1. DB06681
BELATACEPT
C3508H5440N922O1096S32
92.3 kDa (with glycosylation)
CATEGORIES
Antirheumatic Agents
Immunosuppressive Agents

2. DESCRIPTION
Belatacept is a soluble fusion protein, which links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Structurally, abatacept is a glycosylated fusion protein with a MALDI-MS molecular weight of 92,300 Da and it is a homodimer of two homologous polypeptide chains of 357 amino acids each. It is produced through recombinant DNA technology in mammalian CHO cells. The drug has activity as a selective co-stimulation modulator with inhibitory activity on T lymphocytes. It is approved for the treatment of rheumatoid arthritis. Belatacept selectively blocks the process of T-cell activation. It was developed by Bristol-Myers-Squibb. It differs from abatacept (Orencia) by only 2 amino acids. FDA approved on June 15, 2011.

3. INDICATION
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.

4. 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.
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.

5. 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
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.
HALF LIFE
Mean terminal elimination half-life: 10 mg/kg, kidney transplant recipients= 9.8 days; 5 mg/kg, kidney transplant recipient = 8.2 days
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.

6. DRUG INTERACTIONS
Belimumab Belimumab increases the immunosupressive effect. Interaction is significant so monitor closely.
Denosumab Montinor therapy due to enhanced adverse effects of immunosuppressants and the risk of infections.
Leflunomide Consider therapy modification due to enhanced adverse effects of leflunomide, especially hematologic toxicities.
Mycophenolate mofetil Belatacept increases the Cmax and AUC of mycophenolate mofetil.
Natalizumab Avoid infection due to enhanced adverse effects of natalizumab and the risk of infections.
Pimecrolimus Avoid combination due to enhanced effects of immunosuppressants.
Pralatrexate Increased immunosuppresive effects and risk of infection. Monitor for adverse effects .
Rilonacept Belatacept decreases immunosuppressive effects while rilonacept increases immunosuppressive effects. Potential risk of infection although the effect of interaction is not known; use caution and monitor closely if using both.
Roflumilast Consider modifying therapy due to enhanced immunosuppressive effect.
Sipuleucel-T Monitor therapy due to to potential decrease in therapeutic effect of sipuleucel-t.
Tacrolimus Avoid combination due to enhanced immunosuppressive effect.
Tofacitinib Avoid combination due to enhanced immunosuppressive effect of tofacitinib.
Trastuzumab Monitor therapy due to enhanced neutropenic effect of immunosuppressants.

7. Nulojix Lyophilized powder for injection: 250 mg per vial DESCRIPTION
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.

8. DOSAGE:
Initial dose: 10 mg/kg, intravenously, once daily, on day 1 (day of transplant, prior to implantation) and day 5, and at the end of weeks 2, 4, 8, and 12.
Maintenance dose: 5 mg/kg, intravenously, at the end of week 16 and every 4 weeks (plus or minus 3 days) thereafter.
VIAL Description:
NULOJIX is supplied as a sterile, white or off-white lyophilized powder for intravenous administration. 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 [see DOSAGE AND ADMINISTRATION]. 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).

9. CLEARANCE: 0.5 mL/h/kg
HALF LIFE: 8 to 10 days ADVERSE REACTION: Hives; difficult breathing; swelling of your face, lips, tongue, or throat. DRUG INTERACTION Mycophenolate Mofetil (MMF)

10. PROTEIN SEQUENCE FOR BELATACEPT
MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATYMMGNELTF
LDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYEGIGNGTQIYVIDPEPC
PDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED
PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA
PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN
YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

11. REFERENCES
Yabu JM, Vincenti F: Novel immunosuppression: small molecules and biologics. Semin Nephrol Jul;27(4):479-86
Tedesco Silva H Jr, Pinheiro Machado P, Rosso Felipe C, Medina Pestana JO: Immunotherapy for De Novo renal transplantation: what’s in the pipeline? Drugs. 2006;66(13):
Wekerle T, Grinyo JM: Belatacept: from rational design to clinical application. Transpl Int Feb;25(2): doi: /j ×. Epub 2011 Dec 7
Garnock-Jones KP: Belatacept: in adult kidney transplant recipients. BioDrugs Dec 1;26(6):413-24