Erythropoietin-derived short peptide and its mimics as immuno/inflammatory modulators
Inventors
Yuan, Rui Rong • Li, Wei Ping • Maeda, Yasuhiro • Dowling, Peter C.
Assignees
US Department of Veterans Affairs
Publication Number
US-9765128-B2
Publication Date
2017-09-19
Expiration Date
2026-05-01
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention provides isolated stabilized EPO-derived peptides and their mimics that protect against tissue damage in subjects having diverse forms of neural and non-neural organ system injury, pharmaceutical compositions containing the isolated stabilized EPO-derived peptides, methods for treating symptoms of a disease, disorder or condition having an inflammatory or an autoimmune component in a subject in need thereof, and methods for downregulating immune mediator activity in a subject in need thereof.
Core Innovation
The invention provides isolated stabilized erythropoietin (EPO)-derived peptides and their mimics that protect against tissue damage in subjects with diverse neural and non-neural organ system injuries. The peptides have non-hematopoietic biological activity and can be stabilized chemically, such as by adding small bicyclic molecules or forming disulfide bonds within the peptide sequence, to maintain stability especially when stored at 4° C. Pharmaceutical compositions containing these peptides and methods for treating symptoms of diseases, disorders, or conditions having inflammatory or autoimmune components by downregulating immune mediator activity are also provided.
The problem addressed by the invention stems from the limitations of whole molecule EPO therapy. While EPO has demonstrated neuroprotective capabilities in a variety of neurologic injuries including occlusive cerebral vascular disease, acute brain trauma, epilepsy, and autoimmune demyelinating diseases, its use is restricted due to its strong hematopoietic effect that can cause over-stimulation of erythropoiesis and elevated red blood cell mass. This limits long-term use in non-anemic patients with neurological injury. Furthermore, the domain within EPO responsible for neuroprotection is less stable when the molecule is stored, reducing efficacy. Therefore, there is a need for stabilized small EPO-derived peptides that retain non-hematopoietic activity and protect tissues without the side effects associated with whole EPO.
The invention identifies short, cyclic EPO-derived peptides that modulate the immune-mediated inflammatory network by reducing MHC class I and II over-expression, inflammatory cytokines, and suppressing antigen-specific T cell function in both peripheral lymphoid tissue and brain tissue. These peptides are more stable than linear peptides and do not increase hematocrit or exhibit hematopoietic side effects. The peptides exhibit consistent in vivo therapeutic efficacy in models of experimental autoimmune encephalomyelitis (EAE), acute stroke, spinal cord and brain injury, and arthritis, thus overcoming drawbacks of whole EPO therapy by separating immunomodulatory effects from hematopoietic effects.
Claims Coverage
The patent contains multiple inventive features claimed independently, focusing on methods of treatment involving stabilized isolated EPO-derived peptides with non-hematopoietic activity, their stabilization methods, peptide sequences, and administration routes.
Method of treating inflammatory or autoimmune symptoms using stabilized isolated EPO-derived peptides
Administering therapeutically effective amounts of stabilized isolated EPO-derived peptides comprising amino acid sequences with non-hematopoietic biological activity to subjects needing treatment, while maintaining substantially normal red cell indices during treatment.
Stabilization of EPO-derived peptides by bicyclic molecule addition
Stabilizing isolated EPO-derived peptides by chemically adding a small bicyclic molecule to at least one of the N-terminal or C-terminal ends of the peptide amino acid sequence.
Stabilization of EPO-derived peptides by disulfide bond formation
Stabilizing isolated EPO-derived peptides by forming disulfide bonds between sulfhydral groups of two amino acid residues within the peptide sequence, specifically peptides comprising sequences with at least 6 amino acids including the XAEHYS motif where X and Y contain sulfhydral groups.
Combination stabilization by disulfide bond and bicyclic molecule
Further stabilizing disulfide bond-stabilized EPO-derived peptides through addition of a small bicyclic molecule to the peptide terminal ends, combining dual stabilization methods.
Reduction of clinical symptoms in various inflammatory and autoimmune conditions
When administered in therapeutically effective amounts, stabilized isolated EPO-derived peptides reduce clinical symptoms of diseases, disorders, or conditions having inflammatory or autoimmune components, including acute cerebrovascular injury, spinal cord injury, brain injury, cardiovascular injury, arthritis, autoimmune diseases, demyelinating diseases, and immune-mediated inflammation.
Multiple administration routes indicated
The compositions can be administered via oral, buccal, parenteral, nasal, rectal, or topical routes.
Monitoring red blood cell indices during treatment
The treatment method includes monitoring the subject's red blood cell indices to maintain them at substantially normal levels throughout therapy.
The claims cover methods of treatment using stabilized isolated EPO-derived peptides characterized by specific peptide sequences, stabilization by bicyclic molecules and/or disulfide bonds, non-hematopoietic biological activity, administration via various routes, maintenance of normal red cell indices, and efficacy in treating diverse inflammatory and autoimmune conditions.
Stated Advantages
The stabilized EPO-derived peptides protect against tissue damage in neural and non-neural organ injuries by modulating immune-mediated inflammatory networks without causing hematopoietic side effects.
The peptides demonstrate stability during storage, overcoming the instability problems associated with whole EPO or linear peptides.
Cyclic peptides have consistent and reproducible therapeutic efficacy in multiple animal models of autoimmune and inflammatory diseases.
The peptides reduce MHC class I and II over-expression, inflammatory cytokines, and antigen-specific T cell function, thus suppressing immune-mediated inflammation.
The invention allows long-term treatment without elevation of hematocrit or erythropoietic stimulation.
Documented Applications
Treatment of symptoms of diseases, disorders, or conditions having inflammatory or autoimmune components, such as multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), arthritis, acute stroke, acute spinal cord injury, acute brain injury, acute cardiovascular injury, and immune-mediated inflammation.
Use in animal models for neuroprotection and immunomodulation, including models of EAE (SJL/J and C57BL/6 mice), ischemic stroke, contusive spinal cord injury, and rheumatoid arthritis.
Potential treatment related to immunomodulation in autoimmune diseases, demyelinating diseases, and inflammatory injuries to both neural and non-neural tissues.
Interested in licensing this patent?