title: Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease.
abstract: Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (²¹³Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [²¹³Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)₄SA was 16.5% ± 7.0% injected dose per gram compared with 2.3% ± .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 μ Ci [²¹³Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 ± .02 vs. 203.38 ± 83.03 mm³ after 19 days, respectively). The median survival for the 1F5(scFv)₄SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with ²¹³Bi-labeled anti-CD20 PRIT.
authors: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors: Steven I
authors: SI
authors: Park
authors: Jaideep
authors: J
authors: Shenoi
authors: John M
authors: JM
authors: Pagel
authors: Don K
authors: DK
authors: Hamlin
authors: D Scott
authors: DS
authors: Wilbur
authors: Nural
authors: N
authors: Orgun
authors: Aimee L
authors: AL
authors: Kenoyer
authors: Shani
authors: S
authors: Frayo
authors: Amanda
authors: A
authors: Axtman
authors: Tom
authors: T
authors: Bäck
authors: Yukang
authors: Y
authors: Lin
authors: Darrell R
authors: DR
authors: Fisher
authors: Ajay K
authors: AK
authors: Gopal
authors: Damian J
authors: DJ
authors: Green
authors: Oliver W
authors: OW
authors: Press
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D018951:Antigens, CD20 / Q000378:metabolism*; D001710:Biotin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001729:Bismuth / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001772:Blood Cell Count; D045744:Cell Line, Tumor; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008111:Liver Function Tests; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000532:radiotherapy*; D051379:Mice; D018365:Neoplasm, Residual / Q000188:drug therapy* / Q000276:immunology; D009942:Organometallic Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016019:Survival Analysis; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000912:Antibodies, Neoplasm; D018951:Antigens, CD20; C405616:DOTA-biotin; D007135:Immunoglobulin Variable Region; D009942:Organometallic Compounds; D011993:Recombinant Fusion Proteins; D001710:Biotin; D001729:Bismuth