Epitopes in the rna recognition motif 1 (rrm1) of tdp-43 and misfolding-selective antibodies thereto

Abstract

The disclosure pertains to conformational epitopes in TDP-43, antibodies thereto and methods of making and using immunogens and antibodies specific thereto.

1 . A cyclic compound comprising: a TDP-43 peptide comprising 1) TTE; 2) TTEQ (SEQ ID NO:1) or 3) TEQ and up to 6 TDP-43 contiguous residues, and a linker, wherein the linker is covalently coupled to the TDP-43 peptide N-terminus residue and the peptide C-terminus residue, wherein at least one amino acid in the TDP-43 peptide is an alternate conformation than T, E, and/or Q in a corresponding linear and/or native TDP-43. 
     
     
         2 . The cyclic compound of  claim 1 , wherein the TDP-43 peptide is selected from TTEQ (SEQ ID NO: 1), TTE, TEQ, KTTE (SEQ ID NO: 10), KTTEQ (SEQ ID NO:12), TEQD (SEQ ID NO:8) or TTEQD (SEQ ID NO: 9) optionally wherein the cyclic compound is a compound selected from any one of SEQ ID NOs: 2, 3, 13, 22-39, and 42-44. 
     
     
         3 . The cyclic compound of  claim 1 , wherein the TDP-43 peptide is TTEQ (SEQ ID NO: 1), TEQ or TTE. 
     
     
         4 . The cyclic compound of  claim 1 , wherein the linker comprises or consists of 1-8 amino acids and/or one or more functionalizable moieties. 
     
     
         5 . The cyclic compound of  claim 4 , wherein the linker amino acids are selected from A and G, and/or wherein the functionalizable moiety is C. 
     
     
         6 . The cyclic compound of  claim 1 , wherein the linker comprises or consists of GGCGG (SEQ ID NO: 40), GCGG (SEQ ID NO: 41) or GCG. 
     
     
         7 . The cyclic compound of  claim 1 , wherein the linker comprises one or more PEG molecules. 
     
     
         8 . The cyclic compound of  claim 1 , wherein the cyclic compound has a sequence selected from any one of SEQ ID NOs: 2, 3, 13, 22-39, and 42-44. 
     
     
         9 . An immunogen comprising a cyclic compound: comprising a TDP-43 peptide comprising 1) TTE; 2) TTEQ (SEQ ID NO:1) or 3) TEQ and up to 6 TDP-43 contiguous residues, and a linker, wherein the linker is covalently coupled to the TDP-43 peptide N-terminus residue and the peptide C-terminus residue, wherein at least one amino acid in the TDP-43 peptide is an alternate conformation than T, E, and/or Q in a corresponding linear and/or native TDP-43. 
     
     
         10 . The immunogen of  claim 9 , wherein the cyclic compound, is coupled to a carrier protein or immunogenicity enhancing component and/or formulated with an adjuvant. 
     
     
         11 . The immunogen of  claim 10 , wherein the carrier protein is bovine serum albumin (BSA) or the immunogenicity-enhancing component is keyhole limpet haemocyanin (KLH). 
     
     
         12 . The immunogen of  claim 11 , wherein the adjuvant is selected from aluminum phosphate, aluminum hydroxide alum, monophosphoryl lipid A and QS21. 
     
     
         13 .- 41 . (canceled) 
     
     
         42 . A composition comprising the cyclic compound of  claim 1  or an immunogen comprising the cyclic compound, optionally with a diluent. 
     
     
         43 .- 45 . (canceled) 
     
     
         46 . A kit comprising the cyclic compound of  claim 1 , an immunogen comprising the cyclic compound or a composition comprising the cyclic compound or immunogen. 
     
     
         47 .- 50 . (canceled) 
     
     
         51 . The cyclic compound of  claim 1 , wherein the cyclic compound has a sequence selected from any one of SEQ ID NOs: 2, 3, 22, 23, 28, 29, 30, 31, 32, 33, 34, 35 and 42. 
     
     
         52 . The cyclic compound of  claim 1 , wherein the cyclic compound has a sequence selected from any one of SEQ ID NOs: 2, 3, 22, 23 and 42. 
     
     
         53 . The immunogen of  claim 9 , wherein the TDP-43 peptide is selected from TTEQ (SEQ ID NO: 1), TTE, TEQ, KTTE (SEQ ID NO: 10), KTTEQ (SEQ ID NO:12), TEQD (SEQ ID NO:8) or TTEQD (SEQ ID NO: 9), optionally wherein the TDP-43 peptide is TTEQ (SEQ ID NO: 1), TEQ or TTE, and/or wherein the linker comprises or consists of 1-8 amino acids, optionally selected from A and G, and/or one or more functionalizable moieties, optionally selected from C. 
     
     
         54 . The immunogen of  claim 9 , wherein the cyclic compound has a sequence selected from any one of SEQ ID NOs: 2, 3, 13, 22-39, and 42-44. 
     
     
         55 . The immunogen of  claim 9 , wherein the cyclic compound has a sequence selected from any one of SEQ ID NOs: 2, 3, 22, 23, 28, 29, 30, 31, 32, 33, 34, 35 and 42. 
     
     
         56 . The immunogen of  claim 9 , wherein the cyclic compound has a sequence selected from any one of SEQ ID NOs: 2, 3, 22, 23 and 42.