casdozokitug (SRF388)

P2, N=134, Active, not recruiting, Coherus Biosciences, Inc. | Recruiting --> Active, not recruiting

P1, N=260, Recruiting, Coherus Biosciences, Inc. | Trial completion date: May 2024 --> Aug 2026 | Trial primary completion date: May 2024 --> Dec 2025

Clinical Trial Registration Number NCT05359861 Sponsored by Surface Oncology Background: Casdozo is the first in class and only clinical-stage IL-27 targeting antibody, which neutralizes IL-27 in the tumor microenvironment and stimulates antitumor response. Triplet blockade of the IL-27, VEGF, and PD-(L)1 pathways with casdozo/atezo/bev has an acceptable safety profile to date with promising antitumor activity in uHCC that warrants continued exploration. Toxicity was consistent with the known profiles of the agents, with no new safety signals identified. Biomarker analysis to evaluate immune response and associations of IL-27 pathway and clinical outcomes is ongoing.

Blocking IL-27 activity by SRF388, a first-in-class monoclonal antibody, enhances immune function and demonstrates monotherapy activity in patients with cancer ( NCT04374877 )...IL-27 + cells are found in close proximity to PD-L1 + cells in patient tumors, and IL-27 can regulate levels of PD-L1 expression in immune cells and tumor cell lines, suggesting cross-talk between these molecules to diminish immune activation within the tumor microenvironment. Combined blockade of IL-27 and PD-(L)1 to enhance antitumor immune responses is currently being evaluated in clinical trials.

A Phase 1 trial of SRF388 (NCT04374877), a first-in-class anti–IL-27 antibody, has demonstrated monotherapy antitumor activity in a patient with non-small cell lung cancer (NSCLC).1 The current study aimed to characterize the immunoregulatory impact of IL-27 signaling by gene expression profiling...Conclusions These studies elucidate the transcriptional networks that are engaged after IL-27 signaling in immune and cancer cells and highlight the parallels with interferon-associated immune regulation. Blockade of IL-27 provides a novel therapeutic strategy to alleviate a gene transcriptional program implicated in immune suppression and checkpoint resistance.

To test the feasibility of IL-27 blockade in the treatment of HCC, we used SRF381, a murine surrogate of the IL-27 neutralizing antibody SRF388 that binds the p28 subunit of IL-27 and is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors (NCT04374877). Antibody-mediated blockade of IL-27 with SRF381 recapitulated the findings in the IL-27RA deficient mice, leading to tumor growth inhibition in a NASH-driven HCC model with concomitant enhancement of NK cell activity. Taken together, our data indicate an important role of IL-27 as a novel immunological checkpoint regulating NK cell-mediated control of HCC and suggest IL-27 blockade as a promising therapeutic target in liver cancer.