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

• Main Authors: Miyabe, Yoshishige (Author), Miyabe, Chie (Author), Luster, Andrew D. (Author), Angelini, Alessandro (Contributor), Newsted, Daniel (Contributor), Kwan, Byron Hua (Contributor), Kelly, Ryan Lewis (Contributor), Jamy, Misha N. (Contributor), Wittrup, Karl Dane (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Chemical Engineering (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2018-11-02T20:42:53Z.
• Subjects: Article
• Online Access: Get fulltext

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)