title: Radioimmunotherapy of non-Hodgkin's lymphoma with 90Y-DOTA humanized anti-CD22 IgG (90Y-Epratuzumab): do tumor targeting and dosimetry predict therapeutic response?
abstract: A DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid)-conjugated, (111)In- and (90)Y-labeled humanized antibody to CD22, epratuzumab, was studied in patients with non-Hodgkin's lymphoma (NHL) to assess biodistribution and tumor targeting, pharmacokinetics, dosimetry, and anti-antibody response. Of particular interest was to evaluate whether pretherapy targeting and tumor dosimetry could predict therapeutic responses.
  
  
  METHODS
  Patients received a pretherapy imaging study with (111)In-DOTA-epratuzumab IgG (0.75 mg/kg), followed about 1 wk later with (90)Y-DOTA-epratuzumab starting at a dose level of 0.185 GBq/m(2) (5 mCi/m(2)) in patients who had prior high-dose chemotherapy (group 2), and at 0.370 GBq/m(2) in patients who did not have a prior transplant (group 1), with escalation in 0.185-GBq/m(2) increments.
  
  
  RESULTS
  The effective blood half-life for (111)In-DOTA epratuzumab was 36.1 +/- 7.9 h (n = 25) compared with 35.2 +/- 7.0 h for (90)Y-DOTA-epratuzumab (n = 22). The whole-body half-life for (90)Y-DOTA-epratuzumab estimated from (111)In-DOTA-epratuzumab scintigraphy was 58.3 +/- 4.7 h (n = 20), with urine collection confirming the loss of between 2.2% and 15.9% of the injected activity over 3 d (n = 3). One-hundred sixteen of 165 CT-confirmed lesions were visualized with (111)In-DOTA-epratuzumab. Radiation-absorbed doses to liver, lungs, and kidneys averaged 0.55 +/- 0.13 (n = 17), 0.28 +/- 0.06 (n = 17), and 0.38 +/- 0.07 mGy/MBq (n = 10), respectively, with 0.14 +/- 0.02 and 0.23 +/- 0.04 mGy/MBq delivered to the whole-body and red marrow, respectively. Tumor doses (n = 14 lesions in 10 patients) ranged from 1.0 to as much as 83 mGy/MBq for a 0.5-g lesion (median, 7.15 mGy/MBq). Group 2 patients were more likely to experience significant hematologic toxicities, but doses of up to 0.370 GBq/m(2) of (90)Y-DOTA-epratuzumab were tolerated with standard support measures, whereas patients in group 1 tolerated doses of up to 0.740 GBq/m(2) with the potential for further escalation. Anti-tumor effects were seen in both indolent and aggressive NHL. The data also suggest that anti-tumor responses of potentially equal magnitude can occur irrespective of tumor targeting and tumor size. Hence, tumor response did not correlate with the radiation dose delivered or with the tumor being visualized by external imaging. An anti-antibody response to epratuzumab was detected by an enzyme-linked immunosorbent assay in only 2 of 16 patients.
  
  
  CONCLUSIONS
  These results suggest that (90)Y-DOTA-epratuzmab is a promising agent for the treatment of NHL and warrants further study. There was evidence suggesting that in this system, factors other than tumor radiation dose and targeting may be involved in the success of radioimmunotherapy.
authors.affiliation: Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA. rmsharkey@gscancer.org
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: Arnold
authors.initials: A
authors.lastname: Brenner
authors.forename: Jack
authors.initials: J
authors.lastname: Burton
authors.forename: George
authors.initials: G
authors.lastname: Hajjar
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Toder
authors.forename: Abass
authors.initials: A
authors.lastname: Alavi
authors.forename: Alexander
authors.initials: A
authors.lastname: Matthies
authors.forename: Donald E
authors.initials: DE
authors.lastname: Tsai
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.forename: Dominick
authors.initials: D
authors.lastname: Lamonica
authors.forename: Françoise
authors.initials: F
authors.lastname: Kraeber-Bodere
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mahe
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Chatal
authors.forename: André
authors.initials: A
authors.lastname: Rogatko
authors.forename: George
authors.initials: G
authors.lastname: Mardirrosian
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics; D006801:Humans; D007204:Indium / Q000493:pharmacokinetics; D007554:Isotopes / Q000493:pharmacokinetics; D008228:Lymphoma, Non-Hodgkin / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry / Q000379:methods*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011878:Radiotherapy / Q000379:methods; D011879:Radiotherapy Dosage; D014018:Tissue Distribution; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006573:Heterocyclic Compounds, 1-Ring; D007554:Isotopes; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D007204:Indium; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C448700:epratuzumab