title: Highly Potent, Anthracycline-based Antibody-Drug Conjugates Generated by Enzymatic, Site-specific Conjugation.
abstract: Antibody-drug conjugates (ADC) are highly potent and specific antitumor drugs, combining the specific targeting of mAbs with the potency of small-molecule toxic payloads. ADCs generated by conventional chemical conjugation yield heterogeneous mixtures with variable pharmacokinetics, stability, safety, and efficacy profiles. To address these issues, numerous site-specific conjugation technologies are currently being developed allowing the manufacturing of homogeneous ADCs with predetermined drug-to-antibody ratios. Here, we used sortase-mediated antibody conjugation (SMAC) technology to generate homogeneous ADCs based on a derivative of the highly potent anthracycline toxin PNU-159682 and a noncleavable peptide linker, using the anti-HER2 antibody trastuzumab (part of Kadcyla) and the anti-CD30 antibody cAC10 (part of Adcetris). Characterization of the resulting ADCsin vitroandin vivoshowed that they were highly stable and exhibited potencies exceeding those of ADCs based on conventional tubulin-targeting payloads, such as Kadcyla and Adcetris. The data presented here suggest that such novel and highly potent ADC formats may help to increase the number of targets available to ADC approaches, by reducing the threshold levels of target expression required.Mol Cancer Ther; 16(5); 879-92. ©2017 AACR.
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Stefan
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Rémy
authors.initials: R
authors.lastname: Gébleux
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Waldmeier
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Tamara
authors.initials: T
authors.lastname: Hell
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Escher
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Fabian I
authors.initials: FI
authors.lastname: Wolter
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Grawunder
authors.affiliation: NBE-Therapeutics AG, Basel, Switzerland. roger.beerli@nbe-therapeutics.com.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Beerli
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D019881:Aminoacyltransferases / Q000737:chemistry; D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage* / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry; D000079963:Brentuximab Vedotin; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D017730:Ki-1 Antigen / Q000737:chemistry / Q000276:immunology; D008453:Maytansine / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D000068878:Trastuzumab / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D019881:Aminoacyltransferases; D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D000079963:Brentuximab Vedotin; D003546:Cysteine Endopeptidases; D004317:Doxorubicin; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C502356:3'-deamino-3'',4'-anhydro-(2''-methoxy-3''-oxy-4''-morpholinyl)doxorubicin; C120542:sortase A; C508053:ERBB2 protein, human