• Corpus ID: 6169824

Large Molecule Therapeutics Preclinical Evaluation of Multistep Targeting of Diasialoganglioside GD 2 Using an IgG-scFv Bispeci fi c Antibody with High Af fi nity for GD 2 and DOTA Metal Complex

@inproceedings{Cheal2014LargeMT,
  title={Large Molecule Therapeutics Preclinical Evaluation of Multistep Targeting of Diasialoganglioside GD 2 Using an IgG-scFv Bispeci fi c Antibody with High Af fi nity for GD 2 and DOTA Metal Complex},
  author={Sarah M. Cheal and Hong Xu and Hong-fen Guo and Pat Zanzonico and Steven M. Larson and Nai-Kong V. Cheung},
  year={2014}
}

• S. Cheal, Hong Xu, +3 authors N. Cheung
• Published 2014
• Biology, Medicine

Bispecific antibodies (BsAb) haveproven to beuseful targeting vectors for pretargeted radioimmunotherapy (PRIT). We sought to overcome key PRIT limitations such as high renal radiation exposure and immunogenicity (e.g., of streptavidin–antibody fusions), to advance clinical translation of this PRIT strategy for diasialoganglioside GD2-positive [GD2(þ)] tumors. For this purpose, an IgG-scFv BsAbwas engineered using the sequences for the anti-GD2humanizedmonoclonal antibodyhu3F8 andC825, amurine scFv antibodywith high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with b-particle–emitting radiometals such as Lu and Y. A three-step regimen, including hu3F8-C825, a dextranbased clearing agent, and p-aminobenzyl-DOTA radiolabeledwith Lu (as Lu-DOTA-Bn; t1/21⁄4 6.71 days), was optimized in immunocompromised mice carrying subcutaneous human GD2(þ) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were approximately 85 cGy/MBq and 3.7 cGy/ MBq, respectively, with therapeutic indices (TI) of 142 for blood and 23 for kidney. A therapy study (n 1⁄4 5/ group; tumor volume, 240 160 mm) with three successive PRIT cycles (total Lu: 33 MBq; tumor dose 3,400 cGy), revealed complete tumor response in 5 of 5 animals, with no recurrence up to 28 days after treatment. Tumor ablation was confirmed histologically in 4 of 5 mice, and normal organs showed minimal overall toxicities. All nontreatedmice required sacrificewithin 12 days (>1.0-cm tumor volume).We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate subcutaneous GD2(þ)-NB in mice while sparing kidney and bone marrow. Mol Cancer Ther; 13(7); 1803–12. 2014 AACR.