Myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein compositions and methods of use
Inventors
Lenardo, Michael J. • Li, Jian • Zheng, Lixin • Lee, Jae W. • Lu, Wei
Assignees
US Department of Health and Human Services
Publication Number
US-10759838-B2
Publication Date
2020-09-01
Expiration Date
2036-03-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed is a protein comprising no more than three human autoantigenic proteins, wherein a first human autoantigenic protein comprises a truncated myelin oligodendrocyte glycoprotein (MOG) amino acid sequence, a second human autoantigenic protein comprises a myelin basic protein (MBP) amino acid sequence, and a third human autoantigenic protein comprises a truncated proteolipid protein (PLP) amino acid sequence. Also disclosed are related nucleic acids, pharmaceutical compositions, methods of treating a demyelinating disease, and methods of producing the proteins.
Core Innovation
Demyelinating diseases involve damage to the myelin sheath of neurons, exemplified by multiple sclerosis (MS) which is an autoimmune demyelinating disease of the central nervous system affecting millions globally and causing severe disability. Despite advancements, improved treatments for demyelinating diseases are needed.
The invention provides a protein comprising no more than three human autoantigenic proteins: a truncated myelin oligodendrocyte glycoprotein (MOG) amino acid sequence, a myelin basic protein (MBP) amino acid sequence, and a truncated proteolipid protein (PLP) amino acid sequence. Related nucleic acids, pharmaceutical compositions, methods of treating demyelinating diseases such as MS, and methods of producing the proteins are also disclosed.
Contrary to expectations that administration of MOG, MBP, and PLP sequences would exacerbate autoimmune aspects of demyelinating disease, the invention surprisingly finds that these combinations ameliorate autoimmune and inflammatory aspects. It is believed the combination induces immunologic tolerance of one or more of MOG, MBP, and PLP, thus acting as a tolerogen. The compositions and methods may be useful for treating or preventing demyelinating diseases such as MS.
Claims Coverage
The claims encompass a fusion protein and its specific structural features comprising three human autoantigenic proteins as a core inventive concept, with further features relating to protein modifications and pharmaceutical formulations.
Fusion protein comprising three human autoantigenic proteins
A fusion protein comprising a truncated MOG amino acid sequence (SEQ ID NO: 1 or 25), a MBP amino acid sequence (SEQ ID NO: 2 or 28), and a truncated PLP amino acid sequence (SEQ ID NO: 3).
Conjugation or fusion via linker
The MOG amino acid sequence is conjugated or fused to the MBP amino acid sequence via a linker.
Protein consisting of specific amino acid sequence
The protein comprising the fusion sequence as specified by SEQ ID NO: 9.
Inclusion of Tobacco Etch Virus (TEV) cleavage sequence
The protein further comprises a Tobacco Etch Virus (TEV) cleavage sequence.
Inclusion of histidine tag
The protein further comprises a histidine tag to facilitate purification.
Pharmaceutical composition with excipient
The protein can be admixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition.
The claims define a fusion protein integrating truncated MOG, MBP, and PLP sequences with specific linkers and tags and extend to pharmaceutical formulations thereof, covering the inventive features related to the composition and structure.
Stated Advantages
Depletion of autoimmune T cells, macrophages, dendritic cells, and microglial cells in the spinal cord.
Decrease of inflammatory cytokines including interferon-gamma and interleukin-1 beta.
Induction of restimulation-induced cell death (RICD) of autoimmune T cells.
Increase of apoptotic T cells in the spinal cord and rapid reduction of inflammation.
Remyelination of axons in spinal cord tissue.
Targeted depletion of autoimmune T cells with minimal impact on other cells and little or no side effects.
Capability to treat demyelinating disease patients regardless of MHC allele expression.
Documented Applications
Treating or preventing autoimmune demyelinating diseases such as multiple sclerosis (MS).
Treatment or prevention of autoimmune inflammatory myelitis and demyelination in mammals.
Interested in licensing this patent?