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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