Effect of production method on the systemic clearance rate of a human monoclonal antibody in the rat.
Pharmacologic studies of human immunoglobulins (IgM) in non-primate animal models, whether directed toward efficacy or toxicity, rely on pharmacokinetic parameters to achieve optimal doses and schedules. In rodents, human IgMs have an effective circulatory half-life of 11 h and a plasma clearance rate of 0.044 ml/min/kg. Studies of a new group of human monoclonal antibodies (hMAb) specific for Gram-negative bacteria and endotoxin revealed an IgM molecule, hMAb-10058, which, when purified from tissue culture medium, exhibited a suprisingly short circulatory lifetime in rodents. Investigations into possible explanations for this short circulatory half-life resulted in the development of a simple and efficient method for producing hMAbs in the immunodeficient NIH-3 mouse (bg x nu x XID). This method of production of hMAb-10058 had dramatic effects on its half-life. Whereas hMAb-10058 produced in serum-free, defined medium had a clearance rate of 14.4 ml/min/kg and an effective half-life of 0.12 h, the same hMAb-10058 raised in mouse ascites had a decreased clearance rate of 0.092 ml/min/kg and an increased effective half-life of 12 h. This 100-fold enhancement of the hMAb's half-life was not affected by the purification process. Some potential molecular structures involved in the circulatory half-life of this hMAb are discussed.
Gauny
S S
SS
Department of Pharmacology, Cetus Corporation, Emeryville, CA.
Andya
J
J
Thomson
J
J
Young
J D
JD
Winkelhake
J L
JL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M