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Preliminary evaluation of cG250 and fragments for imaging hypoxia-regulated gene expression in solid tumors

¹ Medical Physics; ² Radiology, MSKCC, New York, New York

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Objectives: The chimeric antibody cG250 binds with high affinity to carbonic anhydrase 9 (CA9). The expression of CA9 is mediated by the HIF1 transcription factor, which is upregulated under hypoxic conditions. We examined the ability of intact cG250 and lower molecular weight fragments thereof to localize in tumor regions where CA9 expression was elevated.

Methods: The HT29 colorectal adenocarcinoma model shows strong CA9 induction under hypoxic conditions. Xenograft tumors growing in nude mice were used to model heterogeneous tumor CA9 expression. Fab(50 kDa)and F(ab’)2(100 kDa)fragments were generated from intact cG250 (150 kDa). All three species were then conjugated to DOTA, labeled with 111In and administered intravenously. The intratumoral distribution of radiotracer was assessed by digital autoradiography. This was compared with the distributions of Hoechst 33342 (perfusion), pimonidazole (hypoxia) and CA9 expression as assessed by fluorescent microscopy.

Results: Intact 111In-cG250 showed poor tumor penetration, localizing primarily in highly-perfused tumor regions that were negative for CA9 expression. Both 111In-Fab and 111In-F(ab’)2 showed improved tumor penetration and localization to CA9-expressing regions in comparison to intact IgG assessed at 24-48 hours post-administration.

Conclusions: Low pO2 in tumors is associated with low blood perfusion. This restricted the ability of intact cG250 to reach those regions where CA9 was highly expressed. The lower molecular weight fragments were more successful in rapidly reaching regions of antigen excess. It is possible that the optimal agents for imaging hypoxia-regulated gene expression in solid tumors may be small peptides with specificity for the requisite antigen. Further studies on this concept are warranted.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Carlin, S. Articles by O'Donoghue, J. PubMed Articles by Carlin, S. Articles by O'Donoghue, J.