Engineered antibody Fc variants with enhanced effector function

被引：605

作者：

Lazar, GA ^{[1
]}

Dang, W ^{[1
]}

Karki, S ^{[1
]}

Vafa, O ^{[1
]}

Peng, JS ^{[1
]}

Hyun, L ^{[1
]}

Chan, C ^{[1
]}

Chung, HS ^{[1
]}

Eivazi, A ^{[1
]}

Yoder, SC ^{[1
]}

Vielmetter, J ^{[1
]}

Carmichael, DF ^{[1
]}

Hayes, RJ ^{[1
]}

Dahiyat, BI ^{[1
]}

机构：

[1] Xencor Inc, Monrovia, CA 91016 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2006年 / 103卷 / 11期

关键词：

antibody-dependent cell-mediated cytotoxicity; Fc gamma R; protein engineering; cancer;

D O I：

10.1073/pnas.0508123103

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fc gamma receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fc gamma receptor affinity and specificity. The designed variants display > 2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.

引用

页码：4005 / 4010

页数：6

共 41 条

[31] MAPPING AND COMPARISON OF THE INTERACTION SITES ON THE FC REGION OF IGG RESPONSIBLE FOR TRIGGERING ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY (ADCC) THROUGH DIFFERENT TYPES OF HUMAN FC-GAMMA RECEPTOR [J].