Generation and characterization of a therapeutic human antibody to melanoma antigen TYRP1.
TYRP1 (tyrosinase-related protein 1) is a melanoma antigen expressed in melanosomes and on the surface of melanoma cells. Previous studies have shown that mouse antibodies to TYRP1 localized to melanomas in vivo and inhibited tumor growth and metastasis. Here, we describe the characterization of a novel fully human anti-TYRP1 MAb (20D7) generated by immunizing HuMAb mice (Medarex). 20D7 recognized recombinant and native human TYRP1 by Western blotting and ELISA, and native TYRP1 in melanoma cells as determined by flow cytometry analysis. 20D7 cross-reacted with mouse TYRP1. The binding affinity to human TYRP1 for the human MAb was in the low nM range as determined by surface plasmon resonance kinetics. 20D7 can bind to human and mouse Fc receptor and induce a strong ADCC response against human melanoma cells in vitro. The antitumor activity of 20D7 was tested in human melanoma xenografts and mouse metastatic melanoma models in athymic nude mice. Growth of s.c. human melanoma tumors and metastatic nodules of murine B16 tumor were significantly suppressed by 20D7 compared to human IgG control. These results suggest that human anti-TYRP1 MAb may be a potent therapeutic for the treatment of malignant melanoma.
Patel
Dipa
D
ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA.
Balderes
Paul
P
Lahiji
Armin
A
Melchior
Maxine
M
Ng
Stanley
S
Bassi
Rajiv
R
Wu
Yan
Y
Griffith
Heather
H
Jimenez
Xenia
X
Ludwig
Dale L
DL
Hicklin
Daniel J
DJ
Kang
Xiaoqiang
X
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D010088:Oxidoreductases / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D008562:Membrane Glycoproteins; D003165:Complement System Proteins; D010088:Oxidoreductases; C489799:TYRP1 protein, human