UM  > 健康科學學院
A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitro characterization and pharmacokinetics in macaques
Feng Y.2; Zhao Q.3; Chen W.2; Wang Y.2; Crowder K.; Dimitrov D.S.2
2014-09-16
Source PublicationExperimental and Molecular Pathology
ISSN10960945 00144800
Volume97Issue:3Pages:359-367
Abstract

The insulin-like growth factor 2 (IGF2) is an important target for cancer therapy. We have previously proposed an approach for fast and irreversible removal of IGF2 from the circulation by using monoclonal antibodies (mAbs) that bind to two or more non-overlapping epitopes on the same molecule. We provided initial evidence for the formation of oligomeric antibody-ligand complexes that can bind to cells expressing Fc gamma receptors (FcγRs) with high avidity using an antibody domain with relatively low affinity as one of the anti-IGF2 mAbs. Recently, we identified a mAb, m708.5, in a scFv format which binds to both IGF2 and IGF1 with very high (pM) affinity. Interestingly, and rather surprisingly, this mAb did not compete with our other high affinity mAb, m610.27, for binding to IGF2. Therefore, we generated a new bispecific mAb, m67, by combining m708.5 and m610.27. As expected m67 potently inhibited binding of IGF2 to cells expressing the IGF1R and its phosphorylation, and resulted in formation of multimolecular complexes when incubated with IGF2 and bound with high avidity to cells expressing FcγRII; the complexes were internalized in a macrophage-like cell line. However, although m67 exhibited a reasonably long half-life (6.4 ± 0.6. days) in cynomolgus macaques and high stability in serum, its administration to three animals did not result in any measurable decrease in the IGF2 concentration likely due to the complexity of the IGF2 interactions in the blood and the relatively low (2. mg/kg) dose of the mAb leading to a relatively low maximal blood concentration of 120. nM. In spite of the lack of effect on the IGF2 concentration in this particular experimental setup, m67 exhibited good drugability properties and could be highly effective in other animal models and in humans. Studies with animal models of cancer are ongoing to evaluate the potential of m67 as a new candidate mAb-based therapeutic.

KeywordBispecific Antibodies Cynomolgus Macaques Half-life Igf Ligand
DOI10.1016/j.yexmp.2014.09.007
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPathology
WOS SubjectPathology
WOS IDWOS:000346685700007
Fulltext Access
Citation statistics
Cited Times [WOS]:10   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Geneva Foundation
2.National Cancer Institute
3.Shenzhen Institute of Advanced Technology
Recommended Citation
GB/T 7714
Feng Y.,Zhao Q.,Chen W.,et al. A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitro characterization and pharmacokinetics in macaques[J]. Experimental and Molecular Pathology,2014,97(3):359-367.
APA Feng Y.,Zhao Q.,Chen W.,Wang Y.,Crowder K.,&Dimitrov D.S..(2014).A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitro characterization and pharmacokinetics in macaques.Experimental and Molecular Pathology,97(3),359-367.
MLA Feng Y.,et al."A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitro characterization and pharmacokinetics in macaques".Experimental and Molecular Pathology 97.3(2014):359-367.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Feng Y.]'s Articles
[Zhao Q.]'s Articles
[Chen W.]'s Articles
Baidu academic
Similar articles in Baidu academic
[Feng Y.]'s Articles
[Zhao Q.]'s Articles
[Chen W.]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Feng Y.]'s Articles
[Zhao Q.]'s Articles
[Chen W.]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.