belatacept; BMS-224818; CTLA4-Ig mutant; cytotoxic T-lymphocyte- associated antigen 4--Immunoglobulin G1 fragment fusion protein, mutant
Status: marketed in U.S. and EU
Organizations involved:
Bristol-Myers Squibb Co. – Manuf.; R&D; Tech.; World mark.
Repligen Corp. – Patent dispute
ZymoGenetics, Inc. – Patent dispute
Bristol-Myers Squib Co. (BMS) – Parent
Emery University –R&D; Tech.
University of Michigan – R&D; Tech.
U.S. Navy – R&D; Tech.
Novartis AG – Former
Cross ref.: See the entry for Orencia also from BMS, with its active agent, abatacept, differing from that of belatacept by just two amino acids.
Description: This product (trade name not yet announced) is a lyophilized (freeze-dried) formulation of belatacept, a glycosylated fusion protein composed of two homologous cytotoxic T-lymphocyte- associated antigen-4 (CTLA4) receptor extracellular domain polypeptide chains fused together by a modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (human heavy chain fragment) chain expressed by transformed Chinese hamster ovary (CHO) cells.
Belatacept differs from abatacept, the active agent in Orencia also from BMS (see related entry), by only two amino acid substitutions (point mutations at L104E and A29Y; thus, the acronyms L104EA29YIg and LEA-29Y). Belatacept is comprised of two homologous glycosylated CTLA receptor polypeptide chains (N-glycosylation sites at N76, N108 and N207) of ~45,700 Da each fused together by one disulfide bond (C120-C120) and non-covalent interactions. As wth abatacept, two CTLA4-Ig chains form a homodimer (single protein composed of two identical CTLA4-Ig chains), with each chain linked by one disulfide bond and non-covalent interactions. The calculated molecular formula is C3508H5440N922O1096S32, and the molecular weight is 91.5 kDa. Or restated, belatacept (L104EA29YIg) is a recombinant fusion protein that is a soluble CTLA4 mutant molecule comprising an extracellular domain of wildtype CTLA4 with amino acid changes A29Y (a tyrosine amino acid residue substituting for an alanine at position 29) and L104E (a glutamic acid amino acid residue substituting for a leucine at position +104) that binds a B7 molecule.
Belatacept is a second-generation,higher-affinity mutant of abatacept that has 2-fold greater binding avidity for human CD80 and a 4-fold greaterbinding avidity for human CD86 than abatacept. Extrapolations from data obtained with abatacept suggest that each belatacept homodimer is able to form a 2:2 molecular complex with soluble CD86.
Biological: Like abatacept (Orencia), belatacept is a fusion protein designed to be a selective co-stimulation blocker that binds to a specific site on certain cells of the immune system (i.e., antigen presenting cells) to block the second signal necessary to activate naïve T-cells, which coordinate immune-mediated rejection of transplanted organs. Belatacept is intended to provide extended graft survival while limiting the toxicity generated by standard immune suppressing regimens, such as calcineurin inhibitor
The rationale for developing belatacept was to generate a second-generation molecule with better immunosuppressive properties than abatacept. This was achievedby creating a mutant of abatacept with slower dissociation rates from CD80 and particularly CD86, and therefore higher avidity for these B7 ligands [588329]. For the mutagenesis and screening strategy adopted, mutagenic PCR primers were designed to create random codon changes within sequences of abatacept previously determined to be crucial for high-avidity receptor binding (ie, the CDR1- and CDR3-analagous loops and the region C-terminal to the CDR3-like loop). The PCR products were cloned into the piLN expression vector, which contains an avian sarcoma virus long-terminal repeat promoter, and the recombinant mutagenic plasmids were used to transiently transfect COS cells. Mutant molecules with 'off-rates' (dissociation constants) slower than that observed for abatacept were identified by screening the culture media collected from the transfected COS cells with a BIAcore biosensor chip derivatized with CD86-Ig or CD80-Ig. cDNA were sequenced and larger-scale COS transfections were performed to generate enough protein for further BIAcore kinetic and equilibrium binding studies. Belatacept was selecte d for its ability to bind CD86 and CD80 with 4- and 2-fold increased avidity, respectively, compared with abatacept, as measured with the BIAcore sensor technique. The increased avidity was due to the slower dissociation of belatacept from the B7 ligands (belatacept; koff = 1.08 ± 0.05 x 10-3 and 2.06 ± 0.03 s-1 for CD80 and CD86, respectively; abatacept koff = 2.21 ± 0.18 and 8.16 ± 0.52 s for CD80 and CD86, respectively), as its association rates were similar to those measured for abatacept. Iincreased binding avidity of belatacept for CD86, but not CD80, was confirmed by cell binding assays using Chinese hamster ovary (CHO) cells stably transfected with CD80 and CD86.
The increased binding avidity of belatacept for the B7 ligands over abatacept resulted in more potent inhibition of T-cell stimulation. The increased avidity resulted in a 10-fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre-clinical primate model. In humans, this provides extended graft survival while limiting the toxicity generated by standard immune suppressing regimens, such as calcineurin inhibitor.
Nomenclature: CTLA4-Ig, rDNA/belatacept [BIO]; belatacept [USAN; INN]; CTLA-4 (antigen) [29-tyrosine, 104-glutamic acid] (human extracellular domain-containing fragment) fusion protein with immunoglobulin G1 ·human monoclonal Fc domain-containing fragment bimol. (12--->120')-disulfide [CAS]; [Tyr29,Glu104,Gln125,Ser130,Ser136,Ser139,Ser148](antigen CTLA-4 human-3-126]-peptide (fragment containing the human extracellular domain) fusion protein with immunoglobulin G1-[233 amino acids from the C-terminal of the heavy chain]-peptide (fragment containing the human monoclonal Fc domain), bimolecular (120-->120')-disulfide [CAS]; 706808-37-9 [CAS RN]; BMS-224818 [SY]; BMS224818 [SY]; CTLA4-Ig mutant [SY]; L104EA29YIg [SY]; LEA [SY]; LEA29Y [SY]
Companies: The development of belatacept is closely linked to that of abatacept (Orencia), the first generation CTLA-binding agent from BMS (see related entry).
Researchers from Emery University collaborated with Repligen Corp and later BMS in the discovery and early development of abatacept and belatacept.
In Oct. 2000, BMS and Novartis AG signed an agreement to develop belatacept and abatacept (Orencia). Transplantation indications were to be developed by Novartis and autoimmune indications by BMS. In Oct. 2001, Novartis discontinued its development activities and, presumably, returned its all development rights to BMS.
Belatacept is manufactured by Bristol-Myers Squibb Co. (BMS), which has worldwide marketing rights.
In May 2012, BMS received FDA approval for manufacture of Orencia at its new Devens, MA, facility. Orencia will be the first product manufactured at Devens, followed by belatacept.
Manufacture: DNA encoding an embodiment of the L104EA29YIg (belatacept ) molecule has been deposited as ATCC PTA 2104.
FDA class: Biologic BLA
Indications: [Full text of the "INDICATIONS AND USAGE" section of product labeling/insert]
Status: On Sept. 9, 2009, FDA accepted the BLA filed by BMS for belatacept for prophylaxis of organ rejection and preservation of a functioning allograft in adult patients receiving renal transplants with use in combination with an interleukin-2 (IL-2) receptor antagonist, a mycophenolic acid (MPA), and corticosteroids. The Prescription Drug User Fee Act (PDUFA) goal date was May 1, 2010.
On Feb. 25, in association with an upcoming review committee meeting, FDA noted some concerns over post-transplantation complications and the occurrence of progressive multifocal leukoencephalopathy (PML) associated with Belatacept treatment in clinical development. FDA noted more patients taking Belatacept survived two years following a kidney transplant compared with patients taking older drugs. Belatacept patients also showed improved kidney function and lower blood pressure, both key predictors of survival. However, FDA reviewers also noted higher rates of severe kidney rejection in certain patients, as well as instances of a rare neurological disease, progressive multifocal leukoencephalopathy (PML), a viral infection which attacks the brain and central nervous system and is usually fatal. BMS responded that its data showed Belatacept avoids toxicities seen with cyclosporine (CsA), another rejection drug, with fewer deaths and serious infections, and that its therapy reduced the risk of diabetes and improved blood pressure..
In March 2010, the Cardiovascular and Renal Drugs Advisory Committee, FDA, voted 13 to 5 to recommend approval of belatacept for the prophylaxis of acute rejection in de novo kidney transplant patients. The committee recomended approval of the less-intensive (LI) regimen of Belatacept in Epstein-Barr virus positive kidney transplant patients. Most panel members agreed the safety profile was sufficient to support approval despite being nervous about PML. However, half the panel noted that they'd prefer long-term data to make a decision on the efficacy profile, with noninferiority studies difficult to interpret and “rest on a very unstable foundation.” These panel members agreed that three-year data would be required to properly analyze the drug's efficacy.
On May 1, 2010, the PDUFA date for the BLA, FDA issued BMS a "complete response" letter. No new clinical studies were requested, but the letter requested 36-month data from the ongoing Phase III studies to further evaluate the long-term effect of belatacept. The orginal BLA submitted for belatacept included 24-month data from the Phase III studies.
On June 15, 2011, FDA approved Nulojix.
On June 20, 2011, EU approved Nulojix for prevention of acute rejection in adult patients who have had a kidney transplant. It was specifically approved for usein combination with corticosteroids and a mycophenolic acid (MPA)for the prophylaxis of graft rejection in adults receiving a renal transplant. It is recommended to add an interleukin (IL)-2 receptor antagonist for induction therapy to this belatacept-based regimen. Nulojix is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) seronegative or serostatus unknown.
Tech transfer: With belatacept being a variation of abatacept (Orencia; see related entry), various patents, licensing and disputes discussed in the Orencia entry, including use patents, also likely cover belatacept. Many of the inventions/patents licensed by BMS for Orencia (see related entry) also apply to belatacept, e.g., the technologies licensed from the Univ. of Michigan, U.S. Navy. and Emory University.
BMS has receiveing patents including U.S.:
a) 7,094,874, 'Soluble CTLA4 mutant molecules," with claims including L104EA29YIg (belatacept);
b) 7,455,835, "Methods for treating immune system diseases using a soluble CTLA4 molecule," with claims for treatment of rheumatoid arthritis and with Example 3 discussing clinical trials with belatacept, expiring May 23, 2021;
c) 7,482,327, "Methods for treating immune disorders associated with graft transplantation with soluble CTLA4 mutant molecules," concerning use of L104EA29YIg for treatment of graft rejection, expiring Apr 6, 2026; and
d) 7,439,230, "Methods of treatment using CTLA4 mutant molecules," claiming recombinant L104EA29YIg for treating transplant rejection, expiring May 23, 2021.
EP2281568 and EP1935427, "Uses of soluble CTLA4 mutant molecules," expire in 2021. EP1868635, "METHODS FOR TREATING IMMUNE DISORDERS ASSOCIATED WITH GRAFT TRANSPLANTATION WITH SOLUBLE CTLA4 MUTANT MOLECULES," expires in 2025, EP1397153, "METHODS FOR PROTECTING ALLOGENEIC ISLET TRANSPLANT USING SOLUBLE CTLA4 MUTANT MOLECULES," expires in 2022. EP1372696, "METHODS FOR TREATING RHEUMATIC DISEASES USING A SOLUBLE CTLA4 MOLECULE," expires in 2021. EP1372696. "METHODS FOR TREATING RHEUMATIC DISEASES USING A SOLUBLE CTLA4 MOLECULE," expires in 2021. EP0988047, "SOLUBLE CTLA4 MUTANT MOLECULES AND USES THEREOF," expires in 2018.
EP0682039, "CTLA4 molecules and IL4-binding molecules and uses thereof," expires in 2015, and EP0613944, with the same title, expires in 2014.
Major international filings include WO-09833513, WO-09300431, WO-00202638, WO-02094202 (filed by Emory University), WO-2004058944, WO-20004058800, WO-03088991. WO-2004058944 claims mammalian cell culture processes for the production of belatacept.
With both abatacept and belatacept being antibody-like molecules formed from two CTLA receptors joined by an antibody-derived hinge portion, both of these agents appear to be immunoadhesins, as defined and patented by Genentech (now Roche). See the Tech. transfer sction, Monoclonal Antibodies (nonrecombinant) entry for further information. It is not known whether BMS has licensed these patents or not.
Medical: Current immunosuppressive therapies such as calcineurin inhibitors, including ciclosporin (CsA) and tacrolimus, have reduced the incidence of early graft failure. However these agents compromise long-term health and may not sustain permanent acceptance of the transplant. This is in part because these drugs target signaling pathways or enzymes with near ubiquitous cellular distribution, leading to non-immunological toxicities. In contrast, a therapy, e.g., belatacept and abatacept, designed to target co-stimulatory receptors directly targets the cells involved in launching the rejection response and should theoretically circumvent toxicities associated with conventional agents. Continuous treatment with calcineurin inhibitors commonly results in hypertension and dyslipidemia, which in turn accelerates cardiovascular disease, a major cause of mortality in long- term transplant recipients. Nephrotoxicity almost always occurs after ten years of calcineurin-inhibitor therapy, and new-onset immunosuppressive-related diabetes mellitus occurs in almost 30% of patients in the first two years after a renal transplant. With more than 23,000 new solid organ transplants/year in the US alone, a longer-term solution for maintaining transplant rejection will be welcomed.
Trials: In support of the BLA, data were submitted from Phase II and two Phase III trials that included more than 1,000 patients who received Belatacept. One of the Phase III studies was in standard criteria (living or deceased) donor kidney transplants and one in extended criteria donor kidney transplants.Disease.
Market: Market adoption of Nulojix has apparently been tempered due to its 30-minute infusion formulation, with the current standard treatment being cyclosporine, an oral drug.
Leerinck Swann analysts had projected a market of $650 million by 2016.
BMS reported total sales of $11 million in 2012 and $3 milion in 2011.
Companies involvement:
Full monograph
123.5 CTLA4/Ig, rDNA/belatacept
• NULOJIX is a selective T-cell costimulation blocker indicated for prophylaxis of
organ rejection in adult patients receiving a kidney transplant.
• Use in combination with basiliximab induction, mycophenolate mofetil, and
corticosteroids.
Limitations of Use:
• Use only in patients who are EBV seropositive.
• Use has not been established for the prophylaxis
Nomenclature:
CTLA4-Ig, rDNA/belatacept [BIO]
Nulojix [TR]
belatacept [USAN; INN]
CTLA-4 (antigen) [29-tyrosine, 104-glutamic acid] (human extracellular domain-containing fragment) fusion protein with immunoglobulin G1 ·human monoclonal Fc domain-containing fragment bimol. (12--->120')-disulfide [CAS]
[Tyr29,Glu104,Gln125,Ser130,Ser136,Ser139,Ser148](antigen CTLA-4 human-3-126]-peptide (fragment containing the human extracellular domain) fusion protein with immunoglobulin G1-[233 amino acids from the C-terminal of the heavy chain]-peptide (fragment containing the human monoclonal Fc domain), bimolecular (120→120')-disulfide [CAS]
706808-37-9 [CAS RN]
[29-tyrosine, 104-glutamic acid] (human extracellular domain-containing fragment) fusion protein with immunoglobulin G1 (human monoclonal Fc domain-containing fragment, bimol. (120-->120')-disulfide [SY]
BMS-224818 [SY]
BMS224818 [SY]
CTLA4-Ig mutant [SY]
L104EA29YIg [SY]
LEA [SY]
LEA29Y [SY]
NDC 0003-0371-13 [NDC]
molecular weight (kDa) = 91.5
FDA Class: Biologoic BLA
Year of approval (FDA) = 2011
Date of 1st FDA approval = 20110615
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2026, based on 7,482,327 use patent |
U.S. Patent Expiration Year: | |
U.S. Biosimilars Data Exclusivity Expiration: | 2023 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2018 |
U.S. Biosimilars Launchability Year: | 2026 |
U.S. Biobetters Launchability Year: | 2026 |
Biosimilars/biobetters-related EU Patents: | 2021, based n multiple use patents |
EU Patent Expiration Year: | 2021 |
EU Biosimilars Data Exclusivity Expiration: | 2021 |
EU Biosimilars Orphan Exclusivity Expiration: | 2021 |
EU Biosimilars Launchability Year: | 2021 |
EU Biobetters Launchability Year: | 2021 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
conjugates
exempt from CBER lot release requirements
fusion protein, proinsulin-tryptophan synthetase
hamster source materials
immune modulator
recombinant DNA
rodent source materials
ATCC HB8832
Chinese hamster ovary (CHO) cells
cytomegalovirus major immediate early region 2 mRNA
lyophilized (freeze-dried)
monkey source materials
sodium chloride
sucrose
ribose
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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