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IA-Hu5A8: A single gene–encoded tandem bispecific immunoadhesin molecule BiIA-SG was developed, where 2 single-chain variable fragment (scFv) binding domains against the V3 glycan epitope recognized by the PGT128 mAb and the CD4 receptor recognized by the Hu5A8 mAb are simultaneously present. Engineered immunoadhesin (IA) is an antibody-like molecule, and in this study, IA refers to molecules that contain the antigen-binding domain of scFv of bNAbs in fusion with the immunoglobulin constant region, including the hinge and Fc fragment, but without CL)/CH1). Before engineering BiIAs, codon-optimized scFvs of bnAbs PG9, PG16, PGT128, VRC01, and Hu5A8 were synthesized. The VL/VH domain of each scFv was engineered as a corresponding IA by fusion with human IgG1-Fc to generate IA-PG9, IA-PG16, IA-PGT128, IA-VRC01, and IA-Hu5A8. (Hu5A8 is an alternative name for iMab, which binds to the human CD4 receptor.) While all IAs exhibited specific anti–HIV-1 activity, only IA-PGT128 displayed similar potency and the same sigmoidal slope of 100% neutralization as previously described for the native PGT128, and IA-PGT128 in combination with IA-Hu5A8 exhibited the best synergistic effect based on computational synergy volumes. IA-PGT128 and IA-Hu5A8 were therefore used for BiIA construction. 2 BiIAs were constructed: a double gene–encoded (DG) bispecific IA (BiIA-DG) with the modified IgG1-Fc domain, and a single gene–encoded (SG) BiIA (BiIA-SG) through fusion of the PGT128 VL/VH to the N-terminal of IA-Hu5A8 VL/VH in tandem, resulting in a structurally unique molecule with 4 scFv binding domains (2 for HIV-1 gp120 and 2 for CD4) as compared with BiIA-DG or other bispecific bnAbs that contain 2 scFv binding domains (1 for each of the 2 target antigens). The neutralizing breadth and potency of the new BiIA-SG molecule were higher than those of the original neutralizing PGT128 mAb, or the BiIA-DG with a single scFv domain. BiIA-SG neutralized all 124 HIV-1–pseudotyped viruses tested, and in humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains.
(antibody generation, bispecific/trispecific)
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Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, and Zhiwei Chen. Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice. J Clin Invest, 128(6):2239-2251, Jun 1 2018. PubMed ID: 29461979.
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