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Title: Tumor targeting by a multivalent single-chain Fv (scFv) anti-Lewis Y antibody construct.
Austin Authors: Kelly, Marcus P;Lee, Fook-Thean;Tahtis, Kiki;Power, David Anthony;Smyth, Fiona E;Brechbiel, Martin W;Hudson, Peter J;Scott, Andrew M 
Affiliation: Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 1-Aug-2008
Publication information: Cancer Biotherapy & Radiopharmaceuticals; 23(4): 411-23
Abstract: The use of single-chain variable fragment (scFv) constructs has been investigated in cancer radioimmunotherapy (RIT) and radioimmunodetection, as these molecules permit rapid tumor penetration and clearance from the serum relative to whole IgG. Multimerization of scFv constructs has demonstrated improvements in functional affinity (i.e., avidity) and maximal tumor uptake. In this paper, we report the first biodistribution and pharmacokinetics studies of a noncovalent, direct-linked scFv (V(L)-0-V(H)) trimeric/tetrameric "multimer" of the anti-Lewis Y monoclonal antibody, hu3S193. The in vitro binding and in vivo biodistribution of the hu3S193 multimer was characterized alongside the hu3S193 F(ab')(2) following radiolabeling with the Indium-111 ((111)In) radioisotope. Immunoreactivities of the radiolabeled multimer and F(ab')(2) were 73% and 53.2%, and binding affinities (K(a)) were 1.58 x 10(7) M(1) and 4.31 x 10(6) M (1) for the multimer and F(ab')(2), respectively. Maximal tumor uptake in Le(y)-positive MCF-7 breast cancer xenografted BALB/c nude mice was 12.6 +/- 2.5 percent injected dose/per gram (%ID/g) at 6 hours postinjection for the multimer and 15.7 +/- 2.1 %ID/g at 24 hours postinjection for the F(ab')(2). However, limited in vitro stability and high renal localization of radiolabeled constructs were observed, which, despite the observed tumor targeting of the hu3S193 multimer, most likely preclude its use in RIT and imaging modalities.
Gov't Doc #: 18771345
DOI: 10.1089/cbr.2007.0450
Journal: Cancer biotherapy & radiopharmaceuticals
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal.chemistry.genetics
Antibodies, Monoclonal, Humanized
Area Under Curve
Cell Line, Tumor
Chromatography, Gel
Drug Stability
Immunoglobulin Fab Fragments.chemistry.immunology.metabolism
Immunoglobulin Variable Region.genetics.immunology.metabolism
Indium Radioisotopes
Lewis Blood-Group System.immunology
Mammary Neoplasms, Experimental.immunology.metabolism.radionuclide imaging
Mice, Inbred BALB C
Mice, Nude
Neoplasms.immunology.metabolism.radionuclide imaging
Radionuclide Imaging
Recombinant Proteins.blood.immunology.pharmacokinetics
Tissue Distribution
Transplantation, Heterologous
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