Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341, Republic of Korea.
AprilBio Co., Ltd, Kangwon National University, Rm. B602, Biomedical Science Building, Chuncheon, 24341, Republic of Korea.
Biochem Biophys Res Commun. 2020 Jun 11;526(4):941-946. doi: 10.1016/j.bbrc.2020.03.133. Epub 2020 Apr 10.
Human serum albumin (HSA) has been used to extend the serum half-lives of various protein therapeutics through genetic fusion because HSA exhibits an exceptionally long circulation time as a result of neonatal Fc receptor (FcRn)-mediated recycling. As another serum half-life extender, the human antibody Fab SL335 that strongly binds HSA was developed. When SL335 was fused to a protein therapeutic, SL335 was shown to prolong the half-life of the drug. Despite the significance of SL335-HSA binding in the extension of drug circulation time, it remains unclear how SL335 interacts with HSA at a molecular structural level. To reveal the structural basis of HSA recognition by SL335, we determined the crystal structure of the SL335-HSA complex at a resolution of 2.95 Å. SL335 binds HSA at a 1:1 stoichiometry. SL335 uses the exposed loops of its heavy and light chains to specifically recognize the IIa and IIb subdomains of HSA. The SL335 epitope is located on the opposite side of the FcRn-binding site and does not overlap with it, suggesting that SL335 extends the serum half-lives of itself and its fusion partner through an FcRn-dependent recycling mechanism.
人血清白蛋白（HSA）已被用于通过基因融合来延长各种蛋白质治疗药物的血清半衰期，因为 HSA 由于新生 Fc 受体（FcRn）介导的再循环而表现出异常长的循环时间。作为另一种血清半衰期延长剂，开发了与人血清白蛋白结合力强的人抗体 Fab SL335。当 SL335 融合到蛋白质治疗药物上时，SL335 被证明可以延长药物的半衰期。尽管 SL335-HSA 结合在延长药物循环时间方面具有重要意义，但仍不清楚 SL335 如何在分子结构水平上与 HSA 相互作用。为了揭示 SL335 识别 HSA 的结构基础，我们确定了 SL335-HSA 复合物的晶体结构，分辨率为 2.95 Å。SL335 以 1:1 的化学计量比结合 HSA。SL335 使用其重链和轻链的暴露环特异性识别 HSA 的 IIa 和 IIb 亚结构域。SL335 表位位于 FcRn 结合位点的对面，不与其重叠，表明 SL335 通过 FcRn 依赖的再循环机制延长自身和其融合伙伴的血清半衰期。
