Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model.
The receptor protein tyrosine phosphatase beta (RPTPbeta) is a functional biomarker for several solid tumor types. RPTPbeta expression is largely restricted to the central nervous system and overexpressed primarily in astrocytic tumors. RPTPbeta is known to facilitate tumor cell adhesion and migration through interactions with extracellular matrix components and the growth factor pleiotrophin. Here, we show that RPTPbeta is expressed in a variety of solid tumor types with low expression in normal tissue. To assess RPTPbeta as a potential target for treatment of glioblastoma and other cancers, antibodies directed to RPTPbeta have been developed and profiled in vitro and in vivo. The recombinant extracellular domain of human short RPTPbeta was used to immunize mice and generate monoclonal antibodies that selectively recognize RPTPbeta and bind to the antigen with low nanomolar affinities. Moreover, these antibodies recognized the target on living tumor cells as measured by flow cytometry. These antibodies killed glioma cells in vitro when coupled to the cytotoxin saporin either directly or via a secondary antibody. Finally, in vivo studies showed that an anti-RPTPbeta immunotoxin (7E4B11-SAP) could significantly delay human U87 glioma tumors in a mouse xenograft model. Unconjugated 7E4B11 provides a modest but statistically significant tumor growth delay when delivered systemically in mice bearing U87 glioma tumors.
Foehr
Erik D
ED
AGY Therapeutics, Inc., South San Francisco, California 94080, USA. efoehr@agyinc.com
Lorente
Gustavo
G
Kuo
Jane
J
Ram
Rosie
R
Nikolich
Karoly
K
Urfer
Roman
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000201:enzymology* / Q000628:therapy*; D006801:Humans; D007114:Immunization; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000276:immunology*; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000276:immunology*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D009419:Nerve Tissue Proteins; C516895:PTPRZ1 protein, human; D017027:Protein Tyrosine Phosphatases; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5