Abstract
BackgroundComplementarity-determining regions (CDRs) are immunoglobulin (Ig) hypervariable domains that determine specific antibody (Ab) binding. We have shown that synthetic CDR-related peptides and many decapeptides spanning the variable region of a recombinant yeast killer toxin-like antiidiotypic Ab are candidacidal in vitro. An alanine-substituted decapeptide from the variable region of this Ab displayed increased cytotoxicity in vitro and/or therapeutic effects in vivo against various bacteria, fungi, protozoa and viruses. The possibility that isolated CDRs, represented by short synthetic peptides, may display antimicrobial, antiviral and antitumor activities irrespective of Ab specificity for a given antigen is addressed here.Methodology/Principal FindingsCDR-based synthetic peptides of murine and human monoclonal Abs directed to: a) a protein epitope of Candida albicans cell wall stress mannoprotein; b) a synthetic peptide containing well-characterized B-cell and T-cell epitopes; c) a carbohydrate blood group A substance, showed differential inhibitory activities in vitro, ex vivo and/or in vivo against C. albicans, HIV-1 and B16F10-Nex2 melanoma cells, conceivably involving different mechanisms of action. Antitumor activities involved peptide-induced caspase-dependent apoptosis. Engineered peptides, obtained by alanine substitution of Ig CDR sequences, and used as surrogates of natural point mutations, showed further differential increased/unaltered/decreased antimicrobial, antiviral and/or antitumor activities. The inhibitory effects observed were largely independent of the specificity of the native Ab and involved chiefly germline encoded CDR1 and CDR2 of light and heavy chains.Conclusions/SignificanceThe high frequency of bioactive peptides based on CDRs suggests that Ig molecules are sources of an unlimited number of sequences potentially active against infectious agents and tumor cells. The easy production and low cost of small sized synthetic peptides representing Ig CDRs and the possibility of peptide engineering and chemical optimization associated to new delivery mechanisms are expected to give rise to a new generation of therapeutic agents.
Highlights
Immunoglobulins are composed of polymorphic heavy and light chains
The survival curves correlated well with differences in fungal burden in kidney tissue, in animals treated with mAb C7 L1 Complementarity-determining regions (CDRs)
On day 5 post-infection, the colony forming unit (CFU) counts in kidney tissue were 160.3646.6, 53.4652.0, 119.6635.5, and 133.4643.5 for mice treated with saline, mAb C7 L1, mAb C7/ pc42 H1 and H2 CDRs, respectively
Summary
The idiotypic variability is related to the diversity of the antigen binding site and in particular to the hypervariable domains called complementarity-determining regions (CDRs). There are 6 CDRs in both variable regions of light (VL) and heavy chains (VH) with background variability on each side of the CDRs. Antibodies (Abs) of different specificities can assemble identical VL domains with different VH domains. Idiotypic vaccination with a murine monoclonal Ab (mAb KT4), that neutralizes the wide-spectrum antimicrobial activity of a yeast killer toxin (KT) against eukaryotic and prokaryotic microorganisms presenting specific cell wall receptors (KTR), elicited the production of a special sub-set of antiidiotypic Abs (KT-antiId) characterized by in vitro microbicidal and in vivo therapeutic effects [1]. We have shown that synthetic CDR-related peptides and many decapeptides spanning the variable region of a recombinant yeast killer toxin-like antiidiotypic Ab are candidacidal in vitro. The possibility that isolated CDRs, represented by short synthetic peptides, may display antimicrobial, antiviral and antitumor activities irrespective of Ab specificity for a given antigen is addressed here
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