title: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate.
abstract: HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development.
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA. gdl@gene.com
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.forename: Guangmin
authors.initials: G
authors.lastname: Li
authors.forename: Debra L
authors.initials: DL
authors.lastname: Dugger
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Crocker
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsons
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Walter A
authors.initials: WA
authors.lastname: Blättler
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
authors.forename: Ravi V J
authors.initials: RV
authors.lastname: Chari
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lutz
authors.forename: Wai Lee T
authors.initials: WL
authors.lastname: Wong
authors.forename: Frederic S
authors.initials: FS
authors.lastname: Jacobson
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Schwall
authors.forename: Sara R
authors.initials: SR
authors.lastname: Kenkare-Mitra
authors.forename: Susan D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008453:Maytansine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000922:Immunotoxins; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human