Belatacept

Identification

Summary

Belatacept is a selective T-cell costimulation blocker used in the prophylaxis of organ rejection in adult patients receiving a kidney transplant.

Brand Names
Nulojix
Generic Name
Belatacept
DrugBank Accession Number
DB06681
Background

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. Belatacept is only 2 amino acids different from abatacept (Orencia). FDA approved on June 15, 2011.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Fusion proteins
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
  • Belatacept
External IDs
  • BMS-224818
  • BMS224818

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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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
AT-lymphocyte activation antigen CD86
antagonist
Humans
AT-lymphocyte activation antigen CD80
antagonist
Humans
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.

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Belatacept.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Belatacept.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Belatacept.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Belatacept.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Belatacept.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Belatacept.
Allogeneic processed thymus tissueThe therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Belatacept.
AltretamineThe risk or severity of adverse effects can be increased when Altretamine is combined with Belatacept.
AmsacrineThe risk or severity of adverse effects can be increased when Amsacrine is combined with Belatacept.
AnakinraThe risk or severity of adverse effects can be increased when Anakinra is combined with Belatacept.
Interactions
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NulojixInjection, powder, lyophilized, for solution250 mg/1IntravenousE.R. Squibb & Sons, L.L.C.2011-06-15Not applicableUS flag
NulojixInjection, powder, for solution250 mgIntravenousBristol Myers Squibb Pharma Eeig2016-09-08Not applicableEU flag
NulojixInjection, powder, for solution250 mgIntravenousBristol Myers Squibb Pharma Eeig2016-09-08Not applicableEU flag

Categories

ATC Codes
L04AA28 — Belatacept
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
E3B2GI648A
CAS number
706808-37-9

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. [Article]
  2. Garnock-Jones KP: Belatacept: in adult kidney transplant recipients. BioDrugs. 2012 Dec 1;26(6):413-24. doi: 10.2165/11208900-000000000-00000. [Article]
  3. FDA Approved Drug Products: Nulojix (beltacept) for intravenous injection [Link]
KEGG Drug
D03222
PubChem Substance
347910359
RxNav
1112973
ChEMBL
CHEMBL1742990
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Belatacept
FDA label
Download (582 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingDiagnosticImmunosuppression / Rejection; Transplant, Kidney1
4CompletedBasic ScienceRejection, Transplant1
4CompletedPreventionRejection; Transplant, Kidney1
4CompletedSupportive CareKidney Transplantation1
4CompletedTreatmentEBV / Kidney Failure, Kidney Transplant1
4CompletedTreatmentImplant or Graft; Rejection1
4CompletedTreatmentKidney Transplantation2
4CompletedTreatmentNephrotoxicity1
4Not Yet RecruitingTreatmentKidney Transplant Immunosuppression1
4RecruitingTreatmentRejection; Transplant, Kidney1

Pharmacoeconomics

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

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. [Article]
  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. [Article]

Drug created on March 19, 2008 16:48 / Updated on April 30, 2021 13:06