| Primary information |
|---|
| ThPP ID | Th1126 |
| Therapeutic Peptide/Protein Name | Belatacept |
| Sequence | MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAA view full sequnce in fasta |
| Functional Classification | IIa |
| Molecular Weight | 92300 |
| Chemical Formula | C3508H5440N922O1096S32 |
| Isoelectric Point | N.A. |
| Hydrophobicity | N.A. |
| Melting Point (℃) | N.A. |
| Half Life | Mean terminal elimination half-life- 9.8 days. |
| Description | Belatacept 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/Disease | For 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. |
| Pharmacodynamics | Belatacept 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 Action | Belatacept 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. |
| Toxicity | N.A. |
| Metabolism | The 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. |
| Absorption | Following 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 Distribution | Vd, steady state, transplant patients, 10 mg/kg = 0.11 L/kg;Vd, steady state, transplant patients, 5 mg/kg = 0.12 L/kg |
| Clearance | Increased 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. |
| Categories | Antirheumatic Agents and Immunosuppressive Agents |
| Patents Number | N.A. |
| Date of Issue | N.A. |
| Date of Expiry | N.A. |
| Drug Interaction | N.A. |
| Target | T-lymphocyte activation antigen CD86,T-lymphocyte activation antigen CD80 |
| Information of corresponding available drug in the market |
|---|
| Brand Name | Nulojix |
| Company | Bristol-Myers Squibb |
| Brand Discription | NULOJIX (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 for | NULOJIX (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 Name | N.A. |
| Formulation | Prior 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 Appearnce | NULOJIX is supplied as a sterile, white or off-white lyophilized powder for intravenous administration. |
| Route of Administration | Intravenous Injection |
| Recommended Dosage | N.A. |
| Contraindication | Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus |
| Side Effects | PTLD, 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 Link | http://www.rxlist.com/nulojix-drug.htm http://www.nulojix.com/hcp/index.aspx http://www.drugs.com/nulojix.html |
| PubMed ID | 25611834, 25551406, 25448417, 25447131, 22928660, 22151353 |
| 3-D Structure | Th1126 (View) or (Download) |