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

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 8; pp. 2278 - 2280
• Main Authors: Jeffrey, Scott C., Nguyen, Minh T., Moser, Ruth F., Meyer, Damon L., Miyamoto, Jamie B., Senter, Peter D.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-04-2007; Elsevier
• Subjects: Aggregation; Anti-CD30; Anti-CD70; Antibodies, Monoclonal - therapeutic use; Antibody; Antigens, Neoplasm - immunology; Antineoplastic Agents, Alkylating - chemical synthesis; Antineoplastic Agents, Alkylating - pharmacokinetics; Biological and medical sciences; cAC10; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Conjugate; Cross-Linking Reagents; Delivery; Drug; Drug Delivery Systems - methods; Drug-linker; Escherichia coli; Glucuronates - chemistry; Glucuronidase - metabolism; h1F6; Humans; Immunoconjugates - chemistry; Immunoconjugates - metabolism; Immunoconjugates - therapeutic use; Inhibitory Concentration 50; Linker; Medical sciences; Minor groove binder; Miscellaneous; Monoclonal; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Release; Solubility; Targeted; β-Glucuronidase; β-Glucuronide; Drug; β-Glucuronidase; Conjugate; Antibody; Drug-linker; h1F6; Linker; Aggregation; Minor groove binder; Targeted; Anti-CD30; cAC10; Delivery; Monoclonal; β-Glucuronide; Release; Anti-CD70; Cancer; Spacer arm; hlF6; Escherichia coli; Cytotoxicity; Monoclonal antibody; Organic carbamate; Glucuroconjugate; Lymphoproliferative syndrome; Bacteria; Chemical synthesis; Tumor cell; Enterobacteriaceae; Minor groove; Enzyme; Hodgkin disease; Malignant hemopathy; In vitro; Lymphoma; Biological activity; Substrate; Water soluble compound; Cell line; Glycosidases; Uronic acid; Hydrolases; Conjugated compound; O-Glycosidases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.01.071

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.