Compstatin Analogs With Improved Pharmacokinetic Properties

Abstract

Compounds comprising peptides capable of binding C3 protein and inhibiting complement activation are disclosed. The compounds comprise compstatin analogs in which the N-terminus contains an added or substituted component that improves (1) the peptide's binding affinity to C3 or its fragments, (2) the peptide's solubility in aqueous liquids, (3) the peptide's plasma stability, (4) the peptide's in vivo retention and/or (5) the peptide's bioavailability, as compared with an unmodified compstatin peptide under equivalent conditions. Pharmaceutical compositions and methods of using the compounds are also disclosed.

What is claimed: 
     
         1 . A method of inhibiting complement activation in or on a medium in which complement activation is occurring, comprising contacting the medium with a compound comprising a peptide having a sequence of SEQ ID NO:29, which is:
 Xaa1-Xaa2-Cys-Val-Xaa3-Gln-Xaa4-Xaa5-Gly-Xaa6-His-Xaa7-Cys-Xaa8, in which Gly between Xaa5 and Xaa6 is modified to constrain the backbone conformation;   wherein:   Xaa1 is absent or is selected from the group consisting of D-Tyr, D-Phe, Tyr(Me), D-Trp, D-Cha, Cha, Phe, Sar, Arg, mPhe, mVal, Trp, mIle, D-Ala, mAla, Thr or Tyr;   Xaa2 is Ile when Xaa1 is D-Tyr, D-Phe, Tyr(Me), D-Trp, D-Cha, Cha, Phe, Sar, Arg, mPhe, mVal, Trp, mIle, D-Ala, mAla or Thr, or either Ile or Gly when Xaa1 is Tyr, or Ac-Trp when Xaa1 is absent;   Xaa3 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp;   Xaa4 is Asp;   Xaa5 is Trp or an analog of Trp comprising a chemical modification to its indole ring wherein the chemical modification increases the hydrogen bond potential of the indole ring;   Xaa6 is His, Ala, Phe or Trp;   Xaa7 is Arg;   Xaa8 is Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile, wherein a carboxy terminal —OH of any of the Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile optionally is replaced by —NH 2 ; and   the peptide is cyclic through a disulfide or thioether bond between the two Cys residues.   
     
     
         2 . The method of  claim 1 , wherein complement activation is inhibited in one or more of: (a) blood or serum; (b) artificial organs or implants; and (c) in physiological fluids during extracorporeal shunting of the fluids. 
     
     
         3 . The method of  claim 1 , wherein the complement activation is inhibited as part of a treatment of a pathological condition associated with complement activation in an individual, comprising the steps of:
 (1) providing or identifying the individual having the pathological condition associated with complement activation;   (2) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound; and   (3) measuring one or more parameters of complement activation or of the pathological condition in the individual;   wherein administering of the pharmaceutical composition results in inhibition of complement thereby treating the individual having the pathological condition associated with complement activation.   
     
     
         4 . The method of  claim 3 , wherein the pathological condition associated with complement activation is selected from the group consisting of: atypical hemolytic uremic syndrome (aHUS), dense deposit disease, age-related macular degeneration (AMD), paroxysomal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD) rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), autoimmune and autoinflammatory kidney diseases, autoimmune myocarditis, multiple sclerosis, traumatic brain and spinal cord injury, intestinal and renal ischemia-reperfusion (IR) injury, spontaneous and recurrent pregnancy loss, anti-phospholipid syndrome (APS), Alzheimer's disease, asthma, anti-nuclear cytoplasmic antigen-associated pauci-immune vasculitis (Wegener's syndrome), non-lupus autoimmune skin diseases, post-traumatic shock, cancer, and atherosclerosis. 
     
     
         5 . The method of  claim 1 , wherein the compound comprises a peptide of SEQ ID NO:29 wherein:
 the Gly at position 8 is N-methylated;   Xaa1 is D-Tyr or Sar;   Xaa2 is Ile;   Xaa3 is Trp, 1-methyl-Trp or 1-formyl-Trp;   Xaa5 is Trp or halogenated Trp;   Xaa6 is Ala; and   Xaa8 is Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile with optional replacement of the carboxy terminal —OH with —NH 2 .   
     
     
         6 . The method of  claim 5 , wherein the compound comprises a peptide having SEQ ID NO:7 or SEQ ID NO:18. 
     
     
         7 . The method of  claim 1 , wherein the compound comprises a modification selected from one or more of (a) replacement of the C-terminal —OH with —NH 2 , (b) PEGylation of the compound and (c) an additional component that extends the in vivo retention of the compound. 
     
