Phase I/II trial of recombinant methionyl human tumor necrosis factor binding protein PEGylated dimer in patients with active refractory rheumatoid arthritis.
OBJECTIVE
To evaluate the safety, immunogenicity, pharmacokinetics, and efficacy of intravenous administration of tumor necrosis factor binding protein (TNFbp) dimer in patients with rheumatoid arthritis (RA).


METHODS
This phase I/II study was a multicenter, randomized, double blind, placebo controlled, ascending dose study evaluating TNFbp dimer administered by i.v. infusion. Thirty-three patients with RA divided into 3 cohorts received TNFbp dimer (30, 100, 300 microg/kg) or placebo during a 5 min infusion at baseline and at 3 and 6 weeks; patients were followed at routine intervals after each infusion through 77 days postinfusion. Pharmacokinetics were analyzed using a log-linear regimen and comparisons were made between half-life after first, 2nd, and 3rd doses. Plasma TNFbp dimer concentrations and serum antibody levels were used in the measurement of pharmacokinetics.


RESULTS
Administration of 30 microg/kg of TNFbp dimer was generally well tolerated; the maximum tolerated dose was 100 microg/kg. No serious adverse events were reported. A significant antibody response affected the half-life and clearance of TNFbp dimer at each dose group. Anti-TNFbp antibodies were noncytotoxic and nonagonistic. Clinical evaluations provided evidence of in vivo activity of TNFbp dimer in these patients.


CONCLUSIONS
TNFbp dimer administered to patients with long standing RA resulted in significant antibody production to the study drug. This effect reduced the half-life and clearance of the TNFbp. This TNFbp will not be a viable option for treating patients with RA secondary to immunogenicity.
Moreland
L W
LW
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 35294-7201, USA. Larry.Moreland@ccc.uab.edu
McCabe
D P
DP
Caldwell
J R
JR
Sack
M
M
Weisman
M
M
Henry
G
G
Seely
J E
JE
Martin
S W
SW
Yee
C L
CL
Bendele
A M
AM
Frazier
J L
JL
Kohno
T
T
Cosenza
M E
ME
Lyons
S A
SA
Dayer
J M
JM
Cohen
A M
AM
Edwards
C K
CK
D000328:Adult; D000368:Aged; D000917:Antibody Formation; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D017211:Treatment Failure; D053319:Tumor Necrosis Factor Decoy Receptors
D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1