Novel Target, New Therapy: Anti- Renalase Antibody for Tumors Resistant to PD-1Inhibitors

ABSTRACT Most patients with advanced cancer either do not respond durably or do not respond to current interventions, including immune-oncology checkpoint inhibitors. For melanoma, a major focus for immunotherapies, five-year survival improved dramatically, yet only ~ 40% of patients respond to PD-1 inhibitors, and many develop resistance over time. The combination with another checkpoint inhibitor of CTLA-4 yields a higher response rate, but with a higher rate of toxicities, and rt 40% of patients have resistant tumors. In most other tumor types, responses are seen less frequently, and duration of response is shorter. There is, therefore, a great need for additional systemic interventions. In prior studies, including from a Phase 1 grant, the team established the role of the secreted flavoprotein renalase (RNLS) as a new target in melanoma and proof of concept that inhibiting RNLS signaling blocks tumor growth. RNLS knock-out mice also rejected these murine melanomas, providing a rationale for targeting RNLS in tumors. Moreover, RNLS levels inversely correlate with patient outcomes, thus, increased RNLS expression in human tumors, melanoma cells and/or tumor associated macrophages are associated with decreased survival including patients treated with anti-PD-1- based regimens. Anti-RNLS antibodies (anti-RNLS mAb) developed in the project and used as single agents regressed murine melanoma tumors resistant to PD-1 inhibitors. In combination with anti-PD-1, anti-RNLS mAb showed synergy with no apparent toxicity. Tumor rejection was driven by both macrophages and T cells. In Phase I progress was made towards developing a humanized anti-RNLS monoclonal Ab (anti-RNLS mAb) as a 1st in class clinical candidate for tumors resistant to PD-1 inhibitors. Additional studies have yielded a lead anti-RNLS mAb (K16). K16 was effective in two murine melanoma models. Also, two new sensitive and selective ELISA assays were developed and used to: measure plasma RNLS levels and anti-RNLS mAb levels. These will be available for future use. In this grant, non GMP K16 will be scaled up and two murine melanoma models will be used to confirm and extend studies of the mAb. Additionally, pharmacokinetic, and dose-ranging and acute toxicology studies on K16 will be performed and an estimate of a therapeutic Index (≥10x desired) will be calculated. The outcomes from this project, with continuing success, have considerable value, including: 1) elucidation and utility of a new and novel anticancer drug target - RNLS; 2) development of a unique anticancer therapy—anti-RNLS mAb; 3) significantly extending and improving the anticancer activity and cost effectiveness of checkpoint inhibitors and in checkpoint inhibitor resistant cancer patients.