Anti-adrenomedullin (adm) antibody or anti-adm antibody fragment of anti-adm non-ig scaffold for regulating the fluid balance in a patient having a chronic or acute disease

Abstract

Patients having a chronic or acute disease or acute condition, especially patients at the ICU (Intensive Care Unit) suffer from fluid imbalance. The present invention provides a medicament for regulating the fluid balance and/or improving the fluid balance of such patients. 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 regulating the fluid balance in a patient having a chronic or acute disease or acute condition. The present invention also provides a method for regulating the fluid balance in a patient having a chronic or acute disease or acute condition. Subject matter of the present invention is an anti-Adrenomedullin ADM antibody or anti-ADM non-Ig scaffold or an anti-adrenomedullin antibody fragment for use in therapy of a chronic or acute disease or acute condition of a patient for the regulation of fluid balance.

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 the regulation of fluid balance. 
     
     
         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 patient is a patient in need of regulating the fluid balance. 
     
     
         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 anti-ADM antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is a non-neutralizing anti-ADM antibody or a non-neutralizing anti-adrenomedullin antibody fragment or a non-neutralizing anti-ADM non-Ig scaffold. 
     
     
         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  for preventing or reducing edema in said patient. 
     
     
         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 any of  claim 1 , wherein said antibody or antibody fragment or non-Ig scaffold is monospecific. 
     
     
         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 , characterized in that said antibody or fragment or scaffold exhibits a binding affinity to ADM of at least 10 −7  M. 
     
     
         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 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). 
     
     
         8 . 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 binds to a region of preferably at least 4 or at least 5 amino acids within the sequence of aa 1-42 of mature human ADM: 
       
         
           
                 
                 
               
                     
                   (SEQ ID No. 24) 
                 
                     
                   YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA. 
                 
             
                
                
               
            
           
         
       
     
     
         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 antibody fragment or non-Ig scaffold binds to a region of at least 4 or 5 amino acids within the sequence of aa 1-21 of mature human ADM: 
       
         
           
                 
                 
               
                     
                   (SEQ ID No. 23) 
                 
                     
                   YRQSMNNFQGLRSFGCRFGTC. 
                 
             
                
                
               
            
           
         
       
     
     
         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 fragment scaffold recognizes and binds to an epitope containing the N-terminal end amino acid 1 of mature human ADM and wherein said antibody or fragment or scaffold would neither bind N-terminal extended nor N-terminal modified Adrenomedullin nor N-terminal degraded adrenomedullin. 
     
     
         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 is an ADM stabilizing antibody or ADM stabilizing antibody fragment or ADM stabilizing non-Ig scaffold that enhances the half life (t 1/2  half retention time) of adrenomedullin in serum, blood, plasma at least 10%, preferably at least 50%, more preferably >50%, most preferably >100%. 
     
     
         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 antibody or fragment blocks the circulating ADM bioactivity not more than 80%, preferably not more than 50%. 
     
     
         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 selected from the group comprising SIRS, sepsis, diabetes, cancer, heart failure, shock and kidney dysfunction. 
     
     
         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 an antibody or fragment that binds to ADM or an antibody fragment thereof that binds to ADM 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: 
       
         
           
                 
               
                   (AM-VH-C) 
                 
                   SEQ ID NO: 7 
                 
                   QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIG 
                 
                     
                 
                   EILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTE 
                 
                     
                 
                   GYEYDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
                 
                     
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
                 
                     
                 
                   QTYICNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH1) 
                 
                   SEQ ID NO: 8 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMG 
                 
                     
                 
                   RILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTE 
                 
                     
                 
                   GYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
                 
                     
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
                 
                     
                 
                   QTYICNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH2-E40) 
                 
                   SEQ ID NO: 9 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMG 
                 
                     
                 
                   RILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTE 
                 
                     
                 
                   GYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
                 
                     
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
                 
                     
                 
                   QTYICNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH3-T26-E55) 
                 
                   SEQ ID NO: 10 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMG 
                 
                     
                 
                   EILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTE 
                 
                     
                 
                   GYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
                 
                     
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
                 
                     
                 
                   QTYICNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VH4-T26-E40-E55) 
                 
                   SEQ ID NO: 11 
                 
                   QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMG 
                 
                     
                 
                   EILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTE 
                 
                     
                 
                   GYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
                 
                     
                 
                   KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
                 
                     
                 
                   QTYICNVNHKPSNTKVDKRVEPKHHHHHH 
                 
                     
                 
                   (AM-VL-C) 
                 
                   SEQ ID NO: 12 
                 
                   DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSP 
                 
                     
                 
                   KLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSH 
                 
                     
                 
                   IPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR 
                 
                     
                 
                   EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV 
                 
                     
                 
                   YACEVTHQGLSSPVTKSFNRGEC 
                 
                     
                 
                   (AM-VL1) 
                 
                   SEQ ID NO: 13 
                 
                   DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSP 
                 
                     
                 
                   RRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH 
                 
                     
                 
                   IPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR 
                 
                     
                 
                   EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV 
                 
                     
                 
                   YACEVTHQGLSSPVTKSFNRGEC 
                 
                     
                 
                   (AM-VL2-E40) 
                 
                   SEQ ID NO: 14 
                 
                   DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSP 
                 
                     
                 
                   RRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH 
                 
                     
                 
                   IPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR 
                 
                     
                 
                   EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV 
                 
                     
                 
                   YACEVTHQGLSSPVTKSFNRGEC 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         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 modulating fragment or modulating scaffold that enhances the half life (t 1/2  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 bioactivity of ADM 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 , characterized in that said antibody, antibody fragment or non-Ig scaffold does not bind to the C-terminal portion of ADM, being it aa 43-52 of ADM (SEQ ID NO: 25) 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 25) 
                 
                     
                   PRSKISPQGY-NH2. 
                 
             
                
                
               
            
           
         
       
     
     
         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  to be used in combination with catecholamine and/or fluids administered intravenously. 
     
     
         19 . 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 ADM binding protein and/or further active ingredients. 
     
     
         20 . 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 the regulation of fluid balance according to  claim 1 , characterized in that said therapy is not a method of primary treatment to said acute disease or acute condition. 
     
     
         21 . Pharmaceutical formulation comprising an 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 . 
     
     
         22 . Pharmaceutical formulation comprising an 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 21 , wherein said pharmaceutical formulation is a solution, preferably a ready-to-use solution. 
     
     
         23 . Pharmaceutical formulation comprising an 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 22 , wherein said pharmaceutical formulation is in a freeze-dried state. 
     
     
         24 . Pharmaceutical formulation comprising an 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 21 , wherein said pharmaceutical formulation is to be administered to a patient for regulating the systemic fluid balance with the proviso that said patient is in need of regulating the fluid balance.