Use of Carbonic Anhydrase IX Inhibitors for Selective Delivery of Attached Drugs to Solid Tumors

Abstract

Central to the goal of precision medicine lies the ability to target an effective drug specifically to diseased cells, thereby avoiding the uptake and collateral toxicity that arises when good drugs accumulate in healthy cells. While antibody-drug conjugates (ADCs) have pioneered many efforts in this field, small molecule drug conjugates (SMDCs) with high specificities for diseased cell types are now displaying equal if not greater potential because of their improved abilities to penetrate solid tissues. For both technologies, however, success has invariably depended on an ability to identify a receptor that is overexpressed on the desired pathologic cell (e.g., cancer cell, virus-infected cell, inflammatory cell, etc.), but absent or weakly expressed on all other healthy cells. While few cell surface receptors can satisfy these criteria, one that has attracted considerable recent attention has been carbonic anhydrase IX (CA IX), a cell surface enzyme that is expressed in virtually all hypoxic tissues, but minimally expressed, if at all, in healthy tissues. Because most solid tumors are hypoxic, CA IX-targeted SMDCs are now being explored as broad-spectrum agents for the diagnosis and therapy of CA IX-expressing malignancies. The following chapter highlights some of the groundbreaking research in this area and provides key insights into how the design of a CA IX-targeted SMDC can impact efficacy.