Development of an Fc-Enhanced Anti-B7-H3 Monoclonal Antibody with Potent Antitumor Activity

被引：219

作者：

Loo, Deryk ^{[1
]}

Alderson, Ralph F. ^{[2
]}

Chen, Francine Z. ^{[1
]}

Huang, Ling ^{[2
]}

Zhang, Wenjun ^{[2
]}

Gorlatov, Sergey ^{[2
]}

Burke, Steve ^{[2
]}

Ciccarone, Valentina ^{[2
]}

Li, Hua ^{[2
]}

Yang, Yinhua ^{[2
]}

Son, Tom ^{[1
]}

Chen, Yan ^{[1
]}

Easton, Ann N. ^{[1
]}

Li, Jonathan C. ^{[1
]}

Rillema, Jill R. ^{[1
]}

Licea, Monica ^{[1
]}

Fieger, Claudia ^{[1
]}

Liang, Tony W. ^{[1
]}

Mather, Jennie P. ^{[1
]}

Koenig, Scott ^{[2
]}

Stewart, Stanford J. ^{[1
]}

Johnson, Syd ^{[2
]}

Bonvini, Ezio ^{[2
]}

Moore, Paul A. ^{[2
]}

机构：

[1] MacroGenics Inc, San Francisco, CA 94080 USA

[2] MacroGenics Inc, Rockville, MD 20850 USA

来源：

CLINICAL CANCER RESEARCH | 2012年 / 18卷 / 14期

关键词：

METASTATIC BREAST-CANCER; C-RECEPTOR POLYMORPHISMS; HUMAN PANCREATIC-CANCER; HUMAN SOLID TUMORS; T-CELL-ACTIVATION; PROSTATE-CANCER; COSTIMULATORY MOLECULE; B7-H3; LIGAND; B7; FAMILY; IN-VITRO;

D O I：

10.1158/1078-0432.CCR-12-0715

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens. Experimental Design: Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes. Immunohistochemical analyses showed that a subset displayed strong reactivity to a broad range of human cancers while exhibiting limited binding to normal human tissues. A B7-H3 mAb displaying exquisite tumor/normal differential binding was selected for humanization and incorporation of an Fc domain modified to enhance effector-mediated antitumor function via increased affinity for the activating receptor CD16A and decreased binding to the inhibitory receptor CD32B. Results: MGA271, the resulting engineered anti-B7-H3 mAb, mediates potent antibody-dependent cellular cytotoxicity against a broad range of tumor cell types. Furthermore, in human CD16A-bearing transgenic mice, MGA271 exhibited potent antitumor activity in B7-H3-expressing xenograft models of renal cell and bladder carcinoma. Toxicology studies carried out in cynomolgus monkeys revealed no significant test article-related safety findings. Conclusions: This data supports evaluation of MGA271 clinical utility in B7-H3-expressing cancer, while validating a combination of a nontarget biased approach of intact cell immunizations and immunohistochemistry to identify novel cancer antigens with Fc-based mAb engineering to enable potent antitumor activity. Clin Cancer Res; 18(14); 3834-45. (C)2012 AACR.

引用

页码：3834 / 3845

页数：12

共 37 条

[1] Impact of FcγRIIa-FcγRIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan [J].