Pharmacokinetics of Iodine-125 CC49 Monoclonal Antibody in Patients with Colon Cancer

Abstract

Radioimmunoguided Surgery techniques which use radiolabeled tumor specific markers and an intraoperative detector in an attempt to improve therapy and survival in patients with cancer have been under development for over fifteen years. Monoclonal antibody (MAb) CC49 is a second-generation murine IgG₁ which has improved localization properties over its predecessor, MAb B72.3, and has been studied in a number of patients. In order to determine the pharmacokinetics of iodine-125 (¹²⁵I) CC49MAb, size-exclusion, highperformance liquid chromatography (HPLC) was used to assess radioactive components in serum and urine following administration of the drug to colon cancer patients.

Methods

Five patients received an intravenous infusion of 10mg of MAb CC49 labeled with 2mCi ^l25I. Following infusion, serum and urine specimens were collected from patients at predetermined time intervals prior to surgery. HPLC analysis of these specimens was completed to determine the radioactive species in each sample.

Results

Serum and urine specimens showed that serum levels of CC49 decrease exponentially and become unmeasurable by day 14 (half-life 1.89 days, ± 0.19), with a steady, low-level of free ¹²⁵I measurable in postinjection serum until day 21 after infusion. There was no evidence of MAb fragmentation or antibody:antigen (Ab:Ag) complex formation in serum, and no evidence of whole MAb, F(ab')₂, or Fab fragment excretion in urine. Preinjection sera with MAb added in vitro also failed to demonstrate Ab:Ag complex formation. Analysis of urine showed low level excretion of free ¹²⁵I which peaked by day 1 and declined exponentially through day 21, with a very low molecular weight (<1 kDa) MAb fragment excreted in urine between 1 and 21 days.

Conclusion

Radioiodinated ¹²⁵I CC49 MAb remains in serum of cancer patients approximately 14 days, and tissue radioactivity beyond this time may reflect tissue sequestered MAb and/or free ¹²⁵I and not "bloo pool" radioactivity. CC49 MAb appears to be deiodinated in small but significant quantities before it is metabolized, and clearance of radioactivity is mainly in free ^l25I form in urine. Measurable quantities of a < 1 Kda MAb fragment in urine and not serum may suggest a renal mechanism of MAb metabolism, but may also represent a metabolic end product of MAb metabolism with a very short serum half-life (T_1/2) which accumulates in urine.