Anti-adrenomedullin (adm) antibody or anti-adm antibody fragment or anti-adm non-ig scaffold for prevention or reduction of organ dysfunction or organ failure in a patient having a chronic or acute disease or acute condition

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 therapy of a chronical or acute disease or acute condition of a patient for prevention or reduction of organ dysfunction or organ failure. In a preferred embodiment subject matter of the invention is an anti-ADM antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in therapy of a chronical or acute disease or acute condition of a patient for prevention or reduction of kidney dysfunction or kidney failure or liver dysfunction or liver failure.

1 . 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 therapy of an acute disease or acute condition of a patient for prevention or reduction of organ dysfunction or prevention of organ failure in said patient. 
     
     
         2 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said anti-ADM antibody or said anti-adrenomedullin antibody fragment or said anti-ADM non-Ig scaffold is a non-neutralizing ADM antibody or a non-neutralizing adrenomedullin antibody fragment or a non-neutralizing ADM non-Ig scaffold. 
     
     
         3 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said organ is kidney or liver. 
     
     
         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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said organ is heart. 
     
     
         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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or fragment or scaffold binds to the N-terminal part (aa 1-21) of adrenomedullin. 
     
     
         6 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or antibody fragment or non-Ig scaffold is monospecific. 
     
     
         7 . Anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin or anti-ADM non-Ig scaffold binding for use in therapy of an acute disease or acute condition of 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. 
     
     
         8 . Anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin or anti-ADM non-Ig scaffold binding for use in therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or fragment or scaffold is not ADM-binding-Protein-1 (complement factor H). 
     
     
         9 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or fragment or scaffold recognizes and binds to the N-terminal end (aa1) of adrenomedullin. 
     
     
         10 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or said fragment or scaffold is an ADM stabilizing antibody or fragment or scaffold that enhances the half life (t1/2 half retention time) of adrenomedullin in serum, blood, plasma at least 10%, preferably at least 50%, more preferably >50%, most preferably >100%. 
     
     
         11 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or fragment or scaffold blocks the ADM bioactivity not more than 80%, preferably not more than 50%. 
     
     
         12 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said disease is selected from the group comprising sepsis, diabetes, cancer, heart failure, and shock. 
     
     
         13 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said disease is not SIRS, sepsis, or septic shock. 
     
     
         14 . Anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin for use in therapy of an acute disease or acute condition of 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 
                 
                     
                     
                 
                     
                   SEQ ID NO: 5 
                 
                     
                   RVS 
                 
                     
                     
                 
                     
                   SEQ ID NO: 6 
                 
                     
                   FQGSHIPYT. 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         15 . A human monospecific anti-Adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin for use in therapy of an acute disease or acute condition of a patient according to  claim 14 , wherein said antibody or fragment comprises the sequences: 
       
         
           
                 
               
                   SEQ ID NO: 7 
                 
                   (AM-VH-C) 
                 
                   QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGE 
                 
                     
                 
                   ILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGY 
                 
                     
                 
                   EYDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
                 
                     
                 
                   FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
                 
                     
                 
                   CNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   SEQ ID NO: 8 
                 
                   (AM-VH1) 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGR 
                 
                     
                 
                   ILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGY 
                 
                     
                 
                   EYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
                 
                     
                 
                   FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
                 
                     
                 
                   CNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   SEQ ID NO: 9 
                 
                   (AM-VH2-E40) 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGR 
                 
                     
                 
                   ILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGY 
                 
                     
                 
                   EYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
                 
                     
                 
                   FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
                 
                     
                 
                   CNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   SEQ ID NO: 10 
                 
                   (AM-VH3-T26-E55) 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGE 
                 
                     
                 
                   ILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGY 
                 
                     
                 
                   EYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
                 
                     
                 
                   FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
                 
                     
                 
                   CNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   SEQ ID NO: 11 
                 
                   (AM-VH4-T26-E40-E55) 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGE 
                 
                     
                 
                   ILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGY 
                 
                     
                 
                   EYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
                 
                     
                 
                   FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
                 
                     
                 
                   CNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   SEQ ID NO: 12 
                 
                   (AM-VL-C) 
                 
                   DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPK 
                 
                     
                 
                   LLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIP 
                 
                     
                 
                   YTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 
                 
                     
                 
                   VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
                 
                     
                 
                   VTHQGLSSPVTKSFNRGEC 
                 
                     
                 
                   SEQ ID NO: 13 
                 
                   (AM-VL1) 
                 
                   DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPR 
                 
                     
                 
                   RLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIP 
                 
                     
                 
                   YTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 
                 
                     
                 
                   VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
                 
                     
                 
                   VTHQGLSSPVTKSFNRGEC 
                 
                     
                 
                   SEQ ID NO: 14 
                 
                   (AM-VL2-E40) 
                 
                   DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPR 
                 
                     
                 
                   RLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIP 
                 
                     
                 
                   YTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 
                 
                     
                 
                   VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
                 
                     
                 
                   VTHQGLSSPVTKSFNRGEC 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         16 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 , wherein said antibody or fragment or scaffold is a modulating antibody or fragment or scaffold that enhances the half life (t1/2 half retention time) of adrenomedullin in serum, blood, plasma at least 10%, preferably at least 50%, more preferably >50%, most preferably >100% and that blocks the ADM bioactivity not more than 80%, preferably not more than 50%. 
     
     
         17 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1  to be used in combination with vasopressors e.g. catecholamine and/or fluids administered intravenously. 
     
     
         18 . 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 therapy of an acute disease or acute condition of a patient according to  claim 1 . 
     
     
         19 . Pharmaceutical formulation comprising an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in a therapy of an acute disease or acute condition of a patient according to  claim 1 . 
     
     
         20 . Pharmaceutical formulation for use in therapy of an acute disease or acute condition of a patient according to  claim 19 , wherein said pharmaceutical formulation is a solution, preferably a ready-to-use solution. 
     
     
         21 . Pharmaceutical formulation for use in therapy of an acute disease or acute condition of a patient according to  claim 20 , wherein said pharmaceutical formulation is in a freeze-dried state. 
     
     
         22 . Pharmaceutical formulation according to  claim 19 , wherein said pharmaceutical formulation is administered intra-muscular. 
     
     
         23 . Pharmaceutical formulation according to  claim 19 , wherein said pharmaceutical formulation is administered intra-vascular. 
     
     
         24 . Pharmaceutical formulation according to  claim 19 , wherein said pharmaceutical formulation is administered via infusion. 
     
     
         25 . Pharmaceutical formulation according to  claim 19 , wherein said pharmaceutical formulation is to be administered systemically to a patient for prevention or reduction of organ dysfunction or organ failure in a patient having an acute disease or acute condition. 
     
     
         26 . Pharmaceutical formulation according to  claim 19 , wherein said pharmaceutical formulation is to be administered systemically via infusion to a patient for prevention or reduction of organ dysfunction or organ failure in a patient having an acute disease or acute condition.