Targeting the platelet-derived growth factor receptor alpha with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: implications as a potential therapeutic target.
Platelet-derived growth factor receptor alpha (PDGFRalpha) is a type III receptor tyrosine kinase that is expressed on a variety of tumor types. A neutralizing monoclonal antibody to human PDGFRalpha, which did not cross-react with the beta form of the receptor, was generated. The fully human antibody, termed 3G3, has a Kd of 40 pmol/L and blocks both PDGF-AA and PDGF-BB ligands from binding to PDGFRalpha. In addition to blocking ligand-induced cell mitogenesis and receptor autophosphorylation, 3G3 inhibited phosphorylation of the downstream signaling molecules Akt and mitogen-activated protein kinase. This inhibition was seen in both transfected and tumor cell lines expressing PDGFRalpha. The in vivo antitumor activity of 3G3 was tested in human glioblastoma (U118) and leiomyosarcoma (SKLMS-1) xenograft tumor models in athymic nude mice. Antibody 3G3 significantly inhibited the growth of U118 (P=0.0004) and SKLMS-1 (P <0.0001) tumors relative to control. These data suggest that 3G3 may be useful for the treatment of tumors that express PDGFRalpha.
Loizos
Nick
N
Department of Protein Chemistry, ImClone Systems, Inc., 180 Varick Street, New York, NY 10014, USA. NickL@Imclone.com
Xu
Yan
Y
Huber
Jim
J
Liu
Meilin
M
Lu
Dan
D
Finnerty
Bridget
B
Rolser
Robin
R
Malikzay
Asra
A
Persaud
Anita
A
Corcoran
Erik
E
Deevi
Dhanvanthri S
DS
Balderes
Paul
P
Bassi
Rajiv
R
Jimenez
Xenia
X
Joynes
Christopher J
CJ
Mangalampalli
Venkata R M
VR
Steiner
Philipp
P
Tonra
James R
JR
Wu
Yan
Y
Pereira
Daniel S
DS
Zhu
Zhenping
Z
Ludwig
Dale L
DL
Hicklin
Daniel J
DJ
Bohlen
Peter
P
Witte
Larry
L
Kussie
Paul
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000077214:Becaplermin; D001681:Biological Assay; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000737:chemistry; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D000911:Antibodies, Monoclonal; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt