Novel Therapies Antifungal Monoclonal Antibodies

Gordon and Lapa (1964) established that the administration of serum Abs enhances the outcome of antifungal chemotherapy in cryptococcosis. Several fungal infections are marked by significant Ab responses, however, the extent to which they confer protection varies depending on Ab isotype (Casadevall, 1995) and the MHC background of the host (Rivera & Casadevall, 2005). Variations in Ab VH gene usage were reported to significantly influence the specificity and efficacy of Abs, hence the resistance or susceptibility to cryptococcosis (Maitta et al., 2004). Protective Abs may not be made in quantities sufficient to alter the course of the infection; their action may also be countered by blocking or competing nonprotec-tive Abs (Nussbaum et al., 1996).

Unlike vaccines, therapeutic MAbs provide immediate protection irrespective of the immunostatus of the host. Their inherent passive activity to counter fungal infections permits their use in treating immunocompromised hosts. Derivation of effective MAbs as alternative antifungals relies on the identification of immunodo-minant fungal antigens against which MAbs can be raised. The fungal cell wall represents an interface of host-pathogen interactions and hence known to contain a number of structural moieties of significance in fungal pathogenesis and virulence. MAb A9, an IgG1 raised against cell wall extracts of A. fumigatus, was shown to bind to a surface peptide on the hyphal and yeast forms of the fungus, inhibit hyphal development and reduce spore germination time. A9 protected against IA in mice by reducing fungal burden and enhancing survival rates (Chaturvedi et al., 2005). MAbs raised against the glucosylceramide (GlcCer) moiety A-2'-hydroxyhexadecanoyl-1-P-d-glucopyranosyl-9-methyl-4,8-sphingadenine of Fonsecaea pedrosoi reduced fungal growth and enhanced phagocytosis and killing of fungal cells by murine macrophages (Nimrichter et al., 2004). Growth of Fusarium was inhibited by the presence of a fusion protein consisting of recombinant chicken-derived single chain Abs specific to surface antigens and antifungal peptides (Peschen et al., 2004). Expression of the fusion protein in transgenic Arabidopsis thaliana plants was protective against F oxysporum sp. G15, a human IgM MAb raised in xenomice transgenic for human IgM, IgG2, and light chain k challenged with the C. neoformans serotype D strain 24067 could significantly prolong the survival of mice challenged with a lethal dose of the fungus (Maitta et al., 2004). The Ab recognizes an epitope on the capsular polysaccharide glucuronoxylomannan (GXM) of C. neoformans.

MAbs raised against a number of intracellular or expressed fungal cell components have also been developed and tested in animal models. Anti-gp70, a MAb raised against the 70 kDa intracellular/secreted glycoprotein component of P. brasiliensis, abolished lung granuloma formation in infected mice (De Mattos Grosso et al., 2003). C. albicans strains susceptible to the yeast killer toxin (KT) activity take cover by Abs generated in the host against KT (competing Abs) or its receptor (KTR) on C. albican surface (blocking Abs). Anti-idiotypic MAbs that neutralize anti-KT or anti-KTR Ab activity thus allowing KT activity against the fungus to ensue can circumvent the evasiveness of pathogenic C. albicans. An IgM anti-idiotypic MAb generated in mice immunized with the anti-KT MAb (KT4) was reported to have a potent killing activity against KT-sensitive C. albicans strains (Polonelli et al., 1997). A decapeptide containing the first three amino acids of the light chain CDR1 of a KT anti-idiotype optimized by single residue replacement by alanine exerted a strong anticandidacidal activity in vitro, hence the peptide was termed KP for killer peptide (Polonelli et al., 2003). In a rat model of vaginal candidiasis, post-challenge local administration of KP resulted in rapid clearance of infections caused by fluconazole-resistant or susceptible strains of C. albicans. Administration of KP into Balb/c or SCID mice infected with lethal intravenous doses of C. albicans significantly prolonged survival beyond 60 days compared with 3-5 days in control mice (Polonelli et al., 1997).

The molecular chaperon protein hsp90, essential for yeast cell viability, represents an immunodominant antigen that elicits significant antibody responses in animals and in humans. A human recombinant anti-hsp90 MAb (Mycograb) has been derived from the anti-hsp90 antibody cDNA of patients recently recovering from invasive candidiasis (IC) (Matthews & Burnie, 2001). Mycograb was protective against C. tropicalis but not C. albicans, C. krusei, C. glabrata, or C. parapsi-losis infections in mice (Matthews et al., 2003). Combination therapy consisting of Mycograb and AMB resulted in complete resolution of C. albicans, C. krusei, and C. glabrata infections. In mice infected with C. parapsilosis, however, Mycograb-AMB combination therapy cleared the liver and spleen but not the kidneys (Matthews et al., 2003). MAb G5, an anti-C. albicans IgA, was shown to have potent candidacidal activity in vitro and potent prophylactic activity in vivo (Kacishwar & Shulka, 2006).

The safety and pharmacokinetics of MAb 18B7, a monoclonal against the C. neoformans capsular polysaccharide, was tested as an adjunctive therapy in HIV

patients successfully treated for cryptococcal meningitis (Larsen et al., 2005). Despite some minor side effects in subjects receiving a single infusion of 1-2 mg/ kg body weight of the drug, serum antigen titers declined by a median of twofold at week 1 and threefold at week 2 post-infusion. The halflife of the drug in serum was 53 h and the CSF of recipients was free of 18B7. A multinational, double-blind, placebo-controlled clinical trial on the efficacy of Mycograb as an adjunctive therapy in patients receiving LAMB for treating culture-proven IC is now underway (Matthews & Burnie, 2004).

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