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Synergy between trastuzumab and pertuzumab for human epidermal growth factor 2 (Her2) from colocalization: an in silico based mechanism.

Abstract：

INTRODUCTION:Human epidermal growth factor 2 (Her2), a receptor tyrosine kinase, is overexpressed in breast cancers. It has been successfully targeted by small molecule kinase inhibitors and by antibodies. Recent clinical data show a synergistic response in patients when two antibodies, trastuzumab and pertuzumab, are given in combination. METHODS:This unexpected effect is rationalized through computer models and molecular dynamic simulations by hypothesizing that the two antibodies can co-localize on the same molecule of the Her2 extracellular domain. RESULTS:Simulations suggest that the clinical synergism observed for the two antibodies arises partly from enhanced affinity that originates in cooperative interactions between these two antibodies when they are co-localized on Her2 and "clamp" it; this may inhibit dimerization and possibly higher oligomerizations with neighboring receptors. In the presence of trastuzumab, the receptor becomes highly plastic, especially domains I to III, and this appears to promote increased association with pertuzumab. Further, the presence of pertuzumab evokes novel interactions between the receptor and trastuzumab. Indeed, splicing out of this region in silico results in a big reduction in the interactions of the antibody with the receptor. CONCLUSIONS:If validated, these findings will bring about a new direction in the design of antibodies whereby different epitopes on the same antibody may be targeted to lead to synergistic/cooperative inhibition and contribute to generate more potent therapeutics and to increase clinical efficacy.

journal_name

Breast Cancer Res

journal_title

Breast cancer research : BCR

authors

Fuentes G,Scaltriti M,Baselga J,Verma CS

doi

10.1186/bcr2888

subject

Has Abstract

pub_date

2011-05-22 00:00:00

pages

R54

issue

3

eissn

1465-5411

issn

1465-542X

pii

bcr2888

journal_volume

13

pub_type

杂志文章

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