Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library

Andy Chevigné*, Aurélie Fischer, Julie Mathu, Manuel Counson, Nadia Beaupain, Jean Marc Plesséria, Jean Claude Schmit, Sabrina Deroo

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)


Phage display technology is a powerful selection approach to identify strong and specific binders to a large variety of targets. In this study, we compared the efficacy of a phage library displaying human heavy chain complementarity determining region 3 (HCDR3) repertoires with a set of conventional random peptide libraries for the identification of CXCR4 antagonists using a peptide corresponding to the second extracellular loop of the receptor CXCR4 as target. A total of 11 selection campaigns on this target did not result in any specific ligand from the random peptide libraries. In contrast, a single selection campaign with an HCDR3 library derived from the IgM repertoire of a nonimmunized donor resulted in nine specific peptides with lengths ranging from 10 to 19 residues. Four of these HCDR3 sequences interacted with native receptor and the most frequently isolated peptide displayed an affinity of 5.6 μm and acted as a CXCR4 antagonist (IC50 = 23 μm). To comprehend the basis of the highly efficient HCDR3 library selection, its biochemical properties were investigated. The HCDR3 length varied from 3 to 21 residues and displayed a biased amino acid content with a predominant proportion of Tyr, Gly, Ser and Asp. Repetitive and conserved motifs were observed in the majority of the HCDR3 sequences. The strength and efficacy of the HCDR3 libraries reside in the combination of multiple size peptides and a naturally biased sequence variation. Therefore, HCDR3 libraries represent a powerful and versatile alternative to fully randomized peptide libraries, in particular for difficult targets.

Original languageEnglish
Pages (from-to)2867-2878
Number of pages12
JournalFEBS Journal
Issue number16
Publication statusPublished - Aug 2011


  • CXCR4 antagonist
  • HCDR3
  • natural sequence randomization
  • peptide repertoire
  • phage display


Dive into the research topics of 'Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library'. Together they form a unique fingerprint.

Cite this