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.

Non-internalising antibody–drug conjugates

“…Efforts have also focused on targeting proteins other than those expressed on the cancer cell surface, for example, secreted proteins Gal3BP, 30 LRG1, 34 and MMP9. 39 The field has also moved towards targeting the unique physiology of cancer: tumours possess abundant stroma and unique vasculature containing collagen, 40 fibrin, 43 fibronectin, 8,45,46 and tenascin-C [51][52][53]57 -all of which have recently been explored for targeting by non-internalising ADCs. Promising preliminary results have been obtained with stromal-targeting ADCs, this approach may offer a much-needed alternative to internalising ADCs in the future for the treatment of stroma-rich solid tumours.…”

“…11). 39 Specific binding of the antibody to MMP9 thus brought the inhibitor in close contact with MMP9, enabling selective inhibition of only that member of the metalloproteinases. The ADCs did not require internalisation or breakdown of the conjugate since the antibody recognises an epitope close to the MMP9 active site but does not impede inhibitor binding.…”

Matrix Metalloproteinases in Helicobacter pylori–Associated Gastritis and Gastric Cancer

“…Antibodies REGA-3G12, AB0041 (humanized GS-5745), AB0046 to MMP-9, and LEM-2/15, 9E8 and 3A2 antibodies to MT1-MMP have displayed selectivity and promising results in cell cultures and some mouse disease models [90,137]. In addition, antibody REGA-3G12-drug conjugates have been created to improve antibody effectiveness toward MMP-9 activity [138]. Further progress in protein engineering and computational design has suggested some novel antibody-based inhibitors, in particular, a selective MT1-MMP antibody DX-2400.…”

Antibody Conjugates-Recent Advances and Future Innovations

“…In a similar fashion, dasatinib As with other oncology examples, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors d have not succeeded in the clinic due to low therapeutic index with limiting toxicities, but exploitation of ADC targeted delivery of NAMPT inhibitors provides an outlet for these potent payloads [101] in preclinical studies. Similarly, an anti-MMP9 antibody was conjugated to a non-selective MMP inhibitor (CGS27023A, e), showing remarkable selectivity for MMP9 alone, due to the antibody targeting in vitro [102].…”