title: Immunospecific saturable clearance mechanisms for indium-111-labeled anti-melanoma monoclonal antibody 96.5 in humans.
abstract: Liver uptake of 111In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an 111In-labeled anti-melanoma antibody 96.5 (111In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of 111In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to 111In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of 111In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to 111In-96.5 infusion demonstrated a significant drop [P less than 0.001] in the liver/heart ratio of radioactivity [2.81 +/- 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 +/- 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (Vd) and the plasma t1/2 both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration X time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P less than 0.05). Although tissue distribution of 111In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.
authors.affiliation: Department of Clinical Immunology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
authors.forename: J L
authors.initials: JL
authors.lastname: Murray
authors.forename: L M
authors.initials: LM
authors.lastname: Lamki
authors.forename: L J
authors.initials: LJ
authors.lastname: Shanken
authors.forename: M E
authors.initials: ME
authors.lastname: Blake
authors.forename: C E
authors.initials: CE
authors.lastname: Plager
authors.forename: R S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: S
authors.initials: S
authors.lastname: Schweighardt
authors.forename: M W
authors.initials: MW
authors.lastname: Unger
authors.forename: M G
authors.initials: MG
authors.lastname: Rosenblum
mesh_terms: D000911:Antibodies, Monoclonal; D001842:Bone and Bones / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D008099:Liver / Q000378:metabolism; D008545:Melanoma / Q000000981:diagnostic imaging / Q000276:immunology*; D009206:Myocardium / Q000378:metabolism; D011877:Radionuclide Imaging; D013154:Spleen / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes