(164s) Synthesis and Evaluation of Megamolecule Dendrimers in Cancer Therapy

Antibody therapies have the potential to improve treatment outcomes for patients with solid tumors by allowing for selective binding of overexpressed receptors, largely sparing healthy cells. However, we lack the ability to readily tailor the structure of these therapeutics, which contributes to factors such as off-target immunogenic responses, inability to penetrate solid tumors, and both high dosage and infusion requirements. Recent work from the Mrksich group demonstrated a rapid synthesis approach to construct modular protein scaffolds (termed megamolecules), confirming the programmability of these therapeutics. It is believed that tuning the topology of megamolecule nanostructures will enable the generation of a new class of cell-specific biologics. In this talk, I will explore our approach to address current limitations in precise protein engineering and targeted therapy design. Here, we leverage the megamolecule strategy to construct of multi-valent megamolecules with hypervalent affinity for HER2+ tissue. In order to accomplish this, we first evaluate a panel of single domain antibody fragments (nanobodies) that have varied affinity for HER2+ receptors. Programming these affinity domains into multimeric structures – up to the 2nd generation – revealed atomically precise near megadalton protein dendrimers with a controlled number of anti-HER2 domains. We evaluate these structures in vitro for their selective binding affinity to HER2+ tissue and related avid affinity of the dendrimers to structural architecture. Further, in breast cancer tumor mice models, we explored the in vivo effects of our hypervalent megamolecules for improved on-target binding and efficacy through biodistribution studies. The resulting innovation from this study has the potential to enable a shift in our approach to construct high efficacy, programmable nanotherapeutics that results in minimizing off-tumor cytotoxic effects and improves tumor reduction in vivo.