Local complement inhibition for treatment of complement-mediated disorders

Abstract

The present invention features the local administration of complement inhibitors for treatment of complement-mediated disorders. In certain embodiments the invention features inhibiting activation of one or more locally produced complement proteins. The invention provides sustained release formulations and devices comprising a complement inhibitor and methods of use thereof.

We claim: 
     
         1 . A method of treating a complement-mediated disorder comprising the step of:
 administering a complement inhibitor directly to an extravascular location that is a site of local complement activation in said disorder.   
     
     
         2 . The method of  claim 1 , wherein said complement inhibitor is administered in an amount sufficient to inhibit complement activity attributable to at least one complement activation pathway at said location by at least 25%. 
     
     
         3 . The method of  claim 1 , wherein said complement inhibitor is administered in an amount sufficient to reduce complement activity attributable to at least one complement pathway at said location to a level no more than twice the average level found at said location in the absence of said disorder. 
     
     
         4 . The method of  claim 1 , wherein said complement inhibitor is administered at said location multiple times at intervals averaging between 1 week and 1 year, wherein said complement inhibitor is administered in an amount sufficient to produce a clinically significant reduction in severity at least one symptom of the disorder for on average at least 1 week, and wherein said amount is not sufficient to significantly inhibit systemic complement activation. 
     
     
         5 . The method of  claim 1 , wherein the disorder is mediated at least in part by a locally produced soluble complement protein, wherein the complement inhibitor is administered in an amount sufficient to reduce complement activity attributable to said locally produced complement protein to a level no more than twice the average level found at said extravascular location in the absence of said disorder. 
     
     
         6 . The method of  claim 1 , wherein said complement inhibitor inhibits an enzymatic activity of a soluble complement protein. 
     
     
         7 . The method of  claim 1 , wherein said complement inhibitor inhibits cleavage of a complement component selected from the group consisting of: C3, C5, and factor B. 
     
     
         8 . The method of  claim 1 , wherein said complement inhibitor binds to a complement component selected from the group consisting of: C3, C5, factor B, and factor D. 
     
     
         9 . The method of  claim 1 , wherein said complement inhibitor is a peptide, small molecule, or aptamer. 
     
     
         10 . The method of  claim 1 , wherein said complement inhibitor is an antibody. 
     
     
         11 . The method of  claim 1 , wherein said complement inhibitor is a compstatin analog. 
     
     
         12 . The method of  claim 1 , wherein said complement inhibitor is a VCCP. 
     
     
         13 . The method of  claim 1 , wherein said extravascular location is within a joint. 
     
     
         14 . The method of  claim 1 , wherein said extravascular location is within the spinal canal. 
     
     
         15 . The method of  claim 1 , wherein said extravascular location is on or in the skin. 
     
     
         16 . The method of  claim 1 , wherein said extravascular location is within the respiratory tract. 
     
     
         17 . The method of  claim 1 , wherein said disorder is selected from the group consisting of: arthritis, asthma, infection, multiple sclerosis, spinal cord or other nerve injury, chronic pain, Alzheimer's disease, Parkinson's disease, chronic obstructive pulmonary disease, stroke, brain injury, allergic dermatitis, psoriasis, age-related macular degeneration, uveitis, diabetic retinopathy, glaucoma, and pemphigus. 
     
     
         18 . The method of  claim 1 , wherein said complement inhibitor is administered by a route selected from the group consisting of: intraarticular injection, intravitreal injection, sub-Tenon injection, retrobulbar injection, sub-retinal injection, subconjunctival injection, suprachoroidal injection, intrascleral injection, intramuscular injection, intrastromal injection, intracranial injection, intrathecal injection, by inhalation, and topically to the skin. 
     
     
         19 . The method of  claim 1 , wherein said effective amount has essentially no effect on systemic complement activation when administered at said extravascular location. 
     
     
         20 . The method of  claim 1 , wherein said complement inhibitor is released from a sustained release formulation or device that releases the complement inhibitor over time. 
     
