Abstract CT258: A phase 1/2 study of JK08, an IL-15 antibody fusion protein targeting CTLA-4, in patients with advanced solid tumors

Abstract Background: CTLA-4 is a transmembrane receptor that functions as an immune checkpoint and fundamental negative regulator of T cell activation. CTLA-4 is highly expressed on most regulatory T cells (Tregs) but only upregulated in effector T cells following activation. Emerging evidence suggests anti-tumor activity of antibodies targeting CTLA-4 may be modulated by the local presence of NK cells. Interleukin 15 (IL-15) is a pleiotropic cytokine important in both innate and adaptive immunity. The IL-15/IL-15Rα complex can stimulate adjacent cells through the IL-2Rβ/γ complex. This receptor complex is present on many hematopoietic cells; however, IL-2Rβ expression is highest on NK cells and CD8+ T cells. Trans-presentation of IL-15 is believed to be the optimal mode of action for IL-15-induced proliferation and activation of NK cells and CD8+ T cells, two essential mediators of anti-tumor responses. JK08 is a recombinant fusion protein consisting of two functional elements - a fully human monoclonal antibody directed against CTLA-4 and a protein complex consisting of human IL-15 and the Sushi domain of human IL-15Rα. JK08 is intended to widen the therapeutic window for IL-15 cytokine-mediated cancer therapy and CTLA-4-targeted antibody-mediated cancer therapy. This widening of the therapeutic window can be achieved by local activation and expansion of NK cells at sites of Tregs, and by IL-15 enhancement of the activity and potency of the proximal CTLA-4 antibody, mirroring the endogenous trans-presentation orientation. Preclinical studies demonstrate JK08 can elicit ADCC-mediated killing of CTLA-4-expressing cells and interact with IL-2Rβ to promote robust T cell proliferation independent of IL-15Rα expression, suggesting that JK08 could effectively activate IL-2Rβ/γC-expressing cells preferentially at sites of Tregs, and achieve enhanced anti-tumor responses including through ADCC-mediated depletion of T regulatory cells. In vivo studies show JK08 induces robust NK and CD8+ T cell expansion in cynomolgus monkeys and anti-tumor activity in syngeneic murine models. In summary, JK08 treatment may lead to clinical activity in multiple cancer indications by counteracting the contribution of Tregs to cancer progression. Methods: The Phase 1/2 study of JK08 will enroll patients with advanced relapsed/refractory solid tumors. The study will employ an accelerated 3+3 escalation design to explore the safety, PK, immuno-regulatory activity, and preliminary anti-tumor activity of JK08. Patients will receive treatment with JK08 subcutaneously once weekly until confirmed disease progression or intolerable toxicity. Four tumor specific expansion cohorts will be initiated once dose and schedule are established from dose escalation and include melanoma, breast cancer, colorectal cancer, and a basket of advanced solid tumors. Response will be assessed every 9 weeks per RECIST v1.1. Citation Format: Nuria Kotecki, Sylvie Rottey, Elena Garralda, Maria de de Miguel, Omar Saavedra, Valentina Boni, Judit W. Johnson, Jonathan P. McNally, Mohit Mathew, Adam Hughes, Sam Murphy, Naimish Pandya. A phase 1/2 study of JK08, an IL-15 antibody fusion protein targeting CTLA-4, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT258.