title: The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody-Drug Conjugates.
abstract: A strategy for the conjugation of alcohol-containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self-immolative unit. A series of MAC β-glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution-dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β-glucuronidase. To assess the MAC technology for ADCs, the potent microtubule-disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β-glucuronide AE drug linker to the anti-CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self-immolative unit for alcohol-containing payloads within ADCs, a class that has not been widely exploited.
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA. rkolakowski@seagen.com.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Kolakowski
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Haelsig
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Kim K
authors.initials: KK
authors.lastname: Emmerton
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Chris I
authors.initials: CI
authors.lastname: Leiske
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Julia H
authors.initials: JH
authors.lastname: Cochran
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.affiliation: Seattle Genetics, 21823 30th Dr SE, Bothell, WA, 98021, USA. sjeffrey@seagen.com.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
mesh_terms: D062365:Aminobenzoates / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002219:Carbamates / Q000737:chemistry*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006689:Hodgkin Disease / Q000188:drug therapy; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D010665:Phenylpropanolamine / Q000031:analogs & derivatives*; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D062365:Aminobenzoates; D000074322:Antineoplastic Agents, Immunological; D002219:Carbamates; D018796:Immunoconjugates; D009842:Oligopeptides; D050257:Tubulin Modulators; C543533:auristatin; D010665:Phenylpropanolamine
keywords: alcohols; antibodies; cancer; drug delivery; glycoconjugate