A Sustained-Release Biopolymer-Immunotoxin Fusion for Treatment of Brain Tumors

摘要

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor despite extensive treatment measures and intense research efforts. There is an urgent need for innovative therapies that surpass the often debilitating and ineffectual clinical standard of care. We seek to prolong the bioavailability of a promising GBM-specific, highly potent immunotoxin through sustained release from an intratumorally injected, gel-like polypeptide depot. While protein-based drugs are an exciting alternative to chemotherapy and have the potential for high specificity and bioactivity, they are prone to poor pharmacokinetic profiles. Rapid clearance and short half-life can severely limit the clinical relevance of these compounds. We anticipate the intratumoral injection of this immunotoxin depot formulation in vivo will result in slow dissolution into the surrounding tissue and enhanced efficacy. The sustained-release properties will be introduced by the well-characte rized biopolymer elastinlike polypeptide (ELP); a non-immunogenic, thermally responsive, and easily manipulated biomaterial that has been extensively studied in intratumoral drug depots. The kinetics of release from this immunotoxin depot will be optimized using a library of ELPs with a range of phase transition behaviors. The bioactive component of the drug- an Affibody-toxin conjugate-is internalized upon high affinity binding of the Affibody to GBM cell-specific receptors. The appended bacterial toxin is an exceptionally powerful drug, as it is highly cytotoxic regardless of cell cycle status. Beyond inclusion of the depot-forming ELP, our work improves upon a previously studied, GBM-specific immunotoxin by 1) enhancing targeting moiety stability through use of the highly robust Affibody 2) increasing valency and therefore avidity through recombinant fusion of multiple Affibody domains 3) improving biocompatibility with an engineered, non-immunogenic toxin. Given the pi comolar potency of our biopolymer-immunotoxin fusion in relevant cell lines in vitro, we anticipate outstanding therapeutic promise in vivo. We are currently validating this hypothesis in an orthotopic, patient-derived xenograft GBM mouse model.