A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity.
Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGFR) have been implicated in the tumorigenesis of a variety of cancers. Here we propose that simultaneous targeting of both receptors with a bispecific antibody would lead to enhanced antitumor activity. To this end, we produced a recombinant human IgG-like bispecific antibody, a Di-diabody, using the variable regions from two antagonistic antibodies: IMC-11F8 to EGFR and IMC-A12 to IGFR. The Di-diabody binds to both EGFR and IGFR and effectively blocked both EGF- and IGF-stimulated receptor activation and tumor cell proliferation. The Di-diabody also inherited the biological properties from both of its parent antibodies; it triggers rapid and significant IGFR internalization and degradation and mediates effective antibody-dependent cellular cytotoxicity in a variety of tumor cells. Finally, the Di-diabody strongly inhibited the growth of two different human tumor xenografts in vivo. Our results underscore the benefits of simultaneous targeting of two tumor targets with bispecific antibodies.
Lu
Dan
D
Department of Antibody Technology, New York, New York 10014, USA.
Zhang
Haifan
H
Koo
Henry
H
Tonra
James
J
Balderes
Paul
P
Prewett
Marie
M
Corcoran
Eric
E
Mangalampalli
Venkata
V
Bassi
Rajiv
R
Anselma
Deborah
D
Patel
Dipa
D
Kang
Xiaoqiang
X
Ludwig
Dale L
DL
Hicklin
Daniel J
DJ
Bohlen
Peter
P
Witte
Larry
L
Zhu
Zhenping
Z
D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017451:Receptors, Somatomedin / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D017451:Receptors, Somatomedin; D066246:ErbB Receptors