Intraperitoneal pretarget radioimmunotherapy with CC49 fusion protein.
OBJECTIVE
This study examined a pretarget radioimmunotherapy strategy for treatment of an i.p. tumor model (LS174T).


METHODS
The strategy used regional administration (i.p.) of a novel targeting molecule composed of four CC49 anti-tumor-associated glycoprotein 72 (TAG-72) single-chain antibodies linked to streptavidin as a fusion protein (CC49 fusion protein); 24 hours later, a synthetic clearing agent was administered i.v. to produce hepatic clearance of unbound CC49 fusion protein/synthetic clearing agent complexes. Four hours later, a low molecular weight radiolabeled reagent composed of biotin conjugated to the chelating agent 7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) complexed with (111)In-, (90)Y-, or (177)Lu-DOTA-biotin was injected.


RESULTS
Radiolocalization to tumor sites was superior with i.p. administration of radiolabeled DOTA-biotin as compared with i.v. administration. Imaging and biodistribution studies showed excellent tumor localization of radioactivity with (111)In- or (177)Lu-DOTA-biotin. Tumor localization of (111)In-DOTA-biotin was 43% ID/g and 44% ID/g at 4 and 24 hours with the highest normal tissue localization in the kidney with 6% ID/g at 48 and 72 hours. Therapy studies with (90)Y-DOTA-biotin at doses of 400 to 600 microCi or (177)Lu-DOTA-biotin at doses of 600 to 800 microCi produced significant prolongation of survival compared with controls (P = 0.03 and P < 0.01).


CONCLUSIONS
Pretarget radioimmunotherapy using regional administration of CC49 fusion protein and i.p. (90)Y- or (177)Lu-DOTA-biotin represents a successful therapeutic strategy in the LS174T i.p. tumor model and this strategy may be applicable to human trials in patients with i.p. ovarian cancer.
Buchsbaum
Donald J
DJ
Department of Radiation Oncology, University of Alabama at Birmingham, Alabama 35294-6832, USA. djb@uab.edu
Khazaeli
M B
MB
Axworthy
Donald B
DB
Schultz
Jody
J
Chaudhuri
Tandra R
TR
Zinn
Kurt R
KR
Carpenter
Mark
M
LoBuglio
Albert F
AF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000276:immunology; D001710:Biotin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007205:Indium Radioisotopes; D007274:Injections, Intraperitoneal; D007457:Iodine Radioisotopes; D008187:Lutetium; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes; D019809:Streptavidin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C091202:B72.3 antibody; C405616:DOTA-biotin; D006023:Glycoproteins; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D009942:Organometallic Compounds; D011868:Radioisotopes; D015021:Yttrium Radioisotopes; C047052:tumor-associated antigen 72; D008187:Lutetium; D001710:Biotin; D019809:Streptavidin