PMID- 34785706 OWN - NLM STAT- MEDLINE DCOM- 20220126 LR - 20240404 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 11 IP - 1 DP - 2021 Nov 16 TI - Optimization of anti-ADAMTS13 antibodies for the treatment of ADAMTS13-related bleeding disorder in patients receiving circulatory assist device support. PG - 22341 LID - 10.1038/s41598-021-01696-3 [doi] LID - 22341 AB - ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motif 13)-related bleeding disorder has been frequently observed as a life-threatening clinical complication in patients carrying a circulatory assist device. Currently, treatment modalities for the bleeding disorder are very limited and not always successful. To address the unmet medical need, we constructed humanized antibodies of mouse anti-ADAMTS13 antibody A10 (mA10) by using complementarity-determining region (CDR) grafting techniques with human antibody frameworks, 8A7 and 16E8. The characteristics of the two humanized A10 antibodies, namely A10/8A7 and A10/16E8, were assessed in vitro and in silico. Among the two humanized A10 antibodies, the binding affinity of A10/16E8 to ADAMTS13 was comparable to that of mA10 and human-mouse chimeric A10. In addition, A10/16E8 largely inhibited the ADAMTS13 activity in vitro. The results indicated that A10/16E8 retained the binding affinity and inhibitory activity of mA10. To compare the antibody structures, we performed antibody structure modeling and structural similarity analysis in silico. As a result, A10/16E8 showed higher structural similarity to mA10, compared with A10/8A7, suggesting that A10/16E8 retains a native structure of mA10 as well as its antigen binding affinity and activity. A10/16E8 has great potential as a therapeutic agent for ADAMTS13-related bleeding disorder. CI - (c) 2021. The Author(s). FAU - Ito, Toshihiro AU - Ito T AD - Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. FAU - Minamitani, Takeharu AU - Minamitani T AD - Laboratory of Infectious Diseases and Immunity, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. AD - Laboratory of Immunobiologics Evaluation, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. AD - Toyama Prefectural Institute for Pharmaceutical Research, Imizu-City, 17-1 Nakataikoyama, Toyama, 939-0363, Japan. FAU - Hayakawa, Masaki AU - Hayakawa M AD - Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara, 634-8522, Japan. FAU - Otsubo, Ryota AU - Otsubo R AD - Laboratory of Infectious Diseases and Immunity, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. AD - Laboratory of Immunobiologics Evaluation, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. FAU - Akiba, Hiroki AU - Akiba H AD - Laboratory of Advanced Biopharmaceuticals, Center for Drug Design Research (CDDR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. AD - Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachicho, Sakyo-ku, Kyoto, 606-8501, Japan. FAU - Tsumoto, Kouhei AU - Tsumoto K AD - Center for Drug Design Research (CDDR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. AD - Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. AD - Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8656, Japan. FAU - Matsumoto, Masanori AU - Matsumoto M AD - Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara, 634-8522, Japan. mmatsumo@naramed-u.ac.jp. FAU - Yasui, Teruhito AU - Yasui T AD - Laboratory of Infectious Diseases and Immunity, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. tyasui@nibiohn.go.jp. AD - Laboratory of Immunobiologics Evaluation, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan. tyasui@nibiohn.go.jp. AD - Laboratory of Pharmaceutical Integrated Omics, Department of Pharmaceutical Engineering, Facility of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan. tyasui@nibiohn.go.jp. LA - eng GR - 20K16403/Grant-in-Aid for Early-Career Scientists from the Japan Society for the Promotion of Science (JSPS)/ GR - 20lm0203126h0001/Japan Agency for Medical Research and Development of Japan (AMED) Grants/ GR - 20lm0203126h0001/Japan Agency for Medical Research and Development of Japan (AMED) Grants/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211116 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antibodies, Monoclonal, Murine-Derived) RN - EC 3.4.24.87 (ADAMTS13 Protein) RN - EC 3.4.24.87 (ADAMTS13 protein, human) SB - IM MH - ADAMTS13 Protein/*antagonists & inhibitors/metabolism MH - Animals MH - Antibodies, Monoclonal, Humanized/*pharmacology MH - Antibodies, Monoclonal, Murine-Derived/*pharmacology MH - Hemorrhage/*drug therapy/enzymology MH - Humans MH - Mice MH - Purpura, Thrombotic Thrombocytopenic/*drug therapy/enzymology PMC - PMC8595387 COIS- The authors declare no competing interests. EDAT- 2021/11/18 06:00 MHDA- 2022/01/27 06:00 PMCR- 2021/11/16 CRDT- 2021/11/17 06:28 PHST- 2021/08/30 00:00 [received] PHST- 2021/11/02 00:00 [accepted] PHST- 2021/11/17 06:28 [entrez] PHST- 2021/11/18 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/11/16 00:00 [pmc-release] AID - 10.1038/s41598-021-01696-3 [pii] AID - 1696 [pii] AID - 10.1038/s41598-021-01696-3 [doi] PST - epublish SO - Sci Rep. 2021 Nov 16;11(1):22341. doi: 10.1038/s41598-021-01696-3.