期刊
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS
卷 23, 期 4, 页码 411-423出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/cbr.2007.0450
关键词
scFv multimeric construct; hu3S193; biodistribution; Lewis Y antigen
类别
资金
- NHMRC Program [290816]
- NIH
- National Cancer Institute
- Center for Cancer Research
- Melbourne Research Scholarship, University of Melbourne (Melbourne, Australia)
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 (In-111) radioisotope. lmmunoreactivities 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 grain (%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.
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