Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/9308
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.
Authors: Tahtis, K;Lee, Fook-Thean;Smyth, Fiona E;Power, David Anthony;Renner, C;Brechbiel, Martin W;Old, Lloyd J;Hudson, P J;Scott, Andrew M
Affiliation: Tumor Targeting Program, Ludwig Institute for Cancer Research, Melbourne Branch, Austin and Repatriation Medical Centre, Victoria 3084, Australia .
Issue Date: 1-Apr-2001
Citation: Clinical Cancer Research : An Official Journal of the American Association For Cancer Research; 7(4): 1061-72
Abstract: The humanized complementarity determining region-grafted anti-Lewis 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) approximately 54,000 diabody and M(r) approximately 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')(2) fragment was obtained by pepsin digest of parental hu3S193. To facilitate evaluations, the radiometal (111)In 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')(2) displayed effective tumor targeting and may have potential as a therapeutic molecule in patients with Le(y)-expressing tumors.
Internal ID Number: 11309358
URI: http://ahro.austin.org.au/austinjspui/handle/1/9308
URL: http://www.ncbi.nlm.nih.gov/pubmed/11309358
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal
Antibody Affinity
Breast Neoplasms.immunology.metabolism
Disease Models, Animal
Female
Gene Targeting
Humans
Immunoglobulin Fab Fragments.chemistry.immunology.metabolism.pharmacology
Indium Radioisotopes
Isothiocyanates.chemistry.metabolism
Lewis Blood-Group System.immunology
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Pentetic Acid.analogs & derivatives.chemistry.metabolism
Transplantation, Heterologous
Tumor Cells, Cultured
Appears in Collections:Journal articles

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