Anti-adrenomedullin (adm) antibody or anti-adm antibody fragment or anti-adm non-ig scaffold for use in intervention and therapy of congestion in a patient in need thereof

Abstract

Subject matter of the present invention is an anti-Adrenomedullin (ADM) antibody or an anti-Adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient in need thereof.

1 . Anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient in need thereof, wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal part (aa 1-21) of adrenomedullin: 
       
         
           
                 
               
                   (SEQ ID No. 22) 
                 
                   YRQSMNNFQGLRSFGCRFGTC, 
                 
             
                
                
               
            
           
         
         and wherein said patient is resistant against diuretics or is a non-responder to diuretics therapy. 
       
     
     
         2 . Anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient according to  claim 1  wherein said patient has a disease or condition selected from the group comprising: congestive high blood pressure, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease. 
     
     
         3 . Anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient according to  claim 1  wherein said patient has a disease or condition selected from the group comprising: congestive high blood pressure, swelling or water retention (edema), and heart failure, in particular acute heart failure. 
     
     
         4 . Anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin or anti-ADM non-Ig scaffold binding to adrenomedullin for use in intervention and therapy of congestion in a patient according to  claim 1 , wherein said antibody or antibody fragment or non-Ig scaffold is monospecific. 
     
     
         5 . Anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin or anti-ADM non-Ig scaffold binding to adrenomedullin for use in intervention and therapy of congestion in a patient according to  claim 1 , wherein said antibody or fragment or scaffold exhibits a binding affinity to ADM of at least 10 −7  M. 
     
     
         6 . Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient according to  claim 1 , wherein said antibody or fragment or scaffold recognizes and binds to the N-terminal end (aa 1) of adrenomedullin. 
     
     
         7 . Anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin or anti-ADM non-Ig scaffold binding to adrenomedullin for use in intervention and therapy of congestion in a patient according to  claim 1 , characterized in that said antibody, antibody fragment or non-Ig scaffold does not bind to the C-terminal portion of ADM, having the sequence aa 43-52 of ADM
 PRSKISPQGY-NH 2      (SEQ ID NO: 24).   
     
     
         8 . Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient according to  claim 1 , wherein said antibody or fragment or scaffold blocks the bioactivity of ADM not more than 80%, preferably not more than 50%. 
     
     
         9 . Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold for use in intervention and therapy of congestion in a patient according to  claim 1 , wherein said patient is an ICU patient. 
     
     
         10 . Anti-ADM antibody or an anti-adrenomedullin antibody fragment for use in intervention and therapy of congestion in a patient according to  claim 1 , wherein said antibody or fragment is a human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof wherein the heavy chain comprises the sequences: 
       
         
           
                 
               
                   SEQ ID NO: 1 
                 
                   GYTFSRYW 
                 
                     
                 
                   SEQ ID NO: 2 
                 
                   ILPGSGST 
                 
                     
                 
                   SEQ ID NO: 3 
                 
                   TEGYEYDGFDY 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         and wherein the light chain comprises the sequences: 
       
       
         
           
                 
               
                   SEQ ID NO: 4 
                 
                   QSIVYSNGNTY 
                 
                     
                 
                   SEQUENCE: RVS 
                 
                     
                 
                   SEQ ID NO: 5 
                 
                   FQGSHIPYT. 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof for use in intervention and therapy of congestion in a patient according to  claim 10 , wherein said antibody or fragment comprises a sequence selected from the group comprising: 
       
         
           
                 
               
                   (AM-VH-C) 
                 
                   SEQ ID NO: 6 
                 
                   QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEI 
                 
                     
                 
                   LPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEY 
                 
                     
                 
                   DGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
                 
                     
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 
                 
                     
                 
                   HKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH1) 
                 
                   SEQ ID NO: 7 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRI 
                 
                     
                 
                   LPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEY 
                 
                     
                 
                   DGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
                 
                     
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 
                 
                     
                 
                   HKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH2-E40) 
                 
                   SEQ ID NO: 8 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRI 
                 
                     
                 
                   LPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEY 
                 
                     
                 
                   DGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
                 
                     
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 
                 
                     
                 
                   HKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH3-T26-E55) 
                 
                   SEQ ID NO: 9 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEI 
                 
                     
                 
                   LPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEY 
                 
                     
                 
                   DGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
                 
                     
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 
                 
                     
                 
                   HKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH4-T26-E40-E55) 
                 
                   SEQ ID NO: 10 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEI 
                 
                     
                 
                   LPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEY 
                 
                     
                 
                   DGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
                 
                     
                 
                   PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 
                 
                     
                 
                   HKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VL-C) 
                 
                   SEQ ID NO: 11 
                 
                   DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKL 
                 
                     
                 
                   LIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYT 
                 
                     
                 
                   FGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW 
                 
                     
                 
                   KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
                 
                     
                 
                   GLSSPVTKSFNRGEC 
                 
                     
                 
                   (AM-VL1) 
                 
                   SEQ ID NO: 12 
                 
                   DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRR 
                 
                     
                 
                   LIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYT 
                 
                     
                 
                   FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW 
                 
                     
                 
                   KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
                 
                     
                 
                   GLSSPVTKSFNRGEC 
                 
                     
                 
                   (AM-VL2-E40) 
                 
                   SEQ ID NO: 13 
                 
                   DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRR 
                 
                     
                 
                   LIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYT 
                 
                     
                 
                   FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW 
                 
                     
                 
                   KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
                 
                     
                 
                   GLSSPVTKSFNRGEC 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . Anti-ADM antibody or anti-ADM antibody fragment binding to ADM or anti-ADM non-Ig scaffold binding to ADM for use in intervention and therapy of congestion in a patient according to  claim 1  wherein a sample of bodily fluid taken from said patients exhibits an elevated level of proADM and/or fragments thereof having at least 5 amino acids above a certain threshold. 
     
     
         13 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient comprising an antibody or fragment or scaffold according to  claim 1 . 
     
     
         14 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient comprising an antibody or fragment or scaffold according to  claim 1  wherein said patient has a disease or condition selected from the group comprising: congestive high blood pressure, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease. 
     
     
         15 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to  claim 13  wherein said pharmaceutical formulation is a solution, preferably a ready-to-use solution. 
     
     
         16 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to  claim 15  wherein said pharmaceutical formulation is in a freeze-dried state. 
     
     
         17 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to  claim 15 , wherein said pharmaceutical formulation is administered intra-muscular. 
     
     
         18 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to  claim 15 , wherein said pharmaceutical formulation is administered intra-vascular. 
     
     
         19 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to  claim 18 , wherein said pharmaceutical formulation is administered via infusion. 
     
     
         20 . Pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to  claim 15 , wherein said pharmaceutical formulation is to be administered systemically.