title: E-selectin up-regulation allows for targeted drug delivery in prostate cancer.
abstract: We have used the Eos Hu03 GeneChip array, which represents over 92% of the transcribed human genome, to measure gene expression in a panel of normal and diseased human tissues. This analysis revealed that E-selectin mRNA is selectively overexpressed in prostate cancer epithelium, a finding that correlated strongly with E-selectin protein expression as assessed by immunohistochemistry. Antibodies against E-selectin that blocked function failed to impede cancer cell growth, suggesting that overexpression of E-selectin was not essential for cell growth. However, a novel auristatin E-based antibody drug conjugate (ADC), E-selectin antibody valine-citrulline monomethyl-auristatin E, was a potent and selective agent against E-selectin-expressing cancer cell lines in vitro, with the degree of cytotoxicity varying with surface antigen density. Interestingly, sensitivity to the ADC differed among cell lines from different tissues expressing similar amounts of E-selectin and was found to correlate with sensitivity to free auristatin E. Furthermore, E-selectin-expressing tumors grown as xenografts in severe combined immunodeficient mice were responsive to treatment with E-selectin antibody valine-citrulline monomethyl-auristatin E in vivo, with more than 85% inhibition of tumor growth observed in treated mice. These findings demonstrate that an E-selectin-targeting ADC has potential as a prostate cancer therapy and validates a genomics-based paradigm for the identification of cancer-specific antigens suitable for targeted therapy.
authors.affiliation: Protein Design Labs, Inc., 34801 Campus Drive, Fremont, CA 94555, USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhaskar
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Law
authors.forename: Eric
authors.initials: E
authors.lastname: Ibsen
authors.forename: Danna
authors.initials: D
authors.lastname: Breinberg
authors.forename: Kellie M
authors.initials: KM
authors.lastname: Cass
authors.forename: Robert B
authors.initials: RB
authors.lastname: DuBridge
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Evangelista
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
authors.forename: Peter
authors.initials: P
authors.lastname: Hevezi
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Miller
authors.forename: Melody
authors.initials: M
authors.lastname: Pong
authors.forename: Rick
authors.initials: R
authors.lastname: Powers
authors.forename: Peter
authors.initials: P
authors.lastname: Senter
authors.forename: David
authors.initials: D
authors.lastname: Stockett
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Ursula
authors.initials: U
authors.lastname: von Freeden-Jeffry
authors.forename: Dorian
authors.initials: D
authors.lastname: Willhite
authors.forename: Richard
authors.initials: R
authors.lastname: Murray
authors.forename: Daniel E H
authors.initials: DE
authors.lastname: Afar
authors.forename: Vanitha
authors.initials: V
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D019040:E-Selectin / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019040:E-Selectin; D000922:Immunotoxins; D009842:Oligopeptides; C105791:soblidotin