(124)I-huA33 antibody PET of colorectal cancer

Abstract

Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI).

Methods: We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG.

Results: Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33.

Conclusion: Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.

FIGURE 1

Patient 18, with colorectal cancer metastatic to liver. Maximum-intensity-projection images were obtained after HAI infusion of 361.4 MBq of ¹²⁴I-huA33. Images are scaled to same maximum. Initial image at 45 min shows predominant blood-pool activity. Two-day image shows some clearing from blood pool, excellent localization in liver lesions (SUVmax, 11.2), and some uptake in bowel. At 7 d, there is persistent uptake in liver lesions (SUVmax, 11.2), prominent bowel uptake, and significant decrease in blood-pool activity.

FIGURE 2

Patient 19, with colorectal cancer metastatic to liver. Patient received HAI of 368 MBq of ¹²⁴I-huA33. Initial images show blood-pool activity, with foci of uptake in liver that appear as cold defects. At 3 d and 7 d, there is marked and persistent localization of uptake in known liver metastasis. Cold defects represent bilomas (arrows) that persisted as non–antibody-avid.

FIGURE 3

Plasma concentration of ¹²⁴I-huA33 determined by well counting, compared with that estimated from region of interest over blood pool from PET scans. Individual patient samples are plotted, with line connecting values for each patient. Upper family of lines (n = 18) represents early postinjection time, and lower family (n = 20) represents last (presurgical) imaging time. At earliest time after injection, mean concentration in plasma by well counter was 31.8 %ID/L, whereas concentration estimate based on PET was slightly lower, at 28.1 %ID/L (P = 0.0270). At late time, concentration in plasma by well counter was 6.2 %ID/L, whereas estimate based on PET was similar, at 6.9 %ID/L (P = 0.124). ■ = mean value immediately after injection. ▲ = mean value at latest time point that was a mean of 6.9 d after injection.