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Infection and Immunity, November 2003, p. 6205-6212, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6205-6212.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Therapeutic Activity of an Engineered Synthetic Killer Antiidiotypic Antibody Fragment against Experimental Mucosal and Systemic Candidiasis

Sezione di Microbiologia, Dipartimento di Patologia e Medicina di Laboratorio, Università degli Studi di Parma, Parma,¹ Sezione di Chimica Biologica, Dipartimento di Biologia Molecolare, Università degli Studi di Siena, Siena,² Dipartimento Malattie Infettive, Parassitarie ed Immuno-Mediate, Istituto Superiore di Sanità, Rome, Italy³

Received 23 May 2003/ Returned for modification 8 July 2003/ Accepted 28 July 2003

Peptides derived from the sequence of a single-chain, recombinant, antiidiotypic antibody (IdAb; KT-scFv) acting as a functional internal image of a microbicidal, wide-spectrum yeast killer toxin (KT) were synthesized and studied for their antimicrobial activity by using the KT-susceptible Candida albicans as model organism. A decapeptide containing the first three amino acids (SAS) of the light chain CDR1 was selected and optimized by alanine replacement of a single residue. This peptide exerted a strong candidacidal activity in vitro, with a 50% inhibitory concentration of 0.056 µM, and was therefore designated killer peptide (KP). Its activity was neutralized by laminarin, a ß1-3 glucan molecule, but not by pustulan, a ß1-6 glucan molecule. KP also competed with the binding of a KT-like monoclonal IdAb to germinating cells of the fungus. In a rat model of vaginal candidiasis, local, postchallenge administration of KP was efficacious in rapidly abating infections caused by fluconazole-susceptible or -resistant C. albicans strains. In systemic infection of BALB/c or SCID mice preinfected intravenously with a lethal fungal load, KP caused a highly significant prolongation of the median survival time, with >80% of the animals still surviving after >60 days, whereas >90% of control mice died within 3 to 5 days. KP is therefore the first engineered peptide derived from a recombinant IdAb retaining KT microbicidal activity, probably through the interaction with the ß-glucan KT receptor on target microbial cells.

Editor: T. R. Kozel

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