Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu.
The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas.
Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
Huma
H
Mohsin
Fang
F
Jia
Geethapriya
G
Sivaguru
Michael J
MJ
Hudson
Tiffani D
TD
Shelton
Timothy J
TJ
Hoffman
Cathy S
CS
Cutler
Alan R
AR
Ketring
Phillip S
PS
Athey
Jaime
J
Simón
R Keith
RK
Frank
Silvia S
SS
Jurisson
Michael R
MR
Lewis
D000818:Animals; D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism; D006695:Holmium / Q000737:chemistry; D006801:Humans; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D008187:Lutetium / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000276:immunology / Q000532:radiotherapy; D011399:Promethium / Q000737:chemistry; D011868:Radioisotopes / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D028581:Lanthanoid Series Elements; D011868:Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; D006695:Holmium; D011399:Promethium