Bachem support for Multiple Sclerosis therapies


Bachem support for Multiple Sclerosis therapies


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Overview:

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which focal lymphocytic infiltration leads to damage of myelin and axons. It is thought that worldwide more than two million people are affected. MS is typically diagnosed between ages 20 to 50 and predominantly affects Caucasians of northern European ancestry, particularly women. MS signs and symptoms may differ from person to person and over the course of the disease but typically include fatigue, numbness or tingling, walking difficulties, weakness, dizziness and vertigo, bladder and bowel problems, pain, and cognitive changes.

As knowledge increases of the mechanisms of action of MS within the human central nervous system (CNS), peptides have become increasingly important in the fight against the disease with Bachem’s advanced selection of Myelin Oligodendrocyte Glycoprotein (MOG), Myelin Basic Protein (MBP) and Myelin Proteolipid Protein (PLP) peptides providing key components for advanced in-vivo research models of the disease as well as new generation therapies.

Background

The pathologic hallmark of MS is multiple focal areas of myelin loss within the CNS called plaques or lesions. These lesions most commonly affect the white matter in the optic nerve, brain stem, basal ganglia, and spinal cord, or white matter tracts close to the lateral ventricles and can be detected by magnetic resonance imaging (MRI). The peripheral nervous system is rarely involved.

Several types or disease courses have been defined:

  • Clinically Isolated Syndrome (CIS): a first episode of neurologic symptoms caused by inflammation and demyelination in the CNS. 30% to 70% of persons experiencing CIS later develop MS.
  • Relapsing-remitting MS (RRMS): the most common disease course. It is characterized by clearly defined attacks of new or increasing neurological symptoms (relapses) followed by periods of partial or complete recovery (remissions). Approximately 85% of people with MS are initially diagnosed with RRMS.
  • Primary progressive MS (PPMS): characterized by progression of disability from the onset of symptoms, without early relapses or remissions. It occurs in approximately 15% to 20% of individuals. The usual age of onset for PPMS is later than that of RRMS.
  • Secondary progressive MS (SPMS): follows an initial relapsing-remitting course. Approximately 65% of those who are diagnosed with RRMS will eventually transition to a secondary progressive course in which there is a progressive worsening of neurologic function over time.

Diagnosis of MS is based on a careful medical history, a neurologic exam and various tests including magnetic resonance imaging, evoked potentials and spinal fluid analysis in order to rule out other medical problems with similar signs and symptoms.

Multiple Sclerosis treatments

While MS is not a curable disease, current therapies can modify or slow the disease course and manage symptoms. Several disease-modifying medications to treat relapsing forms of MS are available to reduce the frequency and severity of relapses and reduce the accumulation of lesions in the CNS. These are summarized below:

Drug Type Condition Treated
Corticosteroids Anti-inflammatory / immunosuppressive Acute exacerbations
Interferon beta (interferon beta-1a, interferon beta-1b) Interferon beta directly increases expression and concentration of anti-inflammatory agents while downregulating the expression of pro-inflammatory cytokines First-line treatment in relapsing forms of MS
Glatiramer Immunoactive mixture of synthetic polypeptides composed of four amino acids resembling myelin basic protein (MBP) Relapsing forms of MS
Natalizumab Humanized monoclonal antibody against the cell adhesion molecule α4-integrin. Natalizumab appears to reduce the transmission of immune cells into the CNS by interfering with the α4β1-integrin receptor molecules on the surfaces of cells Relapsing forms of MS
Alemtuzumab Humanized therapeutic monoclonal antibody that binds to CD52, a cell-surface antigen present on T and B cells. Alemtuzumab depletes circulating T and B cells through antibody-dependent cellular cytolysis and complement-mediated lysis Relapsing forms of MS
Ocrelizumab Humanized anti-CD20 antibody. Ocrelizumab targets mature B cells Relapsing forms of MS, early primary progressive MS
Dimethyl fumarate Anti-inflammatory / cytoprotective Relapsing forms of MS
Fingolimod Prodrug. Its active metabolite fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator. The mechanism by which fingolimod exerts therapeutic effects may involve reduction of lymphocyte migration into the CNS Relapsing forms of MS
Teriflunomide Immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase Relapsing forms of MS

  

Peptide-based animal models for MS

Bachem has developed a series of protein fragments that can be used to develop experimental animal models of MS that play important roles in studying different aspects of inflammation, demyelination, remyelination, and neurodegeneration in the CNS. These include immune-mediated, virus induced, and toxin induced models where agents such as intercalating ethidium bromide, the detergent lysolecithin, and the chopper-chelator cuprizone are used to induce experimental demyelination and thus studying remyelination processes.

Animal models that involve virus-induced demyelination are generated by Theiler’s virus, canine distemper virus, and mouse hepatitis virus. The best-characterized is the Theiler’s virus model, which induces inflammatory demyelinating disease that in many aspects reflects MS.

Experimental autoimmune encephalitis (EAE) is one of the most studied animal models of MS. It can be induced by active immunization with myelin peptides or by the adoptive transfer of myelin-specific T cells resulting in inflammatory infiltrates and demyelination in the CNS. In actively induced EAE, mice and rats, etc. are subcutaneously immunized with a myelin-related peptide emulsified in complete Freund’s adjuvant. In mice, an additional adjuvant, pertussis toxin, is necessary for active EAE. Although the precise effect of pertussis toxin is unknown, it has been suggested that this microbial product promotes EAE by facilitating the migration of pathogenic T cells to the CNS as well promoting proliferation and cytokine production by T cells and break T cell tolerance. Immune-driven demyelinating models have become standard for pre-clinical screening of candidate MS therapies.

Bachem protein fragments for animal models include:

Catalog Product name Description Sequence References
4003264 Experimental Allergic Encephalitogenic Peptide (human) Active fragment of the myelin basic protein. By a cell-mediated immune response, the peptide causes experimental allergic encephalomyelitis, an inflammatory demyelinating disease of the CNS H-Phe-Ser-Trp-Gly-Ala-Glu-Gly-Gln-Arg-OH R.Shapira et al., Science, 178, 736 (1971) , F.C.Westall et al., Nature, 229, 22 (1971)
4026109 MHC Class II IA β Chain (58-75) Vaccination of mice with this synthetic peptide from the third hypervariable region of the murine class II MHC IAS β chain resulted in the prevention and treatment of experimental autoimmune encephalomyelitis, a T cell mediated, demyelinating disease of the CNS that represents a model for human MS Ac-Ala-Glu-Tyr-Tyr-Asn-Lys-Gln-Tyr-Leu-Glu-Gln-Thr-Arg-Ala-Glu-Leu-Asp-Thr-NH₂ D.J.Topham et al., Proc. Natl. Acad. Sci. USA, 91, 8005 (1994)
4016649 Myelin Basic Protein (4-14) This fragment of the bovine myelin basic protein (residues 4-14) has been described as the most specific substrate for the selective assay of protein kinase C. Its Km value of 7 µM is comparable with the values for H1 histone and intact myelin basic protein, but with twice the velocity of phosphorylation H-Gln-Lys-Arg-Pro-Ser-Gln-Arg-Ser-Lys-Tyr-Leu-OH J.P.McKenna et al., Inflamm. Res., 44, 66 (1995) , T.Nanmori et al., Biochem. Biophys. Res. Commun., 203, 311 (1994) , B.Stauble et al., Biochem. Mol. Biol. Int., 29, 203 (1993), I.Yasuda et al., Biochem. Biophys. Res. Commun., 166, 1220 (1990)
4012638 (Des-Gly⁷⁷,Des-His⁷⁸)-Myelin Basic Protein (68-84) (guinea pig) H-Tyr-Gly-Ser-Leu-Pro-Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-OH M.D.Mannie et al., Proc. Natl. Acad. Sci. USA, 82, 5515 (1985) E.H.Eylar et al., J. Biol. Chem., 246, 5770 (1971)
4028466 Myelin Basic Protein (83-99) (bovine) trifluoroacetate salt MBP (83-99) corresponds to the immunodominant region of myelin basic protein restricted by HLA-DR2, the HLA class II haplotype with the strongest association to MS. T cell responses against this part of the MBP molecule represent a potential therapeutic target in MS H-Glu-Asn-Pro-Val-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro-OH trifluoroacetate salt J.Hong et al., Eur. J. Immunol., 34, 870 (2004) B.Bielekova et al., Nat. Med., 6, 1167 (2000) B.Hemmer et al., Neurology, 49, 1116 (1997)
4049448 Myelin Basic Protein (85-99) Peptide Antagonist trifluoroacetate salt This MBP (85-99) peptide competes with EKPKVEAYKAAAAPA as a major candidate autoantigen in MS for binding to human leukocyte antigen (HLA)-DR2. The peptide also inhibits IL-2 secretion by MBP (85-99) specific T-cell clones and induces the production of Th2 cytokines by splenocytes. The peptide can be further shown to suppress experimental autoimmune encephalomyelitis (EAE) in several models in an equipotent manner to random amino acid copolymers, such as Copaxone [poly (Y,E,A,K)n] H-Glu-Lys-Pro-Lys-Val-Glu-Ala-Tyr-Lys-Ala-Ala-Ala-Ala-Pro-Ala-OH trifluoroacetate salt J.N.H.Stern et al., Proc. Natl. Acad. Sci. USA, 102, 1620 (2005)
4025349 Myelin Basic Protein (87-99) (human, bovine, rat) This MBP fragment has been shown to induce the proliferation of an encephalitogenic, myelin basic protein-specific T cell line. Active immunization of rats with this peptide induced acute experimental autoimmune encephalomyelitis. This protein region is highly conserved among mammalian species H-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro-OH R.E.Jones et al., J. Neuroimmunol., 37, 203 (1992)
4042037 Myelin Oligodendrocyte Glycoprotein (35-55) (human) trifluoroacetate salt In contrast to the encephalitogenic rat homolog, MOG (35-55) (human) does not appear to be a major T-cell epitope in MS probably due to its lower amount of helical structure formed when dissolved in micellar sodium dodecyl sulfate, a membrane mimicking solvent H-Met-Glu-Val-Gly-Trp-Tyr-Arg-Pro-Pro-Phe-Ser-Arg-Val-Val-His-Leu-Tyr-Arg-Asn-Gly-Lys-OH trifluoroacetate salt M.F.Mesleh et al., Neurobiol. Dis., 9, 160 (2002) S.Albouz-Abo et al., Eur. J. Biochem., 246, 59 (1997)N.Kerlero de Rosbo et al., Eur. J. Immunol., 27, 3059 (1997)
4028291 Myelin Oligodendrocyte Glycoprotein (35-55) (mouse, rat) trifluoroacetate salt MOG peptide (35-55) is highly encephalitogenic and can induce strong T and B cell responses. A single injection of this peptide produces a relapsing-remitting neurologic disease with extensive plaque-like demyelination. Because of the clinical, histopathologic, and immunologic similarities with MS, this MOG-induced demyelinating encephalomyelitis may serve as a model for investigating MS H-Met-Glu-Val-Gly-Trp-Tyr-Arg-Ser-Pro-Phe-Ser-Arg-Val-Val-His-Leu-Tyr-Arg-Asn-Gly-Lys-OH trifluoroacetate salt J.Liu et al., Nat. Med., 4, 78 (1998) M.Ichikawa et al., J. Immunol., 157, 919 (1996)
4041119 Myelin Oligodendrocyte Glycoprotein (35-55) amide (rat, mouse) trifluoroacetate salt This MOG peptide acts on the CD4+ T cells that are associated with spasticity, axonal damage and neurodegeneration in NF-L immunized mice. In addition, defined T-cell epitopes in the NF-L protein might be involved in the pathogenesis of the disease H-Met-Glu-Val-Gly-Trp-Tyr-Arg-Ser-Pro-Phe-Ser-Arg-Val-Val-His-Leu-Tyr-Arg-Asn-Gly-Lys-NH₂ trifluoroacetate salt F.Puentes et al., J. Neuroinflammation, 10, 118 (2013)
4037126 Myelin Proteolipid Protein (139-151) (depalmitoylated) (human, bovine, dog, mouse, rat) trifluoroacetate salt Strongly antigenic PLP peptide for inducing autoimmune encephalomyelitis in mice for studying MS H-His-Cys-Leu-Gly-Lys-Trp-Leu-Gly-His-Pro-Asp-Lys-Phe-OH trifluoroacetate salt S.Youssef et al., Nature, 420, 78 (2002)
4003264 Experimental Allergic Encephalitogenic Peptide (human) Active fragment of the myelin basic protein. By a cell-mediated immune response, the peptide causes experimental allergic encephalomyelitis, which is an inflammatory demyelinating disease of the CNS H-Phe-Ser-Trp-Gly-Ala-Glu-Gly-Gln-Arg-OH R.Shapira et al., Science, 178, 736 (1971) F.C.Westall et al., Nature, 229, 22 (1971)
4026109 MHC Class II IA β Chain (58-75) Vaccination of mice with this synthetic peptide from the third hypervariable region of the murine class II MHC IAS β chain resulted in the prevention and treatment of experimental autoimmune encephalomyelitis, a T cell mediated, demyelinating disease of the CNS that represents a model for human MS Ac-Ala-Glu-Tyr-Tyr-Asn-Lys-Gln-Tyr-Leu-Glu-Gln-Thr-Arg-Ala-Glu-Leu-Asp-Thr-NH₂ D.J.Topham et al., Proc. Natl. Acad. Sci. USA, 91, 8005 (1994)
4016649 Myelin Basic Protein (4-14) This fragment of the bovine myelin basic protein (residues 4-14) has been described as the most specific substrate for the selective assay of protein kinase C. Its Km value of 7 µM is comparable with the values for H1 histone and intact myelin basic protein, but its velocity of phosphorylation is twice as fast H-Gln-Lys-Arg-Pro-Ser-Gln-Arg-Ser-Lys-Tyr-Leu-OH J.P.McKenna et al., Inflamm. Res., 44, 66 (1995) T.Nanmori et al., Biochem. Biophys. Res. Commun., 203, 311 (1994) B.Stauble et al., Biochem. Mol. Biol. Int., 29, 203 (1993) I.Yasuda et al., Biochem. Biophys. Res. Commun., 166, 1220 (1990)
4012638 (Des-Gly⁷⁷,Des-His⁷⁸)-Myelin Basic Protein (68-84) (guinea pig) H-Tyr-Gly-Ser-Leu-Pro-Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-OH M.D.Mannie et al., Proc. Natl. Acad. Sci. USA, 82, 5515 (1985) E.H.Eylar et al., J. Biol. Chem., 246, 5770 (1971)

  

Peptide-based MS therapies

While a cure for MS remains elusive, there is increasing need for treatment options to slow down or prevent progression of the disease, along with new focus on oral therapies to provide more convenient options for patients. There are currently 15 disease modifying drugs approved by the U.S Food and Drug Administration (FDA) for treatment of MS including the blockbuster Copaxone® (glatiramer acetate), an injectable peptide-based drug.

The MS drug pipeline is robust with several peptide-based drug candidates advancing through clinical development for the treatment of different forms of MS, as summarized below:

Developer Product Name Active Ingredient Condition Treated Highest Phase
Apitope International NV ATX-MS-1467 Contains four peptides derived from myelin basic protein Relapsing Remitting Multiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis (SPMS) Phase II
Mapi Pharma Ltd. Glatiramer acetate depot glatiramer acetate Primary Progressive Multiple Sclerosis (PPMS), Relapsing Remitting Multiple Sclerosis (RRMS) Phase II
Genervon Biopharmaceuticals LLC GM-6 Six amino acid analog of motoneuronotrophic factor (MNTF) Alzheimer’s Disease, Multiple Sclerosis, Parkinson’s Disease, Acute Ischemic Stroke, Huntington’s Disease, Amyotrophic Lateral Sclerosis Phase II
ReceptoPharm Inc. RPI-78M Chemically modified α-cobratoxin Multiple Sclerosis, Human Immunodeficiency Virus (HIV) Infections (AIDS), Simplexvirus (HSV) Infections, Herpes Zoster (Shingles), Adrenoleukodystrophy (Adrenomyeloneuropathy/ Schilder-Addison Complex) Phase II
Centrum Neurologii Krzysztof Selmaj SMderpept Peptide mixture of MBP 85-99, MOG 35-55 and PLP 139-151 Relapsing Remitting Multiple Sclerosis (RRMS) Phase II
NeuroActiva Inc. NA-831 traneurocin Alzheimer’s Disease, Multiple Sclerosis, Stroke Phase I

  

With several new drugs on the horizon for the treatment of patients with MS and multiple researchers and organizations studying MS, it can thus be seen that Bachem’s MOG, MBP, PLP and other peptides are playing key roles in the war against MS.

Bachem’s peptides are important as key components for promising therapies and also in protein fragment form as the building blocks of advanced in-vivo research, constructing animal models for the disease.

Bachem also offers a comprehensive custom peptide synthesis service and the production of new chemical entities to assist companies with developing peptide-based therapeutics.

Resources

Click on Bachem MS-related peptides for more information.
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Click on Endothelin Related Peptides for product information.


Supplier Information
Supplier: Bachem AG
Address: Hauptstrasse 144, 4416 Bubendorf, Switzerland
Tel: +41 61 935 2323
Fax: +41 61 935 2325
Website: www.bachem.com


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