Pretargeted 177Lu radioimmunotherapy of carcinoembryonic antigen-expressing human colonic tumors in mice.
Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies in combination with a radiolabeled peptide reduces the radiation dose to normal tissues, especially the bone marrow. In this study, the optimization, therapeutic efficacy, and toxicity of PRIT of colon cancer with a (177)Lu-labeled peptide was determined in mice with carcinoembryonic antigen (CEA)-expressing human tumors.


METHODS
To obtain the optimal therapeutic efficacy, several strategies were evaluated to increase the total amount of radioactivity targeted to subcutaneous LS174T colon cancer tumors in BALB/c nude mice. First, the maximum amount of bispecific anti-CEA and antihapten antibody TF2 and the peptide IMP288 that could be targeted was determined. Second, the tumor targeting of repeated administrations of radiolabeled IMP288 was investigated. Mice received 1 TF2 injection, followed by multiple IMP288 injections (3-h interval) or multiple cycles, with each IMP288 administration preceded by a new TF2 injection (72-h interval). PRIT was administered at maximum doses of TF2 and (177)Lu-labeled IMP288 in groups of 9 mice with subcutaneous LS174T tumors. Mice received 1, 2, or 3 successive cycles of treatment (26 MBq/mouse/cycle) or carrier only. The primary endpoint was survival; secondary endpoints were tumor growth, body weight, bone marrow, and renal toxicity.


RESULTS
The highest amount of radioactivity delivered to a subcutaneous colon tumor was achieved by the administration of 5.0 nmol of TF2 and 0.28 nmol of IMP288 in 3 successive cycles, with each IMP288 preceded by a new TF2 injection (72-h interval). PRIT effectively delayed tumor growth and prolonged survival significantly. Higher activity doses, administered in successive cycles, correlated with longer survival: the median survival of untreated mice was 13 d (range, 6-20 d), whereas that of mice treated with 1, 2, or 3 cycles of PRIT was 24 (range, 24-31 d), 45 (range, 38 ≥ 130 d), and 65 (range, 48 ≥ 130 d) days, respectively. Toxicity was limited: no significant changes in mean body weight were measured. Minimal changes in leukocyte counts were measured at 2 and 3 wk after injection, with full recovery within 7 wk after treatment. Platelet counts were unaffected. Serum creatinine levels were not increased significantly; thus, there was no indication of acute renal toxicity.


CONCLUSIONS
This study indicates that PRIT in mice is an effective treatment modality against colon cancer, with limited toxicity.
Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. r.schoffelen@nucmed.umcn.nl
Rafke
R
Schoffelen
Winette T A
WT
van der Graaf
Gerben
G
Franssen
Robert M
RM
Sharkey
David M
DM
Goldenberg
William J
WJ
McBride
Edmund A
EA
Rossi
Annemarie
A
Eek
Wim J G
WJ
Oyen
Otto C
OC
Boerman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D015972:Gene Expression Regulation, Neoplastic; D006241:Haptens / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008187:Lutetium / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D006241:Haptens; D010455:Peptides; D011868:Radioisotopes; D008187:Lutetium