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CN-121991226-A - Antibodies that bind APRIL and uses thereof

CN121991226ACN 121991226 ACN121991226 ACN 121991226ACN-121991226-A

Abstract

Antibodies that bind APRIL and uses thereof. The present application relates to an isolated monoclonal antibody or antigen binding portion thereof capable of specifically binding to APRIL. The application also relates to nucleic acid molecules encoding the antibodies or antigen binding portions thereof, expression vectors, host cells and methods for expressing the antibodies or antigen binding portions thereof, and therapeutic methods using the antibodies or antigen binding portions thereof, nucleic acid molecules, expression vectors and/or host cells.

Inventors

  • LIN GUANGZHONG
  • LI JIANGMEI
  • ZHANG LUNFENG
  • ZHOU XUECHEN
  • SUN MINGZE
  • LI FENG

Assignees

  • 北京天广实生物技术股份有限公司

Dates

Publication Date
20260508
Application Date
20241101

Claims (16)

  1. 1. An isolated monoclonal antibody, or antigen binding portion thereof, capable of binding to APRIL comprising: i) A heavy chain variable region comprising a VH-CDR1 region, a VH-CDR2 region and a VH-CDR3 region, and Ii) a light chain variable region comprising a VL-CDR1 region, a VL-CDR2 region and a VL-CDR3 region, Wherein the VH-CDR1 region, VH-CDR2 region, VH-CDR3 region, VL-CDR1 region, VL-CDR2 region, and VL-CDR3 region each comprise an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs 1,2, 3,4, 5 or 6.
  2. 2. The isolated monoclonal antibody, or antigen-binding portion thereof, of claim 1, wherein the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID No. 7.
  3. 3. The isolated monoclonal antibody, or antigen-binding portion thereof, of claim 1, wherein the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID No. 8.
  4. 4. The isolated monoclonal antibody, or antigen-binding portion thereof, of claim 2, wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs 7 and 8, respectively.
  5. 5. An isolated monoclonal antibody, or antigen binding portion thereof, capable of binding to APRIL comprising: i) A heavy chain variable region comprising a VH-CDR1 region, a VH-CDR2 region and a VH-CDR3 region, wherein the VH-CDR1 region, VH-CDR2 region and VH-CDR3 region have at least 95%, 96%, 97%, 98%, 99% or 100% identity to a VH-CDR1 region, VH-CDR2 region and VH-CDR3 region, respectively, comprising the amino acid sequence set forth in SEQ ID No. 7, and Ii) a light chain variable region comprising a VL-CDR1 region, a VL-CDR2 region, and a VL-CDR3 region, wherein the VL-CDR1 region, the VL-CDR2 region, and the VL-CDR3 region are at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the VL-CDR1 region, the VL-CDR2 region, and the VL-CDR3 region, respectively, of a VL sequence comprising the amino acid sequence set forth in SEQ ID No. 8.
  6. 6. The isolated monoclonal antibody, or antigen-binding portion thereof, of claim 1 or 5, further comprising a heavy chain constant region linked to a heavy chain variable region, and a light chain constant region linked to a light chain variable region.
  7. 7. The monoclonal antibody, or antigen binding portion thereof, of claim 6, wherein the heavy chain constant region comprises strong FcRn binding under acidic conditions.
  8. 8. The monoclonal antibody, or antigen binding portion thereof, of claim 7, wherein the heavy chain constant region does not comprise fcrγ binding, or comprises weak fcrγ binding.
  9. 9. The monoclonal antibody or antigen-binding portion thereof according to claim 7, wherein the heavy chain constant region comprises an amino acid sequence set forth in any one of SEQ ID NOs 9-17, optionally the heavy chain constant region comprises an amino acid sequence set forth in any one of SEQ ID NOs 10-16, further optionally the heavy chain constant region comprises an amino acid sequence set forth in SEQ ID NO 10 or 14.
  10. 10. The monoclonal antibody, or antigen-binding portion thereof, according to claim 6, wherein the light chain constant region comprises the amino acid sequence set forth in SEQ ID No. 18.
  11. 11. A nucleic acid molecule encoding the isolated monoclonal antibody or antigen-binding portion thereof of any one of claims 1-10.
  12. 12. An expression vector comprising the nucleic acid molecule of claim 11.
  13. 13. A host cell comprising the nucleic acid molecule of claim 11 integrated into its genome, or comprising the expression vector of claim 12.
  14. 14. A composition comprising the isolated monoclonal antibody or antigen-binding portion thereof of any one of claims 1-10, the nucleic acid molecule of claim 11, the expression vector of claim 12, or the host cell of claim 13.
  15. 15. Use of a composition according to claim 14 for the manufacture of a medicament for the treatment of APRIL-related disorders.
  16. 16. The use of claim 15, wherein the APRIL-associated disorder is immunoglobulin a kidney disease.

