Biodistribution Study of 188Re-Labeled Trisuccin-HuCC49 and Trisuccin-HuCC49ΔCH2 Conjugates in Athymic Nude Mice Bearing Intraperitoneal Colon Cancer Xenografts

Academic Article

Abstract

  • The trihydroxamate bifunctional chelating agent (BCA), trisuccin, has been shown to be a potential ligand for radiolabeling of monoclonal antibodies (MAbs) with rhenium radioisotopes, through an indirect postconjugation approach. The use of this trihydroxamate BCA made it possible to prepare stable BCA-MAb conjugates in pure form that could be radiolabeled with carrier-free 188Re. The anti-TAG-72 murine MAb, CC49, and its humanized derivatives are promising agents in the treatment of a number of malignancies with the CH2 domain-deleted MAb (HuCC49ΔCH2), which is of particular interest due to its rapid blood clearance. The biodistribution of 188Re-labeled conjugates of trisuccin with both humanized CC49 (HuCC49) and HuCC49ΔCH2 in athymic nude mice implanted i.p. with LS174T human colon carcinoma was studied. Trisuccin-MAb conjugates were synthesized at different BCA:MAb ratios by the 6-oxoheptanoic acid method using trisuccin hydrazide. The conjugates were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy for the number of incorporated trisuccin molecules. The conjugates were radiolabeled with carrier-free, generator-produced 188Re and purified by gel filtration on Sephadex G-25. Labeling yields and homogeneity of the labeled conjugates were analyzed by high-pressure liquid chromatography and instant TLC. Athymic nude mice were injected i.p. with LS174T human colon carcinoma cells, 7 days prior to injection of the labeled antibodies, 188Relabeled MAbs were injected i.p., and the mice were sacrificed 24 h postinjection. Matrix-assisted laser desorption/ionization time-of-flight analyses showed stable incorporation of trisuccin into each MAb, with the measured ligand:MAb values positively correlating with the theoretical ratios. Labeling of the conjugates with 188Re proceeded with high yields, producing homogeneous 188Re-MAbs with good stabilities as shown by instant TLC and biodistrihution analyses. Biodistribution of the radiolabeled MAbs at 24 h after injection showed median tumor uptake values of 23.5 %ID/g and 17.6%ID/g for the 188Re-HuCC49ΔCH2 and 188Re-HuCC49, respectively. The blood clearance of the domaindeleted MAb was faster than that of the intact antibody. The blood values at 24 h after injection were 0.7%ID/g for 188Re-HuCC49ΔCH2 and 3.2%ID/g for 188Re-HuCC49. The results indicate that trisuccin is a promising agent for postconjugation labeling of antibodies with 188Re. Additionally, these results illustrate the potential of 188Re-HuCC49ΔCH2 in radioimmunodiagnosis and radioimmunotherapy of cancer. © 1999, American Association for Cancer Research. All rights reserved.
  • Author List

  • Safavy A; Khazaeli MB; Safavy K; Mayo MS; Buchsbaum DJ
  • Volume

  • 5
  • Issue

  • 10