US-20260125451-A1 - FUSION PROTEIN COMPRISING TACI POLYPEPTIDE AND USE THEREOF

US20260125451A1US 20260125451 A1US20260125451 A1US 20260125451A1US-20260125451-A1

Abstract

The present disclosure provides a fusion protein comprising a TACI polypeptide and a use thereof, particularly a use for preventing or treating autoimmune diseases.

Inventors

Han Gao
Huan WANG
Chongqi ZHANG
Yuan Lin
Kan Lin
Cheng Liao

Assignees

JIANGSU HENGRUI PHARMACEUTICALS CO., LTD.
SHANGHAI SHENGDI PHARMACEUTICAL CO., LTD.

Dates

Publication Date: 20260507
Application Date: 20230829
Priority Date: 20220829

Claims (20)

1 . A fusion protein, comprising: (a) a TACI polypeptide and an anti-IFNAR1 antibody or an antigen-binding fragment thereof, or (b) a TACI polypeptide, a BCMA polypeptide, and an anti-IFNAR1 antibody or an antigen-binding fragment thereof, or (c) a TACI polypeptide and a BCMA polypeptide, wherein the TACI polypeptide comprises a CRD1 and/or a CRD2 of a TACI extracellular region; and the BCMA polypeptide comprises a CRD1 of a BCMA extracellular region.
2 . The fusion protein according to claim 1 , wherein: the TACI polypeptide comprises a polypeptide selected from any one of (1)-(6) below: (1) the amino acid residues at positions 68-105 of SEQ ID NO: 1, or a variant thereof, (2) SEQ ID NO: 1 or a polypeptide having at least 95% sequence identity thereto; (3) the amino acid residues at positions 33-67 of SEQ ID NO: 1; (4) the amino acid residues at positions 70-104 of SEQ ID NO: 1, or a variant thereof, (5) the amino acid residues at positions 30-110, 69-111, 69-112, 13-118, or 33-104 of SEQ ID NO: 1, or a variant thereof, and (6) the amino acid residues at positions 68-106, 68-107, or 68-108 of SEQ ID NO: 1, or a variant thereof; optionally, the variant has anyone of the following (1)-(3): (1) one or more amino acid mutations selected from positions 69, 72, 73, 77, 85, 102, and 103, (2) one or more amino acid replacements selected from 69T or 69R, 72S, 73E or 73Q, 77E, 85T or 85A, 102A or 102R, and 103Y; or, (3) an amino acid replacement or a combination of amino acid replacements selected from any one of the following: 69T; 72S; 73E; 73Q; 77E; 69R and 85T; 69R and 85A; 102A; 69R, 85T, and 102R; 73E and 77E; 72S, 73E, and 77E; 69T and 102A; 69T and 103Y; 69T, 102A, and 103Y; and 69T, 73E, 77E, and 102A; and amino acid residues are numbered in natural order according to the sequence set forth in SEQ ID NO: 1.
3 . The fusion protein according to claim 1 , wherein the TACI polypeptide comprises an amino acid sequence selected from any one of SEQ ID NOs: 1, 2, and 6-29.
4 . The fusion protein according to claim 1 , wherein the anti-IFNAR1 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises a HCDR1, a HCDR2, and a HCDR3, and the amino acid sequences of the HCDR1, the HCDR2, and the HCDR3 are set forth in SEQ ID NOs: 45-47, respectively; and the light chain variable region comprises a LCDR1, a LCDR2, and a LCDR3, and the amino acid sequences of the HCDR1, the HCDR2, and the HCDR3 are set forth in SEQ ID NOs: 48-50, respectively.
5 . The fusion protein according to claim 4 , wherein: the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 43 or having at least 90% sequence identity thereto; and the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 44 or having at least 90% sequence identity thereto.
6 . The fusion protein according to claim 1 , comprising an Fc region of an immunoglobulin, wherein optionally the Fc region is an Fc region of IgG1.
7 . The fusion protein according to claim 6 , wherein the Fc region comprises one or more amino acid mutations capable of reducing binding of the Fc to an FcR; optionally, the one or more amino acid mutations are capable of reducing binding of the Fc to an FcγR; or, the one or more amino acid mutations are any one of the following amino acid mutations or combinations of amino acid mutations: 234A; 235A; 234F; 235E; 234F and 235E; 234A and 235A; and 234F, 235E, and 331S; mutation sites are defined according to the EU numbering scheme.
