Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response.
The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer.
Dong
Jianying
J
Department of Discovery Oncology, Biogen Idec, Inc., San Diego, California 92122, USA. Jianying.dong@biogenidec.com
Demarest
Stephen J
SJ
Sereno
Arlene
A
Tamraz
Susan
S
Langley
Emma
E
Doern
Adam
A
Snipas
Tracey
T
Perron
Keli
K
Joseph
Ingrid
I
Glaser
Scott M
SM
Ho
Steffan N
SN
Reff
Mitchell E
ME
Hariharan
Kandasamy
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D012516:Osteosarcoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1