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: | , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Published: |
Nature Publishing Group
2018
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| 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 |
| Summary: | 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. |
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