title: Metabolite production in patients with lymphoma after radiometal-labeled antibody administration.
abstract: Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (111In/90Y-2IT-BAD-Lym-1).
  
  
  METHODS
  Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111In- and 90Y-2IT-BAD-Lym-1; 111In was used as a surrogate tracer for 90Y, which emits no gamma-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111In in organs and tumors.
  
  
  RESULTS
  Metabolites and complexes were observed in the plasma of every patient who received 111In-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111In in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111In-2IT-BAD-m170, 91% and 94% of 111In in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111In/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites.
  
  
  CONCLUSIONS
  Metabolites of 111In/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111In/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.
authors.affiliation: Department of Internal Medicine, University of California Davis Medical Center, Sacramento, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: DeNardo
authors.forename: S J
authors.initials: SJ
authors.lastname: DeNardo
authors.forename: D L
authors.initials: DL
authors.lastname: Kukis
authors.forename: R T
authors.initials: RT
authors.lastname: O'Donnell
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: G R
authors.initials: GR
authors.lastname: Mirick
authors.forename: C F
authors.initials: CF
authors.lastname: Meares
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D015021:Yttrium Radioisotopes / Q000378:metabolism
chemical_list: C410508:2IT-BAD-Lym-1 monoclonal antibody; D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes