Slaga, Ellerman, and Lombana et al. used HER2 as a target to explore how bivalent avidity effects can improve the therapeutic index of T cell-redirecting bispecific (TDB) antibodies. When used in an anti-HER2 TDB construct, Fabs with reduced monovalent HER2 affinity showed 1000x improved selectivity for high vs low HER2-expressing tumor cell lines in binding and cytotoxicity assays, low cytotoxicity to low HER2-expressing tumor or normal cells, and effective tumor control in human PBMC reconstituted mouse xenografts. No untoward pharmacological effects were observed in cynomolgus monkeys, supporting clinical translation.
A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab-immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell-directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.