scFv-Based "Grababody" as a General Strategy to Improve Recruitment of Immune Effector Cells to Antibody-Targeted Tumors

被引：12

作者：

Cai, Zheng ^{[1
]}

Fu, Ting ^{[1
]}

Nagai, Yasuhiro ^{[1
]}

Lam, Lian ^{[1
]}

Yee, Marla ^{[1
]}

Zhu, Zhiqiang ^{[1
]}

Zhang, Hongtao ^{[1
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

CANCER RESEARCH | 2013年 / 73卷 / 08期

关键词：

STAPHYLOCOCCAL PROTEIN-A; DEPENDENT CELLULAR CYTOTOXICITY; IMMUNOGLOBULIN-BINDING; STRUCTURAL BASIS; AUREUS; GLYCOSYLATION; ONCOGENE; COMPLEX; GROWTH; DOMAIN;

D O I：

10.1158/0008-5472.CAN-12-3920

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Recruitment of immune cells to tumor cells targeted by a therapeutic antibody can heighten the antitumor efficacy of the antibody. For example, p185(her2/neu)-targeting antibodies not only downregulate the p185(her2/neu) kinase (ERBB2) but also trigger complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) through the antibody Fc region. Here, we describe a generalized strategy to improve immune cell recruitment to targeted cancer cells, using a modified scFv antibody we call a "Grababody" that binds the target protein and endogenous immunoglobulins. The model system we used to illustrate the use of this platform recognizes p185(her2/neu) and includes an IgG binding domain. The recombinant scFv Grababody that was created recruited circulating human IgGs and attracted immune cells carrying Fc receptors to tumor cells that expressed p185(her2/neu). The presence of the IgG binding domain significantly enhanced CDC and ADCC activity and improved antitumor activity in vivo. Our results illustrate a novel general approach to improve antibody-like proteins for therapeutic applications. Cancer Res; 73(8); 2619-27. (C) 2013 AACR.

引用

页码：2619 / 2627

页数：9

共 44 条

[1] The role of differential IgG glycosylation in the interaction of antibodies with FcγRs in vivo [J].

Anthony, Robert M. ;

Nimmerjahn, Falk .

CURRENT OPINION IN ORGAN TRANSPLANTATION, 2011, 16 (01) :7-14

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

Bibeau, Frederic ;

Lopez-Crapez, Evelyne ;

Di Fiore, Frederic ;

Thezenas, Simon ;

Ychou, Marc ;

Blanchard, France ;

Lamy, Aude ;

Penault-Llorca, Frederique ;

Frebourg, Thierry ;

Michel, Pierre ;

Sabourin, Jean-Christophe ;

Boissiere-Michot, Florence .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (07) :1122-1129

[3] Minimizing a binding domain from protein A [J].

Braisted, AC ;

Wells, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (12) :5688-5692

[4] Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes [J].

Cai, Z. ;

Zhang, G. ;

Zhou, Z. ;

Bembas, K. ;

Drebin, J. A. ;

Greene, M. I. ;

Zhang, H. .

ONCOGENE, 2008, 27 (27) :3870-3874

[5] Therapeutic enzyme deimmunization by combinatorial T-cell epitope removal using neutral drift [J].

Cantor, Jason R. ;

Yoo, Tae Hyeon ;

Dixit, Aakanksha ;

Iverson, Brent L. ;

Forsthuber, Thomas G. ;

Georgiou, George .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (04) :1272-1277

[6] MUTATIONAL ANALYSIS OF THE INTERACTION BETWEEN STAPHYLOCOCCAL PROTEIN-A AND HUMAN IGG(1) [J].

CEDERGREN, L ;

ANDERSSON, R ;

JANSSON, B ;

UHLEN, M ;

NILSSON, B .

PROTEIN ENGINEERING, 1993, 6 (04) :441-448

[7] Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab [J].

Cho, HS ;

Mason, K ;

Ramyar, KX ;

Stanley, AM ;

Gabelli, SB ;

Denney, DW ;

Leahy, DJ .

NATURE, 2003, 421 (6924) :756-760

[8] Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose [J].

Chung, Christine H. ;

Mirakhur, Beloo ;

Chan, Emily ;

Le, Quynh-Thu ;

Berlin, Jordan ;

Morse, Michael ;

Murphy, Barbara A. ;

Satinover, Shama M. ;

Hosen, Jacob ;

Mauro, David ;

Slebos, Robbert J. ;

Zhou, Qinwei ;

Gold, Diane ;

Hatley, Tina ;

Hicklin, Daniel J. ;

Platts-Mills, Thomas A. E. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (11) :1109-1117

[9] CRYSTALLOGRAPHIC REFINEMENT AND ATOMIC MODELS OF A HUMAN FC FRAGMENT AND ITS COMPLEX WITH FRAGMENT-B OF PROTEIN-A FROM STAPHYLOCOCCUS-AUREUS AT 2.9-A AND 2.8-A RESOLUTION [J].

DEISENHOFER, J .

BIOCHEMISTRY, 1981, 20 (09) :2361-2370

[10] ERBB-2 IS A POTENT ONCOGENE WHEN OVEREXPRESSED IN NIH/3T3 CELLS [J].

DIFIORE, PP ;

PIERCE, JH ;

KRAUS, MH ;

SEGATTO, O ;

KING, CR ;

AARONSON, SA .

SCIENCE, 1987, 237 (4811) :178-182

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