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

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.

SUBMITTER: Angelini A

PROVIDER: S-EPMC5899157 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Angelini Alessandro A Miyabe Yoshishige Y Newsted Daniel D Kwan Byron H BH Miyabe Chie C Kelly Ryan L RL Jamy Misha N MN Luster Andrew D AD Wittrup K Dane KD

Nature communications 20180413 1

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<sup>+</sup> CXC chemokines. The engineered molecules recognize functional epitopes of ELR<sup>+</sup> CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of ...[more]

PMID: 29654232

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