JPWO2019195712A5

JPWO2019195712A5 -

Info

Publication number: JPWO2019195712A5
Application number: JP2020554521A
Authority: JP
Publication date: 2022-04-01
Anticipated expiration: 2039-04-05

Claims

(a) Compstatin or comp having the amino acid sequence represented by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7 Statin analogs; and
(B) C3, iC3b, C3b or C3c binding affinity of the peptide, (2) solubility of the peptide at physiological pH, (3) peptide compared to unmodified Compstatin peptide under equivalent conditions. End-modification with added terminal components to improve plasma stability and / or plasma residence time of the peptide, and / or (4) vitreous stability and / or vitreous residence time of the peptide;
It is a compound containing
The added terminal component is:
(i) A C-terminal component containing hydrophilic / charged amino acid residues selected from the group consisting of two or more lysine, arginine, ornithine, or any combination thereof, or
(ii) An N-terminal component containing polyethylene glycol (PEG) with an average molecular weight of about 3 kDa or less, or
(iii) A compound that is both (i) and (ii).

The compound according to claim 1, wherein the added terminal component is a C-terminal component containing two or more hydrophilic / charged amino acid residues.

The compound according to claim 1 or 2, wherein the two or more hydrophilic / charged amino acid residues are lysine.

The compound according to any one of claims 1 to 3, comprising a compstatin analog having the amino acid sequence represented by SEQ ID NO: 7.

The compound according to any one of claims 1 to 4, comprising a compstatin analog having the amino acid sequence represented by SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

The compound according to claim 5, wherein the amino acid sequence is represented by SEQ ID NO: 9.

The compound according to claim 5, wherein the amino acid sequence is represented by SEQ ID NO: 10.

The compound according to claim 1, wherein the added terminal component is an N-terminal component containing PEG.

The compound according to claim 8, wherein the PEG is a monodisperse PEG having a molecular weight of about 0.5 kDa to about 3 kDa.

The compound according to claim 8, wherein the PEG is a polydisperse PEG having a molecular weight of about 0.5 kDa to about 3 kDa.

The compound according to claim 1, which comprises an amino acid sequence represented by SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10 having PEG bonded to the N-terminal.
A compound in which the PEG is a monodisperse PEG having a molecular weight of about 0.5 kDa to about 3 kDa, or the EG is a polydisperse PEG having a molecular weight of about 0.5 kDa to about 3 kDa.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

The pharmaceutical composition according to claim 12, which is formulated for oral administration of a compound, topical administration of a compound, pulmonary administration of a compound, subcutaneous or intramuscular administration of a compound, or intravenous administration of a compound.

The pharmaceutical composition according to claim 12, which is formulated for intraocular administration of a compound.

The pharmaceutical composition according to claim 14, which is formulated for intravitreal administration of a compound.

The pharmaceutical composition according to claim 12, which is formulated for periodontal administration of a compound.

The pharmaceutical composition according to claim 16, which is formulated for gingival administration or intranipple infiltration injection of a compound.

Atypical hemolytic urinary toxicosis syndrome (aHUS); high density deposition (DDD); C3 glomerular nephritis (C3GN); C3 glomerular disorder; complement-mediated nephropathy and glomerular inflammatory disease; age-related macular degeneration Disease (AMD); eye disorders characterized by macular degeneration, choroidal angiogenesis (CNV); retinal angiogenesis (RNV), proliferative vitreous retinopathy, glaucoma, vasculitis, eye inflammation, or any of these Combination of; paroxysmal nocturnal hemoglobinuria (PNH); cold agglutininosis (CAD); warm antibody autoimmune hemolytic anemia (wAIHA); macular degeneration; transplant-related thrombotic microangiopathy; rheumatoid arthritis ( RA), systemic erythematosus (SLE); autoimmune and autoinflammatory renal disease; autoimmune myocarditis; polysclerosis; traumatic brain and spinal cord injury; ischemia-reperfusion (IR) of the brain, intestines and kidneys Injury; Spontaneous and recurrent pregnancy loss; Antiphospholipid antibody syndrome (APS); Parkinson's disease; Alzheimer's disease; Abnormal synaptic remodeling, excessive microglial activity and neurodegenerative inflammatory conditions backed by cognitive decline; Asthma; Antinuclear cytoplasmic antigen-related microimmune vasculitis (Wegener's syndrome); non-lupus autoimmune skin diseases such as macular degeneration, macular degeneration, and epidermal vesicular disease; post-traumatic shock, cancer; periodontitis; gingival The invention of any one of claims 12-17 for use as a therapeutic agent for a pathological condition associated with complement activation, selected from the group consisting of inflammation; and atherosclerosis; Pharmaceutical composition.

SEQ ID NO: A peptide having the sequence of SEQ ID NO: 9.

SEQ ID NO: A peptide having the sequence of SEQ ID NO: 10.

SEQ ID NO: 9 peptide.

SEQ ID NO: A peptide consisting of 10.

The peptide according to any one of claims 19 to 22, which is arranged in a pharmaceutical composition comprising a pharmaceutically acceptable carrier for the peptide.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 11 for inhibiting complement activation in an individual .

24. The pharmaceutical composition of claim 24, wherein the compound comprises the amino acid sequence represented by SEQ ID NO: 9 or SEQ ID NO: 10.

24. The pharmaceutical composition of claim 24, wherein the compound further comprises a monodisperse PEG having a molecular weight of about 1 kDa to about 3 kDa, wherein the monodisperse PEG is covalently attached to the N-terminus of the compstatin analog.

The pharmaceutical composition according to any one of claims 24-26, wherein the pharmaceutical composition is formulated for intravenous or subcutaneous administration at a therapeutically effective dose of about 0.125 mg / kg to about 10 mg / kg.

The pharmaceutical composition according to any one of claims 24-26, wherein the pharmaceutical composition is formulated for intramuscular administration at a therapeutically effective dose of about 0.25 mg / kg to about 50 mg / kg.

The pharmaceutical composition according to any one of claims 24 to 26, wherein the pharmaceutical composition is formulated for intravitreal administration at a therapeutically effective dose of about 1 μg to about 10 mg.

The pharmaceutical composition according to any one of claims 24 to 26, wherein the pharmaceutical composition is formulated for oral administration at a therapeutically effective dose of about 1 mg to about 20 mg.

The pharmaceutical composition according to any one of claims 24 to 26, wherein the pharmaceutical composition is formulated for administration by intrapapillary infiltration injection at a therapeutically effective dose of about 1 μg to about 1,000 μg.

The pharmaceutical composition according to any one of claims 24 to 31, wherein the pharmaceutical composition is formulated for administration as a single dose.

The pharmaceutical composition according to any one of claims 24-31, wherein the pharmaceutical composition is formulated for administration at regular intervals ranging from once every 12 hours to once every 3 months.

The pharmaceutical composition is formulated for intravenous or subcutaneous administration at a first therapeutically effective dose of about 0.125 mg / kg to about 10 mg / kg, and then the pharmaceutical composition is (i) about 0.25 mg / kg. Is it formulated for intramuscular administration at a second therapeutically effective maintenance dose of ~ 50 mg / kg; or (ii) oral administration at a second therapeutically effective maintenance dose of about 1 mg / kg ~ 20 mg / kg The pharmaceutical composition according to any one of claims 24 to 26, which is formulated for use .

The pharmaceutical composition according to any one of claims 24-26, wherein the pharmaceutical composition is formulated for administration by an ocular implant at a therapeutically effective dose of about 100 μg to about 50 mg.

A method for detecting compstatin analogs in biological samples.
(1) A first plurality of compounds in which at least a portion of the compstatin analog molecule binds to C3 and / or its fractions C3b, iC3b, and C3c to form multiple C3-linked compstatin analog molecules. Steps to provide a biological sample containing a compstatin analog molecule;
(2) The step of heat-inactivating a biological sample to generate a heat-inactivated sample, in which the compstatin molecule dissociates from its target C3 molecule;
(3) A step of providing a CM5 sensor chip to which a second plurality of Compstatin analog molecules are covalently bound;
(4) The heat-inactivated sample is present in the biological sample by mixing a predetermined amount of C3 / C3b / iC3b / C3c or human plasma (as a source of C3) and contacting the mixture with the CM5 sensor chip. Steps in which the heat-releasing compstatin analog molecule competes for binding to C3 with the immobilized compstatin analog molecule; and
(5) By detecting the binding of free C3 / C3b / iC3b / C3c to the compstatin analog molecule on the CM5 chip, the reduction of bound C3 / C3b / iC3b / C3c in the heat-inactivated biological sample. Steps proportional to the presence of the Compstatin analog molecule;
How to include.

36. The method of claim 36, wherein the detection comprises surface plasmon resonance.

36 or 37. The method of claim 36 or 37, wherein the biological sample is a vitreous fluid sample or plasma sample extracted from a human or non-human primate.

The first plurality of Compstatin analog molecules, the second plurality of Compstatin analog molecules, or both the first plurality of Compstatin analog molecules and the second plurality of Compstatin analog molecules are sequence number: 7, sequence. If the polypeptide comprises a polypeptide having an amino acid sequence selected from the group consisting of number: 9 and SEQ ID NO: 10, and the amino acid sequence is SEQ ID NO: 7, the compstatin analog molecule is shared at the N-terminal of the compstatin analog. The method of any one of claims 36-38, further comprising a bound PEG having a molecular weight of about 1 kDa to about 3 kDa.