that addresses and overcomes the major limitations of aldesleukin. Using our chemical protein synthesis technology, we introduced select modified amino acids including site-specific chemical conjugation handles to optimize the properties of IL-2 for cancer therapy while maintaining high homology to the wild-type IL-2 sequence. Bright Peak’s enhanced cytokine shows increased binding to CD122/IL2Rβ and does not interact with CD25/IL2Rα to improve safety and prevent the preferential activation of Tregs compared to CD8+ T effector cells. Site-specific conjugation to a 30 kDa PEG for half-life extension resulted in the generation of BPT-143, which is equipotent to aldesleukin in activating CD8+ T cells in vitro. In mice, BPT-143 induces a strong expansion of CD8+ T cells with only transient and minor effects on Tregs in vivo and exhibits improved PK properties allowing for a convenient dosing schedule. In the syngeneic CT26 tumor model, BPT-143 showed strong anti-tumor efficacy as a single agent as well as enhanced efficacy in combination with an anti-PD-1 antibody. BPT-143 induced a 55% complete response rate and, upon tumor re-challenge, all cured animals rejected CT26 tumor cells indicating the development of immunologic memory. In multiple-dose PK/PD studies in non-human primates (NHP), BPT-143 was well tolerated and induced robust and repeated expansion of CD8+ T cells, CD4+ conventional T cells and NK cells while showing only negligible effects on Tregs and eosinophils. Both in vivo efficacy studies in murine tumor models as well as PD effects observed in NHP indicate that BPT-143 has a best-in-class profile among “not-alpha” IL-2 compounds currently in development. IND-enabling studies are ongoing and a first in human trial is planned to start in 2022. Citation Format: Jean-Philippe Carralot, Rubén Alvarez Sanchez, Matilde Arévalo Ruiz, Magali Muller, Vijaya R. Pattabiraman, Bertolt Kreft. BPT-143: a fully synthetic alpha-dead IL-2 with a best-in-class preclinical pharmacodynamic and efficacy profile supporting first-in-human clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4224.