Belatacept

Identification

Name
Belatacept
Accession Number
DB06681
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Fusion proteins
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.

Protein chemical formula
C3508H5440N922O1096S32
Protein average weight
92300.0 Da (with glycosylation)
Sequences
> sequence for belatacept
MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATYMMGNELTF
LDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYEGIGNGTQIYVIDPEPC
PDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED
PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA
PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN
YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Download FASTA Format
Synonyms
Not Available
External IDs
BMS-224818 / BMS224818
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NulojixInjection, powder, for solution250 mgIntravenousBristol Myers Squibb Pharma Eeig2011-06-17Not applicableEu
NulojixInjection, powder, for solution250 mgIntravenousBristol Myers Squibb Pharma Eeig2011-06-17Not applicableEu
NulojixInjection, powder, lyophilized, for solution250 mg/1IntravenousE.R. Squibb & Sons, L.L.C.2011-06-15Not applicableUs
Categories
UNII
E3B2GI648A
CAS number
706808-37-9

Pharmacology

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.

Structured Indications
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.

TargetActionsOrganism
UT-lymphocyte activation antigen CD86Not AvailableHuman
UT-lymphocyte activation antigen CD80Not AvailableHuman
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

Protein binding
Not Available
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.

Route of elimination
Not Available
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.

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Belatacept.Investigational
BelimumabThe risk or severity of adverse effects can be increased when Belatacept is combined with Belimumab.Approved
Clostridium tetani toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Belatacept.Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Belatacept.Approved
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Belatacept.Approved
FingolimodBelatacept may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe therapeutic efficacy of G17DT can be decreased when used in combination with Belatacept.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Belatacept.Investigational
Hepatitis A VaccineThe therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Belatacept.Approved
Hepatitis B Vaccine (Recombinant)The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Belatacept.Approved, Withdrawn
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Belatacept.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Belatacept.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Belatacept is combined with Leflunomide.Approved, Investigational
NatalizumabThe risk or severity of adverse effects can be increased when Belatacept is combined with Natalizumab.Approved, Investigational
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Belatacept.Approved, Investigational
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Belatacept.Approved
RindopepimutThe therapeutic efficacy of Rindopepimut can be decreased when used in combination with Belatacept.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Belatacept.Approved
Rotavirus VaccineThe therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Belatacept.Approved
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Belatacept.Approved
Salmonella typhi ty21a live antigenThe therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Belatacept.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Belatacept.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Belatacept.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Belatacept.Approved, Investigational
TecemotideThe therapeutic efficacy of Tecemotide can be decreased when used in combination with Belatacept.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Belatacept.Investigational
TofacitinibBelatacept may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the neutropenic activities of Belatacept.Approved, Investigational
Yellow fever vaccineThe therapeutic efficacy of Yellow fever vaccine can be decreased when used in combination with Belatacept.Approved
Zoster vaccineThe therapeutic efficacy of Zoster vaccine can be decreased when used in combination with Belatacept.Approved
Food Interactions
Not Available

