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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

Luciano Polonelli,1 Walter Magliani,1 Stefania Conti,1 Luisa Bracci,2 Luisa Lozzi,2 Paolo Neri,2 Daniela Adriani,3 Flavia De Bernardis,3 and Antonio Cassone3*

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.

* Corresponding author. Mailing address: Department of Infectious Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. Phone: 390649387113. Fax: 390649387112. E-mail: cassone{at}iss.it.

Editor: T. R. Kozel

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.



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