title: Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates.
abstract: The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody-maytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo.
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States. robert.zhao@immunogen.com
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Zhao
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Wilhelm
authors.forename: Charlene
authors.initials: C
authors.lastname: Audette
authors.forename: Gregory
authors.initials: G
authors.lastname: Jones
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leece
authors.forename: Alexandru C
authors.initials: AC
authors.lastname: Lazar
authors.forename: Victor S
authors.initials: VS
authors.lastname: Goldmacher
authors.forename: Rajeeva
authors.initials: R
authors.lastname: Singh
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kovtun
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Widdison
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
authors.forename: Ravi V J
authors.initials: RV
authors.lastname: Chari
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry*; D008453:Maytansine / Q000737:chemistry*; D051379:Mice; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry; D013388:Succinimides / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry
chemical_list: D000906:Antibodies; D018796:Immunoconjugates; D013388:Succinimides; D013450:Sulfones; D008453:Maytansine; D011092:Polyethylene Glycols; C001426:N-hydroxysuccinimide