Pharmacokinetics and clinical evaluation of 125I-radiolabeled humanized CC49 monoclonal antibody (HuCC49deltaC(H)2) in recurrent and metastatic colorectal cancer patients.
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.
Xiao
Jim
J
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Horst
Sara
S
Hinkle
George
G
Cao
Xianhua
X
Kocak
Ergun
E
Fang
Jing
J
Young
Donn
D
Khazaeli
M
M
Agnese
Doreen
D
Sun
Duxin
D
Martin
Edward
E
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
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D007457:Iodine Radioisotopes