This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tahtis, K. Articles by Scott, A. M. Search for Related Content PubMed PubMed Citation Articles by Tahtis, K. Articles by Scott, A. M.

Biodistribution Properties of ¹¹¹Indium-labeled C-Functionalized trans-Cyclohexyl Diethylenetriaminepentaacetic Acid Humanized 3S193 Diabody and F(ab')₂ Constructs in a Breast Carcinoma Xenograft Model

Tumor Targeting Program, Ludwig Institute for Cancer Research, Melbourne Branch, Austin and Repatriation Medical Centre, Victoria 3084, Australia [K. T., F-T. L., F. E. S., C. R., A. M. S.] and CRC for Diagnostic Technologies and CSIRO Division of Health Sciences and Nutrition [B. E. P., P. J. H.], Victoria 3052, Australia; Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, DCS, National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. W. B.]; and Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [L. J. O.]

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 54,000 diabody and M_r 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 ¹¹¹In 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 10⁶ M^-1 and 5.33 x 10⁶ 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.

This article has been cited by other articles:

				M. Friedman, E. Nordberg, I. Hoiden-Guthenberg, H. Brismar, G.P. Adams, F.Y. Nilsson, J. Carlsson, and S. Stahl Phage display selection of Affibody molecules with specific binding to the extracellular domain of the epidermal growth factor receptor Protein Eng. Des. Sel., April 23, 2007; (2007) gzm011v1. [Abstract] [Full Text] [PDF]

				J. Shi, Y. Liu, Y. Zheng, Y. Guo, J. Zhang, P.-t. Cheung, R. Xu, and D. Zheng Therapeutic Expression of an Anti-Death Receptor 5 Single-Chain Fixed-Variable Region Prevents Tumor Growth in Mice Cancer Res., December 15, 2006; 66(24): 11946 - 11953. [Abstract] [Full Text] [PDF]

				C.-Y. Xiong, A. Natarajan, X.-B. Shi, G. L. Denardo, and S. J. Denardo Development of tumor targeting anti-MUC-1 multimer: effects of di-scFv unpaired cysteine location on PEGylation and tumor binding Protein Eng. Des. Sel., August 1, 2006; 19(8): 359 - 367. [Abstract] [Full Text] [PDF]

				M. P. Kelly, F. T. Lee, F. E. Smyth, M. W. Brechbiel, and A. M. Scott Enhanced Efficacy of 90Y-Radiolabeled Anti-Lewis Y Humanized Monoclonal Antibody hu3S193 and Paclitaxel Combined-Modality Radioimmunotherapy in a Breast Cancer Model J. Nucl. Med., April 1, 2006; 47(4): 716 - 725. [Abstract] [Full Text] [PDF]

				D. Berndorff, S. Borkowski, S. Sieger, A. Rother, M. Friebe, F. Viti, C. S. Hilger, J. E. Cyr, and L. M. Dinkelborg Radioimmunotherapy of Solid Tumors by Targeting Extra Domain B Fibronectin: Identification of the Best-Suited Radioimmunoconjugate Clin. Cancer Res., October 1, 2005; 11(19): 7053s - 7063s. [Abstract] [Full Text] [PDF]

				F. T. Lee, A. J. Mountain, M. P. Kelly, C. Hall, A. Rigopoulos, T. G. Johns, F. E. Smyth, M. W. Brechbiel, E. C. Nice, A. W. Burgess, et al. Enhanced Efficacy of Radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling with EGFR Tyrosine Kinase Inhibitor AG1478 Clin. Cancer Res., October 1, 2005; 11(19): 7080s - 7086s. [Abstract] [Full Text] [PDF]

				F. Le Gall, U. Reusch, M. Little, and S. M. Kipriyanov Effect of linker sequences between the antibody variable domains on the formation, stability and biological activity of a bispecific tandem diabody Protein Eng. Des. Sel., April 1, 2004; 17(4): 357 - 366. [Abstract] [Full Text] [PDF]

				B. E. Power, L. Doughty, D. R. Shapira, J. E. Burns, A. M. Bayly, J. M. Caine, Z. Liu, A. M. Scott, P. J. Hudson, and A. A. Kortt Noncovalent scFv multimers of tumor-targeting anti-Lewisy hu3S193 humanized antibody Protein Sci., April 1, 2003; 12(4): 734 - 747. [Abstract] [Full Text] [PDF]

				O. Dolezal, R. De Gori, M. Walter, L. Doughty, M. Hattarki, P. J. Hudson, and A. A. Kortt Single-chain Fv multimers of the anti-neuraminidase antibody NC10: the residue at position 15 in the VL domain of the scFv-0 (VL-VH) molecule is primarily responsible for formation of a tetramer-trimer equilibrium Protein Eng. Des. Sel., January 1, 2003; 16(1): 47 - 56. [Abstract] [Full Text] [PDF]