Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: Influence of radiation dose and dose rate on toxicity and anti-tumor efficacy.
Whereas bivalent fragments have been widely used for radio-immunotherapy, no systematic study has been published on the therapeutic performance of monovalent conjugates in vivo. The aim of our study was, therefore, to determine the therapeutic performance of (131)I-labeled Fab as compared to bivalent conjugates and to analyze factors that influence dose-limiting organ toxicity and anti-tumor efficacy. The maximum tolerated doses (MTDs) and dose-limiting organ toxicities of the (131)I-labeled anti-CEA antibody MN-14 [IgG, F(ab')2 and Fab] were determined in nude mice bearing s.c. human colon cancer xenografts. Mice were treated with or without bone marrow transplantation (BMT) or inhibition of the renal accretion of antibody fragments by D-lysine or combinations thereof. Toxicity and tumor growth were monitored. Radiation dosimetry was calculated from biodistribution data. With all 3 (131)I-labeled immunoconjugates [IgG, F(ab')2 and Fab], the red marrow was the only dose-limiting organ; MTDs were 260 microCi for IgG, 1,200 microCi for F(ab')2 and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG and 3 times higher as compared to F(ab')2. The MTD of all 3 immunoconjugates was increased by BMT by approximately 30%. In accordance with renal doses below 10 Gy, no signs of nephrotoxicity were observed. Despite lower absorbed tumor doses, at equitoxic dosing, Fab fragments were more effective at controlling tumor growth than the respective bivalent fragment or IgG, probably due to higher intratumoral dose rates. Our data indicate that the improved anti-tumor effectiveness of antibody fragments as compared to IgG and the higher myelotoxicity at comparably lower red marrow doses are most likely due to the higher initial dose rates observed with antibody fragments.
Department of Nuclear Medicine, Georg-August-University, Göttingen, Germany. tmbehr@WisLAN1.med.uni-goettingen.de
T M
TM
Behr
S
S
Memtsoudis
R M
RM
Sharkey
R D
RD
Blumenthal
R M
RM
Dunn
S
S
Gratz
E
E
Wieland
K
K
Nebendahl
H
H
Schmidberger
D M
DM
Goldenberg
W
W
Becker
D000818:Animals; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes