title: cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity.
abstract: The chimeric monoclonal antibody cAC10, directed against CD30, induces growth arrest of CD30+ cell lines in vitro and has pronounced antitumor activity in severe combined immunodeficiency (SCID) mouse xenograft models of Hodgkin disease. We have significantly enhanced these activities by conjugating to cAC10 the cytotoxic agent monomethyl auristatin E (MMAE) to create the antibody-drug conjugate cAC10-vcMMAE. MMAE, a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to cAC10 through a valine-citrulline peptide linker. The drug was stably attached to the antibody, showing only a 2% release of MMAE following 10-day incubation in human plasma, but it was readily cleaved by lysosomal proteases after receptor-mediated internalization. Release of MMAE into the cytosol induced G2/M-phase growth arrest and cell death through the induction of apoptosis. In vitro, cAC10-vcMMAE was highly potent and selective against CD30+ tumor lines (IC50 less than 10 ng/mL) but was more than 300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin disease, cAC10-vcMMAE was efficacious at doses as low as 1 mg/kg. Mice treated at 30 mg/kg cAC10-vcMMAE showed no signs of toxicity. These data indicate that cAC10-vcMMAE may be a highly effective and selective therapy for the treatment of CD30+ neoplasias.
authors.affiliation: Seattle Genetics, Bothell, WA 98021, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Francisco
authors.forename: Charles G
authors.initials: CG
authors.lastname: Cerveny
authors.forename: Damon L
authors.initials: DL
authors.lastname: Meyer
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Mixan
authors.forename: Kerry
authors.initials: K
authors.lastname: Klussman
authors.forename: Dana F
authors.initials: DF
authors.lastname: Chace
authors.forename: Starr X
authors.initials: SX
authors.lastname: Rejniak
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Gordon
authors.forename: Ron
authors.initials: R
authors.lastname: DeBlanc
authors.forename: Brian E
authors.initials: BE
authors.lastname: Toki
authors.forename: Che-Leung
authors.initials: CL
authors.lastname: Law
authors.forename: Svetlana O
authors.initials: SO
authors.lastname: Doronina
authors.forename: Clay B
authors.initials: CB
authors.lastname: Siegall
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wahl
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000079963:Brentuximab Vedotin; D002453:Cell Cycle / Q000187:drug effects; D004355:Drug Stability; D006689:Hodgkin Disease / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D000922:Immunotoxins / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D017730:Ki-1 Antigen / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D000922:Immunotoxins; D017730:Ki-1 Antigen; D009842:Oligopeptides; D000079963:Brentuximab Vedotin