References

General References
  1. Wekerle T, Grinyo JM: Belatacept: from rational design to clinical application. Transpl Int. 2012 Feb;25(2):139-50. doi: 10.1111/j.1432-2277.2011.01386.x. Epub 2011 Dec 7. [PubMed:22151353]
  2. Garnock-Jones KP: Belatacept: in adult kidney transplant recipients. BioDrugs. 2012 Dec 1;26(6):413-24. doi: 10.2165/11208900-000000000-00000. [PubMed:22928660]
External Links
KEGG Drug
D03222
PubChem Substance
347910359
ChEMBL
CHEMBL1742990
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Belatacept
ATC Codes
L04AA28 — Belatacept
FDA label
Download (582 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentDelayed Graft Function1
1Active Not RecruitingTreatmentImpaired Renal Function / Kidney Failure,Chronic1
1CompletedSupportive CareTransplantations1
1, 2CompletedTreatmentDiabetes, Diabetes Mellitus Type 11
1, 2CompletedTreatmentRheumatoid Arthritis1
2Active Not RecruitingTreatmentAcute Antibody Mediated Rejection / Mild Immunologic Risk Factor / Transplant, Kidney1
2Active Not RecruitingTreatmentProteinuria1
2Active Not RecruitingTreatmentTransplantation, Kidney1
2Active Not RecruitingTreatmentTransplantation, Organ1
2CompletedPreventionRejection, Transplant / Transplantation, Kidney / Transplantation, Renal1
2CompletedTreatmentDiabetes, Diabetes Mellitus Type 12
2CompletedTreatmentDisorder Related to Renal Transplantation1
2CompletedTreatmentTransplant, Kidney2
2CompletedTreatmentTransplantation, Renal1
2RecruitingTreatmentDelayed Graft Function / Transplant, Kidney1
2RecruitingTreatmentImmunosuppression1
2TerminatedTreatmentPrimary Renal Allograft Candidate / Transplantation, Kidney1
2TerminatedTreatmentPrimary Simultaneous Kidney and Pancreas Allograft Candidates / Simultaneous Kidney and Pancreas Transplantation1
2TerminatedTreatmentTransplant, Kidney1
2TerminatedTreatmentTransplantation, Kidney / Transplantation, Renal1
3Active Not RecruitingTreatmentTransplantation, Kidney1
3RecruitingTreatmentFailing Renal Allograft / Transplant, Kidney1
4Active Not RecruitingPreventionKidney Transplant Rejection1
4Active Not RecruitingTreatmentTransplantation, Renal1
4CompletedBasic ScienceRejection, Transplant1
4CompletedTreatmentNephrotoxicity1
4CompletedTreatmentTransplantation, Kidney1
4Not Yet RecruitingTreatmentTransplantations1
4RecruitingSupportive CareTransplantation, Kidney1
4RecruitingTreatmentAntibody Mediated Rejection / End Stage Renal Disease (ESRD)1
4RecruitingTreatmentEBV / Transplant; Failure, Kidney1
4RecruitingTreatmentImplant or Graft; Rejection1
4Unknown StatusNot AvailableNew Onset Diabetes After Transplant / Transplantation, Kidney1
Not AvailableActive Not RecruitingNot AvailableTransplantation, Kidney1
Not AvailableApproved for MarketingNot AvailableTransplantation, Renal1
Not AvailableCompletedNot AvailableRheumatoid Arthritis1
Not AvailableRecruitingTreatmentEnd-Stage Renal Disease (ESRD)1
Not AvailableWithdrawnTreatmentDiabetes, Diabetes Mellitus Type 1 / Islets of Langerhans Transplantation / Transplantation, Kidney1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous250 mg
Injection, powder, lyophilized, for solutionIntravenous250 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Virus receptor activity
Specific Function
Receptor involved in the costimulatory signal essential for T-lymphocyte proliferation and interleukin-2 production, by binding CD28 or CTLA-4. May play a critical role in the early events of T-cel...
Gene Name
CD86
Uniprot ID
P42081
Uniprot Name
T-lymphocyte activation antigen CD86
Molecular Weight
37681.97 Da
References
  1. Vincenti F: Costimulation blockade in autoimmunity and transplantation. J Allergy Clin Immunol. 2008 Feb;121(2):299-306; quiz 307-8. doi: 10.1016/j.jaci.2008.01.002. [PubMed:18269922]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Virus receptor activity
Specific Function
Involved in the costimulatory signal essential for T-lymphocyte activation. T-cell proliferation and cytokine production is induced by the binding of CD28, binding to CTLA-4 has opposite effects an...
Gene Name
CD80
Uniprot ID
P33681
Uniprot Name
T-lymphocyte activation antigen CD80
Molecular Weight
33047.625 Da
References
  1. Yabu JM, Vincenti F: Novel immunosuppression: small molecules and biologics. Semin Nephrol. 2007 Jul;27(4):479-86. [PubMed:17616278]
  2. 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):1665-84. [PubMed:16978033]

Drug created on March 19, 2008 10:48 / Updated on November 06, 2017 06:45