Yttrium-90-labeled monoclonal antibody for therapy: labeling by a new macrocyclic bifunctional chelating agent.

Yttrium-90 (90Y) is a promising radiometal for therapy of cancer due to its high-energy beta emission and a physical half-life of 2.67 days. Bifunctional chelating agents based on DTPA cyclic anhydride or EDTA do not form Y(III) complexes that are stable under physiologic conditions. A new macrocyclic bifunctional chelating agent based on 1,4,7,10-tetraazacylododecane-N,N',N",N"'-tetraacetic acid (DOTA) forms a stable Y(III) complex. It was converted to p-bromoacetamidobenzyl-DOTA (BAD), and conjugated to monoclonal antibody Lym-1 via 2-iminothiolane, either as the free ligand or as the 88Y chelate. Stability studies of Lym-1-2IT-BAD-88Y in human serum in vitro showed no measurable loss of Y(III) from the ligand over a 25-day period. In Raji-tumored mice, tumor uptake was 16.8% of the injected dose per gram of tissue on Day 3. The bone uptake was 2.0, 3.6, and 2.1% injected dose per gram of tissue on Day 1, 3, and 5, respectively. The biodistribution of the control 88Y-citrate demonstrated continuous increase in bone uptake from 13.8% injected dose per gram on Day 1 to 24.9% injected dose per gram on Day 4.

Copper-67-labeled monoclonal antibody Lym-1, a potential radiopharmaceutical for cancer therapy: labeling and biodistribution in RAJI tumored mice.

Copper-67 (67Cu) is one of the most promising radiometals for radioimmunotherapy because of its 61.5 hr physical half-life, abundant beta particles, and gamma emissions suitable for imaging. However, 67Cu is readily transferred from the usual chelates of EDTA or DTPA to albumen. We developed a new macrocycle (6-p-nitrobenzyl-TETA) to chelate copper. Bifunctional chelating agent p-bromoacetamidobenzyl-TETA was conjugated to Lym-1, a monoclonal antibody against human B cell lymphoma, without significantly altering its immunoreactivity. This conjugate was stably labeled with 67Cu under conditions chosen to optimize the yield of a high specific activity radiopharmaceutical. The biodistribution in RAJI tumor bearing mice demonstrated significant tumor uptake (14.7% ID per gram) and extended residence time (120 hr) in contrast to normal organs. After 24 hr, radioactivity was continuously cleared from all tissues except the tumor. This study suggests 67Cu labeled Lym-1 to be a promising radiopharmaceutical for potential use for radioimmunotherapy of B cell lymphoma.