title: Interferon-induced changes in pharmacokinetics and tumor uptake of 111In-labeled antimelanoma antibody 96.5 in melanoma patients.
abstract: The type I interferons [both partially purified human leukocyte interferon (HuIFN-alpha) and recombinant alpha interferon] and the type II interferons have been shown to increase the expression of tumor-associated antigens in vitro. To determine whether HuIFN-alpha could increase tumor acquisition of the antimelanoma antibody 96.5 in vivo, five patients with metastatic malignant melanoma were treated with HuIFN-alpha at a dose of 3 X 10(6) units daily by im administration. Twenty-four hours after the first dose of HuIFN-alpha, 1 mg of antibody 96.5 labeled with 5 mCi of 111In was coadministered with 19 mg of unlabeled 96.5. Five patients matched for metastatic site and lesion size who had not received HuIFN-alpha were also given a dose of 5 mCi of radiolabeled 96.5 at the same total antibody dose (20 mg). In patients treated with HuIFN-alpha, there was a statistically significant increase in the plasma half-life of the 111In label (39.7 +/- 3.3 hr) compared to the untreated control group (29.8 +/- 3.2 hr). In addition, there was an increase in the apparent volume of distribution of the antibody in the HuIFN-alpha group (5.56 +/- 0.67 L) compared to controls (3.15 +/- 0.5 L) suggesting both an increased immediate extravascular distribution of radiolabeled antibody and a decrease in the subsequent rate of clearance of antibody from plasma. These two phenomena result in a 28% decrease in the area under the concentration curve in the HuIFN-alpha-treated group compared to controls. Computer analysis of whole-body scans from patients showed a threefold increase in radiolabeled antibody distributed to tumor relative to blood pool but no change in organ:blood ratios for liver, spleen, bone, or kidney compared to controls. This pilot study suggests that treatment of patients with HuIFN-alpha results in an improved distribution of radiolabeled antibody to tumor target without a concomitant increase of label in normal nontarget tissues. In addition, this change in whole-body distribution of antibody is manifested by changes in the pharmacokinetic parameters measured for monoclonal antibody.
authors.affiliation: Department of Clinical Immunology and Biological Therapy, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston 77030.
authors.forename: M G
authors.initials: MG
authors.lastname: Rosenblum
authors.forename: L M
authors.initials: LM
authors.lastname: Lamki
authors.forename: J L
authors.initials: JL
authors.lastname: Murray
authors.forename: D J
authors.initials: DJ
authors.lastname: Carlo
authors.forename: J U
authors.initials: JU
authors.lastname: Gutterman
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use; D007370:Interferon Type I / Q000627:therapeutic use*; D007700:Kinetics; D008545:Melanoma / Q000000981:diagnostic imaging / Q000532:radiotherapy* / Q000628:therapy; D011877:Radionuclide Imaging
chemical_list: D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D007370:Interferon Type I