     
         21 . The method of  claim 20 , wherein said sustained release formulation comprises a plurality of microparticles or nanoparticles. 
     
     
         22 . The method of  claim 20 , wherein said sustained release formulation comprises a gel. 
     
     
         23 . The method of  claim 20 , wherein said sustained release formulation comprises a gel that forms in the body following administration of a liquid that contains the complement inhibitor. 
     
     
         24 . The method of  claim 20 , wherein said sustained release formulation is a solid article of manufacture. 
     
     
         25 . The method of  claim 20 , wherein said sustained release formulation comprises a biodegradable polymeric matrix. 
     
     
         26 . The method of  claim 20 , wherein said complement inhibitor is released in an amount sufficient to inhibit complement activity attributable to at least one complement activation pathway at said location by at least 25% over at least a portion of said time. 
     
     
         27 . The method of  claim 20 , wherein said complement inhibitor is released in an amount sufficient to reduce complement activity attributable to at least one complement pathway at said location to a level no more than twice the average level found at said location in the absence of said disorder for at least a portion of said time. 
     
     
         28 . The method of  claim 20 , wherein said complement inhibitor is released in an amount sufficient to produce a clinically significant reduction in severity at least one symptom of the disorder for on average at least one week, and wherein said amount is not sufficient to significantly inhibit systemic complement activity during most or all of said time. 
     
     
         29 . The method of  claim 20 , wherein said complement inhibitor is released in an amount sufficient to reduce complement activity attributable to said locally produced complement protein to a level no more than twice the average level found at said extravascular location in the absence of said disorder over at least a portion of said time. 
     
     
         30 . The method of  claim 1 , further comprising the step of administering a second agent effective against said disorder. 
     
     
         31 . The method of  claim 30 , wherein said complement inhibitor and said second agent are administered as part of the same composition. 
     
     
         32 . The method of  claim 1 , further comprising the step of:
 determining whether complement activity is aberrantly high in an extravascular location in the subject's body.   
     
     
         33 . The method of  claim 32 , comprising the step of: selecting said amount based on an assessment of the level of complement activity at said location. 
     
     
         34 . The method of  claim 32 , comprising the step of: selecting said amount based on an assessment of the absolute amount or concentration of at least one soluble complement protein at said location. 
     
     
         35 . A composition comprising a complement inhibitor, wherein said composition comprises a gel, cream, lotion, or ointment suitable for application to the skin. 
     
     
         36 . The composition of  claim 23 , wherein said complement inhibitor is a compstatin analog. 
     
     
         37 . An inhalable composition comprising a complement inhibitor. 
     
     
         38 . The composition of  claim 37 , wherein said complement inhibitor is a compstatin analog. 
     
     
         39 . The composition of  claim 37 , which is a dry powder suitable for delivering the complement inhibitor to the lung. 
     
     
         40 . A sustained release composition comprising a complement inhibitor and a compound selected from the group consisting of: steroidal or nonsteroidal anti-inflammatory agents, local anesthetic agents, leukotriene or leukotriene receptor antagonists, cytokine or cytokine receptor antagonists, matrix metalloprotease inhibitors, phosphodiesterase inhibitors, anti-histamines, anti-angiogenic, and anti-infective agents. 
     
     
         41 . The composition of  claim 40 , wherein the complement inhibitor is a compstatin analog. 
     
     
         42 . A method of treating inflammatory arthritis comprising administering a complement inhibitor directly to a joint or bursa, wherein said complement inhibitor is administered in an amount effective to substantially inhibit activation of a locally produced soluble complement component. 
     
     
         43 . The method of  claim 42 , wherein said amount is not sufficient to significantly inhibit systemic complement activation when administered directly to said joint. 
     
     
         44 . The method of  claim 42 , wherein said inflammatory arthritis is rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, juvenile arthritis, or gout. 
     
     
         45 . The method of  claim 42 , wherein said complement inhibitor is a compstatin analog. 
     
     
         46 . The method of  claim 42 , wherein said complement inhibitor is a VCCP. 
     
