Abstract:
:In this study we constructed two phage libraries displaying non-immunized natural human IgM derived HCDR3 repertoires. One library was structurally constrained by a Gly to Cys substitution at position 104 enabling the formation of a disulfide bridge with the Cys at position 92. Panning of these libraries on an anti-human influenza hemagglutinin (HA) antibody resulted in the selection of 16 different HCDR3 loops displaying different degrees of sequence homology with the HA epitope. The specificity of the HCDR3 loops recovered from the structurally constrained library was confirmed by competition assays using the HA epitope. Only one of these HCDR3 peptides contained Cys104. Structural analysis of these sequences revealed that the loss of Cys104 was associated with an increased preference for the formation of the type I beta-turn required for high affinity binding to the antibody. Affinity studies confirmed that the HCDR3 peptides containing the sequence YDVPDY and Gly104 had affinities in the nanomolar range (K(d)=7.6 nM) comparable to the HA epitope. These findings provided evidence that the recovered HCDR3 sequences may bind to their target in a conformation that is unreachable by the parental antibody from which the HCDR3 was derived. Furthermore, the isolation of target-specific and high affinity binders demonstrates the value of HCDR3 libraries as a source of 'biologically randomized' sequences of human origin for the identification of peptidic lead molecules.
journal_name
Mol Immunoljournal_title
Molecular immunologyauthors
Deroo S,Fischer A,Beaupain N,Counson M,Boutonnet N,Pletinckx J,Loverix S,Beirnaert E,De Haard H,Schmit JC,Lasters Idoi
10.1016/j.molimm.2007.09.001subject
Has Abstractpub_date
2008-03-01 00:00:00pages
1366-73issue
5eissn
0161-5890issn
1872-9142pii
S0161-5890(07)00733-Xjournal_volume
45pub_type
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