MT-5111: A novel HER2 targeting engineered toxin body in clinical development.

433 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 binds an epitope on HER2 distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2 targeting agents. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration capability in solid tumor settings. Methods: HER2 expression and activity of MT-5111 was assessed in vitro by flow cytometry and cell viability assays. Serum exposure and tolerability of MT-5111 was measured in non-human primate (NHP) studies. Results: MT-5111 effectively kills 8/9 cell lines (2 gastric) with moderate to high HER2 surface expression, as well as two additional gastric cell lines with lower HER2 expression. No cytotoxicity is observed on multiple HER2- cell lines. As a protein, MT-5111 is not a substrate of drug efflux transporters that limit efficacy of ADCs. MT-5111 demonstrates effective cell-killing in vitro against cell lines expressing HER2 but resistant to trastuzumab (HCC1954) or T-DM1 (JIMT-1 and gastric SNU-216), highlighting the benefit of a novel mechanism of action to treat resistant disease. MT-5111 binds human and NHP HER2 protein. Based on serum exposure of MT-5111 in NHPs used to model pharmacokinetics, planned MT-5111 dosing in humans is above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 has a short half-life that, while allowing for efficient tumor cell targeting, minimizes serum exposure to avoid systemic effects over time. Conclusions: A Phase 1, first in human, open-label dose escalation and expansion study of MT-5111 (NCT04029922) in subjects with HER2+ solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. MT-5111 represents a novel HER2 targeted therapy for patients with HER2+ cancers with potential to overcome mechanisms of tumor resistance to existing therapies.