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Adams Gregory P , Tai Mei-Sheng , McCartney John E , Marks James D , Stafford Walter F III , Houston LL , Huston James S , Weiner Louis M
Avidity-Mediated Enhancement of In vivo Tumor Targeting by Single-Chain Fv Dimers
Clinical Cancer Research. 2006 ;12(5) :1599-1605
PMID: AN 2006:205525   
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Abstract
Radiolabeled single-chain Fv (sFv) mols. display highly specific tumor retention in the severe combined immunodeficient (SCID) mouse model; however, the abs. quantity of sFv retained in the tumors is diminished by the rapid renal elimination resulting from the small size of the sFv mols. (Mr 27,000) and by dissocn. of the monovalent sFv from tumor-assocd. antigen. We previously reported significant improvement in tumor retention without a loss of targeting specificity on converting monovalent sFv into divalent [(sFv')2] dimers, linked by a disulfide bond between COOH-terminal cysteinyl peptides engineered into the sFv'. However, our data for enhanced dimer localization in tumors could not distinguish between the contributions of enhanced avidity and increased systemic retention assocd. with the larger size of 54 kDa [(sFv')2] dimers relative to 27-kDa sFv. In this investigation, we have compared tumor targeting of divalent anti-c-erbB-2/HER2/neu 741F8-1 (sFv')2 homodimers with monovalent 741F8/26-10 (sFv')2 heterodimers (Mr 54,000) and 741F8 sFv monomers (741F8 sFv has binding specificity for erbB-2/HER2/neu and 26-10 sFv specificity for digoxin and related cardiac glycosides). These studies allowed us to distinguish the dominant effect of valency over mol. wt. in accounting for the superior tumor retention of 741F8-1 (sFv')2 homodimers. Each of the radioiodinated species was administered i.v. to SCID mice bearing SK-OV-3 human tumor xenografts and tumor localization at 24 h post i.v. injection was detd. for 125I-741F8-1 (sFv')2 (3.57 %ID/g), 125I-741F8/26-10 (sFv')2 (1.13 %ID/g), and 125I-741F8-1 sFv (1.25 %ID/g). These findings substantiate that the improved tumor retention of (sFv')2 homodimers over sFv monomers results from the availability of dual binding sites rather than from the slower systemic clearance of homodimers. [on SciFinder (R)]
Notes
15 Immunochemistry Department of Medical Oncology,Fox Chase Cancer Center,Philadelphia,PA,USA. Journal 1078-0432 written in English.