Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis
Open accessAbstract
A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans . This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.
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In a phase I/II trial in patients with AIDS-related cryptococcal meningitis, administration of 18B7 was safe.
“Administration of 18B7 was safe and transiently reduced serum antigen levels at high doses but exhibited poor cerebrospinal fluid penetration132.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [132]
18B7 transiently reduced serum antigen levels at high doses.
“Administration of 18B7 was safe and transiently reduced serum antigen levels at high doses but exhibited poor cerebrospinal fluid penetration132.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [132]
18B7 exhibited poor cerebrospinal fluid penetration.
“Administration of 18B7 was safe and transiently reduced serum antigen levels at high doses but exhibited poor cerebrospinal fluid penetration132.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [132]
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Cites
Bennett, J. E., Dismukes, W. E., Duma, R. J., Medoff, G., Sande, M. A., Gallis, H. A., Leonard, J. M., Fields, B. T., Bradshaw, M. W., Haywood, H. B., et al. (1979) · New England Journal of Medicine · doi:10.1056/nejm197907193010303 · Cited by 861 · see citing works
Self-citationTreatment of Cryptococcal Meningitis Associated with the Acquired Immunodeficiency Syndrome
van der Horst, C. M., Saag, M. S., Cloud, G. A., Hamill, R. J., Graybill, J. R., Sobel, J. D., Johnson, P. C., Tuazon, C. U., Kerkering, T. M., Moskovitz, B. L., et al. (1997) · New England Journal of Medicine · doi:10.1056/nejm199707033370103 · Cited by 808 · see citing works
Self-citationBiopharmaceutics and clinical pharmacokinetics
(1991) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(91)90260-d · Cited by 693 · see citing works
Saag, M. S., Powderly, W. G., Cloud, G. A., Robinson, P. A., Grieco, M. H., Sharkey, P. K., Thompson, S. E., Sugar, A. M., Tuazon, C. U., Fisher, J. F., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199201093260202 · Cited by 625 · see citing works
Self-citationFluconazole Compared with Amphotericin B plus Flucytosine for Cryptococcal Meningitis in AIDS
Larsen, R. A., Leal, M. A. E., & Chan, L. S. (1990) · Annals of Internal Medicine · doi:10.7326/0003-4819-113-3-183 · Cited by 359 · see citing works
Self-citationHuman Immune Respone to Monoclonal Antibodies
Khazaeli, M. B., Conry, R. M., & LoBuglio, A. F. (1994) · Journal of Immunotherapy · doi:10.1097/00002371-199401000-00006 · Cited by 301 · see citing works
Casadevall, A., Cleare, W., Feldmesser, M., Glatman-Freedman, A., Goldman, D. L., Kozel, T. R., Lendvai, N., Mukherjee, J., Pirofski, L.-A., Rivera, J., et al. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.6.1437 · Cited by 298 · see citing works
Self-citationProtective murine monoclonal antibodies to Cryptococcus neoformans
Mukherjee, J., Scharff, M. D., & Casadevall, A. (1992) · Infection and Immunity · doi:10.1128/iai.60.11.4534-4541.1992 · Cited by 282 · see citing works
Self-citationDromer, F., Charreire, J., Contrepois, A., Carbon, C., & Yeni, P. (1987) · Infection and Immunity · doi:10.1128/iai.55.3.749-752.1987 · Cited by 243 · see citing works
The capsule of Cryptococcus neoformans passively inhibits phagocytosis of the yeast by macrophages
Kozel, T. R., & Gotschlich, E. C. (1983) · The Journal of Immunology · doi:10.4049/jimmunol.130.4.1994 · Cited by 239 · see citing works
Immunoregulation by capsular components of Cryptococcus neoformans
Vecchiarelli, A. (2000) · Medical Mycology · doi:10.1080/mmy.38.6.407.417 · Cited by 213 · see citing works
The capsule of cryptococcus neoformans passively inhibits phagocytosis of the yeast by macrophages.
