Immunospecific saturable clearance mechanisms for indium-111-labeled anti-melanoma monoclonal antibody 96.5 in humans.
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.
Murray
J L
JL
Department of Clinical Immunology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Lamki
L M
LM
Shanken
L J
LJ
Blake
M E
ME
Plager
C E
CE
Benjamin
R S
RS
Schweighardt
S
S
Unger
M W
MW
Rosenblum
M G
MG
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
D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes