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Experimental Therapeutics

Preclinical Assessment of the Efficacy of Mycograb, a Human Recombinant Antibody against Fungal HSP90

Ruth C. Matthews, Gordon Rigg, Samantha Hodgetts, Tracey Carter, Caroline Chapman, Carl Gregory, Chris Illidge, James Burnie
Ruth C. Matthews
1Department of Medical Microbiology, University of Manchester
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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Gordon Rigg
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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Samantha Hodgetts
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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Tracey Carter
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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Caroline Chapman
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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Carl Gregory
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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Chris Illidge
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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James Burnie
1Department of Medical Microbiology, University of Manchester
2NeuTec Pharma plc, Manchester M13 9WL, United Kingdom
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  • For correspondence: james.burnie@cmmc.nhs.uk
DOI: 10.1128/AAC.47.7.2208-2216.2003
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  • FIG. 1.
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    FIG. 1.

    Lane 1, C. albicans extract immunoblotted against Mycograb; lane 2, molecular mass markers (31, 52, 98, and 185 kDa; Invitrogen, Paisley, United Kingdom); lane 3, silver stain of purified Mycograb showing monomer (28 kDa) and dimer (52 kDa).

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    FIG. 2.

    Two-dimensional electrophoresis and Western blot of C. albicans extract versus Mycograb.

Tables

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  • TABLE 1.

    Checkerboard assay of FLC and Mycograb versus yeast isolates examined

    SpeciesAgentMIC (μg/ml) of each agentFIC (μg/ml)FICIOutcome
    AloneIn combination
    C. albicans (FLC-S)FLC1.560.40.260.34Synergy
    Mycograb128100.08
    C. albicans (FLC-R)FLC5012.50.250.64Indifference
    Mycograb2561000.39
    C. krusei FLC100500.51.28Indifference
    Mycograb1281000.78
    C. tropicalis FLC3.123.121.01.78Indifference
    Mycograb1281000.78
    C. glabrata FLC6.251.560.250.75Indifference
    Mycograb128640.5
    C. parapsilosis (NCPF3104)FLC1.561.5611.39Indifference
    Mycograb2561000.39
    C. parapsilosis (clinical isolate)FLC1.561.5611.39Indifference
    Mycograb2561000.39
  • TABLE 2.

    Checkerboard assay of AMB and Mycograb versus yeast isolates examined

    SpeciesAgentMIC (μg/ml) of each agentFIC (μg/ml)FICIOutcome
    AloneIn combination
    C. albicans (FLC-S)AMB10.030.030.09Synergy
    Mycograb12880.06
    C. albicans (FLC-R)AMB0.50.1250.250.27Synergy
    Mycograb25640.02
    C. krusei AMB10.250.250.28Synergy
    Mycograb12840.03
    C. tropicalis AMB0.1250.0160.130.16Synergy
    Mycograb12840.03
    C. glabrata AMB10.250.250.31Synergy
    Mycograb12880.062
    C. parapsilosis (NCPF3104)AMB10.250.250.27Synergy
    Mycograb25640.016
    C. parapsilosis (clinical isolate)AMB10.250.250.27Synergy
    Mycograb25640.016
  • TABLE 3.

    Pharmacokinetic parameters of Mycograb in mice given a single dose

    Mycograb dose (mg/kg) (sample studied)Cmax (μg/ml)AUC0-t (μg · min/ml)AUC0-∞ (μg · min/ml)t1/2α (min)t1/2β (h)MRT (h)
    2 (serum)4.71551573.752.343.17
    10 (serum)54.92,857.42,859.67.052.512.35
    10 (renal biopsy specimen)21.79,1089,12010.210.949.3
  • TABLE 4.

