Binding agonist for treatment of neurological and other disorders

Abstract

The present invention relates to TrkB binding agonists, and to the use of such agonists in the treatment of neurological disorders and other disorders. The present invention also relates to specific TrkB binding agonists comprising CDRs, variable regions, heavy and light chains, and variant sequences thereof.

1 - 55 . (canceled) 
     
     
         56 . A TrkB binding agonist that either:
 a) interacts with one or more residues of human TrkB: Thr290, Glu293, Ser294, Asp358, Ser375, Lys372, Gln373 and Glu341;   b) approaches to less than or equal to 4.5 Å one or more residues of human TrkB: T288, 1289, T290, F291, L292, E293, S294, K308, D358, E371, K372, Q373, I374, and S375;   c) binds to human TrkB extracellular domain in which a residue from E210, F285, T288, T290, F291, E293, D370 and K372 (numbering according to full length human TrkB) is mutated with an altered affinity compared to human TrkB extracellular domain with no mutation;   d) binds to human TrkB and results in peptides derived from human TrkB containing part or the whole of the sequence from residues 284-291 (numbering according to full length human TrkB) being more resistant to deuterium incorporation compared to corresponding peptides derived from uncomplexed human TrkB; or   e) binds to a peptide having the amino acid sequence set forth in SEQ ID NO: 71.   
     
     
         57 . The TrkB binding agonist of  claim 56 , wherein the TrkB binding agonist binds to human TrkB and results in peptides derived from human TrkB containing part or the whole of the sequence from residues 284-291 (numbering according to full length human TrkB) being more resistant to deuterium incorporation compared to corresponding peptides derived from uncomplexed human TrkB. 
     
     
         58 . The TrkB binding agonist of  claim 56 , wherein the TrkB binding agonist binds to a peptide having the amino acid sequence set forth in SEQ ID NO: 71. 
     
     
         59 . The TrkB binding agonist of  claim 56 , wherein the TrkB binding agonist does not compete with BDNF and/or NT-4 for binding to TrkB. 
     
     
         60 . The TrkB binding agonist of  claim 56 , wherein the TrkB binding agonist potentiates BDNF-induced and/or NT-4 induced agonism of TrkB. 
     
     
         61 . The TrkB binding agonist of  claim 60 , wherein the potentiation is measured by an increased activation of TrkB in the presence of a saturating concentration of BDNF or NT-4 in the presence of the TrkB binding agonist, compared with the absence of the TrkB binding agonist. 
     
     
         62 . The TrkB binding agonist of  claim 61 , wherein the increased activation of TrkB is measured by an increased level of phosphorylation of TrkB. 
     
     
         63 . The TrkB binding agonist of  claim 62 , wherein the phosphorylation of TrkB in the presence of a saturating concentration of BDNF or NT-4 is 100% in the absence of the TrkB binding agonist, compared with the increased level of at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, or at least 150% in the presence of the TrkB binding agonist. 
     
     
         64 . The TrkB binding agonist of  claim 56 , wherein the TrkB binding agonist exhibits less than or equal to a 5 fold difference in EC50 between phosphorylation of human and cynomolgus TrkB. 
     
     
         65 . The TrkB binding agonist of  claim 56 , wherein the TrkB binding agonist maintains TrkB levels on a cell surface. 
     
     
         66 . One or more nucleic acid sequences encoding the TrkB binding agonist of  claim 56 . 
     
     
         67 . The one or more nucleic acid sequences of  claim 66 , comprising SEQ ID NO: 44 encoding a heavy chain and/or SEQ ID NO: 45 encoding a light chain. 
     
     
         68 . One or more expression vectors comprising the one or more nucleic acid sequences of  claim 66 . 
     
     
         69 . A recombinant host cell comprising the one or more nucleic acid sequences of  claim 66 . 
     
     
         70 . A method for the production of a TrkB binding agonist, comprising culturing the recombinant host cell of  claim 69 , under conditions suitable for expression of the one or more nucleic acid sequences. 
     
     
         71 . A pharmaceutical composition comprising the TrkB binding agonist of  claim 56 , and one or a combination of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent. 
     
     
         72 . A method of treating a sensorineural hearing loss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the TrkB binding agonist of  claim 56 . 
     
     
         73 . The method of  claim 72 , wherein the hearing loss results from an acoustic trauma. 
     
     
         74 . The method of  claim 72 , wherein the hearing loss is a sensory hearing loss. 
     
     
         75 . The method of  claim 72 , wherein the hearing loss is an 8 th  nerve related hearing loss. 
     
     
         76 . The method of  claim 72 , wherein the hearing loss is a hidden hearing loss. 
     
     
         77 . The method of  claim 72 , wherein the hearing loss is tinnitus. 
     
     
         78 . The method of  claim 72 , wherein the hearing loss is presbycusis. 
     
     
         79 . The method of  claim 72 , wherein the hearing loss is ototoxic hearing loss, sudden sensorineural hearing loss, cochlear deafness, or caused by a bacterial or viral infection. 
     
     
         80 . The method of  claim 72 , wherein the TrkB agonist is used in combination with a cochlear implant. 
     
     
         81 . The method of  claim 72 , wherein the TrkB agonist is used in combination with a steroid. 
     
     
         82 . The method of  claim 72 , wherein the TrkB agonist is administered in a sustained release formulation. 
     
     
         83 . The method of  claim 72 , wherein the TrkB agonist is administered by an injection. 
     
     
         84 . The method of  claim 72 , wherein the TrkB agonist is administered in an infusion. 
     
     
         85 . The method of  claim 72 , wherein the TrkB agonist is administered intracochlearly. 
     
     
         86 . The method of  claim 72 , wherein the TrkB agonist is administered transtympanically. 
     
     
         87 . A TrkB binding agonist that competes for binding to TrkB with a reference antibody having: (a) a heavy chain sequence of SEQ ID NO: 27 and a light chain sequence of SEQ ID NO: 28, wherein the competition is determined by more than 60% binding of the TrkB binding agonist to the TrkB in the presence of the reference antibody.