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

Posted by on in 2018
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Angelini A
1,2,3Miyabe Y4Newsted D5Kwan BH5,6Miyabe C4Kelly RL5,6Jamy MN5Luster AD4Wittrup KD7,8,9Nat Commun. 2018 Apr 13;9(1):1461. doi: 10.1038/s41467-018-03687-x.

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA. alessandro.angelini@unive.it.
2
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. alessandro.angelini@unive.it.
3
Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Via Torino 155, Venezia Mestre, 30172, Italy. alessandro.angelini@unive.it.
4
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Charlestown, MA, 02129, USA.
5
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA.
6
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
7
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA. wittrup@mit.edu.
8
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. wittrup@mit.edu.
9
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. wittrup@mit.edu.

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.

*The Chicken anti-CMYC used in this publication is a product of Gallus Immunotech Inc.

PMID:
 
29654232
 
DOI:
 
10.1038/s41467-018-03687-x
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