Synthesis and Activity\nof T‑Cell Tumor-Directing\nMegaMolecules

This paper describes the synthesis, characterization,\nand functional\nactivity of 26 MegaMolecule-based bispecific antibody mimics for T-cell\nredirection toward HER2+ cancer cells. The work reports functional\nbispecific MegaMolecules that bind both receptor targets, and recruit\nand activate T-cells resulting in lysis of the target tumor cells.\nChanging the orientation of linkage between Fabs against either HER2\nor CD3ε results in an approximately 150-fold range in potency.\nIncreasing scaffold valency from Fab dimers up to tetramers improves\nthe potency of the antibody mimics up to 5-fold, but with diminishing\nreturns in effective dose beyond trimeric formats. Antibody mimics\nthat present either one or two Fabs against either receptor target\nallows for initial engagement of one cell type over the other. Finally,\nthe antibody mimics significantly reduce HER2+ tumor volumes in a\nhumanized xenograft model of breast cancer.