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1596 details
Primary information
ThPP IDTh1126
Therapeutic Peptide/Protein NameBelatacept
SequenceMHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAA view full sequnce in fasta
Functional ClassificationIIa
Molecular Weight92300
Chemical FormulaC3508H5440N922O1096S32
Isoelectric PointN.A.
HydrophobicityN.A.
Melting Point (℃)N.A.
Half LifeMean terminal elimination half-life- 9.8 days.
DescriptionBelatacept is a recombinant (CHO cells derived) soluble fusion protein, which links the extracellular domain of human cytotoxic CTLA-4 to the modified Fc portion of human IgG1, thereby selectively blocking the process of T-cell activation. It is a glycosylated fusion protein, which is a homodimer of two homologous polypeptide chains of 357 amino acids each. The drug acts as a selective co-stimulation modulator with inhibitory activity on T lymphocytes. It differs from abatacept (Orencia) by only 2 amino acids. It is approved for the treatment of rheumatoid arthritis. It was developed by Bristol-Myers-Squibb. FDA approved on June 15, 2011.
Indication/DiseaseFor prophylaxis of organ rejection. It is also used concomitantly with basiliximumab for induction therapy, mycophenolate, and corticosteriods in kidney transplant recepients that are seropositive for the Epstein-Barr virus.
PharmacodynamicsBelatacept binds to CD86 with a 4-fold higher affinity than abatacept. It also binds to CD80 with a 2-fold higher affinity than abatacept. It was observed in non-human primates that belatacept prolongs graft survival due to a decrease in antibody production against the donor organ. Furthermore, belatacept also inhibits the primary humoral immune response which is indicated by the decrease in post-transplant levels of IgG, IgM, and IgA. The magnitude of this effect is more significant in belatacept than it is in cyclosporine.
Mechanism of ActionBelatacept is a fusion protein in which the Fc portion of human IgG1 is attached onto the extracellular portion of human CTLA-4 (CD152). Belatacept specifically binds to CD80 and CD86 receptors that are found on the antigen-presenting cell (B cells, macrophages, dendritic cells) to block selective T-cell lymphocyte costimulation. CD80 and CD86 would normally act as the ligands to the CD28 receptor T-cells in which this interaction triggers the activation of T lymphocytes. However in the presence of belatacept, because the extracellular CTLA-4 component binds to CD28 with higher affinity than CD80 or CD86, T lymphyocyte anergy, a state of antigen specific tolerance, occurs instead. The T cell is also no longer able to respond to their antigen.
ToxicityN.A.
MetabolismThe cytochrome P450 enzyme system or uridine diphosphate-glucuronosyltransferases are not expected to be involved with the metabolism of belatacept. Because the drug is a protein, belatacept is degraded into smaller peptides and amino acids by proteolytic enzymes.
AbsorptionFollowing multiple intravenous doses of an initial 10 mg/kg dose and followed by a maintenance dose of 5 mg/kg in kidney transplant recipients, these are the following pharmacokinetic parameters: Cmax, 10 mg/kg = 247 µg/mL; Cmax, 5 mg/kg = 139 µg/mL; AUC, 10 mg/kg = 22,252 µg · h/mL; AUC, 5 mg/kg = 14,090 µg · h/mL; Belatacept had linear and dose-dependent pharmacokinetic profile.
Volume of DistributionVd, steady state, transplant patients, 10 mg/kg = 0.11 L/kg;Vd, steady state, transplant patients, 5 mg/kg = 0.12 L/kg
ClearanceIncreased body weight may increase the clearance rate of belatacept.Mean systemic clearance:10 mg/kg, kidney transplant recipients= 0.49 mL/h/kg;5 mg/kg, kidney transplant recipient = 0.51 mL/h/kg.
CategoriesAntirheumatic Agents and Immunosuppressive Agents
Patents NumberN.A.
Date of IssueN.A.
Date of ExpiryN.A.
Drug InteractionN.A.
TargetT-lymphocyte activation antigen CD86,T-lymphocyte activation antigen CD80
Information of corresponding available drug in the market
Brand NameNulojix
CompanyBristol-Myers Squibb
Brand DiscriptionNULOJIX (belatacept), a selective T-cell costimulation blocker, is a soluble fusion protein consisting of the modified extracellular domain of CTLA-4 fused to a portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced by recombinant DNA technology in a mammalian cell expression system. Two amino acid substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4. As a result of these modifications, belatacept binds CD80 and CD86 more avidly than abatacept, the parent CTLA4-Immunoglobulin (CTLA4-Ig) molecule from which it is derived. The molecular weight of belatacept is approximately 90 kilodaltons.
Prescribed forNULOJIX (belatacept) is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. NULOJIX is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.
Chemical NameN.A.
FormulationPrior to use, the lyophile is reconstituted with a suitable fluid to obtain a clear to slightly opalescent, colorless to pale yellow solution, with a pH in the range of 7.2 to 7.8. Suitable fluids for constitution of the lyophile include SWFI, 0.9% NS, or D5W. Each 250 mg single-use vial of NULOJIX also contains: monobasic sodium phosphate (34.5 mg), sodium chloride (5.8 mg), and sucrose (500 mg).
Physcial AppearnceNULOJIX is supplied as a sterile, white or off-white lyophilized powder for intravenous administration.
Route of AdministrationIntravenous Injection
Recommended DosageN.A.
ContraindicationEpstein-Barr virus (EBV) seronegative or with unknown EBV serostatus
Side EffectsPTLD, predominantly CNS PTLD, and other malignancies, EBV Seropositive Subpopulation, Progressive Multifocal Leukoencephalopathy, Bacterial, Mycobacterial, Viral, and Fungal Infections, Proteinuria, Immunogenicity, New-Onset Diabetes After Transplantation, Hypertension, Dyslipidemia
Useful Linkhttp://www.rxlist.com/nulojix-drug.htm http://www.nulojix.com/hcp/index.aspx http://www.drugs.com/nulojix.html
PubMed ID25611834, 25551406, 25448417, 25447131, 22928660, 22151353
3-D StructureTh1126 (View) or (Download)