Pharmacokinetics of pretargeted monoclonal antibody 2D12.5 and 88Y-Janus-2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) in BALB/c mice with KHJJ mouse adenocarcinoma: a model for 90Y radioimmunotherapy.
Three-step pretargeting for radioimmunotherapy in BALB/c mice with KHJJ tumors was done with monoclonal antibody (mAb) 2D12.5, which is specific for yttrium-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) but nonspecific for the tumor. Tumor uptake was by passive diffusion of mAb through leaky neovasculature in the tumor. The three steps were: (a) anti-hapten mAb 2D12.5 (0 h); (b) polyvalent haptenprotein conjugate chase (20 h); and (c) 88Y-labeled monovalent DOTA or bivalent Janus-DOTA haptens (21 h) and organ and tumor bioassay (24 h). Rapid tumor (T) uptake and high tumor:blood ratio (T:BL) was seen 3 h after injection after step c. For monovalent 88Y-DOTA, T = 1.7%/g* and T:BL = 16:1; for bivalent 88Y-Janus-DOTA, T = 4.41%/g* and T:BL = 21:1 at 3 h (*, P < 0.001). Blood and bone plus marrow were << 1%/g, and liver was < 1%/g. The 24-h whole body retention was approximately 5% of injected dose with 1% in tumor (20% of total), 1.8% in other organs, and 2.2% in carcass; the 24-h whole body retention of covalent nonspecific antibody conjugates was > 80% of injected dose. The biological half-life in the tumor of 0.9 microCi 88Y-Janus-DOTA was approximately 24 h, measured daily for 5 days. Activity in microCi/g of tumor and blood for 90Y equimolar to the amount of 88Y injected (0.9 microCi 88Y = 0.744 pmol = 36.47 microCi 90Y) was used for calculating the area under the curve of tumor and blood in microCi-h/g of 90Y. The 90Y radiation absorbed dose (RAD) from multiplying microCi-h/g x the 90Y absorbed dose constant, 1.99 RAD-g/microCi-h, gave T = 89 RAD and BL = 3.7 RAD. The therapeutic ratio from RAD T:RAD BL = 24:1. These results indicate that pretargeting 90Y hapten-specific mAb for radioimmunotherapy has considerable promise.
Nuclear Medicine Service, Veterans Administration Medical Center, Palo Alto, California 94304.
D A
DA
Goodwin
C F
CF
Meares
N
N
Watanabe
M
M
McTigue
W
W
Chaovapong
C M
CM
Ransone
O
O
Renn
D P
DP
Greiner
D L
DL
Kukis
S I
SI
Kronenberger
D000085:Acetates / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000378:metabolism* / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*
D000085:Acetates; D000911:Antibodies, Monoclonal; D006571:Heterocyclic Compounds; D015021:Yttrium Radioisotopes; C069408:12-(4-nitrobenzyl)-1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid