Antiarthritic activity of soluble tumor necrosis factor receptor type I forms in adjuvant arthritis: correlation of plasma levels with efficacy.
OBJECTIVE
To determine the importance of tumor necrosis factor (TNF) in the pathogenesis of adjuvant disease in rats and to determine plasma levels of recombinant soluble TNF receptor type I (sTNF-RI) necessary for efficacy, to project dosing for human clinical trials.


METHODS
Rats with adjuvant arthritis were treated by continuous infusion with sTNF-RI forms to maintain blood levels of this TNF-alpha inhibitory protein. In addition, rats were given bolus injections of polyethylene glycol linked sTNF-RI and efficacy and plasma levels were determined. Effects of treatment in the rats were monitored by sequential volume or diameter measurement of ankle joints, final paw weights, and histologic evaluation of ankle joints, with particular emphasis on bone erosive lesions.


RESULTS
In all studies and regardless of dosing methodology (bolus vs continuous infusion), minimal plasma levels for efficacy were in the 0.3-0.5 microg/ml range. Higher plasma levels resulted in greater efficacy, with maximal effects achieved when plasma levels were in the 5 microg/ml range. Beneficial effects of treatment were seen on body weight, paw swelling, splenomegaly, hepatomegaly, and bone resorption.


CONCLUSIONS
TNF-alpha is an important mediator of all aspects of rat adjuvant disease including both the destructive processes in the joints as well as the systemic manifestations of adjuvant disease. Studies using various forms of sTNF-RI consistently show that plasma levels of 0.3-0.5 microg/ml are required for minimal efficacy and that higher plasma levels show dose-responsive enhanced efficacy.
McComb
J
J
Department of Pharmacology, Amgen Boulder, Inc., CO, USA.
Gould
T
T
Chlipala
E
E
Sennelo
G
G
Frazier
J
J
Kieft
G
G
Seely
J
J
Edwards
C K
CK
Bendele
A
A
D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D007249:Inflammation / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013643:Tarsus, Animal / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
D015703:Antigens, CD; D004337:Drug Carriers; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011092:Polyethylene Glycols