Targeted delivery of heat shock protein 90 inhibitors prevents growth of HER2-positive tumor

Abstract

Heat shock protein 90 (HSP90) plays a crucial role in the survival of cancer cells. When an inhibitor blocks the signaling pathway of HSP90, its client proteins are degraded, destabilized, and inactivated. Although HSP90 inhibitors are in various clinical trials, there are no HSP90 inhibitor-immunoconjugates due to the difficulty in chemical modification of HSP90 inhibitors. Here we show that biological affinity binding enables the incorporation of HSP90 inhibitors to an antibody without the need for chemical conjugation. We constructed a recombinant fusion protein composed of an anti-HER2 scFv and an HSP90 inhibitor-binding domain (HER2 scFv-HBD). The HBD spontaneously captures a HSP90 inhibitor, resulting in the formation of an HER2 scFv-HBD/HSP90 inhibitor complex. In an HER2-positive cancer mouse model, targeted delivery of HSP90 inhibitors was confirmed and improved anti-cancer efficacy was observed. We have proven the promise of tumor-directed HSP90 inhibition as a new form of targeted therapy.

Keywords: Antibody-drug conjugate; Geldanamycin; HER2; HSP90 inhibitor; Targeted delivery.