E-selectin up-regulation allows for targeted drug delivery in prostate cancer.
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.
Bhaskar
Vinay
V
Protein Design Labs, Inc., 34801 Campus Drive, Fremont, CA 94555, USA.
Law
Debbie A
DA
Ibsen
Eric
E
Breinberg
Danna
D
Cass
Kellie M
KM
DuBridge
Robert B
RB
Evangelista
Ferdinand
F
Henshall
Susan M
SM
Hevezi
Peter
P
Miller
Jennifer C
JC
Pong
Melody
M
Powers
Rick
R
Senter
Peter
P
Stockett
David
D
Sutherland
Robert L
RL
von Freeden-Jeffry
Ursula
U
Willhite
Dorian
D
Murray
Richard
R
Afar
Daniel E H
DE
Ramakrishnan
Vanitha
V
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
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019040:E-Selectin; D000922:Immunotoxins; D009842:Oligopeptides; C105791:soblidotin