Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth.
Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways.
MedImmune, Gaithersburg, Maryland 20878, USA. gaoj@medimmune.com
Jin
J
Gao
Jon W
JW
Chesebrough
Susan A
SA
Cartlidge
Sally-Ann
SA
Ricketts
Leonard
L
Incognito
Margaret
M
Veldman-Jones
David C
DC
Blakey
Mohammad
M
Tabrizi
Bahija
B
Jallal
Pamela A
PA
Trail
Steven
S
Coats
Klaus
K
Bosslet
Yong S
YS
Chang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography; D020033:Protein Isoforms; D019275:Radiopharmaceuticals; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D020033:Protein Isoforms; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin