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.
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.
Park
Steven I
SI
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Shenoi
Jaideep
J
Pagel
John M
JM
Hamlin
Don K
DK
Wilbur
D Scott
DS
Orgun
Nural
N
Kenoyer
Aimee L
AL
Frayo
Shani
S
Axtman
Amanda
A
Bäck
Tom
T
Lin
Yukang
Y
Fisher
Darrell R
DR
Gopal
Ajay K
AK
Green
Damian J
DJ
Press
Oliver W
OW
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
D000912:Antibodies, Neoplasm; D018951:Antigens, CD20; C405616:DOTA-biotin; D007135:Immunoglobulin Variable Region; D009942:Organometallic Compounds; D011993:Recombinant Fusion Proteins; D001710:Biotin; D001729:Bismuth