Skip to main content

New Drug Approvals 2011 - Pt. XIX Belatacept (NulojixTM)



ATC code: L04AA28


On June 15th 2011, the FDA has approved Belatacept (trade name: Nulojix; Research Code: BMS-224818), a selective T-cell (lymphocyte) costimulation blocker indicated for phophylaxis of organ rejection in adult patients receiving a kidney transplant. Belatacept is approved for use in combination with other immunosuppressants, specifically basiliximab, mycophenolate mofetil and corticosteroids.

Belatacept is a potent antagonist that inhibits T-lymphocyte activation by binding to the B7-ligands, namely CD80 (Uniprot: P33681; Pfam: PF08205, PF07686) and CD86 (Uniprot: P42081; Pfam: PF07686), present on antigen-presenting cells, and thereby blocking interaction with CD28 (Uniprot: P10747; Pfam: PF07686), the receptor of these two ligands. This interaction provides a costimulary signal necessary for full activation of T-lymphocytes. Activated T-cells are the predominant mediators of immunologic rejection. In vitro, Belatacept inhibits T-cell proliferation and the cytokines interleukin-2, interferon-γ, interleukin-4 and TNF-α.

There are some protein structures known for the B7-ligands, CD80 and CD86. Here are two typical entries for CD80 (PDBe:1i8l) and CD86 (PDBe:1i85) in complex with CTLA-4.
Belatacept is derived from Abatacept (trade name: Orencia; approved in 2005 for the treatment of rheumatoid arthritis, ChEMBLID: CHEMBL1201823), a soluble fusion protein that consists of the extracellular domain of the human cytotoxic T-lymphocyte antigen-4 (CTLA-4; Uniprot: P16410; Pfam: PF07686), linked to a modified Fc (hinge-CH2-CH3 domains) portion of human immunoglobulin G1 (CTLA4-Ig). CTLA-4 is similar to the T-cell costimulatory protein CD28, and both molecules bind to CD80 and CD86 on antigen-presenting cells. However, CTLA-4 transmits an inhibitory signal to T-cells, whereas CD28 transmits a stimulatory signal. Although Abatacept binds to the B-7 ligands with higher affinity when compared with CD28, it has never reached the market as an organ transplantation therapy due to the fact that it does not completely and equally block of the costimulation pathway (the difference in antagonistic effect to CD80 compared with CD86 is a 100-fold decrease in affinity to the CD86). Given this, Belatacept was developed by altering two amino acids in the B-7 ligand-binding portion of the Abatacept molecule (a leucine and an alanine were replaced by a glutamic acid and a tyrosine, respectively). These modifications have resulted in a 4-fold increase in binding affinity to the CD86 and a 2-fold increase in CD80 binding affinity in comparison to Abatacept. Also, it has been shown that, in vitro, this increase in binding affinity to the B-7 ligands resulted in a 10-fold increase in inhibiting T-cell activation when compared with Abatacept. 


>Belatacept
MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQ
GLRAMDTGLYICKVELMYPPPYYEGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA
PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Other immunosuppressive therapies to treat transplant rejection are available on the market and these include calcineurin inhibitors, such as Tacrolimus (ChEMBLID: CHEMBL1237096), mTOR inhibitors, such as Everolimus (ChEMBLID: CHEMBL1201755), anti-proliferatives, such as Mycophenolic acid (ChEMBLID: CHEMBL866), corticosteroids, such as Hydrocortisone (ChEMBLID: CHEMBL389621) and antibodies, such as Basiliximab (ChEMBLID: CHEMBL1201439) and Rituximab (ChEMBLID: CHEMBL1201576).


Belatacept recommended dosage is a 10 mg/kg intravenous infusion on days 1 (day of transplantation) and 5, end of weeks 2, 4, 8, and 12 after transplantation in the initial phase, followed by a maintenance phase of 5 mg/kg at the end of week 16 after transplantation and every 4 weeks thereafter. The molecular weight of Belatacept is approximately 90 kDa. After a 10 mg/kg intravenous infusion at week 12, Belatacept has a volume of distribution (Vd) of 0.11 L/kg, a systemic clearance (CL) of 0.49 mL/h/kg and a terminal half-life (t1/2) is 9.8 days. The full prescribing information can be found here


The license holder is Bristol-Myers Squibb Company and the product website is www.nulojix.com.

Comments

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site:   https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29 .  Please see ChEMBL_29 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29/chembl_29_release_notes.txt New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no