Toxicologic evaluations of an immunotoxin, H65-RTA.
A series of acute and multiple dose toxicology studies were performed to support the clinical dose and to evaluate the systemic toxicity of an immunotoxin, H65-RTA. H65-RTA consists of a murine anti-CD5 monoclonal antibody and ricin A chain (RTA). The LD50 of H65-RTA was estimated to be between 60 and 62.5 mg/kg in the rat. H65-RTA was administered to the rat and the monkey as a bolus injection at doses of 0.1, 0.5, and 2 mg/kg and over 1-hr infusion at 0.2 and 2 mg/kg, respectively. Two to three weeks of postdosing recovery was included in the study design. Following repeated doses of H65-RTA, the following findings were demonstrated: peripheral edema, decreased body weight, decreased body temperature (monkey only) in addition to a general inflammatory reaction evidenced by changes in hematology, clinical chemistry, and urinalysis parameters. Histopathologically, chronic inflammation in the nonarticular soft tissue was found in the rat at doses of 0.1 mg/kg and higher and monkeys developed much more severe toxicity when compared to the rat at the same doses. Inflammation, hemorrhage, and/or edema were evident in a variety of tissues. Myeloid hyperplasia was also evident. Additional findings resulting from the drug-related stress involved adrenals, spleen, thymus, and lymph nodes. All toxicity was reversible. The antibody response was evident in rats at doses of 0.5 mg/kg and higher and in all monkeys at doses of 0.2 and 2 mg/kg. In conclusion, since H65 antibody does not cross-react with the T cells from either the rat or the cynomolgus monkey, the toxicity observed in the studies described above was not related to T lymphocytes and was probably due to a series of acute to subacute inflammatory reactions caused largely by the RTA moiety of H65-RTA.
Kung
A H
AH
XOMA Corporation, Berkeley, California 94710, USA.
Cavagnaro
J A
JA
Makin
A
A
White
M A
MA
Kong
K N
KN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D000917:Antibody Formation; D001772:Blood Cell Count; D001774:Blood Chemical Analysis / Q000662:veterinary; D001831:Body Temperature; D001835:Body Weight; D005260:Female; D000922:Immunotoxins / Q000008:administration & dosage / Q000633:toxicity*; D007249:Inflammation / Q000209:etiology; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012276:Ricin / Q000008:administration & dosage / Q000633:toxicity*; D018675:Toxicity Tests; D016482:Urinalysis / Q000662:veterinary
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; C068230:zolimomab aritox; D012276:Ricin