Pretargeted radioimmunotherapy (PRIT) of disialoganglioside GD2-positive solid tumors using a bispecific antibody (BsAb) with high affinity for GD2 and DOTA metal complex: A theranostic approach (TPRIT)

1486 Objectives PRIT of solid tumors has been limited by low therapeutic indices (TIs) due primarily to hematopoietic and renal toxicities. We combined 2 strategies to overcome these limitations: 1) a novel BsAb with more favorable in vivo biodistribution and 2) radiolabeled hapten moieties as a theranostic, i.e. to be used for quantitative imaging plus dosimetry and for RIT. We report here our initial results with a BsAb built from humanized IgG 3F8 with high affinity for GD2 and single-chain Fv fragment (scFv) for DOTA metal complex (Orcutt et al., Nucl. Med. Biol. 38:223, 2011) combined with 177Lu-DOTA for theranostic PRIT (TPRIT). Our aim was to achieve TIs of >50 for hematopoietic tissues and ~10 for kidney in nude mice bearing s.c. human GD2-positive neuroblastomas at tumoricidal doses (>4200 cGy; see Cheung et al., J. Natl. Cancer Inst. 77:739, 1986). Methods Non-invasive serial imaging and biodistribution experiments were performed varying TPRIT doses and administration schedules. A pilot therapy study was performed to test if an optimized dosing strategy was effective. Results Radiation doses to tumor and normal tissues were ~80 and ≤7.6 cGy/MBq, respectively, with TIs of 58 ± 35 for blood and 10 ± 5 for kidney. Treatment with three successive TPRIT cycles (33 MBq; ~6000 cGy to tumor) showed complete tumor response in 5/5 mice (control mice: 5/5 dead at 12 days), with survival of all treated animals at 30 days and tumor-free by bioluminescence and no obvious toxicities. Conclusions Using an optimized TPRIT approach, a highly effective therapeutic regimen was devised which resulted in complete responses in mice bearing GD2-positive solid tumors. Research Support NIH R25T Molecular Imaging in Oncology Fellowship (5R25CA096945-07), the Center for Targeted Radioimmunotherapy and Diagnosis, Ludwig Center for Cancer Immunotherapy, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center, MSKCC; Kids Walk for Kids with Cancer NYC; the Robert Steel Foundation.