Biodistribution of anti-breast mucin HuBrE3-derived inverted Fabs (IFabs) in nude mice carrying MX-1 xenografts.
In radioimmunotherapy, the long circulation times of antibody radioconjugates correlate with high relative radiation doses to nontumor tissues. Tumor/normal tissue ratios can be significantly improved by using targeting molecules with shorter circulation times. IFabs are multimers of VH-CH1-linker-VK-CK monomers. The lack of the Fc region in IFabs should lead to circulation times that are shorter than those of IgG molecules. The monomers assemble into disulfide-bond-stabilized multimers, 90% of which are 100 kDa dimers (IFab2). IFab2s should not be rapidly eliminated through kidney filtration because their molecular weight is above the threshold for renal passage. We report the first experimental in vivo tests for 125I-IFab radioconjugates derived from a humanized version of the anti-breast mucin monoclonal antibody BrE-3. Biodistributions are reported for athymic nude mice carrying human mammary tumor MX-1 xenografts. The T1/2 beta's for the different tissues ranged from 13.3 h for blood to 19.9 h for tumor. Therefore, IFab radioconjugates cleared the body with a rate comparable to that of F(ab')2 fragments. Except for stomach, tumor/nontumor dose ratios were significantly better for IFabs than for the parent antibody (BrE-3)4 days after injection.
Speck
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RR
Department of Pharmacology, Johns Hopkins University, Baltimore, Maryland 21218, USA.
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Couto
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism* / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D008321:Mammary Glands, Animal / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1 / Q000276:immunology; D009077:Mucins / Q000276:immunology*; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D018396:Mucin-1; D009077:Mucins