Preclinical evaluation of intravenously administered 111In- and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs.
B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation.
Quadri
S M
SM
Johns Hopkins Oncology Center, Section of Radiobiology, Baltimore, MD 21205.
Shao
Y
Y
Blum
J E
JE
Leichner
P K
PK
Williams
J R
JR
Vriesendorp
H M
HM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000912:Antibodies, Neoplasm / Q000008:administration & dosage; D004285:Dogs; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007262:Infusions, Intravenous; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007205:Indium Radioisotopes; D009842:Oligopeptides; D015021:Yttrium Radioisotopes; C062250:glycyl-tyrosyl-lysine-DTPA; D004369:Pentetic Acid