Minor groove binder antibody conjugates employing a water soluble β-glucuronide linker

The minor groove binder β-glucuronide drug-linker 3 was constructed from amino CBI 1 and determined to be a substrate for Escherichia coli β-glucuronidase (EC 3.2.1.31), resulting in facile drug release. Compound 3 was conjugated to mAbs cAC10 (anti-CD30) and h1F6 (anti-CD70) to give antibody-drug conjugates (ADCs) with potencies comparable to that of free drug 1. The ADCs were largely monomeric at intermediate loading levels (4–5 drug/mAb), in contrast to highly aggregated p-aminobenzylcarbamate dipeptide-based ADCs of 1 previously reported. Significant levels of immunologic specificity were observed with cAC10-3 by comparing antigen positive versus negative cell lines and binding versus non-binding control ADCs. The water soluble β-glucuronide linker is stable in plasma and effectively delivers drugs to target cells leading to potent cytotoxic activities.