Reduced myelotoxicity with sustained tumor concentration of radioimmunoconjugates in rats after extracorporeal depletion.
The aim of this study was to evaluate the possibility of decreasing the myelotoxicity associated with radioimmunotherapy (RIT) by extracorporeal depletion of radioimmunoconjugates (RIC) from the circulation. The optimal combination of radionuclide and the time interval between injection of the RIC and the subsequent extracorporeal depletion procedure was assessed in immunocompetent rats, with respect to both myelotoxicity and tumor concentration of RIC.


METHODS
Rats were injected with 177Lu- or 90Y-labeled antibody conjugate (mAb-DOTA-biotin) (mAb is monoclonal antibody; DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) and subjected to removal of the conjugate from the circulation by extracorporeal affinity adsorption treatment (ECAT) 12, 24, or 48 h after injection. Myelotoxicity was assessed by analysis of blood parameters for 10 wk. The effect of ECAT on the tumor concentration of RIC was evaluated in parallel by scintillation camera imaging in rats injected with 111In-labeled RIC.


RESULTS
ECAT reduced the blood content of RIC by 95%. Thus, myelotoxicity was significantly milder in animals subjected to ECAT than that in controls. The timing of ECAT influenced the rate and level of bone marrow recovery, with an earlier recovery in animals subjected to ECAT early after injection. The toxicity-reducing effect of ECAT was more distinct in animals injected with 177Lu-labeled RIC than in animals injected with 90Y-labeled RIC. Scintillation camera imaging of tumors before and after ECAT revealed that subjecting animals to ECAT at 12 h after injection considerably reduced the total activity in tumors (34%), whereas the effect was lower at both 24 h (18%) and 48 h (18%) after injection.


CONCLUSIONS
ECAT can efficiently reduce myelotoxicity associated with RIT, and the concentration of RIC in tumor can be sustained, provided ECAT is performed at an optimal time after antibody administration. The choice of radionuclide for RIT in combination with ECAT is important, as the physical half-life is crucial for the toxicity-reducing potential of ECAT at a specific time.
Mårtensson
Linda
L
Department of Oncology, Lund University, Lund, Sweden. linda.martensson@med.lu.se
Nilsson
Rune
R
Ohlsson
Tomas
T
Sjögren
Hans-Olov
HO
Strand
Sven-Erik
SE
Tennvall
Jan
J
D000327:Adsorption; D000818:Animals; D000911:Antibodies, Monoclonal; D001855:Bone Marrow Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D005112:Extracorporeal Circulation; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D000922:Immunotoxins / Q000276:immunology; D007205:Indium Radioisotopes; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011832:Radiation Injuries / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051381:Rats; D011914:Rats, Inbred BN; D014185:Transplantation, Isogeneic
D000911:Antibodies, Monoclonal; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D000922:Immunotoxins; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid