Pharmacokinetics, metabolic stability, and subcutaneous bioavailability of a genetically engineered analog of DcR3, FLINT [DcR3(R218Q)], in cynomolgus monkeys and mice.
Decoy receptor 3 (DcR3) is a novel member of the tumor necrosis factor receptor superfamily, which binds to and blocks the activities of the ligands, FasL and LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor), that play an important role in regulating apoptosis in normal physiology. DcR3 was rapidly degraded to a major circulating metabolic fragment, DcR3(1-218), after subcutaneous administration in primates and mice. DcR3 was molecularly engineered by changing the arginine residue at position 218 to glutamine to generate a potentially stable analog, DcR3(R218Q), which we termed FasLigand inhibitor protein [FLINT (LY498919)]. The influence of this modification on the kinetics and bioavailability of DcR3 was evaluated in primates and mice. After i.v. administration of FLINT and DcR3, both compounds were cleared from the plasma in a bi-phasic manner, with the terminal phase half-life being somewhat longer for FLINT than for DcR3. After s.c. administration, the exposure to the full-length form of FLINT was 5.7- to 6-fold greater than for DcR3. In both primates and mice, greater than 90% of circulating immunoreactivity after s.c. administration of FLINT was associated with intact molecule, whereas only 17 to 37% was associated with intact molecule after administration of DcR3. The absolute s.c. bioavailability of intact FLINT was approximately 4- to 6-fold higher than for DcR3. The improved s.c. bioavailability of FLINT is related to the increased metabolic stability afforded to the molecule as a result of the amino acid mutation at position 218 of the primary sequence of DcR3 and may translate to the need for lower therapeutic doses in a number of disease indications.
Wroblewski
Victor J
VJ
Department of Drug Disposition Development/Commercialization, Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. wroblewski_victor@lilly.com
McCloud
Christy
C
Davis
Kelly
K
Manetta
Joseph
J
Micanovic
Radmila
R
Witcher
Derrick R
DR
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004333:Drug Administration Routes / Q000662:veterinary; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D010949:Plasma / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D011991:Receptors, Virus / Q000378:metabolism; D013997:Time Factors
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D011991:Receptors, Virus; C506028:TNFRSF14 protein, human; C505911:TNFRSF6B protein, human; C506029:Tnfrsf14 protein, mouse