     
         47 . The method of  claim 42 , wherein said complement inhibitor is administered by a sustained release formulation or device comprising the complement inhibitor. 
     
     
         48 . A method of treating an inflammatory condition of the respiratory system comprising administering a complement inhibitor directly to the respiratory tract, wherein said complement inhibitor is a peptide or antibody that binds to a locally produced soluble complement protein. 
     
     
         49 . The method of  claim 48 , wherein said inflammatory condition of the respiratory system is selected from the group consisting of: asthma, COPD, allergic rhinitis, and infection-associated inflammation. 
     
     
         50 . The method of  claim 48 , wherein said complement inhibitor is a compstatin analog. 
     
     
         51 . The method of  claim 48 , wherein said complement inhibitor is a VCCP. 
     
     
         52 . The method of  claim 48 , wherein said complement inhibitor is administered as a component of a sustained release formulation comprising the complement inhibitor. 
     
     
         53 . The method of  claim 48 , wherein said complement inhibitor is administered as a component of an inhalable dry powder. 
     
     
         54 . The method of  claim 48 , wherein said complement inhibitor is administered as a component of an inhalable liquid aerosol. 
     
     
         55 . The method of  claim 48 , wherein said complement inhibitor is administered as a component of a nasal spray. 
     
     
         56 . A method of treating a complement-mediated disorder of the nervous system comprising administering a complement inhibitor to a region of the nervous system by a route selected from the group consisting of: intrathecal, intranasal, and by local injection into a nerve sheath. 
     
     
         57 . The method of  claim 56 , wherein said complement inhibitor is a peptide or antibody that binds to a locally produced soluble complement protein. 
     
     
         58 . The method of  claim 56 , wherein said complement inhibitor is a compstatin analog. 
     
     
         59 . The method of  claim 56 , wherein said complement inhibitor is a VCCP. 
     
     
         60 . The method of  claim 56 , wherein said complement-mediated disorder is selected from the group consisting of: spinal cord injury, multiple sclerosis, Alzheimer's disease, Parkinson's Disease, stroke, and chronic pain. 
     
     
         61 . The method of  claim 56 , wherein said complement inhibitor is a compstatin analog. 
     
     
         62 . The method of  claim 56 , wherein said complement inhibitor is a VCCP. 
     
     
         63 . The method of  claim 56 , wherein said complement inhibitor is administered by a sustained release formulation or device comprising the complement inhibitor. 
     
     
         64 . A method of treating a skin condition comprising administering a complement inhibitor directly to the skin, wherein said complement inhibitor is administered in an amount effective to inhibit activation of a locally produced soluble complement component or in an amount effective to inhibit local activation of complement and is not sufficient to significantly inhibit systemic complement activation when administered directly to the skin. 
     
     
         65 . The method of  claim 64 , wherein said complement inhibitor is a compstatin analog. 
     
     
         66 . The method of  claim 64 , wherein said complement inhibitor is a VCCP. 
     
     
         67 . The method of  claim 64 , wherein said skin condition is selected from the group consisting of: psoriasis, pemphigus, scleroderma, and lupus. 
     
     
         68 . The method of  claim 64 , wherein said complement inhibitor is administered as a component of a cream, paste, ointment, gel, or lotion. 
     
     
         69 . A method of treating a complement-mediated disorder of the eye comprising administering a complement inhibitor to a region of the eye by a route selected from the group consisting of: intravitreal, sub-Tenon, retrobulbar, sub-retinal, subconjunctival, suprachoroidal, or intrascleral injection. 
     
     
         70 . The method of  claim 69 , wherein said complement inhibitor is a peptide or antibody that binds to a locally produced soluble complement protein. 
     
     
         71 . The method of  claim 69 , wherein said complement inhibitor is a compstatin analog. 
     
     
         72 . The method of  claim 69 , wherein said complement inhibitor is a VCCP. 
     
     
         73 . The method of  claim 69 , wherein said complement-mediated disorder is selected from the group consisting of: age-related macular degeneration, diabetic retinopathy, uveitis, and glaucoma. 
     
