title: Minor groove binder antibody conjugates employing a water soluble beta-glucuronide linker.
abstract: The minor groove binder beta-glucuronide drug-linker 3 was constructed from amino CBI 1 and determined to be a substrate for Escherichia coli beta-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 (4-5drug/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 beta-glucuronide linker is stable in plasma and effectively delivers drugs to target cells leading to potent cytotoxic activities.
authors.affiliation: Seattle Genetics Inc., 21823 30th Drive S.E., Bothell, WA 98021, USA. sjeffrey@seagen.com
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
authors.forename: Minh T
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Moser
authors.forename: Damon L
authors.initials: DL
authors.lastname: Meyer
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents; D016503:Drug Delivery Systems / Q000379:methods*; D005965:Glucuronates / Q000737:chemistry*; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D005965:Glucuronates; D018796:Immunoconjugates; D011355:Prodrugs; D005966:Glucuronidase