P02.11 TREM1 agonist PY159 promotes myeloid cell reprogramming and unleashes anti-tumor immunity

Background Tumor-associated myeloid cells can impede productive anti-tumor immunity. One strategy for targeting immunosuppression is myeloid reprogramming, which drives immunosuppressive myeloid cells to acquire an immunostimulatory phenotype. Triggering receptor expressed on myeloid cells-1 (TREM1) is an immunoglobulin superfamily cell surface receptor expressed on neutrophils and subsets of monocytes and tissue macrophages. TREM1 associates with DAP12 adaptor and induces proinflammatory signaling, amplifies innate immune responses, and is implicated in the development of acute and chronic inflammatory diseases. TREM1 is also enriched in tumors, specifically on tumor-associated myeloid cells. To investigate the potential of TREM1 modulation as an anti-cancer therapeutic strategy, we developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody, and characterized it in the pre-clinical assays described below. Materials and Methods An FcγR binding ELISA and a Jurkat TREM1/DAP12 NFAT-luciferase reporter cell line were used to assess PY159 binding to human FcγRs and TREM1 signaling, respectively. PY159 responses in human whole blood in vitro were evaluated by flow cytometry, transcriptional analysis of sorted leukocyte subsets, and measurement of secreted cytokines/chemokines by MSD. A Transwell system was used to evaluate PY159 effects on neutrophil chemotaxis. TREM1 expression in human tumors was validated by scRNAseq, immunohistochemistry, and flow cytometry. Anti-tumor efficacy of a surrogate anti-mouse TREM1 antibody, PY159m, was evaluated using syngeneic mouse tumor models, either as a single agent or in combination with anti-PD-1. Results PY159 afucosylation increased its binding affinity for FcγR and its ability to activate TREM1/DAP12 signaling. In human blood assays, PY159 treatment did not induce depletion of TREM1-expressing cells. Rather, it upregulated monocyte activation markers, promoted neutrophil chemotaxis, and induced proinflammatory cytokines and chemokines, which was dependent on PY159 afucosylation. In human tumors, TREM1 was detected on tumor-associated neutrophils, tumor-associated macrophages, and monocytic myeloid-derived suppressive cells. PY159 induced proinflammatory cytokines and chemokines in dissociated human tumors in vitro, demonstrating that PY159 can reprogram tumor-associated myeloid cells. A surrogate anti-mouse TREM1 antibody, PY159m, exhibited anti-tumor efficacy in several syngeneic mouse tumor models, both as single-agent and in combination with anti-PD-1. Conclusions These results show that PY159 is a TREM1 agonist that reprograms myeloid cells and unleashes anti-tumor immunity. PY159 safety and efficacy are currently being evaluated in first-in-human clinical trial (NCT04682431) involving patients resistant and refractory to standard of care therapies. Disclosure Information V. Juric: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. E. Mayes: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. M. Binnewies: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. P. Canaday: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. T. Lee: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. S. Dash: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. J.L. Pollack: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. J. Rudolph: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. V. Huang: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. X. Du: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. N. Jahchan: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. A.J. Ramoth: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. S. Mankikar: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. M. Norng: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. C. Santamaria: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. K.P. Baker: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc. L. Liang: A. Employment (full or part-time); Significant; Pionyr Immunotherapeutics Inc.