title: 177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi.
abstract: OBJECTIVE
  (213)Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the β-emitter (177)Lu has proven to be beneficial in targeted therapy, (177)Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of (213)Bi-d9MAb.
  
  
  METHODS
  Nude mice were inoculated intraperitoneally with HSC45-M2 gastric cancer cells expressing d9-E-cadherin and were treated intraperitoneally 1 or 8 days later with different activities of specific (177)Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific (177)Lu-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of (177)Lu-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically.
  
  
  RESULTS
  Treatment with (177)Lu-immunoconjugates (1.85, 7.4, 14.8 MBq) significantly prolonged survival. As expected, treatment on day 1 after tumour cell inoculation was more effective than treatment on day 8, and specific (177)Lu-d9MAb conjugates were superior to nonspecific (177)Lu-d8MAb. Treatment with 7.4 MBq of (177)Lu-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of (177)Lu-d9MAb was not free of toxic side effects. In some animals lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen but were not observed after treatment with (213)Bi-d9MAb at comparable therapeutic efficacy.
  
  
  CONCLUSIONS
  The therapeutic efficacy of (177)Lu-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with (213)Bi-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis.
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany. christof.seidl@lrz.tum.de
authors.forename: Christof
authors.initials: C
authors.lastname: Seidl
authors.forename: Christine
authors.initials: C
authors.lastname: Zöckler
authors.forename: Roswitha
authors.initials: R
authors.lastname: Beck
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001729:Bismuth / Q000737:chemistry*; D001772:Blood Cell Count; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004355:Drug Stability; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008187:Lutetium / Q000737:chemistry*; D051379:Mice; D010534:Peritoneal Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes / Q000737:chemistry*; D011879:Radiotherapy Dosage; D013274:Stomach Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D011868:Radioisotopes; D008187:Lutetium; D001729:Bismuth