Epitopes in the RNA recognition motif 1 (RRM1) of TDP-43 and misfolding-selective antibodies thereto

Patent metadata

Field	Value
Publication number	US-11214613-B2
Application number	US-201816616832-A
Country	US
Kind code	B2
Filing date	May 30, 2018
Priority date	May 30, 2017
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

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

First claim

The invention claimed is:

1. An antibody that selectively binds TDP-43, wherein the antibody comprises a light chain variable region and a heavy chain variable region, the heavy chain variable region comprising complementarity determining regions CDR-H1, CDR-H2 and CDR-H3, the light chain variable region comprising complementarity determining regions CDR-L1, CDR-L2 and CDR-L3 and with the amino acid sequences of said CDRs comprising the sequences:

A)
CDR-H1: GYTFTDYS;
SEQ ID NO: 67

CDR-H2: INTETGEP;
SEQ ID NO: 68

CDR-H3: ASRRWYPYYFDY;
SEQ ID NO: 69

CDR-L1: TGAVTTSNY;
SEQ ID NO: 70

CDR-L2: GPN; and
SEQ ID NO: 71

CDR-L3: ALWYSNHWV;
SEQ ID NO: 72

or

B)
CDR-H1: GFTFSDYY;
SEQ ID NO: 73

CDR-H2: ISNGGGST;
SEQ ID NO: 74

CDR-H3: AREGGTAWFAY;
SEQ ID NO: 75

CDR-L1: QSIVHSNGNTY;
SEQ ID NO: 76

CDR-L2: KVS; and
SEQ ID NO: 77

CDR-L3: FQGSHVPYT;
SEQ ID NO: 78

or

C)
CDR-H1: GFTFSDYY;
SEQ ID NO: 73

CDR-H2: ISDGGSYT;
SEQ ID NO: 79

CDR-H3: ARDYYGSSSYTSGFAY;
SEQ ID NO: 80

CDR-L1: QSIVHSNGNTY;
SEQ ID NO: 76

CDR-L2: KVS; and
SEQ ID NO: 77

CDR-L3: FQGSHVPGT
SEQ ID NO: 81

or

D)
CDR-H1: GYTFTDYS;
SEQ ID NO: 67

CDR-H2: INTETGEP;
SEQ ID NO: 68

CDR-H3: ARGYGNWFAY;
SEQ ID NO: 82

CDR-L1: SSVSSSY;
SEQ ID NO: 83

CDR-L2: STS; and
SEQ ID NO: 84

CDR-L3: HQYHRSPLT;
SEQ ID NO: 85

or

E)
CDR-H1: GFTFSDFY;
SEQ ID NO: 86

CDR-H2: SRSKAHDYTT; and
SEQ ID NO: 87

CDR-H3: ARDTWYGSWFAY;
SEQ ID NO: 88

CDR-L1: QSIVHSNGNTY;
SEQ ID NO: 76

CDR-L2: KVS; and
SEQ ID NO: 77

CDR-L3: FQGSHVPPT;
SEQ ID NO: 92

or

F)
CDR-H1: GYAFTNYL;
SEQ ID NO: 89

CDR-H2: INPGSGGT; and
SEQ ID NO: 90

CDR-H3: ARWGGNYSGYAMDY;
SEQ ID NO: 91

CDR-L1: QSIVHSNGNTY;
SEQ ID NO: 76

CDR-L2: KVS; and
SEQ ID NO: 77

CDR-L3: FQGSHVPPT
SEQ ID NO: 92.

2. The antibody of claim 1 , wherein the antibody selectively binds misfolded TDP-43 polypeptide compared to native TDP-43 polypeptide.

3. The antibody of claim 2 , wherein the antibody is at least 2 fold, 3 fold, at least 5 fold, at least 10 fold or at least 20 fold more selective for misfolded TDP-43 polypeptide compared to native TDP-43 polypeptide.

4. The antibody of claim 1 , wherein the antibody comprises:
a) a heavy chain variable region comprising: i) the amino acid sequence as set forth in SEQ ID NO: 46; ii) an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 46, wherein the CDR sequences are as set forth in SEQ ID NO: 67, 68 and 69, or iii) a conservatively substituted amino acid sequence of i), wherein the CDR sequences are as set forth in SEQ ID NO: 67, 68 and 69; and/or wherein the antibody comprises a light chain variable region comprising i) the amino acid sequence as set forth in SEQ ID NO: 48, ii) an amino acid sequence with a

Assignees

• Univ British Columbia

Inventors

• Plotkin Steven S
• Cashman Neil R
• Peng Xubiao

Classifications

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• G01N33/6872 Primary

  Intracellular protein regulatory factors and their receptors, e.g. including ion channels · CPC title

• C07K14/4703

  Inhibitors; Suppressors · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title