–Ruth Matthews, MD, PhD, FRCPath
Genetically recombinant antibodies may represent a new approach to the treatment of candidiasis. The first such antibody has a broad spectrum of activity against Candida species. Preclinical studies demonstrate synergy with amphotericin B, both in vitro and in mouse models of candidiasis. It could also act synergistically with other cell-wall—active antifungal agents, such as caspofungin.
Thus far, combination therapy with amphotericin B and the antibody has been associated with regression of infection in 3 patients with culture-confirmed candidiasis. An ongoing phase 2 trial, begun last year, involves 60 patients with culture-confirmed invasive candidiasis who are receiving liposomal amphotericin B plus the antibody or placebo. Efficacy evaluations include clinical response and clearance of fungal cultures. The antibody was designed to be given with other antifungal agents to increase efficacy, reduce mortality, and reduce amphotericin B toxicity. It may also reduce the risk of resistance.
(Advanced Studies in Medicine. 2002;3(1A):S18-S19)
Genetically recombinant antibodies may represent a new approach to the treatment of candidiasis. The first such antibody developed for candidiasis treatment is described here, along with findings from the first open-label, dose-ranging safety and pharmacokinetics studies in humans.
The sequence of the genetically recombinant antibody, Mycograb®, was derived from patients who had recovered from systemic candidiasis and seroconverted to hsp90, the therapeutic target. The antibody itself has a broad spectrum of activity against Candida species that can be measured by inhibition of fungal growth in vitro and therapeutic activity in mouse models of invasive candidiasis. Affinity of the antibody against its target, the immunodominant LKVIRK epitope of hsp90, can be measured by the enzyme-linked immunosorbent assay.
Several in vitro studies of the effect of the antibody on antifungal minimal inhibitory concentrations (MICs) have shown that the MIC of fluconazole against most Candida species shifts very little at the antibody concentrations attained in humans (1-100 µg/mL), thus demonstrating the lack of synergy with fluconazole.
By comparison, the same concentrations of the antibody caused the MIC of amphotericin B against all Candida species tested to fall to one half or one quarter of its initial value, demonstrating synergy with this antifungal agent. The synergy may occur because amphotericin B increases the permeability of the yeast cell wall and facilitates the antibody’s access to hsp90, the therapeutic target. Synergy could also exist between the antibody and other cell-wall—active antifungal agents, including echinocandins such as caspofungin.
The antibody was specifically designed to work with other antifungal agents in combination regimens to increase efficacy, reduce mortality, reduce amphotericin B toxicity, and reduce the risk of resistance. Thus far, the antibody has been given to 5 patients with culture-confirmed invasive candidiasis who were receiving a lipid-associated formulation of amphotericin B. Of these patients, 3 received 24 hours of treatment at the therapeutic dose. The first of these patients was a 53-year-old woman with invasive candidiasis that was complicating acute pancreatitis. She was not responding to amphotericin B lipid complex, but showed some clinical improvement (including cultures becoming negative) following 4 escalating doses of the antibody.
The second patient was a 45-year-old man who developed invasive candidiasis after bowel surgery, with multiple sites (including ascitic fluid) that were positive for C albicans. He had fever, an elevated white blood cell count, and tachycardia, despite therapy with amphotericin B lipid complex. After 4 escalating doses of the antibody, his fever resolved, his white blood cell count decreased, and he improved clinically. Subsequent recovery was complicated by an episode of bacterial sepsis, which responded to antibiotics, and the patient made a full recovery.
The third patient was a 57-year-old man with C albicans empyema. After 6 days of therapy with amphotericin B lipid complex, cultures taken from a chest drain were still growing Candida. The patient had an elevated white blood cell count and was deteriorating clinically. After 24 hours of treatment with the antibody, he made a full clinical recovery, and subsequent cultures were negative.
Pharmacokinetic and dose-ranging studies have determined that the optimal dose of the antibody is 1 mg/kg twice daily. Safety studies have found that the antibody is well tolerated, with no adverse changes in vital signs, hematologic variables, clinical chemistry values, and coagulation times.
A double-blind, placebo-controlled, phase 2 trial was initiated in England in 2001 and is expanding to include other countries. The 60 participating patients will have culture-confirmed invasive candidiasis being treated with liposomal amphotericin B. In addition, they will receive a 5-day course of either the genetically recombinant antibody or placebo. Evaluation of efficacy will include clinical response to treatment and clearing of fungal cultures. For further information regarding patient recruitment for this trial, please contact Prof Ruth Matthews via e-mail at firstname.lastname@example.org; or Prof James P. Burnie at email@example.com.
*Based on a presentation given by Prof Matthews at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
Address correspondence to: Ruth Matthews, MD, PhD, FRCPath, Clinical Sciences Building, 2nd Floor, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom.
Volume 3, Number 1A - January 2003
This CME Expires on January 15, 2005; no tests will be accepted after this date.
This course is accredited by
Johns Hopkins University School of Medicine Advanced Studies in Medicine