On May 6, 2022 Pionyr Immunotherapeutics, Inc., a company developing first-in-class Myeloid TuningTM antibody therapeutics that enhance the body’s antitumor immunity by altering, or "tuning," immune cells within the tumor microenvironment, reported that PY314, a monoclonal antibody targeting TREM2 (triggering receptor expressed on macrophages 2), was safe and well-tolerated in a Phase 1a dose-escalation study as a single agent and in combination with pembrolizumab at its label-approved dose (Press release, Pionyr Immunotherapeutics, MAY 26, 2022, View Source [SID1234615132]). A maximum tolerated dose (MTD) was not observed over the range of PY314 doses tested and a dose for study expansion was recommended based on an analysis of clinical data (including PK exposure) in the context of supportive preclinical data models. The study will be featured in a poster presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, held June 3-7 virtually and in Chicago.

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"Pionyr developed PY314 to precisely bind human TREM2 and retune the tumor microenvironment by driving the selective depletion of TREM2 positive tumor-associated macrophages. Removing these macrophages shifts the balance of myeloid cells towards more pro-inflammatory populations and is expected to increase and promote anti-tumor immune responses," said Leonard Reyno, EVP and Chief Medical Officer of Pionyr Immunotherapeutics. "We have applied what we have learned from the Phase 1a study to identify a recommended dose for Phase 1b expansion studies. We have already begun enrolling patients in these studies and expect to have new data this year and into 2023."

Safety and Tolerability as a Monotherapy and in Combination with Pembrolizumab Support Additional Clinical Studies

The Phase 1a dose-escalation study of PY314 was a non-randomized, open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PY314 as a single agent and in combination with checkpoint inhibitor pembrolizumab in 28 subjects with advanced solid tumors. Dosing was intravenous and administered once every three weeks. Four predefined dose levels of PY314 were delivered both as a single agent and in combination with pembrolizumab. No dose-limiting toxicities, drug-related serious adverse reactions, or high-grade treatment-related adverse events (TRAEs) that resulted in treatment discontinuance were seen. Twelve patients experienced at least one TRAE, and these were low-grade in all but one subject who experienced a treatment-related immune system disorder. Eight patients experienced serious adverse events, all unrelated to treatment.

Linear Dose-Response Observed and Recommended Dose for Expansion Studies Determined

PY314 pharmacokinetics were linear and dose-proportional, with a half-life of five to nine days and no evidence of interference by pembrolizumab. The best radiographic response was stable disease, observed in eleven subjects (39.3%), which ranged in duration from nine to 42 weeks. Ten mg/kg PY314 was determined to be the recommended dose for expansion. Five expansion cohorts in patients with metastatic refractory solid tumors (triple-negative or HR-positive HER2 negative metastatic breast cancer, non-small cell lung cancer, renal cell carcinoma, colorectal cancer, ovarian cancer) are enrolling. Information about the ongoing Phase 1b expansion study is available at www.clinicaltrials.gov.

Poster Presentation at ASCO (Free ASCO Whitepaper) 2022

The poster titled, "A Phase 1a Dose Escalation Study of PY314, a TREM2 (Triggering Receptor Expressed on Myeloid Cells 2)-Targeting Monoclonal Antibody," will be featured in a poster session at the ASCO (Free ASCO Whitepaper) 2022 Annual Meeting on Sunday, June 5, 2022, 8:00 AM-11:00 AM CDT. The abstract is currently available on the ASCO (Free ASCO Whitepaper) 2022 website here, and the poster will be available on the Pionyr company website here after the completion of the ASCO (Free ASCO Whitepaper) poster session.

About Myeloid TuningTM

Pionyr has developed a therapeutic platform called Myeloid Tuning, a process that rebalances the tumor microenvironment (TME) to promote anti-tumor immunity. Myeloid cells are a type of immune cell and are part of a family of cell types that play an important role in both the activation and suppression of the immune response to cancer.

One such critical type of myeloid cell, tumor-associated macrophages (TAM), are a key component of the TME. TAMs are generally categorized into two functionally contrasting subtypes called M1-like and M2-like macrophages: M1-like typically exerts anti-tumor functions, including directly mediating antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells; M2-like macrophages can promote the occurrence and metastasis of tumor cells, inhibit T cell-mediated anti-tumor immune response, promote tumor angiogenesis and lead to tumor progression.

Myeloid Tuning TM effectively describes the mechanism of introducing agents that shift the balance of inhibitory myeloid cells – including M2-like TAMs – towards more inflammatory M1-like TAMs to promote anti-tumor immune responses in the TME and destroy solid tumors.

About PY314

PY314 is a humanized IgG1 afucosylated monoclonal antibody, delivered by intravenous infusion, that binds Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) on the surface of immunosuppressive, pro-tumorigenic myeloid cells. It is designed to deplete TREM2-expressing TAMs, leading to productive anti-tumor immunity. Preclinical data generated by Pionyr suggest that when TAMs are depleted from tumors, pro-inflammatory, anti-tumorigenic immune cells such as CD8 T-cells, natural killer (NK), and M1-like macrophages become activated and penetrate tumors leading to tumor destruction. PY314 is currently being evaluated in a Phase 1b dose-expansion study as a single agent and in combination with pembrolizumab (Keytruda) as a treatment for refractory solid tumors and gynecologic cancer, colorectal cancer, lung adenocarcinoma, renal cell carcinoma, triple-negative breast cancer, hormone receptor/growth factor receptor-negative breast cancer, and ovarian cancer.