title: Intraperitoneal radioimmunotherapy with a humanized anti-TAG-72 (CC49) antibody with a deleted CH2 region.
abstract: The application of intraperitoneal (i.p.) radioimmunotherapy to treat i.p. tumor loci has been limited by bone marrow toxicity secondary to circulating radiolabeled antibodies. The generation of novel genetically engineered monoclonal antibodies, which can achieve high tumor uptake and rapid blood clearance, should enhance the therapeutic index of i.p. radioimmunotherapy. In this regard, a novel humanized anti-TAG-72 monoclonal antibody with a deleted CH2 region (HuCC49DeltaCH2) has been described, which localized well to subcutaneous xenograft tumors and had a rapid plasma clearance. The aim of this study was to examine the characteristics of this radiolabeled reagent when administered through the i.p. route in mice bearing i.p. tumor (LS174T). The DeltaCH2 molecule and intact humanized CC49 (HuCC49) monoclonal antibody were conjugated to PA-DOTA and radiolabeled with (177)Lu. Both molecules retained high-affinity binding to TAG-72 positive LS174T tumor cells in vitro. The radiolabeled DeltaCH2 molecule had a modest decrease in tumor localization, as compared to the intact molecule when administered i.p. to tumor-bearing mice and a dramatically shorter plasma disappearance T(1/2) at 2.7 hours compared to 61.2 hours for the intact antibody. The radiolabeled DeltaCH2 molecule thus had very high tumor:blood ratios. Using an (131)I-labeled system, the maximum tolerated dose of DeltaCH2 was >3x that of intact HuCC49. Autoradiography of tumors showed low radiation dose rates at tumor centers early (1 and 4 hours), as compared to higher dose rates at tumor periphery but a more uniform distribution by 24 hours. Dose-rate distributions were similar for both reagents. Animals bearing LS174T i.p. tumors were treated with 300 microCi of (177)Lu-labeled DeltaCH2 or intact HuCC49 by i.p. route daily x 3. The (177)Lu-DeltaCH(2) molecule mediated an increase in median survival compared to controls (67.5 +/- 7.5 days versus controls of 32 +/- 3.3) while the same dose of (177)Lu-HuCC49 produced early toxic deaths. These studies suggest that i.p. radioimmunotherapy using radiolabeled HuCC49DeltaCH2 should allow higher radiation doses to be administered with less marrow toxicity and potentially improved efficacy.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35294, USA.
authors.forename: Buck E
authors.initials: BE
authors.lastname: Rogers
authors.forename: Peter L
authors.initials: PL
authors.lastname: Roberson
authors.forename: Sui
authors.initials: S
authors.lastname: Shen
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: Mark
authors.initials: M
authors.lastname: Carpenter
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001345:Autoradiography; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D017353:Gene Deletion; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments; D007136:Immunoglobulins; D007263:Infusions, Parenteral; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D011878:Radiotherapy; D011879:Radiotherapy Dosage; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C091202:B72.3 antibody; D006023:Glycoproteins; D007128:Immunoglobulin Fragments; D007136:Immunoglobulins; C047052:tumor-associated antigen 72