title: Effect of recombinant alpha-interferon on pharmacokinetics, biodistribution, toxicity, and efficacy of 131I-labeled monoclonal antibody CC49 in breast cancer: a phase II trial.
abstract: Preclinical studies have demonstrated that recombinant IFN-alpha (rIFN-alpha) can enhance the tumor associated glycoprotein 72 (TAG-72) on tumors. To determine whether rIFN-alpha could enhance TAG-72 expression in vivo in patients, 15 women with breast cancer were randomized to receive daily injections of rIFN-alpha (3 x 10(6) units/m2 for 14 days) beginning on day 1 (group 1 = 7 patients) or on day 6 (group 2 = 8 patients). On day 3, all patients received a 10-20-mCi tracer dose of 131I-CC49, a high-affinity murine monoclonal antibody reactive against TAG-72, followed by a therapy dose of 60-75 mCi/m2 of 131I-CC49 on day 6. Whole body and single-photon emission computed tomography scans along with whole blood pharmacokinetics were performed following tracer and treatment phases. Hematological toxicity was considerable; reversible grade 3-4 neutropenia and thrombocytopenia was observed in 12 of 15 patients. Twelve of 14 patients tested developed human antimouse antibodies 3-6 weeks after treatment. For group 1 patients, whole blood residence time increased significantly between that predicted from the tracer doses and therapy doses (42.6 +/- 4.7 versus 51.5 +/- 4.8 h, respectively; P < 0.01). The calculated radiation absorbed dose to red marrow from therapy compared to tracer activity was also significantly higher for this group (1.25 +/- 0.35 versus 1. 07 +/- 0.26 cGy/mCi; P < 0.05). Treatment with rIFN-alpha was found to enhance TAG-72 expression in tumors from patients receiving rIFN-alpha (group 1) by 46 +/- 19% (P < 0.05) compared to only 1.3 +/- 0.95% in patients not initially receiving IFN (group 2). The uptake of CC49 in tumors was also significantly increased in rIFN-alpha-treated patients. One partial and two minor tumor responses were seen. In summary, rIFN-alpha treatment altered the pharmacokinetics and tumor uptake of 131I-CC49 in patients at the expense of increased toxicity.
authors.affiliation: National Cancer Institute, Bethesda, Maryland 20815, and the University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Macey
authors.forename: E J
authors.initials: EJ
authors.lastname: Grant
authors.forename: L
authors.initials: L
authors.lastname: Kasi
authors.forename: M G
authors.initials: MG
authors.lastname: Rosenblum
authors.forename: H Z
authors.initials: HZ
authors.lastname: Zhang
authors.forename: R L
authors.initials: RL
authors.lastname: Katz
authors.forename: P T
authors.initials: PT
authors.lastname: Rieger
authors.forename: D
authors.initials: D
authors.lastname: LeBherz
authors.forename: M
authors.initials: M
authors.lastname: South
authors.forename: J W
authors.initials: JW
authors.lastname: Greiner
authors.forename: J
authors.initials: J
authors.lastname: Schlom
authors.forename: D A
authors.initials: DA
authors.lastname: Podoloff
authors.forename: J L
authors.initials: JL
authors.lastname: Murray
mesh_terms: D000328:Adult; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000528:radiation effects; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008207:Lymphatic Metastasis / Q000532:radiotherapy; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D016499:Radioimmunotherapy; D011994:Recombinant Proteins; D013921:Thrombocytopenia / Q000139:chemically induced; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D006023:Glycoproteins; D018796:Immunoconjugates; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; C047052:tumor-associated antigen 72