Characterization of a murine monoclonal antibody to Cryptococcus neoformans polysaccharide that is a candidate for human therapeutic studies.
The murine monoclonal antibody (MAb) 18B7 [immunoglobulin G1(kappa)] is in preclinical development for treatment of Cryptococcus neoformans infections. In anticipation of its use in humans, we defined the serological and biological properties of MAb 18B7 in detail. Structural comparison to the related protective MAb 2H1 revealed conservation of the antigen binding site despite several amino acid differences. MAb 18B7 was shown by immunofluorescence and agglutination studies to bind to all four serotypes of C. neoformans, opsonize C. neoformans serotypes A and D, enhance human and mouse effector cell antifungal activity, and activate the complement pathway leading to deposition of complement component 3 (C3) on the cryptococcal capsule. Administration of MAb 18B7 to mice led to rapid clearance of serum cryptococcal antigen and deposition in the liver and spleen. Immunohistochemical studies revealed that MAb 18B7 bound to capsular glucuronoxylomannan in infected mouse tissues. No reactivity of MAb 18B7 with normal human, rat, or mouse tissues was detected. The results show that both the variable and constant regions of MAb 18B7 are biologically functional and support the use of this MAb in human therapeutic trials.
Casadevall
A
A
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA. casadeva@aecom.yu.edu
Cleare
W
W
Feldmesser
M
M
Glatman-Freedman
A
A
Goldman
D L
DL
Kozel
T R
TR
Lendvai
N
N
Mukherjee
J
J
Pirofski
L A
LA
Rivera
J
J
Rosas
A L
AL
Scharff
M D
MD
Valadon
P
P
Westin
K
K
Zhong
Z
Z
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D000946:Antigens, Fungal / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects*; D011134:Polysaccharides / Q000276:immunology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D007074:Immunoglobulin G; D011134:Polysaccharides