A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitrocharacterization and pharmacokinetics in macaques

	A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitrocharacterization and pharmacokinetics in macaques
	Feng, Yang; Zhao, Qi; Chen, Weizao; Wang, Yanping; Crowder, Karalyne; Dimitrov, Dimiter S.
刊名	EXPERIMENTAL AND MOLECULAR PATHOLOGY
	2014
英文摘要	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 ofIGF2 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 (Fc gamma Rs) 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 bothIGF2 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 Fc gamma RII; 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 theIGF2 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. Published by Elsevier Inc.
收录类别	SCI
原文出处	http://www.sciencedirect.com/science/article/pii/S0014480014001488
语种	英语
内容类型	期刊论文
源URL	[http://ir.siat.ac.cn:8080/handle/172644/6087]
专题	深圳先进技术研究院_医药所
作者单位	EXPERIMENTAL AND MOLECULAR PATHOLOGY
推荐引用方式 GB/T 7714	Feng, Yang,Zhao, Qi,Chen, Weizao,et al. A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitrocharacterization and pharmacokinetics in macaques[J]. EXPERIMENTAL AND MOLECULAR PATHOLOGY,2014.
APA	Feng, Yang,Zhao, Qi,Chen, Weizao,Wang, Yanping,Crowder, Karalyne,&Dimitrov, Dimiter S..(2014).A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitrocharacterization and pharmacokinetics in macaques.EXPERIMENTAL AND MOLECULAR PATHOLOGY.
MLA	Feng, Yang,et al."A new bispecific antibody targeting non-overlapping epitopes on IGF2: Design, in vitrocharacterization and pharmacokinetics in macaques".EXPERIMENTAL AND MOLECULAR PATHOLOGY (2014).