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KR-20260068139-A - Combination therapy containing anti-CTHRC1 antibody and method of using the same

KR20260068139AKR 20260068139 AKR20260068139 AKR 20260068139AKR-20260068139-A

Abstract

The present invention relates to an anti-CTHRC1 antibody, a composition comprising the same, and a method for using the antibody and the composition for the prevention, diagnosis, and treatment of diseases or disorders, such as cancer, bone disease, fibrotic disease, arthritis, and osteoporosis.

Inventors

  • 쿠퍼 샘
  • 하비 크리스토퍼
  • 브리스킨 마이클
  • 버클리 에이미
  • 라이스 린지
  • 런던 맥스
  • 마틴 그렉

Assignees

  • 페노믹 에이아이

Dates

Publication Date
20260513
Application Date
20240110
Priority Date
20230110

Claims (20)

  1. As a method of treating a subject with cancer, A method comprising administering an anti-CTHRC1 antibody that binds to human CTHRC1 together with chemotherapy, radiation therapy, or immunotherapy.
  2. The method of claim 1, wherein the anti-CTHRC1 antibody (i) selectively binds to CTHRC1 and/or, (ii) blocks cell adhesion to CTHRC1 and/or, or (iii) becomes internalized when bound to a cell expressing CTHRC1.
  3. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7 and 9.
  4. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising an amino acid sequence selected from Table 3.
  5. A method according to any one of claims 1 to 4, wherein the anti-CTHRC1 antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8 and 10.
  6. A method according to any one of claims 1 to 4, wherein the anti-CTHRC1 antibody comprises a light chain variable region comprising an amino acid sequence selected from Table 4.
  7. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs: 150-154; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 180-184; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210-214.
  8. A method according to any one of claims 1 to 2 and 7, wherein the anti-CTHRC1 antibody comprises a light chain variable region comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs: 240-244; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 270-274; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 300-304.
  9. The method of claim 1, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising a CDR1 sequence comprising SEQ ID NO: 150; a CDR2 sequence comprising SEQ ID NO: 180; and a CDR3 sequence comprising SEQ ID NO: 210, and a light chain variable region comprising a CDR1 sequence comprising SEQ ID NO: 240; a CDR2 sequence comprising SEQ ID NO: 270; and a CDR3 sequence comprising SEQ ID NO: 300.
  10. A method according to any one of claims 1 to 9, wherein the anti-CTHRC1 antibody has a binding affinity (K D ) for CTHRC1 of less than 10 nM, preferably less than 5 nM, more preferably less than 1 nM.
  11. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2.
  12. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising SEQ ID NO: 3 and a light chain variable region comprising SEQ ID NO: 4.
  13. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising SEQ ID NO: 5 and a light chain variable region comprising SEQ ID NO: 6.
  14. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising SEQ ID NO: 7 and a light chain variable region comprising SEQ ID NO: 8.
  15. A method according to any one of claims 1 to 2, wherein the anti-CTHRC1 antibody comprises a heavy chain variable region comprising SEQ ID NO: 9 and a light chain variable region comprising SEQ ID NO: 10.
  16. A method according to any one of claims 1 to 15, wherein the anti-CTHRC1 antibody is a chimeric, humanized, or human antibody.
  17. A method according to any one of claims 1 to 15, wherein the anti-CTHRC1 antibody is a monoclonal antibody.
  18. A method according to any one of claims 1 to 15, wherein the anti-CTHRC1 antibody is an antibody fragment.
  19. A method according to any one of claims 1 to 15, wherein the anti-CTHRC1 antibody comprises a single-strand antibody.
  20. A method according to any one of paragraphs 3 to 4, wherein the anti-CTHRC1 antibody is a heavy chain monoclonal antibody (single-domain antibody).

