HER2-scFv-granzyme B

HER2-scFv-granzyme B (also known as GrB-Fc-4D5 or MRT-201) is a preclinical-stage recombinant fusion protein and targeted immunotoxin being developed by AbBC Therapies and Mirata BioPharma, in collaboration with MD Anderson Cancer Center and the Clayton Foundation for Research. The therapeutic construct consists of a humanized single-chain variable fragment (scFv) derived from trastuzumab (4D5) targeting human epidermal growth factor receptor 2 (HER2/neu), fused to human granzyme B (GrB), a potent pro-apoptotic serine protease. Often linked via an IgG1 Fc domain to facilitate dimerization, optimize pharmacokinetics, and eliminate the need for endosomal escape, the fusion protein binds to HER2 on the surface of tumor cells and undergoes receptor-mediated endocytosis. Once internalized, granzyme B is delivered directly into the cytosol, where it initiates a multimodal apoptotic cascade by directly activating caspases (such as Caspase-3) and cleaving BID to induce mitochondrial outer membrane permeabilization. Additionally, the treatment triggers immunogenic cell death (ICD), leading to the release of damage-associated molecular patterns (DAMPs) like HMGB1, ATP, and calreticulin, which recruit and activate immune cells in the tumor microenvironment. This dual mechanism of direct cytotoxicity and secondary immune activation allows the therapeutic to target both antigen-positive and antigen-negative tumor cells, overcoming resistance to conventional anti-HER2 therapies. It is currently in preclinical development for HER2-expressing solid tumors, including breast, gastric, bladder, and gallbladder cancers.

Other names

HER2-targeted granzyme B fusion proteinHER-2-targeted granzyme B fusion proteinHER 2-targeted granzyme B fusion proteinimmunoGrB