Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammato...
| Main Authors: | , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Published: |
Nature Publishing Group
2018
|
| Online Access: | http://hdl.handle.net/1721.1/118861 https://orcid.org/0000-0001-5923-3843 https://orcid.org/0000-0002-9851-7029 https://orcid.org/0000-0001-5003-9104 https://orcid.org/0000-0003-2398-5896 |
| _version_ | 1810991756457541632 |
|---|---|
| author | Miyabe, Yoshishige Miyabe, Chie Luster, Andrew D. Angelini, Alessandro Newsted, Daniel Kwan, Byron Hua Kelly, Ryan Lewis Jamy, Misha N. Wittrup, Karl Dane |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Miyabe, Yoshishige Miyabe, Chie Luster, Andrew D. Angelini, Alessandro Newsted, Daniel Kwan, Byron Hua Kelly, Ryan Lewis Jamy, Misha N. Wittrup, Karl Dane |
| author_sort | Miyabe, Yoshishige |
| collection | MIT |
| description | Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR+CXC chemokines. The engineered molecules recognize functional epitopes of ELR+CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics. |
| first_indexed | 2024-09-23T12:58:45Z |
| format | Article |
| id | mit-1721.1/118861 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T12:58:45Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1188612022-10-01T12:18:14Z Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis Miyabe, Yoshishige Miyabe, Chie Luster, Andrew D. Angelini, Alessandro Newsted, Daniel Kwan, Byron Hua Kelly, Ryan Lewis Jamy, Misha N. Wittrup, Karl Dane Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Angelini, Alessandro Newsted, Daniel Kwan, Byron Hua Kelly, Ryan Lewis Jamy, Misha N. Wittrup, Karl Dane Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR+CXC chemokines. The engineered molecules recognize functional epitopes of ELR+CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics. Swiss National Science Foundation (Fellowship for Advanced Researchers) National Science Foundation (U.S.). Graduate Research Fellowship Program National Institute of General Medical Sciences (U.S.) (Graduate Research Fellowship) Samsung (Firm) 2018-11-02T20:42:53Z 2018-11-02T20:42:53Z 2018-04 2018-10-10T14:11:35Z Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/118861 Angelini, Alessandro, et al. “Directed Evolution of Broadly Crossreactive Chemokine-Blocking Antibodies Efficacious in Arthritis.” Nature Communications, vol. 9, no. 1, Dec. 2018. © 2018 The Authors https://orcid.org/0000-0001-5923-3843 https://orcid.org/0000-0002-9851-7029 https://orcid.org/0000-0001-5003-9104 https://orcid.org/0000-0003-2398-5896 http://dx.doi.org/10.1038/s41467-018-03687-x Nature Communications Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature |
| spellingShingle | Miyabe, Yoshishige Miyabe, Chie Luster, Andrew D. Angelini, Alessandro Newsted, Daniel Kwan, Byron Hua Kelly, Ryan Lewis Jamy, Misha N. Wittrup, Karl Dane Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis |
| title | Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis |
| title_full | Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis |
| title_fullStr | Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis |
| title_full_unstemmed | Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis |
| title_short | Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis |
| title_sort | directed evolution of broadly crossreactive chemokine blocking antibodies efficacious in arthritis |
| url | http://hdl.handle.net/1721.1/118861 https://orcid.org/0000-0001-5923-3843 https://orcid.org/0000-0002-9851-7029 https://orcid.org/0000-0001-5003-9104 https://orcid.org/0000-0003-2398-5896 |
| work_keys_str_mv | AT miyabeyoshishige directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT miyabechie directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT lusterandrewd directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT angelinialessandro directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT newsteddaniel directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT kwanbyronhua directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT kellyryanlewis directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT jamymishan directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis AT wittrupkarldane directedevolutionofbroadlycrossreactivechemokineblockingantibodiesefficaciousinarthritis |