Pharmacokinetics and biodistribution of intravenous Lu-177 CC49 murine monoclonal antibody (MAb) in patients with metastatic adenocarcinoma

The pharmacokinetics of Lu-177 labeled CG49, a murine monoclonal antibody that is undergoing testing for radioimmunotherapy, was evaluated. CC49 is a second generation murine MAb that recognizes TAG-72, a pan-carcinoma tumor associated antigen. Labeling of CC49 MAb with Lu-177, a beta emitter was performed by first labeling a derivative of 1,4,5,10-tetraazacyclododecane-tetraacetic acid (PA-DOTA) with Lu-177 and then attaching the Lu-177 labeled PA-DOTA to CC49. CC49 was labeled with Lu-177 at a maximum specific activity of 185 MBq/mg. HPLC showed 96-100% protein bound Lu-177 and <4% aggregate formation. A Phase I dose escalation study was performed. Nine patients with TAG-72 positive, advanced metastatic adenocarcinoma (5- breast, 3- colorectal and 1- lung) were treated with escalating iv doses of Lu-177-(PA-DOTA) CC49: 370 MBq/m2, 555 MBq/m2 and 925 MBq/m2 (range 560-1575 MBq). Pharmacokinetics showed that the plasma cleared with a T1/2 of {approximately}67 hrs which is in the range seen with I-131 CC49. The whole body retention of Lu-177 was prolonged with a biological T1/2 of 223 hr. Urinary excretion ranged from 7 to 26% in the first 96 hrs. Serial images showed early blood pool distribution with prominent uptake in the liver, spleen and marrow. Some intestinal excretion was noted. Tumor imagingmore » was seen in all patients although riot all tumors were visualized. Bone marrow biopsies were obtained in all patients and suggested that the accumulation seen on scan was predominantly in the marrow rather than the bone. MIRDOSE estimates from the first 6 patients suggested doses to the marrow in the range of {approximately}4 cG/37 MBq. This study indicated that while the serum pharmacokinetics of Lu-177-(PA-DOTA)-CC49 are similar to those seen with I-131 CC49, the whole body retention and bone marrow accumulation are different and therefore require further investigation to minimize the bone marrow accumulation.« less