     
         74 . The method of  claim 69 , wherein said complement inhibitor is administered by a sustained release formulation or device comprising the complement inhibitor. 
     
     
         75 . A method of treating a complement-mediated disorder comprising administering a sustained release formulation comprising an effective amount of a compstatin analog to an extravascular location where complement activation occurs, wherein said location is not the eye. 
     
     
         76 . The method of  claim 75 , wherein said composition does not significantly inhibit systemic complement activation when administered at said location. 
     
     
         77 . The method of  claim 75 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3), where X′aa and Xaa are selected from Trp, analogs of Trp. 
     
     
         78 . The method of  claim 75 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly-X″aa (SEQ ID NO: 4), where X′aa and Xaa are each independently selected from Trp and analogs of Trp and X″aa is selected from His, Ala, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp. 
     
     
         79 . The method of  claim 78 , wherein the peptide has a sequence of X′aa1-X′aa2-X′aa3-X′aa-Gln-Asp-Xaa-Gly-X″aa-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), and X′aa1, X′aa2, X′aa3, X″aa2, X″aa3-X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin. 
     
     
         80 . The method of  claim 78 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, and the peptide is cyclized via a bond between X′aa2 and X″aa4. 
     
     
         81 . The method of  claim 80 , wherein X′aa1, X′aa2, X′aa3, X″aa2, X″aa3, X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         82 . The method of  claim 75 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 6) 
                 
                     
                   Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly-Xaa3-His- 
                 
                     
                     
                 
                     
                   Arg-Cys-Xaa4; 
                 
             
                
                
                
                
               
            
           
         
       
       wherein:
 Xaa1 is Ile, Val, Leu, B 1 -Ile, B 1 -Val, B 1 -Leu or a dipeptide comprising Gly-Ile or B 1 -Gly-Ile, and B 1  represents a first blocking moiety; 
 Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; 
 Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; 
 Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B 2 ; and 
 the two Cys residues are joined by a disulfide bond. 
 
     
     
         83 . The method of  claim 82 , wherein the peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus. 
     
     
         84 . The method of  claim 82 , wherein
 Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile;   Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp;   Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;   Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —NH 2 .   
     
     
         85 . The method of  claim 82 , wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp. 
     
     
         86 . The method of  claim 82 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components. 
     
     
         87 . The method of  claim 82 , wherein Xaa2* is an analog of Trp having an electronegative substituent on the indole ring and not having increased hydrophobic character relative to Trp. 
     
     
         88 . The method of  claim 75 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 9-32. 
     
     
         89 . The method of  claim 75 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 14, 21, 28, 29, and 32. 
     
     
         90 . The method of  claim 75 , wherein the compstatin analog has a sequence selected from the group consisting of: SEQ ID NOs: 30 and 31. 
     
     
         91 . The method of  claim 75 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, X′aa2 and X″aa4 are not Cys, and the peptide is cyclized via a bond between X′aa2 and X″aa4. 
     
     
         92 . The method of  claim 91 , wherein X′aa1, X′aa3, X″aa2, X″aa3, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         93 . The method of  claim 91 , wherein the bond is an amide bond, wherein one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine, the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group, and the bond is an amide bond. 
     
     
         94 . The method of  claim 75 , wherein the composition is locally administered as a liquid. 
     
     
         95 . The method of  claim 75 , wherein the composition is locally administered as a liquid that forms a gel following administration. 
     
     
         96 . The method of  claim 75 , wherein the composition is locally administered as a lotion, cream, ointment, or gel. 
     
     
         97 . The method of  claim 75 , wherein the composition comprises soluble collagen. 
     
     
         98 . The method of  claim 75 , wherein the composition comprises soluble collagen and fibrillar collagen solids. 
     
     
         99 . The method of  claim 75 , wherein the composition comprises a multivalent compound comprising a plurality of compstatin analog moieties covalently or noncovalently linked to a polymeric backbone or scaffold. 
     
     
         100 . A composition comprising:
 (i) a complement inhibitor; and   (ii) a moiety that binds to a component present at an extravascular location where local complement activation occurs in a complement-mediated disorder, wherein said extravascular location is not the eye or a portion thereof.   
     
