PY314, TREM2 and “re-tuning” the tumor microenvironment (TME) through targeted depletion of tumor associated macrophages (TAMs)

Pionyr Immunotherapeutics is developing PY314 for the treatment of advanced solid tumors refractory to or relapsed with the current standard of care (SOC). PY314 is a humanized monoclonal antibody (mAb) that specifically binds Triggering receptor expressed on myeloid cells 2 (TREM2) and is designed to deplete TREM2-expressing tumor associated macrophages (TAMs) through antibody dependent cell mediated cytotoxicity (ADCC) and/or antibody dependent cell mediated phagocytosis (ADCP). Pionyr’s PY314 program has been cleared by the FDA for the initiation of Phase 1 clinical trials.

Why target TAMs?

The rationale for developing PY314 as a therapeutic for cancer is based on the substantial evidence from the scientific literature that links the presence of specific types of immune cells called tumor associated macrophages (TAMs) with the growth and maintenance human tumors. TAMs are believed to be a major source of checkpoint inhibitor (CPI) resistance as they employ a multitude of mechanisms to subvert anti-tumor immunity and to directly promote tumor growth. Macrophages are also one of the most abundant immune cells within the tumor microenvironment (TME). Clinically, high levels of TAMs correlate with poor patient prognosis across multiple solid tumor indications, including pancreatic, breast, lung, cervix, and bladder tumors. Consequently, reducing TAM frequency and/or modulating the suppressive TAM function is a promising strategy to convert checkpoint inhibitor resistant patients into checkpoint inhibitor sensitive patients.

TREM2 expression on TAMs

TREM2 is a transmembrane protein which is highly enriched on the surface of TAMs to the exclusion of most other cell types in the body making it a highly attractive target for therapeutic antibodies.  Shown above, TREM2 is specifically expressed in TAMs from single cell immune profiling of stage III renal cell carcinoma.

TREM2 is expressed within the TME and is associated with poorer outcomes

The level of expression of TREM2 has been shown to be higher in cancerous tissues vs normal tissues, likely due to the presence of TREM2 positive myeloid cells infiltrating cancerous tissue. TREM2 levels have also been shown to correlate with poorer patient outcomes across multiple solid tumor types. Shown here is gastric cancer in particular where high levels of TREM2 have been shown to correlate with a lower probability of patient survival.

PY314 Mechanism of Action

PY314 is a monoclonal antibody that binds onto a cell surface receptor named TREM2. Binding leads to targeted depletion of TREM2 positive cells through processes called antibody dependent cell mediated cytotoxicity (ADCC) and/or antibody dependent cell mediated phagocytosis (ADCP). Preclinical data generated within Pionyr suggest that when TAMs are depleted from tumors, pro-inflammatory, anti-tumor immune cells, such as CD8 T-cells, natural killer (NK) and M1-like macrophages become activated and penetrate tumors leading to tumor destruction.

PY314 preclinical model chart

PY314 preclinical model chart

PY314 preclinical model chart

PY314 demonstrates single agent and combinatorial efficacy in preclinical models

Therapeutic administration of PY314 alone or in combination with CPIs resulted in complete regressions of tumors in multiple mouse syngeneic tumor models. In the mice cured of tumors, Pionyr confirmed long-term immunity by reimplanting the same tumor cell lines and finding no tumor growth after a month of treatment-free period.