title: Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using an IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex.
abstract: Bispecific antibodies (BsAb) have proven to be useful 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(+)] tumors. For this purpose, an IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 and C825, a murine scFv antibody with high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with β-particle-emitting radiometals such as (177)Lu and (90)Y. A three-step regimen, including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with (177)Lu (as (177)Lu-DOTA-Bn; t1/2 = 6.71 days), was optimized in immunocompromised mice carrying subcutaneous human GD2(+) 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 = 5/group; tumor volume, 240 ± 160 mm(3)) with three successive PRIT cycles (total (177)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 nontreated mice required sacrifice within 12 days (>1.0-cm(3) tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate subcutaneous GD2(+)-NB in mice while sparing kidney and bone marrow.
authors.affiliation: Authors' Affiliations: Departments of Radiology and.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Cheal
authors.affiliation: Pediatrics;
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Pediatrics;
authors.forename: Hong-fen
authors.initials: HF
authors.lastname: Guo
authors.affiliation: Molecular Pharmacology and Therapy Service; and.
authors.forename: Pat B
authors.initials: PB
authors.lastname: Zanzonico
authors.affiliation: Molecular Pharmacology and Therapy Service; and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Pediatrics; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York cheungn@mskcc.org.
authors.forename: Nai-Kong
authors.initials: NK
authors.lastname: Cheung
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology*; D008187:Lutetium / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D015282:Octreotide / Q000031:analogs & derivatives; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D018033:Antibodies, Bispecific; D005732:Gangliosides; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D008187:Lutetium; C019403:ganglioside, GD2; D015282:Octreotide