Abstract:
:Monoclonal antibodies recognize antigens with high affinity and specificity, but the structural basis for molecular mimicry remains unclear. It is often assumed that cross-reactive antigens share some structural similarity that is specifically recognized by a monoclonal antibody. Recent studies using combinatorial libraries, which are composed of millions of sequences, have examined antibody cross-reactivity in a manner entirely different from traditional epitope mapping approaches. Here, peptide libraries were screened against an anti-carbohydrate monoclonal antibody for the identification of peptide mimics. Positional scanning libraries composed of all-l or all-d hexapeptides were screened for inhibition of monoclonal antibody HGAC 39.G3 binding to an antigen displaying N-acetyl-d-glucosamine (GlcNAc) residues on a polyrhamnose backbone. Inhibitory activity by mixtures from the all-d hexapeptide library was greater than the activity from the all-l libraries. The most active d-amino acid residues defined in each of the six positions of the library were selected to prepare 27 different individual hexapeptides. The sequence Ac-yryygl-NH2 was specifically recognized by mAb HGAC 39.G3 with a relative affinity of 300 nM when measured in a competitive binding assay. The contributions to overall specificity of the residues of the all-d peptide (Ac-yryygl-NH2) in binding to mAb HGAC 39.G3 were examined with a series of truncation, l and d-amino acid substitution, and retro analogs. Dimeric forms of the all-d peptide were recognized with tenfold to 100-fold greater affinities relative to the monomer. The all-d peptide was found to inhibit mAb HGAC 39.G3 binding to an anti-idiotype antibody with approximately 1000-fold greater affinity than GlcNAc. As demonstrated here, the study of immune recognition using combinatorial chemistry may offer new insights into the molecular basis of cross-reactivity.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Pinilla C,Appel JR,Campbell GD,Buencamino J,Benkirane N,Muller S,Greenspan NSdoi
10.1006/jmbi.1998.2137subject
Has Abstractpub_date
1998-11-13 00:00:00pages
1013-25issue
5eissn
0022-2836issn
1089-8638pii
S0022-2836(98)92137-4journal_volume
283pub_type
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