8 . The fusion protein according to claim 1 , wherein the anti-IFNAR1 antibody comprises a heavy chain and a light chain; the heavy chain comprises an amino acid sequence set forth in SEQ ID NO: 55 or 61 or having at least 90% sequence identity thereto, and the light chain comprises an amino acid sequence set forth in SEQ ID NO: 54 or having at least 90% sequence identity thereto.
9 . The fusion protein according to am claim 1 , comprising polypeptide chains set forth in any one of (I)-(VIII) below: (I) a first polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide]-[linker 1]a-[antibody heavy chain], and a second polypeptide chain that is an antibody light chain; (II) a first polypeptide chain that is, from the N-terminus to the C-terminus, [antibody heavy chain]-[linker 2]b-[TACI polypeptide], and a second polypeptide chain that is an antibody light chain; (III) a first polypeptide chain that is an antibody heavy chain, and a second polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide]-[linker 3]c-[antibody light chain]; (IV) a first polypeptide chain that is an antibody heavy chain, and a second polypeptide chain that is, from the N-terminus to the C-terminus, [antibody light chain]-[linker 4]d-[TACI polypeptide]; (V) a first polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide 1]-[linker 1]a-[antibody heavy chain], and a second polypeptide chain that is, from the N-terminus to the C-terminus, [antibody light chain]-[linker 4]d-[TACI polypeptide 2]; (VI) a first polypeptide chain that is, from the N-terminus to the C-terminus, [antibody heavy chain]-[linker 2]b-[TACI polypeptide 1], and a second polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide 2]-[linker 3]c-[antibody light chain]; (VII) a first polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide 1]-[linker 1]a-[antibody heavy chain]-[linker 2]b-[TACI polypeptide 2], and a second polypeptide chain that is an antibody light chain; and (VIII) a first polypeptide chain that is an antibody heavy chain, and a second polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide 1]-[linker 3]c-[antibody light chain]-[linker 4]d-[TACI polypeptide 2]; wherein: represents a peptide bond; linker 1, linker 2, linker 3, and linker 4 may be identical or different; the TACI polypeptide, the TACI polypeptide 1, and the TACI polypeptide 2 are each independently selected from the TACI polypeptide defined in claim 1 , and TACI polypeptide 1 and TACI polypeptide 2 may be identical or different; a, b, c, and d are each independently 0 or 1; and the antibody is the anti-IFNAR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises a HCDR1, a HCDR2, and a HCDR3, and the amino acid sequences of the HCDR1, the HCDR2, and the HCDR3 are set forth in SEQ ID NOs: 45-47, respectively; and the light chain variable region comprises a LCDR1, a LCDR2, and a LCDR3, and the amino acid sequences of the HCDR1, the HCDR2, and the HCDR3 are set forth in SEQ ID NOs: 48-50, respectively; optionally, the linker 1, linker 2, linker 3, and linker 4 are each independently (GxS)y, wherein x is an integer of 1-5, and y is an integer of 1-6; or, the amino acid sequences of the linker 1, linker 2, linker 3, and linker 4 are each independently set forth in any one of SEQ ID NOs: 39-41.
10 . (canceled)
11 . The fusion protein according to claim 1 , wherein the BCMA polypeptide comprises the amino acid residues at positions 7-41 of SEQ ID NO: 30; or the amino acid sequence of the BCMA polypeptide comprises a sequence selected from any one of SEQ ID NOs: 30, 67, and 68.
