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Abstract
While achieving rapid developments in recent years, bispecific antibodies are still difficult to design and manufacture, due to mispair of both heavy and light chains. Here we report a novel technology to make bispecific molecules. The knob-into-hole method was used to pair two distinct heavy chains as a heterodimer. IgG4 S228P CH1-CL interface was then partially replaced by T-cell receptor α/β constant domain to increase the efficiency of cognate heavy and light chain pairing. Following expression and purification, the bispecific antibody interface exchange was confirmed by Western blotting and LC–MS/MS. To ensure its validity, we combined a monovalent bispecific antibody against PD-1 (sequence from Pembrolizumab) and LAG3 (sequence from Relatlimab). The results showed that the molecule could be assembled correctly at a ratio of 95% in cells. In vitro functional assay demonstrated that the purified bispecific antibody exhibits an enhanced agonist activity compared to that of the parental antibodies. Low immunogenicity was predicted by an open-access software and ADA test.
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Details
1 Fudan University, School of Pharmacy, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); China State Institute of Pharmaceutical Industry, Shanghai, China (GRID:grid.419098.d) (ISNI:0000 0004 0632 441X)
2 China State Institute of Pharmaceutical Industry, Shanghai, China (GRID:grid.419098.d) (ISNI:0000 0004 0632 441X)
3 Fudan University, School of Pharmacy, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); The National Center for Drug Screening, Shanghai, China (GRID:grid.410611.3) (ISNI:0000 0004 7699 6713)