Comparative evaluationof capsular polysaccharide-specific IgM and IgG antibodies and F(ab′)2 and Fab fragments as delivery vehicles for radioimmunotherapy of fungal infection

Ekaterina Dadachova, Ruth A. Bryan, Xianchun Huang, Geraldina Ortiz, Tiffany Moadel, Arturo Casadevall

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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 = 1.7 × 109 mol/L-1 and 5.4 × 107 mol/L-1, respectively). Substantial killing of 24067 and H99 CN cells was achieved with 1 μCi 188Re-18B7 (55 cGy dose), whereas no killing was observed for 1 μCi 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.

Original languageEnglish (US)
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007

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Radioimmunotherapy
Immunoglobulin Fab Fragments
Cryptococcus neoformans
Mycoses
Polysaccharides
Immunoglobulin M
Immunoglobulin G
Antibodies
Monoclonal Antibodies
Lung
Virus Diseases
Infection
Bacterial Infections
Communicable Diseases
Fungi
Research Design
Theoretical Models
Antigens
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Comparative evaluationof capsular polysaccharide-specific IgM and IgG antibodies and F(ab′)2 and Fab fragments as delivery vehicles for radioimmunotherapy of fungal infection. / Dadachova, Ekaterina; Bryan, Ruth A.; Huang, Xianchun; Ortiz, Geraldina; Moadel, Tiffany; Casadevall, Arturo.

In: Clinical Cancer Research, Vol. 13, No. 18, 15.09.2007.

Research output: Contribution to journalArticle

Dadachova, Ekaterina ; Bryan, Ruth A. ; Huang, Xianchun ; Ortiz, Geraldina ; Moadel, Tiffany ; Casadevall, Arturo. / Comparative evaluationof capsular polysaccharide-specific IgM and IgG antibodies and F(ab′)2 and Fab fragments as delivery vehicles for radioimmunotherapy of fungal infection. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 18.
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abstract = "Purpose: 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. Experimental Design: 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 = 1.7 × 109 mol/L-1 and 5.4 × 107 mol/L-1, respectively). Substantial killing of 24067 and H99 CN cells was achieved with 1 μCi 188Re-18B7 (55 cGy dose), whereas no killing was observed for 1 μCi 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.",
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T1 - Comparative evaluationof capsular polysaccharide-specific IgM and IgG antibodies and F(ab′)2 and Fab fragments as delivery vehicles for radioimmunotherapy of fungal infection

AU - Dadachova, Ekaterina

AU - Bryan, Ruth A.

AU - Huang, Xianchun

AU - Ortiz, Geraldina

AU - Moadel, Tiffany

AU - Casadevall, Arturo

PY - 2007/9/15

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N2 - Purpose: 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. Experimental Design: 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 = 1.7 × 109 mol/L-1 and 5.4 × 107 mol/L-1, respectively). Substantial killing of 24067 and H99 CN cells was achieved with 1 μCi 188Re-18B7 (55 cGy dose), whereas no killing was observed for 1 μCi 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.

AB - Purpose: 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. Experimental Design: 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 = 1.7 × 109 mol/L-1 and 5.4 × 107 mol/L-1, respectively). Substantial killing of 24067 and H99 CN cells was achieved with 1 μCi 188Re-18B7 (55 cGy dose), whereas no killing was observed for 1 μCi 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.

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