Biodistribution properties of (111)Indium-labeled C-functionalized trans-cyclohexyl diethylenetriaminepentaacetic acid humanized 3S193 diabody and F(ab ')(2) constructs in a breast carcinoma xenograft model Journal Article


Authors: Tahtis, K.; Lee, F. T.; Smyth, F. E.; Power, B. E.; Renner, C.; Brechbiel, M. W.; Old, L. J.; Hudson, P. J.; Scott, A. M.
Article Title: Biodistribution properties of (111)Indium-labeled C-functionalized trans-cyclohexyl diethylenetriaminepentaacetic acid humanized 3S193 diabody and F(ab ')(2) constructs in a breast carcinoma xenograft model
Abstract: The humanized complementarity determining region-grafted anti-le,vis Y (Le(y)) monoclonal antibody [humanized 3S193 (hu3S193)] was developed for targeting Le(y)-expressing epithelial tumors such as breast, colon, lung, prostate, and ovarian carcinoma. We are exploring the potential use of smaller molecular size, bivalent analogues of hu3S193, because the faster blood clearance of M-r similar to 54,000 diabody and M-r similar to 110,000 F(ab')(2) molecules may be advantageous in achieving optimal and rapid tumor uptake for diagnostic and potential therapeutic applications, The single-chain variable fragment-5 residue linker construct (diabody) was expressed using the bacterial secretion vector pPOW3, and soluble product was purified without refolding processes. The F(ab'), fragment was obtained by pepsin digest of parental hu3S193. To facilitate evaluations, the radiometal In-111 was used to label C-functionalized trans-cyclohexyl diethylenetriaminepentaacetic acid chelated diabody and F(ab')(2), The immunoreactivity of the radiolabeled constructs was 41.3 and 58.6%, and the K-a was 1.68 x 10(6) M-1 and 5.33 x 10(6) M-1 for the diabody and F(ab')(2), respectively. Radioconjugates were injected into mice bearing Le(y)-positive MCF-7 tumors, and biodistribution properties were determined at various time points after injection. The uptake of radiolabeled diabody in xenografts was maximal at 1 h after injection (4.7 +/- 0.6% injected dose/g), whereas the F(ab')(2) peaked at 8 h after injection (14.2 +/- 2.4% injected dose/g), The tumor:blood ratio at 4 h for the diabody and F(ab')(2) was 5:1 and 2:1, which increased to 20:1 and 5:1, respectively, at 8 h and increased further to 40:1 and 130:1, respectively, at 48 h, These results demonstrate that the diabody construct may have applications as a diagnostic imaging reagent, whereas F(ab'), displayed effective tumor targeting and may have potential as a therapeutic molecule in patients with Le(y)-expressing tumors.
Keywords: in-vivo; solid tumors; monoclonal-antibodies; nude-mice; single-chain fv; anticarcinoembryonic; antigen-antibody; recombinant antibody fragments; colon-cancer xenografts; blood-group antigens; scfv multimers
Journal Title: Clinical Cancer Research
Volume: 7
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2001-04-01
Start Page: 1061
End Page: 1072
Language: English
ACCESSION: WOS:000168297800040
PROVIDER: wos
PUBMED: 11309358
Notes: Article -- Source: Wos
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MSK Authors
  1. Lloyd J Old
    593 Old