title: Pharmacokinetics and clinical evaluation of 125I-radiolabeled humanized CC49 monoclonal antibody (HuCC49deltaC(H)2) in recurrent and metastatic colorectal cancer patients.
abstract: BACKGROUND
  CC49 is an antitumor monoclonal antibody that is promising for use in radioimmunoguided surgery (RIGS). However, the murine antibody has been limited by human antimouse antibody (HAMA) response and slow clearance. This study examined the pharmacokinetics and tissue localization of a humanized domain-deleted CC49 antibody (HuCC49DeltaC(H)2 MAb) in humans.
  
  
  METHODS
  Twenty-one patients with colorectal carcinoma were given 1 mg intravenous (I.V.) bolus of HuCC49DeltaC(H)2 MAb radiolabeled with 2 mCi (125)I after thyroid blockade. The level of circulating HuCC49DeltaC(H)2 MAb was measured daily as precordial counts using a handheld gamma-detecting probe. Each patient underwent an exploratory laparotomy on postinjection days 3-20. Gamma counts were measured at normal organs, aortic bifurcation (AB), and both clinically evident and occult tumors.
  
  
  RESULTS
  Precordial and AB gamma counts showed an excellent linear correlation. HuCC49DeltaC(H)2 MAb followed a two-compartment pharmacokinetic model. Normal organs and AB showed similar exposures to HuCC49DeltaC(H)2 MAb, while HuCC49DeltaC(H)2 MAb favorably distributed into tumors from day 3. Intestinal and metastatic liver lesions showed the highest partition coefficients. All patients showed no HAMA response.
  
  
  CONCLUSIONS
  C(H)2 region deletion of HuCC49DeltaC(H)2 MAb did not alter the pharmacokinetics compared to murine CC49. The favorable partition coefficient K of HuCC49DeltaC(H)2 MAb into tumors supports its use in RIGS.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiao
authors.forename: Sara
authors.initials: S
authors.lastname: Horst
authors.forename: George
authors.initials: G
authors.lastname: Hinkle
authors.forename: Xianhua
authors.initials: X
authors.lastname: Cao
authors.forename: Ergun
authors.initials: E
authors.lastname: Kocak
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Donn
authors.initials: D
authors.lastname: Young
authors.forename: M
authors.initials: M
authors.lastname: Khazaeli
authors.forename: Doreen
authors.initials: D
authors.lastname: Agnese
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Edward
authors.initials: E
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000601:surgery / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017434:Protein Structure, Tertiary; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D012008:Recurrence; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D007457:Iodine Radioisotopes