title: 177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.
abstract: BACKGROUND
  CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.
  
  
  RESULTS
  Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.
  
  
  CONCLUSIONS
  177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.
authors: Nordic Nanovector AS, Oslo, Norway; Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors: Ada H V
authors: AH
authors: Repetto-Llamazares
authors: Sciencons Ltd., Oslo, Norway.
authors: Roy H
authors: RH
authors: Larsen
authors: Accelera Srl., Nerviano (Milano), Italy.
authors: Anna Maria
authors: AM
authors: Giusti
authors: Accelera Srl., Nerviano (Milano), Italy.
authors: Elena
authors: E
authors: Riccardi
authors: Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Øyvind S
authors: ØS
authors: Bruland
authors: Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors: Pål Kristian
authors: PK
authors: Selbo
authors: Nordic Nanovector AS, Oslo, Norway.
authors: Jostein
authors: J
authors: Dahle
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D005260:Female; D018796:Immunoconjugates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008187:Lutetium; D051379:Mice; D008819:Mice, Nude; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D059470:Tetraspanins / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C059071:CD37 protein, human; D018796:Immunoconjugates; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D059470:Tetraspanins; D008187:Lutetium