Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis

Alessandro Angelini (), Yoshishige Miyabe, Daniel Newsted, Byron H. Kwan, Chie Miyabe, Ryan L. Kelly, Misha N. Jamy, Andrew D. Luster and K. Dane Wittrup ()
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Alessandro Angelini: Massachusetts Institute of Technology
Yoshishige Miyabe: Harvard Medical School
Daniel Newsted: Massachusetts Institute of Technology
Byron H. Kwan: Massachusetts Institute of Technology
Chie Miyabe: Harvard Medical School
Ryan L. Kelly: Massachusetts Institute of Technology
Misha N. Jamy: Massachusetts Institute of Technology
Andrew D. Luster: Harvard Medical School
K. Dane Wittrup: Massachusetts Institute of Technology

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03687-x

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