12 . The fusion protein according to claim 1 , comprising polypeptide chains set forth in any one of (i)-(viii) below: (i) a first polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide and BCMA polypeptide domain]-[linker 1]a-[antibody heavy chain], and a second polypeptide chain that is an antibody light chain; (ii) a first polypeptide chain that is, from the N-terminus to the C-terminus, [antibody heavy chain]-[linker 2]b-[TACI polypeptide and BCMA polypeptide domain], and a second polypeptide chain that is an antibody light chain; (iii) a first polypeptide chain that is an antibody heavy chain, and a second polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide and BCMA polypeptide domain]-[linker 3]c-[antibody light chain]; (iv) a first polypeptide chain that is an antibody heavy chain, and a second polypeptide chain that is, from the N-terminus to the C-terminus, [antibody light chain]-[linker 4]d-[TACI polypeptide and BCMA polypeptide domain]; (v) a first polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide and BCMA polypeptide domain 1]-[linker 1]a-[antibody heavy chain], and a second polypeptide chain that is, from the N-terminus to the C-terminus, [antibody light chain]-[linker 4]d-[TACI polypeptide and BCMA polypeptide domain 2]; (vi) a first polypeptide chain that is, from the N-terminus to the C-terminus, [antibody heavy chain]-[linker 2]b-[TACI polypeptide and BCMA polypeptide domain 1], and a second polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide and BCMA polypeptide domain 2]-[linker 3]c-[antibody light chain]; (vii) a first polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide and BCMA polypeptide domain 1]-[linker 1]a-[antibody heavy chain]-[linker 2]b-[TACI polypeptide and BCMA polypeptide domain 2], and a second polypeptide chain that is an antibody light chain; and (viii) a first polypeptide chain that is an antibody heavy chain, and a second polypeptide chain that is, from the N-terminus to the C-terminus, [TACI polypeptide and BCMA polypeptide domain 1]-[linker 3]c-[antibody light chain]-[linker 4]d-[TACI polypeptide and BCMA polypeptide domain 2]; wherein: the [TACI polypeptide and BCMA polypeptide domain], the [TACI polypeptide and BCMA polypeptide domain 1], and the [TACI polypeptide and BCMA polypeptide domain 2] are, from the N-terminus to the C-terminus: [TACI polypeptide]-[linker 5]e-[BCMA polypeptide] or [BCMA polypeptide]-[linker 5]e-[TACI polypeptide]; the [TACI polypeptide and BCMA polypeptide domain 1] and the [TACI polypeptide and BCMA polypeptide domain 2] may be identical or different, and the BCMA polypeptide domain 1 and the BCMA polypeptide domain 2 may be identical or different; or the TACI polypeptide is selected from the TACI polypeptide defined in claim 1 , the BCMA polypeptide is selected from the BCMA polypeptide defined in claim 1 , and the antibody is selected from the anti-IFNAR1 comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises a HCDR1, a HCDR2, and a HCDR3, and the amino acid sequences of the HCDR1, the HCDR2, and the HCDR3 are set forth in SEQ ID NOs: 45-47, respectively; and the light chain variable region comprises a LCDR1, a LCDR2, and a LCDR3, and the amino acid sequences of the HCDR1, the HCDR2, and the HCDR3 are set forth in SEQ ID NOs: 48-50, respectively; wherein: represents a peptide bond; the linker 1, linker 2, linker 3, linker 4, and linker 5 may be identical or different; a, b, c, d, and e are each independently 0 or 1; optionally, the linker 1, linker 2, linker 3, linker 4, and linker 5 are each independently (GxS)y, wherein x is an integer of 1-5, and y is an integer of 1-6; or, the amino acid sequences of the linker 1, linker 2, linker 3, linker 4, and linker 5 are each independently set forth in any one of SEQ ID NOs: 39-41.
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . (canceled)
17 . (canceled)
18 . (canceled)
19 . (canceled)
20 . (canceled)

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is the U.S. national stage application, filed under 35 U.S.C. § 371, of International Patent Application No. PCT/CN2023/115448, filed on Aug. 29, 2023, which claims priority to Chinese Patent Application No. CN202211041405.0, titled “FUSION PROTEIN COMPRISING TACI POLYPEPTIDE AND USE THEREOF” and filed on Aug. 29, 2022, both of which are incorporated herein by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING This application contains a Sequence Listing, which has been submitted electronically in xml format and is hereby incorporated by reference in its entirety. Said xml copy, created on Jan. 8, 2026, is named SeqList-166928-00019.xml and is 96,147 bytes in size. TECHNICAL FIELD The present disclosure relates to the field of biopharmaceuticals and particularly to a fusion protein comprising a TACI polypeptide and use thereof in the treatment of diseases, especially autoimmune diseases. BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune disease that affects various tissues and organs in the human body, such as the skin on the face and the kidneys. A distinguishing characteristic of SLE is the production of antibodies against the patient's own tissue antigens, such as antinuclear antibodies (ANAs). The causes of SLE are complex and involve factors such as genetic predisposition, environments, hormones, and autoantibodies. The disease has a prolonged course with highly variable clinical symptoms among individuals, reflecting its significant heterogeneity. In addition, SLE has a high incidence rate. In China alone, there are over one million SLE patients. The global incidence rate is approximately (30 to 50)/100,000 people, and the incidence rate in women is 10 times higher than in men. The activation of the type I interferon pathway plays a critical role in the pathogenesis of SLE. It can promote the activation of multiple types of immune cells closely related to SLE development, such as plasmacytoid dendritic cells (pDCs) and B cells. 60% to 80% of SLE patients exhibit high expression of type I interferons, and there is a positive correlation between type I interferon levels and SLE disease activity index (SLEDAI) scores. Anifrolumab, developed by AstraZeneca, is a monoclonal antibody targeting type I interferon (IFN) receptor subunit 1 (IFNART). It antagonizes the related activities of all type I interferons (IFN-α, IFN-β, IFN-ω, etc.), thereby controlling the progression of SLE. In the phase III TULIP-2 clinical trial, 47.8% of patients treated with anifrolumab showed improvement in the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) score, compared to 31.5% in the placebo group, suggesting an improvement in disease activity across all affected organs and a reduction in the use of glucocorticoids. However, in another phase III (TULIP-1) clinical trial with the SLE responder index SRI-4 as the endpoint, no significant improvement in disease scores was observed (36% vs. 40%). These results demonstrate the potential of targeting the type I interferon pathway to treat SLE, but targeting IFNART alone may not provide sufficient efficacy. Both B lymphocyte stimulator (BLyS), also known as BAFF, and A proliferation-inducing ligand (APRIL) are crucial factors for the differentiation and maturation of B lymphocytes and for promoting the survival of plasma cells. They belong to the tumor necrosis factor (TNF) ligand family. The overexpression of these two factors is an important driving force behind several B lymphocyte-related autoimmune diseases, such as SLE. Members of the TNF ligand family are often synthesized as transmembrane proteins, and it is common for membrane-anchored proteins to be hydrolyzed by proteases and then released from the cell surface. BAFF is a type II transmembrane protein that exists in both membrane-bound and soluble forms. After the membrane-bound BAFF is cleaved by Furin convertase, a biologically active trimeric form of BAFF is released. BAFF is expressed on various cell types, including monocytes, dendritic cells, and bone marrow stromal cells. APRIL exists in a different form than TNF ligand family members do. APRIL is processed in the Golgi apparatus by Furin convertase and then secreted directly as a soluble trimeric form into the extracellular space. BAFF and APRIL have been found to have three receptors: B cell maturation antigen (BCMA), transmembrane activator and CAMEL interactor (TACI), and the BAFF receptor (BAFF-R, also known as Br3). They are all members of the TNF receptor family. The extracellular region of TNF receptors contains multiple cysteine-rich domains (CRDs), and each CRD has 6 cysteines that form 3 disulfide bonds. These CRDs fulfill the function of binding to a ligand. BAFF and APRIL have different capabilities to bind to these three receptors: BAFF binds more strongly to TACI than to BCMA, while APRIL binds more strongly to BCMA than t