Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy.
Epidermal growth factor receptor (EGFR) is a validated therapeutic target in cancer and EGFR antagonists with greater effectiveness than existing clinical agents remain of interest. Here, we report a novel approach based on Sym004, a mixture of two anti-EGFR monoclonal antibodies directed against distinct nonoverlapping epitopes in EGFR extracellular domain III. Like anti-EGFR monoclonal antibodies in current clinical use, Sym004 inhibits cancer cell growth and survival by blocking ligand-binding receptor activation and phosphorylation and downstream receptor signaling. However, unlike the other antibodies, Sym004 induces rapid and efficient removal of the receptor from the cancer cell surface by triggering EGFR internalization and degradation. Compared with reference anti-EGFR monoclonal antibodies, Sym004 exhibited more pronounced growth inhibition in vitro and superior efficacy in vivo. Together, these findings illustrate a strategy to target EGFR more effectively than existing clinical antibodies.
Pedersen
Mikkel Wandahl
MW
Symphogen A/S, DK-2800Lyngby, Denmark. mwp@symphogen.com
Jacobsen
Helle Jane
HJ
Koefoed
Klaus
K
Hey
Adam
A
Pyke
Charles
C
Haurum
John Sørensen
JS
Kragh
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology / Q000628:therapy*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000939:Epitopes; D066246:ErbB Receptors