Human monoclonal antibodies to the insulin-like growth factor 1 receptor inhibit receptor activation and tumor growth in preclinical studies.
BACKGROUND
The insulin-like growth factor type 1 (IGF-1) receptor contributes importantly to transformation and survival of tumor cells both in vitro and in vivo, and selective antagonists of the IGF-1 receptor (IGF-1R) activity represent an attractive experimental approach for human cancer therapy.


METHODS
Using a phage display library, we identified several high-affinity fully human monoclonal antibodies with inhibitory activity against both human and rodent IGF.1Rs.


RESULTS
These candidate therapeutic antibodies recognized several distinct epitopes and effectively blocked ligand-mediated receptor signal transduction and cellular proliferation in vitro. They also induced IGF-1R downregulation and catabolism following antibody-mediated endocytosis. These antibodies exhibited activity against human, primate, and rodent IGF-1Rs, and dose-dependently inhibited the growth of established human tumors in nude mice.


CONCLUSIONS
These fully human antibodies therefore have the potential to provide an effective anti-tumor biological therapy in the human clinical setting.
Runnels
Herbert A
HA
Pfizer Global Research and Development, St Louis, Missouri, USA. Herbert.A.Runnels@pfizer.com
Arbuckle
J Alan
JA
Bailey
Karen S
KS
Nicastro
Peter J
PJ
Sun
Duo
D
Pegg
Jodi A
JA
Meyer
Debra M
DM
Evans
Michelle
M
Bono
Christine P
CP
Lie
Wen-Rong
WR
Moffat
Mark A
MA
Casperson
Gerald F
GF
Lennard
Simon
S
Elvin
John
J
Vaughan
Tristan
T
Smith
Christine E
CE
Morton
Phillip A
PA
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000915:Antibody Affinity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D018604:Epitope Mapping; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017526:Receptor, IGF Type 1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D017526:Receptor, IGF Type 1