title: Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.
abstract: OBJECTIVE
  This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti-Lewis Y (Le(y)) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Le(y) antigen.
  
  
  METHODS
  The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Le(y) positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m(2). The first cycle was trace labeled with (111)In for biodistribution assessment using gamma camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA.
  
  
  RESULTS
  Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T(1/2)beta of (111)In-CMD-193 was 102.88 +/- 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects.
  
  
  CONCLUSIONS
  CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development.
authors.affiliation: Ludwig Institute for Cancer Research, Austin Hospital, Melbourne, Australia.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Herbertson
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.forename: David J
authors.initials: DJ
authors.lastname: MacFarlane
authors.forename: Bridget
authors.initials: B
authors.lastname: Chappell
authors.forename: Noel
authors.initials: N
authors.lastname: Micallef
authors.forename: Sze-Ting
authors.initials: ST
authors.lastname: Lee
authors.forename: Timothy
authors.initials: T
authors.lastname: Saunder
authors.forename: Wendie
authors.initials: W
authors.lastname: Hopkins
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Smyth
authors.forename: David K
authors.initials: DK
authors.lastname: Wyld
authors.forename: John
authors.initials: J
authors.lastname: Bellen
authors.forename: Daryl S
authors.initials: DS
authors.lastname: Sonnichsen
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C545870:CMD 195; C522039:Hu3S193 monoclonal antibody; D018796:Immunoconjugates; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen