JPWO2020181062A5

JPWO2020181062A5 -

Info

Publication number: JPWO2020181062A5
Application number: JP2021543386A
Authority: JP
Publication date: 2023-03-09

Claims

A multimeric T-cell regulatory antigen-presenting polypeptide comprising:
a) a first polypeptide,
i) Peptides presenting autoimmune disease-associated epitopes useful for treating autoimmune diseases other than or in addition to type 1 diabetes mellitus (T1D) or celiac disease, wherein said epitopes are associated with the T cell receptor (TCR ) , wherein the peptide has a length of about 4 amino acids to about 25 amino acids ;
ii) a first major histocompatibility complex (MHC) class II polypeptide;
b) a second polypeptide,
i) said second polypeptide comprising a second MHC class II polypeptide;
one or both of said multimeric polypeptides comprise one or more immunomodulatory polypeptides;
wherein said first and said second MHC class II polypeptides are
i) an MHC class II alpha chain polypeptide having at least 90% amino acid sequence identity to the DRA1*01:01 polypeptide and an MHC class II alpha chain polypeptide having at least 90% amino acid sequence identity to the DRB1 polypeptide; or ii) an MHC class II alpha chain polypeptide having at least 90% amino acid sequence identity to the DRA1 polypeptide and the following alleles: DRB1*01:01, DRB1*01:02, DRB1 *01:03, DRB1*0301, DRB1*03:02, DRB1*0304, DRB1*04:01, DRB1*04:02, DRB1*0403, DRB1*04:04, DRB1*04:05, DRB1*04 :06, DRB1*04:08, DRB1*08:03, DRB1*09:01, DRB1*10:01, DRB1*11:04, DRB1*13:01, DRB1*14:02, DRB1*1501, DRB1 *1502, and an MHC class II DRB1 chain polypeptide having at least 90% amino acid sequence identity to one DRB1 polypeptide of DRB1*1503; or iii) the following alleles: DQA1*01:01, DQA at least 90% amino acids for one of the DQA1 polypeptides of *01:02, DQA1*01:04, DQA1*03:01, DQA1*03:02, DQA1*04:01, DQA1*05:01 an MHC class II alpha chain polypeptide having sequence identity and an MHC class II beta chain polypeptide having at least 90% amino acid sequence identity to a DQB1 polypeptide; or iv) at least 90% to a DQA1 polypeptide; with the following alleles: DQB1*02:01, DQB1*03:01, DQB1*03:03, DQB1*04:01, DQB1*04:02, an MHC class II beta chain polypeptide having at least 90% amino acid sequence identity to one DQB1 polypeptide of DQB1*05:01, DQB1*05:03, DQB1*06:01, and DQB1*0602 or v) an MHC class II alpha chain polypeptide having at least 90% amino acid sequence identity to a DRA3 polypeptide and the following alleles: DRB3*01:01 and DR a MHC class II beta chain polypeptide having at least 90% amino acid sequence identity to one DRB3 polypeptide of B3*03:01; or vi) at least 90% amino acid sequence identity to a DRA4 polypeptide and an MHC class II β chain polypeptide having at least 90% amino acid sequence identity to the DRB4*01:01 polypeptide; or vii) at least to the DRA1 polypeptide; an MHC class II alpha chain polypeptide with 90% amino acid sequence identity and an MHC class II beta chain polypeptide with at least 90% amino acid sequence identity to a DRB5*01:01 polypeptide; or viii) DPA1 an MHC class II alpha chain polypeptide having at least 90% amino acid sequence identity to the polypeptide and one of the following alleles: DPB1*03:01, DPB1*09:01, and DPB1*13:01 an MHC class II beta chain polypeptide having at least 90% amino acid sequence identity to one DPB1 polypeptide;
one or both of said multimeric polypeptides optionally comprise an immunoglobulin (Ig) Fc polypeptide or a non-Ig backbone;
said multimeric T-cell regulatory antigen-presenting polypeptide.

a1) the first polypeptide, in order from the N-terminus to the C-terminus,
i) said peptide epitope;
ii) an MHC class II β1 polypeptide, and iii) an MHC class II β2 polypeptide, and b1) said second polypeptide, in order from N-terminal to C-terminal,
i) said one or more immunomodulatory polypeptides;
ii) MHC class II α1 polypeptide,
iii) an MHC class II α2 polypeptide, and iv) an Ig Fc polypeptide, or a2) said first polypeptide, in order from N-terminus to C-terminus,
i) said peptide epitope;
ii) an MHC class II β1 polypeptide, and iii) an MHC class II β2 polypeptide, and b2) said second polypeptide, in order from N-terminal to C-terminal,
i) an MHC class II α1 polypeptide,
ii) an MHC class II α2 polypeptide,
iii) an Ig Fc polypeptide, and iv) said one or more immunomodulatory polypeptides, or a3) said first polypeptide, in order from N-terminus to C-terminus,
i) said peptide epitope;
ii) an MHC class II β1 polypeptide, and iii) an MHC class II β2 polypeptide, and b3) said second polypeptide, in order from N-terminal to C-terminal,
i) an MHC class II α1 polypeptide,
ii) an MHC class II α2 polypeptide,
iii) said one or more immunomodulatory polypeptides, and iv) an Ig Fc polypeptide ,
2. The multimeric T-cell regulatory antigen-presenting polypeptide of claim 1.

a) said MHC class II alpha polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to a DQA1*01:01 polypeptide, and said MHC class II beta polypeptide comprises DQB1*05: or b) said MHC class II alpha polypeptide has at least 95% amino acid sequence identity to a DRA1*01:01 polypeptide. comprises an amino acid sequence having amino acid sequence identity, said MHC class II beta polypeptide comprising an amino acid sequence having at least 95% amino acid sequence identity to a DRB1*04:01 polypeptide, or c) said MHC class II alpha polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to a DRA1*01:01 polypeptide, and said MHC class II beta polypeptide comprises a DRB5*01:01 polypeptide; or d) said MHC class II alpha polypeptide has at least 95% amino acid sequence identity to the DQA1*01:02 polypeptide. or e) said MHC wherein the class II alpha polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to a DQA1*03:01 polypeptide, and said MHC class II beta polypeptide comprises a DQB1*03:03 polypeptide; or f) said MHC class II alpha polypeptide has at least 95% amino acid sequence identity to the DQA1*01:04 polypeptide and said MHC class II beta polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to a DQB1*05:01 polypeptide, or g) said MHC class II wherein the alpha polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the DRA1*01:01 polypeptide; or h) said MHC class II alpha polypeptide comprises DQA1*04: 01 polypeptide, wherein said MHC class II beta polypeptide has at least 95% amino acid sequence identity to a DQB1*04:02 polypeptide; or i) said MHC class II alpha polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to a DQA1*03:02 polypeptide, and said MHC class II the beta polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the DQB1*03:01 polypeptide;
3. The multimeric T cell regulatory antigen-presenting polypeptide of claim 1 or claim 2.

wherein said immunomodulatory polypeptide is
A variant immunomodulatory polypeptide comprising: a) an amino acid sequence of a naturally occurring immunomodulatory polypeptide, or b) an amino acid sequence having from 1 to 10 amino acid substitutions compared to the amino acid sequence of said naturally occurring immunomodulatory polypeptide. is a peptide, wherein said variant immunomodulatory polypeptide has a reduced affinity for said coregulatory polypeptide compared to the affinity of said native immunomodulatory polypeptide for said coregulatory polypeptide;
The T-cell modulatory antigen-presenting polypeptide of any one of claims 1-3.

5. The T-cell modulatory antigen-presenting polypeptide of any one of claims 1-4, wherein said immunomodulatory polypeptide is a PD-Ll polypeptide, a FasL polypeptide, or a TGF-β polypeptide.

The T cell modulatory antigen-presenting polypeptide of any one of claims 1-4, wherein said immunomodulatory polypeptide is a PD-L1 polypeptide.

The T-cell modulatory antigen-presenting polypeptide of any one of claims 1-6 , wherein said peptide is a multiple sclerosis-related peptide , a rheumatoid arthritis-related peptide epitope, or a systemic lupus erythematosus-related peptide epitope .

7. The T-cell regulatory antigen-presenting polypeptide of any one of claims 1-6 , wherein said peptide is an Addison's disease -related peptide, a myasthenia gravis-related peptide epitope, a Sjögren's syndrome-related peptide epitope, or a psoriasis-related peptide epitope. peptide.

a) the first polypeptide, in order from N-terminus to C-terminus,
i) a peptide epitope;
ii) a linker; and
iii) MHC class II beta chain polypeptides
including
b) said second polypeptide, in order from N-terminus to C-terminus,
i) PD-L1 immunomodulatory polypeptides
ii) linker
iii) MHC class II alpha chain polypeptides;
iv) a linker; and
v) an Ig Fc polypeptide comprising an amino acid sequence having at least 90% amino acid sequence identity to the IgG1 Fc amino acid sequence shown in Figure 21A
including,
The T-cell modulatory antigen-presenting polypeptide of any one of claims 1-8 .

10. The T-cell regulatory antigen-presenting polypeptide of claim 9, wherein said Ig Fc polypeptide comprises Ala at position 14 and Ala at position 15, based on the amino acid numbering of Figure 21A.

A pharmaceutical composition comprising the T-cell regulatory antigen-presenting polypeptide of any one of claims 1-10 .

One or more nucleic acids comprising a nucleotide sequence encoding the T-cell regulatory antigen-presenting polypeptide of any one of claims 1-10 .

13. One or more expression vectors comprising one or more nucleic acids of claim 12 .

A host cell genetically modified with one or more nucleic acids according to claim 12 or one or more expression vectors according to claim 13 .

12. A pharmaceutical composition according to claim 11 for use in a ^method of reducing the number and/or activity of CD4 ⁺ T cells specific for an autoimmune disease in an individual, said method comprising with the T-cell regulatory antigen-presenting polypeptide of any one of claims 1-10, wherein said contacting reduces the number and/or activity of said CD4 ⁺ T cells, said The pharmaceutical composition, wherein the autoimmune disease is other than T1D or celiac disease.

12. A pharmaceutical composition according to claim 11 for use in a method of treating an autoimmune disease other than type 1 diabetes in an individual, the method administering to an individual in need thereof an effective amount of claim 1. 11. Said pharmaceutical composition comprising administering the T-cell modulating antigen-presenting polypeptide of any one of claims 1-10 .

The autoimmune disease is Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-related infertility, autoimmune thrombocytopenic purpura disease, bullous pemphigoid, Crohn's disease, Goodpasture's syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Graves' disease, Hashimoto's thyroiditis, mixed connective tissue disease, multiple Sclerosis, myasthenia gravis (MG), pemphigus (e.g. pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), vasculitis , or vitiligo .