CHICAGO--(BUSINESS WIRE)--Dr. Michael Rosenblum and his team at MD Anderson Cancer Center, Houston, TX, presented updated data on TGI (Targeted Granzyme B immunotherapy) at the 2018 American Association of Cancer Research Annual Meeting (AACR). The research was supported by Mirata Biopharma LLC and conducted by the Clayton Foundation for Research (“Clayton Foundation”).
Dr. Rosenblum’s team developed a fusion protein, GrB-Fc-IT4 (MRT-101), that contains a humanized scFv binding domain targeting the cell surface receptor Fn14, an antigen highly expressed in a variety of solid tumors, and containing the human serine protease granzyme B (GrB) as the cytotoxic payload. The construct includes the IgG hinge Fc domain linker for efficient dimerization and an overall high molecular weight, thereby designed to provide a prolonged serum half-life (~40 h in mice). This unique format mimics human immune effector cell function and induces target cell death through the activation of a variety of well described pro-apoptotic cascade signals.
The poster, entitled “Molecular mechanistic and in vivo efficacy studies of Fn14-targeted fusion constructs containing human granzyme B,” demonstrated that Western blot studies on human TNBC cells (MDA-MD-231) have shown that intact MRT-101 is translocated into the cytosol in less than 1 hour after exposure and is detectable in the cytosol for at least 8 hours. The free GrB component is also detected by the Western blot 4 hours after treatment and persists for up to 8 hours. Both of these agents trigger apoptotic cascades through activation of various caspases and induction of mitochondrial damage. Studies demonstrating cytochrome C release and mitochondrial depolarization are ongoing and will be reported. Incubation with the lysosomotropic agent chloroquine did not alter the IC50 of MRT-101, suggesting that the fusion protein is not appreciably held in the endosomal compartment.
In vivo studies have shown that MRT-101 is well tolerated in BALB/c mice after intravenous administration of 5 doses at 20 mg/kg/dose. This dose level showed no evidence of toxicity in any of the major organs such as liver and kidneys. In vivo efficacy studies conducted on NSGNOD scid mice demonstrated significant tumor growth inhibition of established orthotopic breast tumors (MDA-MB-231), with no tumor growth for up to 30 days after implantation. Treatment of nude mice bearing lung PDX tumors showed a 60% tumor growth inhibition when compared to the vehicle control group. These results, in combination with previous in vitro and in vivo studies, demonstrate that the completely human MRT-101 construct is a selective, highly potent, non-toxic and effective antigen-driven drug with significant potential for the treatment of Fn14 positive tumors that acts through a new and unique mechanism of action.
Full poster from the AACR can be accessed via Mirata Biopharma website: http://www.miratabiopharma.com/abstracts-presentations/
Mirata BioPharma was founded in January of 2017 to focus on new immuno-oncology fusion protein technology. Our initial focus is to develop biopharmaceutical compounds licensed from the Research Development Foundation, a nonprofit supporting organization of The Clayton Foundation for Research (“Clayton Foundation”).