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Engineering the hinge region of human IgG1 Fc-fused bispecific antibodies to improve fragmentation resistance.

Abstract：

:Fc domain fusion can improve the therapeutic effects of relatively small biological molecules such as peptides, cytokines, and antibody fragments. Fc fusion proteins can also be used to enhance the cytotoxic effects of small bispecific antibodies (bsAbs). However, fragmentation of Fc fusion proteins, which mainly occurs around the hinge regions during production, storage, and circulation in the blood, is a major issue. In this study, we first investigated the mechanisms of fragmentation around the hinge region during storage using Fc-fused bsAbs with specificity for epidermal growth factor receptor and CD3 as a model. The fragmentation peaks generated by gel filtration analysis indicated that both contaminating proteases and dissolved active oxygen should be considered causes of fragmentation. We designed and constructed variants by introducing a point mutation into the upper hinge region, which reduced the cleavage caused by dissolved active oxygen, and shortened the hinge region to restrict access of proteases. These hinge modifications improved fragmentation resistance and did not affect the biological activity of the bsAbs in vitro. We confirmed the versatility of the hinge modifications using another Fc-fused bsAb. Our results show that hinge modifications to the Fc fusion protein, especially the introduction of a point mutation into the upper hinge region, can reduce fragmentation substantially, and these modifications can be used to improve the fragmentation resistance of other recombinant Fc fusion proteins.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Suzuki S,Annaka H,Konno S,Kumagai I,Asano R

doi

10.1038/s41598-018-35489-y

subject

Has Abstract

pub_date

2018-11-22 00:00:00

pages

17253

issue

1

issn

2045-2322

pii

10.1038/s41598-018-35489-y

journal_volume

8

pub_type

杂志文章

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