Compositions and Method for Treating Complement-Associated Conditions

Abstract

The invention provides methods and compositions for treating various degenerative diseases (e.g., AMD) with a factor D inhibitor (e.g., anti-factor D antibody or antigen-binding fragment thereof). Also provided are methods of selecting or identifying patients for treatment with a factor D inhibitor. Methods include the use of prognostic and/or predictive biomarkers.

1 .- 86 . (canceled) 
     
     
         87 . A method of treating age-related macular degeneration (AMD) in a patient in need thereof comprising:
 (a) identifying a patient with AMD as more likely to respond to a therapy comprising an anti-factor D antibody, or antigen-binding fragment thereof comprising:
 (i) detecting the presence of at least one AMD-associated polymorphism in a biological sample obtained from the patient, wherein the detecting comprises: 
 (1) providing a nucleic acid sample isolated from the biological sample; and 
 (2) detecting the genotype of the nucleic acid sample for the presence of at least one AMD-associated polymorphism, wherein at least one AMD-associated polymorphism is single nucleotide polymorphism (SNP) rs17440077; and 
 (ii) identifying the patient as more likely to respond to a therapy comprising anti-factor D antibody, or an antigen-binding fragment thereof, when at least one risk allele is present, and wherein at least one risk allele comprises a G at SNP rs17440077; and 
   (b) treating the identified patient with AMD by administering an effective amount of a therapy comprising an anti-Factor D antibody, or an antigen-binding fragment thereof, to the identified patient.   
     
     
         88 . The method of  claim 87 , wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, Denaturing Gradient Gel Electrophoresis (DGGE), Temporal Temperature Gradient Electrophoresis (TTGE), Zn(II)-cyclen polyacrylamide gel electrophoresis, homogeneous fluorescent PCR-based single nucleotide polymorphism analysis, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5′ nuclease reaction, Taqman assay, MassArray (single base primer extension coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms, single base primer extension (SBE) assays, PCR amplification, restriction enzyme analysis of PCR products (RFLP methods), allele-specific PCR, multiple primer extension (MPEX), and isothermal smart amplification. 
     
     
         89 . The method of  claim 87 , wherein the presence of one or two alleles of the G genotype at the SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one or two alleles of the A genotype at the SNP rs10737680 in the patient indicates an increased likelihood of response to an anti-factor D antibody treatment. 
     
     
         90 . The method of  claim 87 , wherein the anti-factor D antibody, or fragment thereof is lampalizumab. 
     
     
         91 . The method of  claim 87 , wherein the AMD is early, intermediate, or advanced AMD. 
     
     
         92 . The method of  claim 87 , wherein the nucleic acid sample is amplified by a polymerase chain reaction and at least one polymorphism is detected by polymerase chain reaction. 
     
     
         93 . The method of  claim 87 , wherein the nucleic acid sample is amplified by a polymerase chain reaction and at least one polymorphism is detected by sequencing. 
     
     
         94 . The method of  claim 87 , wherein at least one polymorphism is detected by amplification of a target region containing at least one polymorphism, and hybridization with at least one sequence-specific oligonucleotide that hybridizes under stringent conditions to at least one polymorphism and detecting the hybridization. 
     
     
         95 . The method of  claim 87 , wherein the patient is identified as more likely to respond to a therapy comprising anti-factor D antibody, or an antigen-binding fragment thereof, when the risk allele G at SNP rs4698775 for CFI allele is present along with at least one risk allele G at either SNP rs1329428 for CFH allele or SNP rs429608 for C2/CFB allele. 
     
     
         96 . The method of  claim 95 , wherein the genotype at rs4698775 is detected using a forward primer of SEQ ID NO:17 or 18 combined with a reverse primer of SEQ ID NO:19 or 20 and a labeled probe selected from SEQ ID NOs. 21-24; the genotype at rs429608 (C2) is detected using a forward primer of SEQ ID NO:25 or 26 combined with a reverse primer of SEQ ID NO:27 or 28 and a labeled probe selected from SEQ ID NOs. 29-33; and the genotype at rs1329428 (CFH) is detected using a forward primer of SEQ ID NO:34 or 35 combined with a reverse primer of SEQ ID NO:36 or 37 and a labeled probe selected from SEQ ID NOs. 38-41. 
     
     
         97 . The method of  claim 87 , wherein the method further comprises determining the genotype of a SNP of a CFH allele, a C2 allele, or CFB allele. 
     
     
         98 . The method of  claim 97 , wherein the CFH allele comprises an A at the SNP rs10737680 or a G at the SNP rs1329428, the C2 allele comprises a G at the SNP rs429608, and the CFB allele comprises a G at the SNP rs429608. 
     
     
         99 . The method of  claim 87 , wherein the biological sample is a blood sample, saliva, cheek swab, tissue sample, or a sample of a bodily fluid. 
     
     
         100 . The method of  claim 87 , wherein the nucleic acid sample comprises DNA. 
     
     
         101 . The method of  claim 87 , wherein the nucleic acid sample comprises RNA. 
     
     
         102 . The method of  claim 91 , wherein the advanced AMD is geographic atrophy (GA).