Kozel, T. R., & Gotschlich, E. C. (1982) · The Journal of Immunology · doi:10.4049/jimmunol.129.4.1675 · Cited by 206 · see citing works
Murphy, J. W., & Cozad, G. C. (1972) · Infection and Immunity · doi:10.1128/iai.5.6.896-901.1972 · Cited by 204 · see citing works
Fluconazole Combined with Flucytosine for Treatment of Cryptococcal Meningitis in Patients with AIDS
Larsen, R. A., Bozzette, S. A., Jones, B. E., Haghighat, D., Leal, M. A., Forthal, D. N., Bauer, M., Tilles, J. G., McCutchan, J. A., & Leedom, J. M. (1994) · Clinical Infectious Diseases · doi:10.1093/clinids/19.4.741 · Cited by 202 · see citing works
Self-citationVecchiarelli, A., Retini, C., Monari, C., Tascini, C., Bistoni, F., & Kozel, T. R. (1996) · Infection and Immunity · doi:10.1128/iai.64.7.2846-2849.1996 · Cited by 185 · see citing works
Vecchiarelli, A., Retini, C., Pietrella, D., Monari, C., Tascini, C., Beccari, T., & Kozel, T. R. (1995) · Infection and Immunity · doi:10.1128/iai.63.8.2919-2923.1995 · Cited by 182 · see citing works
Early Mycological Treatment Failure in AIDS‐Associated Cryptococcal Meningitis
Robinson, P. A., Bauer, M., Leal, M. A. E., Evans, S., Holtom, P. D., Diamond, D. M., Leedom, J. M., & Larsen, R. A. (1999) · Clinical Infectious Diseases · doi:10.1086/515074 · Cited by 159 · see citing works
Self-citationMukherjee, S., Lee, S. C., & Casadevall, A. (1995) · Infection and Immunity · doi:10.1128/iai.63.2.573-579.1995 · Cited by 153 · see citing works
Self-citationMukherjee, J., Casadevall, A., & Scharff, M. D. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.177.4.1105 · Cited by 147 · see citing works
Self-citationMukherjee, J., Zuckier, L. S., Scharff, M. D., & Casadevall, A. (1994) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.38.3.580 · Cited by 138 · see citing works
Self-citationEffect of serum IgG1 to Cryptococcus neoformans glucuronoxylomannan on murine pulmonary infection
Feldmesser, M., & Casadevall, A. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.2.790 · Cited by 136 · see citing works
Self-citationRetini, C., Vecchiarelli, A., Monari, C., Tascini, C., Bistoni, F., & Kozel, T. R. (1996) · Infection and Immunity · doi:10.1128/iai.64.8.2897-2903.1996 · Cited by 135 · see citing works
Complement Depletion in Cryptococcal Sepsis
Macher, A. M., Bennett, J. E., Gadek, J. E., & Frank, M. M. (1978) · The Journal of Immunology · doi:10.4049/jimmunol.120.5.1686 · Cited by 122 · see citing works
Antibody-mediated protection in mice with lethal intracerebral Cryptococcus neoformans infection.
