Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity
Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface wh...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/81646 |
| _version_ | 1797816600660803584 |
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| author | Jinyeop Song Bo-Seong Jeong Seong-Woo Kim Seong-Bin Im Seonghoon Kim Chih-Jen Lai Wonki Cho Jae U Jung Myung-Ju Ahn Byung-Ha Oh |
| author_facet | Jinyeop Song Bo-Seong Jeong Seong-Woo Kim Seong-Bin Im Seonghoon Kim Chih-Jen Lai Wonki Cho Jae U Jung Myung-Ju Ahn Byung-Ha Oh |
| author_sort | Jinyeop Song |
| collection | DOAJ |
| description | Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation showed that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 μM, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, the C-terminal fusion of a pair of weakly homodimerizing proteins to three different antibodies enhanced the antigen-binding avidity by at least 110 or 304 folds from the intrinsic binding avidity. Compared with the mother antibody, Obinutuzumab(Y101L) which targets CD20, the same antibody with fused catenators exhibited significantly enhanced binding to SU-DHL5 cells. Together, the homodimerization-induced antibody catenation would be a new powerful approach to improve antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies. |
| first_indexed | 2024-03-13T08:40:03Z |
| format | Article |
| id | doaj.art-63898ee2d57b4962bbcf50134986f256 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-13T08:40:03Z |
| publishDate | 2023-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-63898ee2d57b4962bbcf50134986f2562023-05-30T14:29:22ZengeLife Sciences Publications LtdeLife2050-084X2023-05-011210.7554/eLife.81646Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidityJinyeop Song0https://orcid.org/0000-0002-4113-5185Bo-Seong Jeong1https://orcid.org/0000-0003-0629-6722Seong-Woo Kim2https://orcid.org/0000-0002-4374-2093Seong-Bin Im3https://orcid.org/0000-0003-1488-6386Seonghoon Kim4Chih-Jen Lai5Wonki Cho6Jae U Jung7Myung-Ju Ahn8Byung-Ha Oh9https://orcid.org/0000-0002-6437-8470Department of Physics, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaDepartment of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaDepartment of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaDepartment of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaDepartment of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaCancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaCancer Biology Department, Infection Biology Program, and Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of KoreaDepartment of Biological Sciences, KAIST Institute for the Biocentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaImmunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation showed that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 μM, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, the C-terminal fusion of a pair of weakly homodimerizing proteins to three different antibodies enhanced the antigen-binding avidity by at least 110 or 304 folds from the intrinsic binding avidity. Compared with the mother antibody, Obinutuzumab(Y101L) which targets CD20, the same antibody with fused catenators exhibited significantly enhanced binding to SU-DHL5 cells. Together, the homodimerization-induced antibody catenation would be a new powerful approach to improve antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies.https://elifesciences.org/articles/81646IgG antibodyantibody catenationavidity enhancementnew technologyantibody application |
| spellingShingle | Jinyeop Song Bo-Seong Jeong Seong-Woo Kim Seong-Bin Im Seonghoon Kim Chih-Jen Lai Wonki Cho Jae U Jung Myung-Ju Ahn Byung-Ha Oh Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity eLife IgG antibody antibody catenation avidity enhancement new technology antibody application |
| title | Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity |
| title_full | Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity |
| title_fullStr | Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity |
| title_full_unstemmed | Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity |
| title_short | Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity |
| title_sort | noncovalent antibody catenation on a target surface greatly increases the antigen binding avidity |
| topic | IgG antibody antibody catenation avidity enhancement new technology antibody application |
| url | https://elifesciences.org/articles/81646 |
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