The 2nd International Conference on Drug Discovery & Therapy: Dubai, February 1 - 4, 2010


Session Speaker

Antibodies are Cryptic Reservoirs of Antiinfective, Antitumor and Immunomodulatory Peptides

L. Polonelli, W. Magliani, S. Conti A. Vecchiarelli and L.R. Travassos
Italy

Antibodies (Abs) have emerged as an important class of novel drugs for antigen-driven therapeutic purposes in diverse clinical settings, including infectious diseases and oncology. Abs commonly give rise in the treated host to anti-Ab responses, which may induce adverse reactions and limit their therapeutic efficacy. Abs modular domain architecture has been exploited to generate alternative reduced formats, essentially devoid of the Fc region. Paradigmatic single chain fragment variable region (scFv) Abs mimicking the wide-spectrum antimicrobial activity of a yeast killer toxin (killer Abs) have revealed that, irrespective of the specificity of the native Ab,CDR related peptides may display differential in vitro, ex vivo and /or in vivo antimicrobial (Candida albicans, Cryptococcus neoformans), antiviral (HIV-1, Influenza A), antitumor (melanoma) and immunomodulatory (dendritic cells) activities in a way reminiscent of molecules of early innate immunity. Alanine substitution of single residues of synthetic Ab peptides, used as surrogates of natural point mutations, resulted in further differential increased/unaltered/decreased biological activities. A synthetic CDR-related peptide has proven to be easily taken up by macrophages with subsequent stimulation of proinflammatory cytokine production, PI3K-Akt pathway and TLR-4 expression. Significantly, the Ab-derived peptide showed to exert therapeutic effect against systemic candidiasis without possessing direct candidacidal properties. The finding that Ab fragments may exert extrinsic biological activities raises the hypothesis that, in adaptive immunity, some cryptic functions, potentially diversified by by somatic mutation and clonal selection by antigens, may be exploited beyond the half-life of immunoglobulins making reasonable their apparent redundancy of production. These results open a new scenario about the possibility that Ab fragments may effectively influence the antiinfective and antitumor immune response. Whether there may occur a proteolytic release of Ab active fragments is a debatable hypothesis, that would be reminiscent of the extrinsic activity of a peptide cleaved from bovine haemoglobin that displays antimicrobial activity against Gram-positive bacteria and fungi at µM concentrations, as well as the carboxy-terminal tripeptide of the hormone a-MSH that inhibits Staphylococcus aureus, C. albicans and HIV-1 at picomolar concentrations. Effective delivery is a critical issue in the use of conventional free drugs. Studies on the structure-function relationship of a therapeutic Ab derived candidacidal decapeptide (killer peptide, KP) revealed its ability to spontaneously and reversibly self-assemble in an organized network of fibril-like structures. This process is catalyzed by 1,3-b-glucans, the KP’s target in C. albicans cells. While the self-assembled state may provide protection against proteases and the slow kinetic of dissociation assures a release of the active dimeric form over time, the b-glucans affinity is responsible for targeted delivery. Thus, KP represents a novel paradigm of targeted auto-delivering hydrogel-like drugs. The high frequency of bioactive Ab fragments and recent advances in peptide delivery, stability and design suggest that, according to definition of the mechanism of action, immunoglobulins may represent an unlimited reservoir for the search of new antiinfectious and antitumor agents.













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