    Organ colony counts from a series of experiments

    Expt no.bGroupDose (mg/kg)Colony count (mean log10 CFU/g ± SD)a
    AMBMycograbKidneyLiverSpleen
    110.62(9)e(9)d(9)d
    20.60.2(10)e(10)d(9)d
    30.6 b3.66 ± 0.82 (4)(9)d(10)d
    42 b4.58 ± 0.76 (2) b3.50 ± 0.47 (3) b3.12 ± 0.11 (4)
    50.25.1 ± 0.11 (0)3.85 ± 0.81 (3)3.35 ± 0.33 (3)
    65.5 ± 0.5 (0)4.42 ± 0.59 (2)3.65 ± 0.69 (2)
    210.62(9)d(9)d(8)d,e
    20.60.2(9)d(8)d3.71 ± 0.64 (4)
    30.6(9)d(7) b4.18 ± 0.22 (2)
    42(6) b4.32 ± 0.82 (4) b3.87 ± 0.93 (1)
    50.2(6) b4.35 ± 0.26 (4) b3.81 ± 0.78 (1)
    64.05 ± 0.1 (0)5.15 ± 0.18 (0)4.81 ± 0.33 (0)
    310.62(9)d(6)(8)d,e
    20.60.2(10)d(6)(8)d,e
    30.6(9)d b4.74 ± 1.0 (2) b4.24 ± 0.25 (3)
    42(8)d b5.54 ± 0.18 (0) b5.19 ± 0.31 (0)
    50.25.17 ± 0.19 (2) b6.01 ± 0.25 (0)5.30 ± 0.39 (0)
    65.19 ± 0.90 (0)6.57 ± 0.34 (0)5.86 ± 0.76 (0)
    410.62(8)d(10)d(10)d
    20.60.2(8)d(10)d(10)d
    30.6(8)d(10)d(10)d
    42 b4.24 ± 0.95 (1)(9)d(10)d
    50.2 b4.41 ± 0.72 (1)(10)d(10)d
    65.30 ± 0.13 (0)3.82 ± 0.69 (1)4.41 ± 0.93 (3)
    510.623.82 ± 0.81 (4)(10)d,e(10)d,e
    20.60.23.84 ± 0.78 (1)(9)d3.89 ± 0.94 (2)
    30.64.01 ± 0.93 (1)3.08 ± 0.12 (5)4.10 ± 0.98 (0)
    424.01 ± 0.92 (1)(9)d4.03 ± 0.33 (2)
    50.24.01 ± 0.09 (3)(9)d4.07 ± 0.31 (3)
    64.00 ± 0.04 (0)3.54 ± 0.65 (3)4.05 ± 0.08 (0)
    610.62 b4.56 ± 0.81 (0) b3.66 ± 0.25 (4) b4.08 ± 0.02 (2)
    20.60.2 b4.48 ± 0.34 (0) b4.09 ± 0.27 (2) b4.11 ± 0.29 (1)
    30.6 b4.62 ± 0.94 (0) b3.98 ± 0.06 (3) b4.24 ± 0.29 (2)
    42 b4.60 ± 0.65 (0) b4.07 ± 0.26 (3) b4.32 ± 0.31 (1)
    50.2 b4.77 ± 0.79 (0) b4.28 ± 0.28 (0) b4.48 ± 0.38 (2)
    65.66 ± 0.64 (0)5.31 ± 0.44 (0)5.24 ± 0.16 (0)
    • ↵ a Number of negative biopsy specimen in parentheses.

    • ↵ b Experiments: 1, FLC-resistant C. albicans; 2, C. krusei; 3, C. glabrata 4, C. tropicalis; 5, C. parapsilosis; 6, C. parapsilosis (clinical isolate).

    • c Statistically significant (Scheffe's test, P < 0.05) versus the control group 6.

    • ↵ d Statistically significant number of negative biopsy specimens (Fisher's exact test, P < 0.05) versus the control group 6.

    • ↵ e Statistically significant numbers of negative biopsy specimens (Fisher's exact test, P < 0.05) versus the AMB-treated group 3.

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Preclinical Assessment of the Efficacy of Mycograb, a Human Recombinant Antibody against Fungal HSP90
Ruth C. Matthews, Gordon Rigg, Samantha Hodgetts, Tracey Carter, Caroline Chapman, Carl Gregory, Chris Illidge, James Burnie
Antimicrobial Agents and Chemotherapy Jul 2003, 47 (7) 2208-2216; DOI: 10.1128/AAC.47.7.2208-2216.2003

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Preclinical Assessment of the Efficacy of Mycograb, a Human Recombinant Antibody against Fungal HSP90
Ruth C. Matthews, Gordon Rigg, Samantha Hodgetts, Tracey Carter, Caroline Chapman, Carl Gregory, Chris Illidge, James Burnie
Antimicrobial Agents and Chemotherapy Jul 2003, 47 (7) 2208-2216; DOI: 10.1128/AAC.47.7.2208-2216.2003
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KEYWORDS

Antibodies, Fungal
Candida albicans
candidiasis
HSP90 Heat-Shock Proteins
Recombinant Proteins

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