title: Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibody 170H.82 with autologous stem cell support and cyclosporin A.
abstract: Radioimmunoconjugates of 170H.82 (m170), a panadenocarcinoma monoclonal antibody, are effective for imaging primary and metastatic breast cancer. To evaluate m170 as a targeting agent for therapy, we developed (111)In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-m170 immunoconjugates with 99% purity by molecular sieving and immunoreactivity comparable to unmodified antibody. (111)In-m170 pharmacokinetic studies were performed prior to each therapy to determine the maximum dose of 90Y-m170 that could be administered without exceeding a limit of 800 rad to the liver, lungs, or kidneys or 250 rad to the whole body or bone marrow for each of three cycles of treatment. Peripheral blood stem cells (PBSCs) were harvested and cyclosporin A (5 mg/kg twice daily) was administered as strategies to ameliorate myelosuppression and prevent the development of HAMA, respectively. An (111)In imaging/pharmacokinetic study was performed, and the 90Y dose was calculated and administered. The liver was the 90Y dose-limiting organ. The mean and range of calculated doses (in rad/mCi) for the five patients evaluated were as follows: whole body, 2.3 (2.1-2.4); liver, 17.8 (12.7-22.2); lung, 6.4 (4.8-7.2); kidney, 6.9 (6.3-11.5); marrow, 3.6 (1.9-4.4); and tumors (n = 25), 71.5 (14.1-141.5). Of the three patients treated, with doses of 37, 54, and 57 mCi of 90Y, one had a partial response, one had measurable tumor reduction but less than a partial response, and one had stable disease for more than 1 month. PBSCs prevented prolonged myelosuppression. The therapeutic responses, coupled with an absence, thus far, of significant adverse sequelae, suggest that this dosimetry-based approach combined with PBSCs may lead to effective therapy when higher 90Y doses are reached.
authors.affiliation: Division of Hematology/Oncology, University of California, Davis, Sacramento 95817, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Richman
authors.forename: S J
authors.initials: SJ
authors.lastname: DeNardo
authors.forename: R T
authors.initials: RT
authors.lastname: O'Donnell
authors.forename: D S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: D L
authors.initials: DL
authors.lastname: Kukis
authors.forename: L A
authors.initials: LA
authors.lastname: Kroger
authors.forename: A
authors.initials: A
authors.lastname: Yuan
authors.forename: G R
authors.initials: GR
authors.lastname: Boniface
authors.forename: I J
authors.initials: IJ
authors.lastname: Griffith
authors.forename: G L
authors.initials: GL
authors.lastname: DeNardo
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy*; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D014182:Transplantation, Autologous; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D015021:Yttrium Radioisotopes; D016572:Cyclosporine