期刊
MABS
卷 9, 期 7, 页码 1029-1035出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2017.1356528
关键词
complementarity determining region; cross-interaction; monoclonal antibody; Nonspecificity; natural repertoire; polyreactivity; VH6
资金
- National Institute of General Medical Sciences at the National Institutes of Health [T32 GM008334-25]
- Siebel Scholarship
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008334] Funding Source: NIH RePORTER
Efforts to develop effective antibody therapeutics are frequently hampered by issues such as aggregation and nonspecificity, often only detected in late stages of the development process. In this study, we used a high throughput cross-reactivity assay to select nonspecific clones from a naive human repertoire scFv library displayed on the surface of yeast. Most antibody families were de-enriched; however, the rarely expressed VH6 family was highly enriched among nonspecific clones, representing almost 90% of isolated clones. Mutational analysis of this family reveals a dominant role of CDRH2 in driving nonspecific binding. Homology modeling of a panel of VH6 antibodies shows a constrained beta-sheet structure in CDRH2 that is not present in other families, potentially contributing to nonspecificity of the family. These findings confirm the common decision to exclude VH6 from synthetic antibody libraries, and support VH6 polyreactivity as a possible important role for the family in early ontogeny and cause for its overabundance in cases of some forms of autoimmunity.
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