Further, there was a positive correlation between cover rate and blocking ability of all pro-Ab candidates. The binding kinetics effective concentrations (EC-50) for αPD-1 (200-250-fold), αIL-1β (152-186-fold), αCTLA-4 (68-150-fold) and αTNFα Ab (20-123-fold) were presented as the blocking ability of pro-Ab compared to the Ab drug. The recombinant pro-Abs were generated by MSCS prediction in order to verify the application of molecular simulation for pro-Ab development. The resulting cover rates of the Ab lock with various linkers compared to the Ab drug were in the range 28.33–42.33%. We selected αPD-1, αIL-1β, αCTLA-4 and αTNFα Ab as models and attached the Ab lock with various linkers (L1 to L7) to form pro-Abs by MSCS, respectively. MSCS can precisely adjust the amino acid composition of the linker between the Ab lock and Ab drug with the assistance of molecular simulation.

Here we designed a method which uses structure-based computational simulation (MSCS) to optimize the blocking ability of the Ab lock for all Ab drugs. This is because the same Ab lock linker cannot be applied to every Ab due to the differences in the complementarity-determining region (CDR) loops. However, 30% of pro-Abs do not have such efficient blocking ability.

Previously, we reported that 70% of pro-Abs can achieve more than 100-fold blocking ability compared to the parental Abs. In order to overcome this issue, we “copied” an autologous Ab hinge as an “Ab lock” and “pasted” it on the binding site of the Ab by connecting a protease substrate and linker in between to generate a pro-Ab, which can be specifically activated in the disease region to enhance Ab selectivity and reduce side effects. E-mail: on-target toxicity of monoclonal antibodies (Abs) is mainly due to the fact that Abs cannot distinguish target antigens (Ags) expressed in disease regions from those in normal tissues during systemic administration.

E-mail: b Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan c Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan d Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan e School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan f Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan g Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan h Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan. * abcg a Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Sci., 2021, 12, 9759-9769 Development of a structure-based computational simulation to optimize the blocking efficacy of pro-antibodies †

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