title: Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection.
abstract: Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non-Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non-Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79b. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to the reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans.
authors.affiliation: Genentech, Inc., South San Francisco, California, USA. polson@gene.com
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
authors.forename: Jill
authors.initials: J
authors.lastname: Calemine-Fenaux
authors.forename: Pamela
authors.initials: P
authors.lastname: Chan
authors.forename: Wesley
authors.initials: W
authors.lastname: Chang
authors.forename: Erin
authors.initials: E
authors.lastname: Christensen
authors.forename: Suzanna
authors.initials: S
authors.lastname: Clark
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Dan
authors.initials: D
authors.lastname: Eaton
authors.forename: Kristi
authors.initials: K
authors.lastname: Elkins
authors.forename: J Michael
authors.initials: JM
authors.lastname: Elliott
authors.forename: Gretchen
authors.initials: G
authors.lastname: Frantz
authors.forename: Reina N
authors.initials: RN
authors.lastname: Fuji
authors.forename: Alane
authors.initials: A
authors.lastname: Gray
authors.forename: Kristin
authors.initials: K
authors.lastname: Harden
authors.forename: Gladys S
authors.initials: GS
authors.lastname: Ingle
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Christopher
authors.initials: C
authors.lastname: Nelson
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.forename: Dion S
authors.initials: DS
authors.lastname: Slaga
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.forename: Susan D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.forename: Bernd
authors.initials: B
authors.lastname: Wranik
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.forename: Allen
authors.initials: A
authors.lastname: Ebens
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001402:B-Lymphocytes / Q000276:immunology; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D000922:Immunotoxins; C488736:N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)maytansine; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; C513576:monomethylauristatin F; D008453:Maytansine