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

Background

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. 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 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 on NK & CD8⁺ T cells 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.

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. Tumor specific expansion cohorts will be initiated once dose and schedule are established from dose escalation, with plans to further advance development in combinations. Response will be assessed every 9 weeks per RECIST v1.1.