Developing an Antibody–Drug Conjugate Approach to Selective Inhibition of an Extracellular Protein

Abstract

Antibody-drug conjugates (ADCs) are a growing class of therapeutics that harness the specificity of antibodies and the cell-killing potency of small-molecule drugs. Beyond cytotoxics, there are few examples of the application of an ADC approach to difficult drug discovery targets. Here, we present the initial development of a non-internalising ADC, with a view to selectively inhibiting an extracellular protein. Employing the wellinvestigated matrix metalloproteinase-9 (MMP-9) as our model, we adapted a broad-spectrum, nonselective MMP inhibitor for conjugation and linked this to a MMP-9-targeting antibody. The resulting ADC fully inhibits MMP-9, and ELISA results suggest antibody targeting can direct a nonselective inhibitor.