     
         8 . A method of inhibiting complement activation in or on a medium in which complement activation is occurring, comprising contacting the medium with a compound comprising a peptide having a sequence of SEQ ID NO:29, which is:
 Xaa1-Xaa2-Cys-Val-Xaa3-Gln-Xaa4-Xaa5-Gly-Xaa6-His-Xaa7-Cys-Xaa8, in which Gly between Xaa5 and Xaa6 is modified to constrain the backbone conformation;   wherein:   Xaa1 is absent or is selected from the group consisting of D-Tyr, D-Phe, Tyr(Me), D-Trp, D-Cha, Cha, Phe, Sar, Arg, mPhe, mVal, Trp, mIle, D-Ala, mAla, Thr or Tyr;   Xaa2 is Ile when Xaa1 is D-Tyr, D-Phe, Tyr(Me), D-Trp, D-Cha, Cha, Phe, Sar, Arg, mPhe, mVal, Trp, mIle, D-Ala, mAla or Thr, or either Ile or Gly when Xaa1 is Tyr, or Ac-Trp when Xaa1 is absent;   Xaa3 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp;   Xaa4 is Asp or Asn;   Xaa5 is Trp or an analog of Trp comprising a chemical modification to its indole ring wherein the chemical modification increases the hydrogen bond potential of the indole ring;   Xaa6 is His, Ala, Phe or Trp;   Xaa7 is Arg or Orn, provided that Xaa7 is Orn when Xaa4 is Asp and Xaa4 is Asn when Xaa7 is Arg;   Xaa8 is Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile, wherein a carboxy terminal —OH of any of the Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile optionally is replaced by —NH 2 ; and   the peptide is cyclic through a disulfide or thioether bond between the two Cys residues.   
     
     
         9 . The method of  claim 8 , wherein complement activation is inhibited in one or more of: (a) blood or serum; (b) artificial organs or implants; and (c) in physiological fluids during extracorporeal shunting of the fluids. 
     
     
         10 . The method of  claim 8 , wherein the complement activation is inhibited as part of a treatment of a pathological condition associated with complement activation in an individual, comprising the steps of:
 (1) providing or identifying the individual having the pathological condition associated with complement activation;   (2) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound; and   (3) measuring one or more parameters of complement activation or of the pathological condition in the individual;   wherein administering of the pharmaceutical composition results in inhibition of complement thereby treating the individual having the pathological condition associated with complement activation.   
     
     
         11 . The method of  claim 10 , wherein the pathological condition associated with complement activation is selected from the group consisting of: atypical hemolytic uremic syndrome (aHUS), dense deposit disease, age-related macular degeneration (AMD), paroxysomal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD) rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), autoimmune and autoinflammatory kidney diseases, autoimmune myocarditis, multiple sclerosis, traumatic brain and spinal cord injury, intestinal and renal ischemia-reperfusion (IR) injury, spontaneous and recurrent pregnancy loss, anti-phospholipid syndrome (APS), Alzheimer's disease, asthma, anti-nuclear cytoplasmic antigen-associated pauci-immune vasculitis (Wegener's syndrome), non-lupus autoimmune skin diseases, post-traumatic shock, cancer, and atherosclerosis. 
     
     
         12 . The method of  claim 8 , wherein the compound comprises a peptide of SEQ ID NO:29 wherein:
 the Gly at position 8 is N-methylated;   Xaa1 is D-Tyr or Sar;   Xaa2 is Ile;   Xaa3 is Trp, 1-methyl-Trp or 1-formyl-Trp;   Xaa5 is Trp or halogenated Trp;   Xaa6 is Ala; and   Xaa8 is Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile with optional replacement of the carboxy terminal —OH with —NH 2 .   
     
     
         13 . The method of  claim 8 , wherein the compound comprises a modification selected from one or more of (a) replacement of the C-terminal —OH with —NH 2 , (b) PEGylation of the compound and (c) synthesizing the compound with an additional component that extends the in vivo retention of the compound. 
     
     
         14 . A method of inhibiting complement activation in or on a medium in which complement activation is occurring, comprising contacting the medium with a compound comprising a peptide having SEQ ID NO:3, wherein the peptide comprises an ABM2 albumin binding small molecule conjugated directly or via a spacer to its N-terminus thereby replacing the N-terminal acetyl group. 
     
     
         15 . The method of  claim 14 , wherein complement activation is inhibited in one or more of: (a) blood or serum; (b) artificial organs or implants; and (c) in physiological fluids during extracorporeal shunting of the fluids. 
     
     
         16 . The method of  claim 14 , wherein the complement activation is inhibited as part of a treatment of a pathological condition associated with complement activation in an individual, comprising the steps of:
 (1) providing or identifying the individual having the pathological condition associated with complement activation;   (2) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound; and   (3) measuring one or more parameters of complement activation or of the pathological condition in the individual;   wherein administering of the pharmaceutical composition results in inhibition of complement thereby treating the individual having the pathological condition associated with complement activation.   
     
     
         17 . The method of  claim 16 , wherein the pathological condition associated with complement activation is selected from the group consisting of: atypical hemolytic uremic syndrome (aHUS), dense deposit disease, age-related macular degeneration (AMD), paroxysomal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD) rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), autoimmune and autoinflammatory kidney diseases, autoimmune myocarditis, multiple sclerosis, traumatic brain and spinal cord injury, intestinal and renal ischemia-reperfusion (IR) injury, spontaneous and recurrent pregnancy loss, anti-phospholipid syndrome (APS), Alzheimer's disease, asthma, anti-nuclear cytoplasmic antigen-associated pauci-immune vasculitis (Wegener's syndrome), non-lupus autoimmune skin diseases, post-traumatic shock, cancer, and atherosclerosis. 
     
     
         18 . The method of  claim 14 , wherein the compound comprises the ABM2 albumin binding small molecule conjugated directly to the N-terminal residue of SEQ ID NO:3. 
     
     
         19 . The method of  claim 14 , wherein the compound comprises an additional component that extends the in vivo retention of the compound. 
     
     
         20 . The method of  claim 19 , wherein the additional component is selected from: (a) polyethylene glycol (PEG); (b) an albumin binding small molecule other than the N-terminal ABM2; and (c) an albumin binding peptide.