CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.
OBJECTIVE
Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets.


RESULTS
By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined. GPNMB is predicted to be a transmembrane protein, thus making it a potential immunotherapeutic target in the treatment of this disease. A fully human monoclonal antibody, designated CR011, was generated to the extracellular domain of GPNMB and characterized for growth-inhibitory activity against melanoma. The CR011 monoclonal antibody showed surface staining of most melanoma cell lines by flow cytometry and reacted with a majority of metastatic melanoma specimens by immunohistochemistry. CR011 alone did not inhibit the growth of melanoma cells. However, when linked to the cytotoxic agent monomethylauristatin E (MMAE) to generate the CR011-vcMMAE antibody-drug conjugate, this reagent now potently and specifically inhibited the growth of GPNMB-positive melanoma cells in vitro. Ectopic overexpression and small interfering RNA transfection studies showed that GPNMB expression is both necessary and sufficient for sensitivity to low concentrations of CR011-vcMMAE. In a melanoma xenograft model, CR011-vcMMAE induced significant dose-proportional antitumor effects, including complete regressions, at doses as low as 1.25 mg/kg.


CONCLUSIONS
These preclinical results support the continued evaluation of CR011-vcMMAE for the treatment of melanoma.
Tse
Kam Fai
KF
CuraGen, Branford, Connecticut 06405, USA.
Jeffers
Michael
M
Pollack
Vincent A
VA
McCabe
Denise A
DA
Shadish
Melanie L
ML
Khramtsov
Nikolai V
NV
Hackett
Craig S
CS
Shenoy
Suresh G
SG
Kuang
Bing
B
Boldog
Ferenc L
FL
MacDougall
John R
JR
Rastelli
Luca
L
Herrmann
John
J
Gallo
Michael
M
Gazit-Bornstein
Gadi
G
Senter
Peter D
PD
Meyer
Damon L
DL
Lichenstein
Henri S
HS
LaRochelle
William J
WJ
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000918:Antibody Specificity; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; C541991:CR011-vcMMAE; C503042:GPNMB protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C495575:monomethyl auristatin E