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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

Authors' Affiliations: Departments of ¹ Nuclear Medicine and ² Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: Ekaterina Dadachova, Department of Nuclear Medicine, Albert Einstein College of Medicine, 1695A Eastchester Road, Bronx, NY 10461. Phone: 718-405-8485; Fax: 718-405-8457; E-mail: edadacho{at}aecom.yu.edu.

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 (K_a = 1.7 x 10⁹ mol/L^–1 and 5.4 x 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.