Fate Therapeutics Announces FDA Clearance of IND Application

Fate Therapeutics, Inc. recently announced the US FDA has cleared the company’s Investigational New Drug (IND) application for FT596, the company’s first off-the-shelf chimeric antigen receptor (CAR) natural killer (NK) cell cancer immunotherapy which targets multiple tumor-associated antigens. FT596 is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three functional modalities designed to optimize anti-tumor activity: a proprietary CAR targeting B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor; and an interleukin-15 receptor fusion (IL-15RF). The Company plans to initiate clinical investigation of FT596 as a monotherapy and in combination with CD20-directed monoclonal antibodies for the treatment of B-cell lymphoma and chronic lymphocytic leukemia.

“FT596 is a ground-breaking product candidate with the potential to supplant current-generation patient-specific and allogeneic CAR19 T-cell immunotherapies, which recognize only one antigen and fail to address the significant risk of relapse due to antigen escape,” said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. “Our robust clinical development strategy for FT596 is designed to target multiple tumor-associated antigens for the treatment of B-cell lymphomas and leukemias. We believe the product candidate’s engineered functionality, coupled with its ability to be cost-effectively administered on-demand in multiple treatment cycles, will deliver a deeper and more durable response to patients compared to single-antigen targeted CAR19 T cells.”

While CAR19 T-cell therapies have demonstrated profound initial responses, not all patients respond to therapy and, even for those who initially respond, durability of response remains a significant limitation. Downregulation of target antigen CD19 from the tumor cell surface has been clinically demonstrated to be an important mechanism of resistance.

FT596, which is the first cellular immunotherapy engineered with three active anti-tumor components cleared for clinical investigation by the FDA, is uniquely designed to overcome CD19 antigen escape. In addition to a proprietary CAR targeting CD19, FT596 expresses a novel hnCD16 Fc receptor that has been modified to augment antibody-dependent cellular cytotoxicity, enabling coincident targeting of CD19 and additional antigens such as CD20. FT596 also expresses IL-15RF, a potent cytokine complex that promotes survival, proliferation and trans-activation of NK cells and CD8 T cells without the need for systemic cytokine support. Together, these features of FT596 are intended to maximize potency and minimize toxicity in treated patients.

FT596 is the third off-the-shelf, iPSC-derived NK cell product candidate from the Company’s proprietary iPSC product platform cleared for clinical investigation by the FDA in less than one year. The Company is conducting first-in-human clinical trials of FT516, an off-the-shelf NK cell cancer immunotherapy engineered to express hnCD16, for the treatment of acute myeloid leukemia and B-cell lymphoma, and FT500, an off-the-shelf NK cell cancer immunotherapy, for the treatment of advanced solid tumors.

FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology, which contains a NKG2D transmembrane domain, a 2B4 co-stimulatory domain and a CD3-zeta signaling domain, that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor that has been modified to augment antibody-dependent cellular cytotoxicity by preventing CD16 down-regulation and enhancing CD16 binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that promotes enhanced NK cell activity. In preclinical studies of FT596, the Company has demonstrated that the concurrent activation of the CAR and hnCD16 targeting modalities, in combination with IL-15RF signaling, convey synergistic anti-tumor activity. Increased degranulation and cytokine release were observed upon concurrent receptor activation in lymphoma cancer cells as compared to activation of each receptor alone, indicating that dual-antigen engagement may elicit a deeper and more durable response. Additionally, in a mixed cellular composition cytotoxicity assay comprised of CD19+ and CD19- tumor cells, FT596 combined with rituximab effectively eliminated the heterogeneous population of tumor cells, a result that was not observed with single-antigen targeted CAR19 T cells.

The company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered in repeat doses to mediate more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is fraught with batch-to-batch and cell-to-cell variability that can affect safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 250 issued patents and 150 pending patent applications.

Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for cancer and immune disorders. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Company’s immuno-oncology product candidates include natural killer (NK) cell and T-cell cancer immunotherapies, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens with chimeric antigen receptors (CARs). The Company’s immuno-regulatory product candidates include ProTmune™, a pharmacologically modulated, donor cell graft that is currently being evaluated in a Phase 2 clinical trial for the prevention of graft-versus-host disease, and a myeloid-derived suppressor cell immunotherapy for promoting immune tolerance in patients with immune disorders. Fate Therapeutics is headquartered in San Diego, CA. For more information, visit www.fatetherapeutics.com.