De novo designed protein switches to enable increased specificity of targeted therapeutics

Abstract

Targeted immunotherapies typically rely on the recognition of a single cell-surface marker, and as such, their specificity is limited and prone to incidentally harming healthy cells. This is problematic for developing treatments for solid tumors where ‘tumor-specific’ antigens are also expressed on healthy tissues. Using computational protein design, we developed colocalization- dependent switches which activate only on the surface of cells expressing a precise combination of antigens (Lajoie et al., 2020). We have shown that these designed protein switches are highly effective at discerning between closely related populations of cells in vitro and can selectively recruit CAR T cells to kill only double-positive cells. However, the number of protein components required in our original system make clinical validation complicated.Through design of new protein switches and incorporation of de novo proteins designed to directly engage and activate immune cells, we have developed a simplified system for selectively killing cancer cells without harming closely related healthy cells.