This study evaluates the safety of recombinant epidermal growth factor-bispecific angiotoxin (eBAT), a bispecific ligand-directed toxin targeting both tumors and their vasculature in the tumor microenvironment. eBAT combines EGF and uPA cytokines on a single-chain molecule with truncated Pseudomonas toxin. Prior studies in mice and dogs have shown its efficacy, with mild and self-limiting toxicities in various models, including immunocompetent and tumor-bearing mice, uPAR knockout mice, and species-optimized models. However, at higher doses, eBAT caused dose-dependent liver injury in mice.
The clinical development of eBAT for treating sarcoma and other cancers is supported by its safety profile. Unlike traditional EGFR-targeted therapies, which are associated with significant toxicities (e.g., cutaneous, gastrointestinal, hepatotoxicity), eBAT displayed a more manageable toxicity profile in both preclinical and clinical settings.
Three clinical studies were conducted in dogs with spontaneous hemangiosarcoma. In total, 78 dogs received eBAT at a biologically active dose of 50 µg/kg. Adverse events were mild (grade 3 or lower) and included hypotension (15.3%), seizures (2.6%), and gastrointestinal symptoms (10.2%). All events were reversible with appropriate medical intervention, including fluids for hypotension and maropitant for gastrointestinal toxicity. These results suggest that eBAT may be well-tolerated in dogs, similar to other EGFR-targeted therapies but with a more favorable side-effect profile.
In terms of efficacy, eBAT showed potential in prolonging survival in dogs with advanced hemangiosarcoma, a cancer typically diagnosed at an advanced stage. While eBAT showed promise in treating this aggressive cancer, further studies are needed to better understand its mechanisms of action, including its impact on angiogenesis, tumor inflammation, and the tumor microenvironment.
The study also indicates that eBAT’s dual specificity may confer greater efficacy and lower toxicity compared to monospecific agents, as seen in earlier research where it was less toxic than EGF-PE and uPA-PE. Future research will explore these mechanisms more deeply to optimize its therapeutic potential for human cancer patients.
