Pharmacokinetics of Genetically Engineered Antibody Forms Using Positron Emission Tomography [report]

Nai-Kong V. Cheung, Shakeel Modak, Yukang Lin, Hongfen Guo, Pat Zanzonico, John Chung, Yuting Zuo, James Sanderson, Sibylle Wilbert, Louis J. Theodore, Donald B. Axworthy, Steven M. Larson
2004 unpublished
Multistep targeting can improve the therapeutic index of antibody-based targeting, particularly relevant to pediatric tumors where acute toxicity and late effects of treatment are major concerns. Neuroblastoma is uniquely suited for such investigations because of its abundance of surface ganglioside GD2. Methods: 5F11scFv (scFv ϭ single-chain variable fragment) was constructed from the variable regions of the heavy (V H ) and -light (V L ) chain complementary DNA (cDNA) of anti-GD2 IgM
more » ... 5F11 and ligated to full-length streptavidin cDNA for expression in Escherichia coli. Purified 5F11-scFv-streptavidin (5F11-scFv-SA) was a homotetramer and showed comparable avidity to 5F11 IgM and a 30-fold improvement over monomeric scFv. Biodistribution of 5F11-scFv-SA was studied in nude mice xenografted with neuroblastoma LAN-1. Twenty-four hours after intravenous injection of 300 -900 g 5F11-scFv-SA, 150 -450 g of a thiogalactoside-containing clearing agent, (Gal-NAc) 16 -␣-S-C 5 H 10 -NH-LC-N-Me-biotin (molecular weight, 8,652), were administered intravenously, followed by ϳ2.5 g (1.85-3.7 MBq) 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-biotin ( 111 In-DOTA-biotin) intravenously 4 h later and clocked as time 0. Results: Tumor uptake (percentage of injected dose per gram [%ID/g]) at 2 h was 7 %ID/g and decayed with a half-life of 72 h, whereas blood %ID/g rapidly decreased to Ͻ1/500 of that of tumor after the first 24 h. The tumor-to-nontumor (T/NT) ratio at 72 h was high (median, 106; range, 3.4 [kidney] to 1,660 [blood]). When the area under the radioactivity curve was computed, the T/NT organ ratio was favorable (4.8 for kidney and 162 for blood). When human and murine tumors were surveyed, the T/NT ratio of 111 In-DOTA-biotin uptake correlated with their levels of GD2 expression as assayed by flow cytometry. Biotinylated polypeptides (bovine serum albumin and vasointestinal peptides) achieved selective tumor targeting when the multistep strategy was applied. Conclusion: Improvement in the T/NT ratio using pretargeting strategy may increase the efficacy and safety of scFv-based approaches in cancer therapy. Additionally, since biotinylated polypeptides can be rendered tumor selective, a large repertoire of agents can potentially be explored.
doi:10.2172/828873 fatcat:r32ugatl55cfxihjfkd5zoumuy