HMBD-002 is a novel, neutralizing, anti-VISTA antibody exhibiting strong preclinical efficacy and safety, being developed as a monotherapy and in combination with pembrolizumab.. Abstract

e14569 Background: Inhibition of immune checkpoints has been an effective strategy against several cancers, but efficacy gaps remain. VISTA is an immunoregulatory protein expressed on both hematopoietic and tumor cells and has been shown to induce an immunosuppressive environment by repressing T-cell activation and cytokine production. VISTA expression has been shown to be upregulated following treatment with immune checkpoint inhibitors. Hummingbird Bioscience is developing HMBD-002, an IgG4 antibody against VISTA with high binding specificity across species (human, cyno and rodent) and low pM affinity to the region of VISTA required for engagement with interaction partners, including VSIG3. As HMBD-002 is an IgG4 isotype, it uniquely blocks the inhibitory function of VISTA and releases immune suppression without depleting VISTA+ cells. Here we establish the preclinical efficacy and safety of HMBD-002 along with the rationale for development of HMBD-002 as a monotherapy and in combination with PD1 inhibitors in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Methods: The effect of HMBD-002 in an in vitro model of human immune activation was evaluated using an allogenic Mixed Lymphocyte Reaction (MLR) assay. Tumor growth inhibition studies were conducted in syngeneic murine cell-derived xenograft (CDX) models. The PK and tolerability of HMBD-002 was evaluated in rats and cynomolgus monkeys with a 21 or 28-day observation period. The expression profile of VISTA was examined in different cancers by IHC staining of FFPE TMAs of various solid cancers. Results: HMBD-002 induced a significant dose dependent increase in the levels of inflammatory cytokines, IFN-γ and TNF- α and suppressed the expansion of CD14+ monocytes. Treatment with HMBD-002 significantly inhibited tumor growth and improved survival in CDX models. HMBD-002 is well tolerated in rats and cynomolgus monkeys with acceptable serum half-life, no HMBD-002 related morbidity/mortality or clinical signs, and no HMBD-002 related changes were observed in body weight, food consumption, clinical chemistry, or hematology parameters. HMBD-002 did not induce cytokine release in human PBMCs or whole blood. TNBC and NSCLC patients were found to harbor the highest VISTA expression across cancer types tested, providing a rationale for exploring these indications in upcoming clinical studies. Conclusions: These studies provide the rationale for development of HMBD-002 as a monotherapy and in combination with pembrolizumab to treat patients with solid tumors expressing VISTA in the tumor microenvironment. A Phase 1 study will be initiated in 2021.