Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies

Wolfgang Schaefer; Joerg T. Regula; Monika Bahner; Juergen Schanzer; Rebecca Croasdale; Harald Duerr; Christian Gassner; Guy Georges; Hubert Kettenberger; Sabine Imhof-Jung; Manfred Schwaiger; Kay G. Stubenrauch; Claudio Sustmann; Markus Thomas; Werner Scheuer; Christian Klein

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Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies

机译：免疫球蛋白结构域交换是生产双特异性IgG抗体的通用方法

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摘要

We describe a generic approach to assemble correctly two heavy and two light chains, derived from two existing antibodies, to form human bivalent bispecific IgG antibodies without use of artificial linkers. Based on the knobs-into-holes technology that enables het erodimerization of the heavy chains, correct association of the light chains and their cognate heavy chains is achieved by exchange of heavy-chain and light-chain domains within the antigen binding fragment (Fab) of one half of the bispecific antibody. This "cross over" retains the antigen-binding affinity but makes the two arms so different that light-chain mispairing can no longer occur. Apply ing the three possible "CrossMab" formats, we generated bispecific antibodies against angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A) and show that they can be produced by standard techniques, exhibit stabilities comparable to natural anti bodies, and bind both targets simultaneously with unaltered affin ity. Because of its superior side-product profile, the CrossMab～(CH1-CL) was selected for in vivo profiling and showed potent antiangio genic and antitumoral activity.

机译：我们描述了一种通用方法，可正确组装源自两个现有抗体的两条重链和两条轻链，以形成人二价双特异性IgG抗体，而无需使用人工接头。基于使重链发生异二聚化的多入孔技术，通过交换抗原结合片段（Fab）中的重链和轻链结构域，可以实现轻链及其同源重链的正确结合一半的双特异性抗体。这种“交叉”保留了抗原结合亲和力，但使两个臂如此不同，以致不再发生轻链错配。应用三种可能的“ CrossMab”格式，我们生成了针对血管生成素2（Ang-2）和血管内皮生长因子A（VEGF-A）的双特异性抗体，并表明它们可以通过标准技术生产，表现出与天然抗体相当的稳定性抗体，并以不变的亲和力同时绑定两个目标。由于其优异的副产物特性，CrossMab〜（CH1-CL）被选择用于体内分析，并显示出有效的抗血管生成和抗肿瘤活性。

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2011年第27期|p.11187-11192|共6页
作者
Wolfgang Schaefer; Joerg T. Regula; Monika Bahner; Juergen Schanzer; Rebecca Croasdale; Harald Duerr; Christian Gassner; Guy Georges; Hubert Kettenberger; Sabine Imhof-Jung; Manfred Schwaiger; Kay G. Stubenrauch; Claudio Sustmann; Markus Thomas; Werner Scheuer; Christian Klein;
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作者单位

Biologics Research;

Biologics Research;

Biologics Research;

Biologics Engineering;

Biologics Engineering;

Biologics Research;

Biologics Research;

Biologics Research;

Biologics Research;

Biologics Research;

Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, D-82372 Penzberg, Germany;

Biologics Research;

Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, D-82372 Penzberg, Germany;

Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, D-82372 Penzberg, Germany;

Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, D-82372 Penzberg, Germany;

Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, D-82372 Penzberg, Germany,Discovery Oncology, Pharma Research and Early Development, Roche Glycart AG, CH-8952 Schlieren, Switzerland;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
angiogenesis; domain exchange; dual targeting;

机译：血管生成;结构域交换;双重靶向;

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机译：新型通用平台生产四价IgG1样双特异性抗体的设计和验证
2. Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies [J] . Josée Golay, Sylvie Choblet, Justyna Iwaszkiewicz, The journal of immunology . 2016,第7期

机译：新型通用平台生产四价IgG1样双特异性抗体的设计和验证
3. Single variable domain antibody as a versatile building block for the construction of IgG-like bispecific antibodies. [J] . Shen J, Vil MD, Jimenez X, Journal of Immunological Methods . 2007,第1a2期

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5. A novel approach to control and regulate the classical complement pathway: Highly specific inhibition of C1q globular head binding to human IgG using an engineered single chain antibody variable fragment; recruiting C1q to HER2 /neu positive cells using truncated bispecific antibodies [D] . Hwang, Hee Young 2007

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6. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies [O] . Wolfgang Schaefer, Jörg T. Regula, Monika Bähner, 2011

机译：免疫球蛋白结构域交换是生产双特异性IgG抗体的通用方法
7. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies [O] . Schaefer, Wolfgang, Regula, Jörg T., Bähner, Monika, 2011

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Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies

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