Mukherjee, J., Pirofski, L., Scharff, M. D., & Casadevall, A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3636 · Cited by 116 · see citing works
Self-citationDong, Z. M., & Murphy, J. W. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118466 · Cited by 114 · see citing works
Mukherjee, S., Lee, S., Mukherjee, J., Scharff, M. D., & Casadevall, A. (1994) · Infection and Immunity · doi:10.1128/iai.62.3.1079-1088.1994 · Cited by 114 · see citing works
Self-citationGoldman, D. L., Lee, S. C., & Casadevall, A. (1995) · Infection and Immunity · doi:10.1128/iai.63.9.3448-3453.1995 · Cited by 114 · see citing works
Self-citationEnhancement of HIV-1 infection by the capsular polysaccharide of Cryptococcus neoformans
Pettoello‐Mantovani, M., Rubinstein, A., Goldstein, H., et al. (1992) · The Lancet · doi:10.1016/0140-6736(92)90142-p · Cited by 104 · see citing works
Dong, Z. M., & Murphy, J. W. (1995) · Infection and Immunity · doi:10.1128/iai.63.7.2632-2644.1995 · Cited by 103 · see citing works
Dromer, F., & Charreire, J. (1991) · The Journal of Infectious Diseases · doi:10.1093/infdis/163.5.1114 · Cited by 95 · see citing works
Isotype Can Affect the Fine Specificity of an Antibody for a Polysaccharide Antigen
McLean, G. R., Torres, M., Elguezábal, N., Nakouzi, A. S., & Casadevall, A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.3.1379 · Cited by 94 · see citing works
Self-citationUse of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS
Berry, A. J., Rinaldi, M. G., & Graybill, J. R. (1992) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.36.3.690 · Cited by 80 · see citing works
Hirano, A., Zimmerman, H. M., & Levine, S. (1964) · PubMed · Cited by 64 · see citing works
Fine Structure of Cerebral Fluid Accumulation
Hirano, A. (1965) · Archives of Neurology · doi:10.1001/archneur.1965.00460260079009 · Cited by 62 · see citing works
Fine Structure of Cerebral Fluid Accumulation
Hirano, A., Zimmerman, H. M., & Levine, S. (1967) · Springer eBooks · doi:10.1007/978-3-7091-7545-3_42 · Cited by 62 · see citing works
Mukherjee, S., Feldmesser, M., & Casadevall, A. (1996) · The Journal of Infectious Diseases · doi:10.1093/infdis/173.5.1222 · Cited by 61 · see citing works
Self-citationMathematical Modeling of Pharmacokinetic Data
Bourne, D. W. A. (2018) · Routledge eBooks · doi:10.1201/9780203749401 · Cited by 58 · see citing works
Human microglia mediate anti-Cryptococcus neoformans activity in the presence of specific antibody
Lee, S. C., Kress, Y., Dickson, D. W., & Casadevall, A. (1995) · Journal of Neuroimmunology · doi:10.1016/0165-5728(95)00097-l · Cited by 55 · see citing works
Self-citationHISTOCHEMICAL STUDIES OF NEPHROTOXICITY WITH SUBLETHAL DOSES OF MERCURY IN RATS.
TAYLOR, N. S. (1965) · PubMed · Cited by 54 · see citing works
Monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan enhance fluconazole efficacy
Mukherjee, J., Feldmesser, M., Scharff, M. D., & Casadevall, A. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.7.1398 · Cited by 54 · see citing works
Self-citationPassive immunization in murine cryptococcosis
Graybill, J. R., Hague, M., & Drutz, D. J. (1981) · Medical Mycology · doi:10.1080/00362178185380411 · Cited by 50 · see citing works
Pettoello‐Mantovani, M., Casadevall, A., SMARNWORAWONG, P., et al. (1994) · AIDS Research and Human Retroviruses · doi:10.1089/aid.1994.10.1079 · Cited by 48 · see citing works
Self-citationSerum Protein Enhancement of Antibiotic Therapy in Cryptococcosis
Gordon, M. A., & Lapa, E. W. (1964) · The Journal of Infectious Diseases · doi:10.1093/infdis/114.4.373 · Cited by 47 · see citing works
Serum Therapy for Cryptococcal Meningitis
Gordon, M. A., & Casadevall, A. (1995) · Clinical Infectious Diseases · doi:10.1093/clinids/21.6.1477 · Cited by 42 · see citing works
Self-citationFeldmesser, M., Mukherjee, J., & Casadevall, A. (1996) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/37.3.617 · Cited by 40 · see citing works
