Journal
MABS
Volume 13, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2021.1893888
Keywords
Immunoglobulin A (IgA); albumin-binding-domain (ABD); the neonatal Fc receptor (FcRn); human serum albumin (HSA); half-life; human FcRn transgenic mice
Categories
Funding
- Horizon 2020 Framework Programme [825821]
- KWF Kankerbestrijding [7650]
- Norges Forskningsrad [300740, 230526, 179573]
- South-Eastern Norway Regional Health Authority [40018]
- Research Council of Norway [230526, 179573, 287927]
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In this study, it was demonstrated that ABD-fused IgA1 binds human FcRn pH-dependently and is rescued from cellular degradation in a receptor-specific manner in the presence of albumin. Furthermore, the presence of ABD led to an extended half-life of IgA1 in human FcRn transgenic mice, with the light chain fusion showing the longest half-life. The study suggests that an ABD, which does not interfere with albumin binding to human FcRn, may be used to extend the half-life of IgA.
Albumin has a serum half-life of 3 weeks in humans. This feature can be used to improve the pharmacokinetics of shorter-lived biologics. For instance, an albumin-binding domain (ABD) can be used to recruit albumin. A prerequisite for such design is that the ABD-albumin interaction does not interfere with pH-dependent binding of albumin to the human neonatal Fc receptor (FcRn), as FcRn acts as the principal regulator of the half-life of albumin. Thus, there is a need to know how ABDs act in the context of fusion partners and human FcRn. Here, we studied the binding and transport properties of human immunoglobulin A1 (IgA1), fused to a Streptococcus protein G-derived engineered ABD, in in vitro and in vivo systems harboring human FcRn. IgA has great potential as a therapeutic protein, but its short half-life is a major drawback. We demonstrate that ABD-fused IgA1 binds human FcRn pH-dependently and is rescued from cellular degradation in a receptor-specific manner in the presence of albumin. This occurs when ABD is fused to either the light or the heavy chain. In human FcRn transgenic mice, IgA1-ABD in complex with human albumin, gave 4-6-fold extended half-life compared to unmodified IgA1, where the light chain fusion showed the longest half-life. When the heavy chain-fused protein was pre-incubated with an engineered human albumin with improved FcRn binding, cellular rescue and half-life was further enhanced. Our study reveals how an ABD, which does not interfere with albumin binding to human FcRn, may be used to extend the half-life of IgA.
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