Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site
LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function a...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1713648 |
| _version_ | 1817987931534524416 |
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| author | Karl J. M. Hanf Joseph W. Arndt YuTing Liu Bang Jian Gong Mia Rushe Richelle Sopko Ramiro Massol Benjamin Smith Yan Gao Isin Dalkilic-Liddle Xinhua Lee Shanell Mojta Zhaohui Shao Sha Mi R. Blake Pepinsky |
| author_facet | Karl J. M. Hanf Joseph W. Arndt YuTing Liu Bang Jian Gong Mia Rushe Richelle Sopko Ramiro Massol Benjamin Smith Yan Gao Isin Dalkilic-Liddle Xinhua Lee Shanell Mojta Zhaohui Shao Sha Mi R. Blake Pepinsky |
| author_sort | Karl J. M. Hanf |
| collection | DOAJ |
| description | LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of multiple sclerosis (AFFINITY: clinical trial.gov number NCT03222973). Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC- dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody. |
| first_indexed | 2024-04-14T00:27:36Z |
| format | Article |
| id | doaj.art-90b48837c1134c3892cafeda6316ee68 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-14T00:27:36Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-90b48837c1134c3892cafeda6316ee682022-12-22T02:22:40ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2020.1713648Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding siteKarl J. M. Hanf0Joseph W. Arndt1YuTing Liu2Bang Jian Gong3Mia Rushe4Richelle Sopko5Ramiro Massol6Benjamin Smith7Yan Gao8Isin Dalkilic-Liddle9Xinhua Lee10Shanell Mojta11Zhaohui Shao12Sha Mi13R. Blake Pepinsky14Biotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USAResearch and Early Development, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USAResearch and Early Development, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USAResearch and Early Development, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USAResearch and Early Development, Biogen, Cambridge, MA, USAResearch and Early Development, Biogen, Cambridge, MA, USABiotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, USALINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of multiple sclerosis (AFFINITY: clinical trial.gov number NCT03222973). Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC- dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody.https://www.tandfonline.com/doi/10.1080/19420862.2020.1713648LINGO-1anti-LINGO-1 antibodyopicinumabmultiple sclerosisoligodendrocyteremyelination |
| spellingShingle | Karl J. M. Hanf Joseph W. Arndt YuTing Liu Bang Jian Gong Mia Rushe Richelle Sopko Ramiro Massol Benjamin Smith Yan Gao Isin Dalkilic-Liddle Xinhua Lee Shanell Mojta Zhaohui Shao Sha Mi R. Blake Pepinsky Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site mAbs LINGO-1 anti-LINGO-1 antibody opicinumab multiple sclerosis oligodendrocyte remyelination |
| title | Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site |
| title_full | Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site |
| title_fullStr | Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site |
| title_full_unstemmed | Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site |
| title_short | Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site |
| title_sort | functional activity of anti lingo 1 antibody opicinumab requires target engagement at a secondary binding site |
| topic | LINGO-1 anti-LINGO-1 antibody opicinumab multiple sclerosis oligodendrocyte remyelination |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1713648 |
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