Self-citationLendvai, N. K., Qu, X., Hsueh, W., & Casadevall, A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.8.4367 · Cited by 39 · see citing works
Self-citationVII. REACTIONS OF ASTHOCYTES TO CRYPTOCOCCAL POLYSACCHARIDE IMPLANTATION
Hirano, A., Zimmerman, H. M., & Levine, S. (1965) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-196507000-00002 · Cited by 36 · see citing works
Acute lethal toxicity following passive immunization for treatment of murine cryptococcosis
Savoy, A., Lupan, D. M., Manalo, P. B., et al. (1997) · Infection and Immunity · doi:10.1128/iai.65.5.1800-1807.1997 · Cited by 36 · see citing works
Monari, C., Casadevall, A., Retini, C., Baldelli, F., Bistoni, F., & Vecchiarelli, A. (1999) · AIDS · doi:10.1097/00002030-199904160-00005 · Cited by 36 · see citing works
Self-citationHarrison, T. S., Nong, S., & Levitz, S. M. (1997) · The Journal of Infectious Diseases · doi:10.1086/514068 · Cited by 34 · see citing works
Fine Structure of Cerebral Fluid Accumulation
Hirano, A. (1964) · Archives of Neurology · doi:10.1001/archneur.1964.00460240064009 · Cited by 32 · see citing works
Lendvai, N. K., & Casadevall, A. (1999) · The Journal of Infectious Diseases · doi:10.1086/314946 · Cited by 25 · see citing works
Self-citationBlackstock, R. (1996) · Medical Mycology · doi:10.1080/02681219680000041 · Cited by 17 · see citing works
Khazaeli, M. B. (1989) · Hybridoma · doi:10.1089/hyb.1989.8.231 · Cited by 16 · see citing works
Immunoreactivity of Cryptococcal Antigen Is Not Stable under Prolonged Incubations in Human Serum
McFadden, D. C., Zaragoza, Ó., & Casadevall, A. (2004) · Journal of Clinical Microbiology · doi:10.1128/jcm.42.6.2786-2788.2004 · Cited by 14 · see citing works
Self-citation
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Research works printed but not linked: 1
- Milefchik, E., M. Leal, R. Haubrich, S. Bozzette, J. Tilles, J. Leedom, J. A. McCutchan, and R. A. Larsen. 1997. A phase II dose escalation trial of high dose fluconazole with and without flucytosine for AIDS associated crypto- coccal meningitis. Program Abstr. 4th Conf. Retrovir. Opportunistic Infect.
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Self-citation
- Authors
- Larsen, R. A., Pappas, P. G., Perfect, J., Aberg, J. A., Casadevall, A., Cloud, G. A., James, R., Filler, S., & Dismukes, W. E.
- Affiliations
- University of Southern California (US)
- University of Alabama at Birmingham (US)
- Duke Medical Center (US)
- Washington University in St. Louis (US)
- Albert Einstein College of Medicine (US)
- Rho (United States) (US)
- University of California, Los Angeles (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2005-03
- Volume
- 49
- Issue
- 3
- Pages
- 952-958
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC549259
- OpenAlex
- W2126076750
- Cited by
- 236
- References
- 55
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 13 · 2022: 8 · 2021: 17 · 2020: 13 · 2019: 2 · 2018: 12 · 2017: 21 · 2016: 6 · 2015: 11 · 2014: 13 · 2013: 5 · 2012: 12
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- University of Southern California
- National Institutes of Health (n01ai065296-009)
- National Institute of Allergy and Infectious Diseases (N01AI65296, N01 AI065296)
- National Center for Research Resources (M01RR000030, RR00043, M01RR000032, M01RR000043, RR.00036, M01RR000036)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- cryptococcal meningitis, Cryptococcus neoformans, capsular polysaccharide, passive immunotherapy, adjunctive therapy, HIV infection, pharmacokinetics, safety, maximum tolerated dose, dose escalation, intracranial hypertension, cryptococcal antigen titer, murine antibodies
- MeSH terms
- Animals, Antibodies, Fungal, Antibodies, Monoclonal, Antigens, Fungal, Cryptococcus neoformans, Humans, Immunization, Passive, HIV Infections, Meningitis, Cryptococcal, Area Under Curve, Mice
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