Comparative evaluation of capsular polysaccharide-specific IgM and IgG antibodies and F(ab')2 and Fab fragments as delivery vehicles for radioimmunotherapy of fungal infection.
OBJECTIVE
The applicability of radioimmunotherapy with organism-specific monoclonal antibodies to treatment of infectious disease in experimental models has been recently shown for fungal, bacterial, and viral infections. To identify the best delivery vehicle for radioimmunotherapy of human pathogenic fungus Cryptococcus neoformans (CN), we have done comparative evaluation of capsular polysaccharide-specific antibodies with IgG1 and IgM isotypes and F(ab')2 and Fab fragments.


METHODS
18B7 IgG1 and 13F1 IgM and their isotype-matching controls were radiolabeled with 188Re, and their binding to 24067 and H99 CN strains was evaluated by doing Scatchard and kinetics analyses. The doses delivered during in vitro radioimmunotherapy were estimated using a cellular dosimetry algorithm. The biodistribution of 188Re-labeled 18B7 and 13F1 and of 111In-labeled 18B7 and its F(ab')2 and Fab fragments was done in A/JCr mice systemically infected with 24067 CN strain.


RESULTS
18B7 IgG1 showed superior to 13F1 IgM binding to 24067 CN (Ka=1.7x10(9) mol/L(-1) and 5.4x10(7) mol/L(-1), respectively). Substantial killing of 24067 and H99 CN cells was achieved with 1 microCi 188Re-18B7 (55 cGy dose), whereas no killing was observed for 1 microCi 188Re-13F1 (2 cGy dose). In vivo 188Re-18B7 localized specifically in the lungs of CN-infected mice, whereas uptake of 188Re-13F1 was nonspecific. 111In-F(ab')2 fragments showed higher uptake in the lungs and lower in the liver at the 48-h time point in comparison with intact 111In-18B7.


CONCLUSIONS
Comparative evaluation of IgG and IgM and of F(ab')2 and Fab fragments as potential delivery vehicles for radioimmunotherapy of cryptococcal infection strongly suggests that affinity for the target antigen is an important prerequisite for successful targeting of infection in vivo and that in vitro affinity measurements may predict the in vivo efficacy of candidate monoclonal antibodies.
Dadachova
Ekaterina
E
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA. edadacho@aecom.yu.edu
Bryan
Ruth A
RA
Huang
Xianchun
X
Ortiz
Geraldina
G
Moadel
Tiffany
T
Casadevall
Arturo
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D003453:Cryptococcosis / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D003455:Cryptococcus neoformans / Q000472:pathogenicity / Q000528:radiation effects; D016503:Drug Delivery Systems; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007075:Immunoglobulin M / Q000494:pharmacology* / Q000627:therapeutic use; D000922:Immunotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D007205:Indium Radioisotopes / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011134:Polysaccharides / Q000276:immunology; D016499:Radioimmunotherapy; D012211:Rhenium / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000922:Immunotoxins; D007205:Indium Radioisotopes; D011134:Polysaccharides; D012211:Rhenium