     
         101 . The composition of  claim 100 , wherein the moiety binds to a marker expressed by cells present at said extravascular location. 
     
     
         102 . The composition of  claim 100 , wherein the moiety is directly or indirectly linked to the complement inhibitor. 
     
     
         103 . The composition of  claim 100 , wherein the complement inhibitor is a compstatin analog. 
     
     
         104 . The composition of  claim 100 , which is a sustained release formulation. 
     
     
         105 . A method of treating an ocular disorder characterized by macular degeneration and/or inflammation comprising administering an effective amount of an anti-TNFα agent to a subject in need thereof. 
     
     
         106 . The method of  claim 105 , wherein the anti-TNFα agent comprises an antibody or soluble TNF receptor. 
     
     
         107 . The method of  claim 105 , wherein the anti-TNFα agent is locally administered to the eye. 
     
     
         108 . The method of  claim 105 , wherein the ocular disorder is AMD, diabetic retinopathy, uveitis, or glaucoma. 
     
     
         109 . A sustained release formulation or device suitable for introduction into the eye, wherein the sustained release formulation or device comprises an anti-TNFα agent. 
     
     
         110 . A method of treating an ocular disorder comprising administering an effective amount of the sustained release formulation or device of  claim 109  to the eye of a subject in need thereof. 
     
     
         111 . A sustained release formulation or device comprising a biodegradable drug releasing material, a complement inhibitor, and a detectable moiety. 
     
     
         112 . The sustained release formulation or device of  claim 111 , wherein the complement inhibitor is a compstatin analog. 
     
     
         113 . The sustained release formulation or device of  claim 111 , wherein the detectable moiety is fluorescent. 
     
     
         114 . The sustained release formulation or device of  claim 111 , wherein the detectable moiety is an ultrasound or magnetic resonance contrast enhancer. 
     
     
         115 . A method of treating a subject comprising: (a) administering to the subject a first quantity of a first biodegradable sustained release formulation or device comprising a detectable moiety and a complement inhibitor and (b) detecting the detectable moiety using a non-invasive detection method. 
     
     
         116 . The method of  claim 115 , wherein presence and/or amount of the moiety detected serves as an indication of the amount of the sustained release formulation or device that remains intact or has degraded or serves as an indication of the amount of the complement inhibitor remaining in the sustained release formulation or device; and optionally (c) administering to the subject a second quantity of a second sustained release formulation or device based on the results of step (b). 
     
     
         117 . The method of  claim 111 , further comprising repeating steps (b) and (c) one or more times. 
     
     
         118 . The method of  claim 111 , wherein step (a) comprises locally administering the formulation or device to the eye. 
     
     
         119 . The method of  claim 111 , wherein the detectable moiety comprises an ultrasound or magnetic resonance contrast enhancer. 
     
     
         120 . The method of  claim 111 , wherein the detectable moiety comprises an ultrasound or magnetic resonance contrast enhancer. 
     
     
         121 . The method of  claim 111 , wherein the detectable moiety is fluorescent. 
     
     
         122 . A fusion protein comprising:
 (i) a first domain comprising a compstatin analog; and   (ii) a second domain comprising a moiety that binds to a component present in extravascular location where local complement activation occurs in a complement-mediated disorder, wherein said extravascular location is not the eye or a portion thereof.   
     
     
         123 . The fusion protein of  claim 122  further comprising a third domain that links the first and second domains. 
     
     
         124 . A nucleic acid that encodes the fusion protein of  claim 122 . 
     
     
         125 . A vector comprising the nucleic acid of  claim 122 . 
     
     
         126 . A recombinant host cell comprising the nucleic acid of  claim 122 . 
     
     
         127 . A method of producing a therapeutic agent comprising steps of:
 (i) expressing the nucleic acid of  claim 122  in a recombinant host cell so that a polypeptide comprising the compstatin analog fused to a binding moiety is produced by the host cell; and   (ii) purifying the polypeptide.