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

Abstract

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 IGFstimulated 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.

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…Besides IGF-Ⅱ-binding antibodies that physically inhibit ligand/receptor interaction [87,88] , many neutralizing antibodies specific for IGF-IR have been described such as alpha-IR3 [89] , mAb391 [90] , scFv-FC [91] , CP-751,871 [92] , IMC-A12 [93] , 7H2HM [94] EM164 [95] , h7C10 [96] , 4G11 [97] , 19D12 [98] , R1507 [60] , AMG479 [60] , and 19D12 [60] . Reduced IGF/IGF-IR signaling is presumably based upon lysosome-dependent degradation of IGF-IR [90,91] .…”

Role of insulin-like growth factor-1R system in colorectal carcinogenesis

“…This Di-diabody has been shown to block tumor cell proliferation in vitro, and in vivo antitumor efficacy was demonstrated using HT29 colorectal carcinoma xenografts [38]. This may be a promising agent, as a retrospective study by Cunningham et al documented coexpression of IGF-1R and EGFR in ≥75% of 87 Duke's C colorectal tumors [40].…”

“…Antibodies against the binding domain of IGF-1R block binding of the ligand and subsequent activation of the receptor [31][32][33][34][35][36][37][38]. Binding of these antibodies can trigger receptor internalization and degradation with reduction in the receptor number on the cell surface.…”

Engineering and characterization of a bispecific HER2 × EGFR‐binding affibody molecule

“…Obstacles in the development of bs mAbs have been: (i) the difficulty in producing material with enough quality and yield, e.g. undesired products might be formed because of undesired paring between the polypeptide chains [41], (ii) the high costs related to mammalian cell production, which sometimes is needed, since not all antibody derivatives give functional products upon E. coli expression, and (iii) the stability in vivo of bs proteins that are dependent on stable pairing of polypeptide chains [11]. Affibody molecules could hold a potential here because of their efficient production in E. coli (gram amounts per litre from bacterial cultures are not uncommon) and the straightforward genetic fusion of different affibody molecules to form single polypeptide proteins.…”