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Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments
Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the inst...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240654/ https://www.ncbi.nlm.nih.gov/pubmed/27786600 http://dx.doi.org/10.1080/19420862.2016.1248012 |
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author | Egan, Timothy J. Diem, Dania Weldon, Richard Neumann, Tessa Meyer, Sebastian Urech, David M. |
author_facet | Egan, Timothy J. Diem, Dania Weldon, Richard Neumann, Tessa Meyer, Sebastian Urech, David M. |
author_sort | Egan, Timothy J. |
collection | PubMed |
description | Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the instability of the antibody fragments of which they consist, 2) undesired inter-subunit associations, and 3) the need to include recombinant heterodimerization domains that confer distribution-impairing bulk or enhance immunogenicity. In this paper, we describe a broadly-applicable method for the stabilization of human or humanized antibody Fv fragments that entails replacing framework region IV of a V(κ)1/V(H)3-consensus Fv framework with the corresponding germ-line sequence of a λ-type V(L) chain. We then used this stable Fv framework to generate a novel heterodimeric multispecific antibody format that assembles by cognate V(L)/V(H) associations between 2 split variable domains in the core of the complex. This format, termed multispecific antibody-based therapeutics by cognate heterodimerization (MATCH), can be applied to produce homogeneous and highly stable antibody-derived molecules that simultaneously bind 4 distinct antigens. The heterodimeric design of the MATCH format allows efficient in-format screening of binding domain combinations that result in maximal cooperative activity. |
format | Online Article Text |
id | pubmed-5240654 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-52406542017-02-03 Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments Egan, Timothy J. Diem, Dania Weldon, Richard Neumann, Tessa Meyer, Sebastian Urech, David M. MAbs Report Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the instability of the antibody fragments of which they consist, 2) undesired inter-subunit associations, and 3) the need to include recombinant heterodimerization domains that confer distribution-impairing bulk or enhance immunogenicity. In this paper, we describe a broadly-applicable method for the stabilization of human or humanized antibody Fv fragments that entails replacing framework region IV of a V(κ)1/V(H)3-consensus Fv framework with the corresponding germ-line sequence of a λ-type V(L) chain. We then used this stable Fv framework to generate a novel heterodimeric multispecific antibody format that assembles by cognate V(L)/V(H) associations between 2 split variable domains in the core of the complex. This format, termed multispecific antibody-based therapeutics by cognate heterodimerization (MATCH), can be applied to produce homogeneous and highly stable antibody-derived molecules that simultaneously bind 4 distinct antigens. The heterodimeric design of the MATCH format allows efficient in-format screening of binding domain combinations that result in maximal cooperative activity. Taylor & Francis 2016-10-27 /pmc/articles/PMC5240654/ /pubmed/27786600 http://dx.doi.org/10.1080/19420862.2016.1248012 Text en © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
spellingShingle | Report Egan, Timothy J. Diem, Dania Weldon, Richard Neumann, Tessa Meyer, Sebastian Urech, David M. Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
title | Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
title_full | Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
title_fullStr | Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
title_full_unstemmed | Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
title_short | Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
title_sort | novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240654/ https://www.ncbi.nlm.nih.gov/pubmed/27786600 http://dx.doi.org/10.1080/19420862.2016.1248012 |
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