Overcoming Immune Checkpoint Inhibitor Resistance via Potent and Selective Dual αvβ6/8 Inhibitors Based on Engineered Lasso Peptides
Integrins v{beta}6 and v{beta}8 in the tumor microenvironment (TME) have been shown to activate immunosuppressive TGF-{beta}, which serves as an important mechanism for immune checkpoint inhibitor resistance in a range of tumors. In this study, we demonstrate the utility of lasso peptides as versatile scaffolds for designing new therapeutics. A series of highly potent and selective dual v{beta}6/8 inhibitors were engineered through a combination of epitope scanning, computational design, and directed evolution. Several analogs, such as lassotides 36 and 47, were fully characterized and physicochemical, in vitro pharmacological, and in vivo data are reported. Lassotide 47, a half-life extended derivative of 36, was shown to strongly sensitize anti-mPD-1-resistant tumors in mice when dosed in combination with the checkpoint inhibitor. The 47/anti-mPD-1 combination was shown to halt tumor growth and regress tumors in mouse models of triple negative breast and ovarian cancers. Dual inhibition of v{beta}6/8 integrins expressed in the TME thus represents a promising tumor-specific strategy to overcome TGF-{beta}-driven resistance and enhance the anti-tumor efficacy of immune checkpoint inhibitors.