Barriers to antibody therapy in solid tumors, and their solutions

Abstract

Antibody drugs have become the mainstream of cancer treatment due to advances in cancer biology and Ab engineering. However, several barriers to Ab therapy have also been identified. These include various mechanisms for Ab drug resistance, such as heterogeneity of antigen expression in tumor cells and reduction in antitumor immunity due to expression diversity, polymorphism of Fc receptors (FcR) in effector cells, and reduced function of effector cells. Countermeasures to each resistance mechanism are being investigated. This review focuses on barriers that impede the delivery of Ab drugs due to features of the solid tumor microenvironment. Unlike hematological malignancies, in which the target tumor cells are in blood vessels, clinical solid tumors contain cancer stroma, which interferes with the delivery of Ab drugs. In addition, the cancer mass itself interferes with the penetration of Ab drugs. In this article, I will consider the etiology of cancer stroma and propose a new Ab drug development strategy for solid cancer treatment centering on cancer stromal targeting (CAST) therapy using anti-insoluble fibrin Ab-drug conjugate (ADC), which can overcome the cancer stroma barrier. The recent success of ADCs, chimeric antigen receptor T cells (CAR-Ts), and Bi-specific Abs is changing the category of Ab drugs from molecular-targeted drugs based on growth signal inhibition to cancer-specific targeted therapies. Therefore, at the end of this review, I argue that it is time to reorient the concept of Ab drug development.

Keywords: ADC; CAST therapy; EPR effect; antibody; antibody drug resistance; blood coagulation; cancer specificity; cancer stroma; insoluble fibrin.