SOUTH SAN FRANCISCO, Calif.– Kezar Life Sciences, Inc. (Nasdaq), a clinical-stage biotechnology company discovering and developing breakthrough treatments for immune-mediated and oncologic disorders, today presented preclinical data on the company’s novel protein secretion program during two poster sessions at the American Association for Cancer Research (AACR) 2021 Virtual Annual Meeting.
“The growing body of evidence generated by our team supports the strong therapeutic potential of inhibiting Sec61 and the protein secretion pathway as a way to generate novel therapies to treat multiple tumor indications,” said Christopher Kirk, PhD, Kezar’s President and Chief Scientific Officer. “These data provide a robust scientific framework for identifying which tumor types might be the most sensitive to inhibition of the Sec61 translocon and the protein secretion pathway.”
Kezar examined the activity of KZR-261, a small molecule inhibitor of the Sec 61 translocon, and a closely related representative molecule in hundreds of tumor cell lines. The objective was to compare drug activity and identify sensitivity to gene mutations and impact on gene expression levels. No single gene predicted the activity of KZR-261, consistent with the known impact of KZR-261 on multiple targets. However, representative gene modules identified through mechanism agnostic analysis were associated with sensitivity in tumor cells and show high overlap with key processes involved in protein secretion. Analyses of primary tumor and tissue expression datasets predict that many tumor types will be more sensitive than normal tissues and cells. Data from these analyses will inform selection of tumor types for study in future clinical trials.
Global proteomic profiling of protein secretion in tumor cells and non-transformed cells was also conducted. KZR-261 and the related molecules reduce expression of Sec61 clients, namely secreted and transmembrane proteins. In tumor cells, these compounds reduced expression of approximately 10% of Sec61 clients by at least two-fold. However, in non-transformed cells, KZR-261 inhibited the expression of less than 5% of measured Sec61 clients, many of which can be measured from clinical samples in future clinical trials.
Pending successful completion of drug product manufacturing, submission of an Investigational New Drug (IND) application is anticipated in mid-2021. A first-in-human Phase 1 study to evaluate the safety and anti-tumor activity of KZR-261 in patients with solid tumors is expected to commence shortly thereafter.
