23P - PMC-309: A highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive

Background

PMC-309 is a novel human monoclonal IgG1 antibody (mAb). It binds with human VISTA, an immune checkpoint protein, with the effect of regulating the immunological activity of myeloid cells such as MDSC or myeloid-derived immune cells, thereby improving the antitumor activities of immune cells. In addition to being a novel drug substance, PMC309 will be the first IgG1 monoclonal antibody to act synergistically with other immunotherapies to improve treatment efficacy.

Methods

In vitro T cell activity: human PBMC was employed for the evaluation of T cell activity, and was stimulated with or w/o PMC-309 in the presence of anti-CD3/28 Antibody. In vivo study: MC38-bearing human VISTA knock-in (KI) mice were employed for the assessment of the anti-tumor activity of PMC-309. The tumor infiltrated immune cells: Immune cells in the TME were evaluated by immunohistochemistry (IHC) or flow cytometry (FACS) analysis.

Results

PMC-309 binding to VISTA-expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. PMC-309 enhances the secretion of IFN-gamma, TNF-alpha, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In addition, PMC-309 promoted monocyte differentiation into M1 macrophage which stimulates proinflammatory cytokine secretion of T cells. For the in vivo study, PMC-309 was intravenously administrated in VISTA-KI mice. The tumor growth rate was suppressed accompanied by a synergistic effect with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of cytotoxic T cells, but lowing immune-suppressive MDSC cells into TME as demonstrated with IHC analysis.

Conclusions

PMC-309 enhanced both T-cell activation and monocyte activation. PMC-309 increased the number of T cell infiltration while a decrease of MDSCs in the TME. PMC-309 in combination with chemotherapy or other IO drugs could address the high medical unmet needs of patients with drug resistance to currently available IO treatment options.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

PharmAbcine Inc.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.