HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Kobayashi, H. Articles by Paik, C. H. Search for Related Content PubMed PubMed Citation Articles by Kobayashi, H. Articles by Paik, C. H.

Favorable Effects of Glycolate Conjugation on the Biodistribution of Humanized AntiTac Fab Fragment

Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, and Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence: For correspondence or reprints contact: Jorge A. Carrasquillo, MD, Department of Nuclear Medicine, National Institutes of Health, Bldg. 10, Room 1C-496,10 Center Dr., MSC 1180, Bethesda, MD 20892-1180.

ABSTRACT

One of the major limitations of using intact immunoglobulins for targeting tumors is poor penetration into tissues. Although Fab fragments have been used because of their improved kinetics, they have undesirable high renal accumulation. In this study we tested a new approach to block renal accumulation of Fab. Methods: We conjugated humanized antiTac Fab fragments, which are directed against the interleukin-2 receptor, with glycolate. The biodistribution, pharmacokinetics and catabolism of glycolated Fab (glyco-Fab) were evaluated at two different levels of substitution (heavy and light) compared with nonglycolated Fab in Tac-antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice. The mice received coinjections of ¹²⁵I-labeled glyco-Fab (3 µCi/1 µg) and ¹³¹I-labeled nonglycolated Fab (5 µCi/1 µg). In addition, groups of mice receiving these reagents were also coinfused with 50 mg L-lysine. Results: Significantly less glyco-Fab than nonglycolated Fab accumulated in the kidney (21 versus 189 %ID/g; P < 0.001). A higher proportion of glyco-Fab was excreted into the urine in its intact form. The glyco-Fab survived longer in circulation than nonglycolated Fab. The peak tumor accumulation of glyco-Fab was 2.3-fold greater than that of nonglycolated Fab. Furthermore, the ATAC4 tumor-to-normal tissue ratio of glyco-Fab was much higher in all organs than that of nonglycolated Fab. The heavily glyco-Fab accumulated less in the kidney than the lightly glyco-Fab. The coinjected lysine reduced the renal accumulation of both nonglycolated Fab and glyco-Fab. Conclusion: Glyco-Fab is a promising agent because of its lower renal accumulation, higher tumor uptake and higher tumor-to-normal tissue ratio.

Key Words: Fab fragment • glycolate • radioimmunodetection • monoclonal antibody

This article has been cited by other articles:

				H. J.J.M. Rennen, O. C. Boerman, W. J.G. Oyen, J. W.M. van der Meer, and F. H.M. Corstens Specific and Rapid Scintigraphic Detection of Infection with 99mTc-Labeled Interleukin-8 J. Nucl. Med., January 1, 2001; 42(1): 117 - 123. [Abstract] [Full Text] [PDF]