Description

Antibodies that bind APRIL and uses thereof Technical Field The present invention relates to an antibody or antigen binding portion thereof capable of specifically binding to human APRIL, and its preparation and use, in particular, its use in the treatment of human autoimmune diseases associated with APRIL, such as IgA nephropathy, inflammatory diseases, and other immune diseases associated with B cell dysfunction, and the like. Background Immunoglobulin a nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide, with a global prevalence of about 3/10 ten thousand adults per year, with an incidence of east asia as high as 40-50%. IgAN is characterized by the deposition of immune complexes of galactose-deficient IgA1 (Gd-IgA 1) and autoantibodies targeting Gd-IgA1 in the mesangial region, which generally causes a decrease in renal function, with up to 25% -50% of patients developing end-stage renal disease within 10-20 years after onset (Cheung CK,et al.,(2024)Therole of BAFF and APRIL in IgA nephropathy:pathogenic mechanisms and targetedtherapies.Front Nephrol.3:1346769). IgA1 in normal humans is usually attached to the hinge region with a galactose-terminated O-sugar. Deletion of the O-terminal galactose of the IgA1 hinge region (i.e., to form Gd-IgA 1) exposes the N-acetylgalactosamine (GalNAc) residues in the O-sugar and is recognized by anti-sugar autoantibodies in susceptible humans to form an immune complex that deposits on the glomerular membrane, triggering a series of inflammatory reactions. This is the "4-fold hit" hypothesis of IgAN pathogenesis (SuzukiH, et al, (2011) The pathophysiology of IgA nepropath. J Am Soc Nephrol.22 (10): 1795-803). Furthermore, co-distribution of IgA with complement C3 was also observed in most IgAN patients, suggesting that the complement system may also be activated by Gd-IgA 1. Production of Gd-IgA1 and autoantibodies targeting Gd-IgA1 is driven primarily by mucosal plasma cells (Cheung CK, et al, (2024) supra). At present, the first-line medicine recommended by the international guidelines only comprises RAS blocking agents (pride/sartan medicines), but only can reduce a part of urine protein, and often cannot be treated to reach the standard. The fierce drug of the urine-reducing protein, hormone/immunosuppressant, is not very sensitive to IgAN, and has obvious side effect. The first targeted therapeutic of IgAN worldwide was Nefecon (budesonide delayed release capsule) from CALLIDITAS THERAPEUTICS, which was FDA approved at month 12 of 2021 for the treatment of proteinuria in primary IgA adult kidney disease patients with reduced risk of progression. Currently there are more than 20 drugs in clinical development that target Gd-IgA 1-producing B cells, activation of the complement system, and other downstream pathways activated following Gd-IgA deposition. IgA is produced mainly by plasma cells located in mucosa-associated lymphoid tissue (MALT). In MALT, antigen-presenting cells ingest antigen, causing activation of primary B cells and antibody class switching recombination of T cell-dependent (TD) and T cell-independent (TID), forming B cells capable of producing IgA. The occurrence of IgAN is likely to be related to an abnormality in this step. B cell activating factor (BAFF) and proliferation-inducing ligand (APRIL, also known as CD256 or TNFSF 13) play a key role in driving TD and TID antibody class switching recombination and production of IgA + B cells both (Sallustio F,et al.,(2021)High levels of gut-homingimmunoglobulin A+B lymphocytes support the pathogeneic role of intestinal mucosalhyperresponsiveness in immunoglobulin A nephropathy patients.Nephrol DialTransplant 36:452-64;Cerutti A.(2021)The regulation of IgA class switching.Nat RevImmunol(2021)8:421-34.;Moore JS,et al.,(2007)Reactivities of N-acetylgalactos-amine-specific lectins with human IgA1 proteins.Mol Immunol 44:2598-604;Castigli E,et al.,(2005)TACI and BAFFR mediate isotype switching in B cells.J Exp Med 201:35-9;Mackay F,et al.,(2003)BAFF and APRIL:a tutorial on B cell survival.Annu RevImmunol 21:231-64).BAFF and APRIL bind to B Cell Maturation Antigen (BCMA) and transmembrane activation, calmodulin and cyclophilin ligand-interacting factor (TACI), where BCMA is predominantly expressed in plasma cells and TACI is expressed in mature B cells and activated plasma cells. BAFF supports differentiation of B cells into long-lived plasma cells, which can continue to produce antibodies, including IgA1 and Gd-IgA1, without additional stimulation. APRIL may then cause antibody class switching recombination of the original B cells via TACI and/or BCMA signaling pathways, forming B cells capable of producing IgA. In vitro experiments, B cells from IgAN patients, when incubated with APRIL, increased Gd-IgA1 production, suggested that APRIL may play a role (ZhaiYL,et al.,(2016)Increased APRIL expression induces IgA1 aberrant glycosylation inIgA nephropathy.Medicine 95:e3099). in