Description

Combination therapy containing anti-CTHRC1 antibody and method of using the same The present invention relates to an antibody and antibody domain that specifically bind to CTHCR1, a composition thereof, and a method of using the same in combination therapy for the treatment of cancer and fibrosis. Collagen triple helix contain 1 (CTHRC1) was identified from a subtractive hybridization cDNA library seeking genes involved in the repair of arterial damage (Lindner, V., et al. , Journal of Bone and Mineral Research , 2004). Additionally, CTHRC1 has been found to be involved in bone development. Notably, in vivo overexpression of CTHRC1 led to disorder in bone growth plate chondrocytes and incomplete formation of proteoglycan complexes for collagen fibers, resulting in collagen disorder and severe malformations. Studies have investigated CTHRC1 in fibroblast activation and proper collagen organization in arterial and cardiac repair (LeClair, Ren e J., et al., Circulation research, 2007; Ruiz-Villalba, Adrian, et al., Circulation , 2020) as well as more generally, it has been further associated with wound healing (J. Li et al., EBioMedicine, 2019). However, reports of CTHRC1 expression in normal adult homeostatic tissues are limited. For example, low levels of CTHRC1 expression have been observed in smooth muscle cells, but injury is required to observe significant CTHRC1 expression (Leclair et al., Arterioscler. Thromb. Vasc. Biol., 2008). CTHRC1 contains a short motif (12 Gly-XY repeat sequences) common in collagen-related proteins and is conserved across species (Mei et al., Mediators Inflamm., 2020). At the molecular level, a collection of various reports suggests that CTHRC1 regulates multiple signaling pathways, including TGF-β (J. Li et al., EBioMedicine, 2019; Ni et al., Cancer Med., 2018; Zhang et al., Oncogene , 2021), regular Wnt/β-catenin (Hou et al., Oncotarget., 2015), non-regular Wnt/PCP pathway (Yamamoto et al., Dev. Cell , 2008), and integrin/FAK (Y.-L. Chen et al., J. Ovarian Res. , 2013; Guo et al., PLoS One , 2017). However, there is not yet a consensus on its precise molecular mechanism of action. Therefore, according to early reports, CTHRC1 is important for bone growth in development and wound healing in adults and likely acts downstream of TGF-β/Wnt signaling; however, it remains a largely uncharacterized protein, and there is a clear lack of understanding regarding its precise function in humans. CTHRC1 overexpression in cancer has been reported in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), where CTHRC1 is correlated with stage and reduced survival (W. Liu et al., Oncology Letters, 2016; Ni et al., Cancer Med., 2018; Wang et al., Cancer Sci., 2012). Experiments using CRC, PDAC, and ovarian cancer lineages suggested that CTHRC1 promotes motility and invasive behavior associated with metastasis (Guo et al., J. Ovarian Res., 2017; Ni et al., Cancer Med., 2018; Park et al., Carcinogenesis, 2013) . Finally, in vivo data indicate that CTHRC1 is implicated in angiogenesis; specifically, xenograft growth was impaired in CTHRC1 knockout mice, accompanied by the observation that vascular tissue was significantly destroyed (Lee et al., Exp. & Mol. Med., 2016). Overall, while several reports link CTHRC1 to various anti-tumor-generating roles in cancer, mechanistic details are scarce. In addition to promoting cancer, CTHRC1 is also associated with fibrosis. Notably, recent studies have linked CTHRC1 expression to a subset of pathological fibroblasts in mouse models of pulmonary fibrosis, which is also observed in the lungs of patients with idiopathic pulmonary fibrosis (IPF) (Tsukui et al., Nat. Commun. , 2020). Evidence also suggests that CTHRC1 is upregulated in fibrotic liver disease (J. Li et al., EBioMedicine, 2019). Importantly, depletion of CTHRC1 by genetic knockout inhibited the development of fibrosis in a rodent model of chemically induced liver fibrosis (J. Li et al., EBioMedicine, 2019). Therefore, these data take together to suggest that CTHRC1 is implicated in fibrosis and fibroblast biology, and that its anti-tumorogenic role may also depend on fibroblasts in the tumor microenvironment. In addition to cancer, studies have also associated CTHRC1 with both prophylactic and anti-inflammatory activities in rheumatoid arthritis (Jin et al., Bone, 2017), where blood levels of CTHRC1 can also distinguish between healthy individuals and patients with rheumatoid arthritis (Myngbay et al., Frontiers in Immunology, 2019). CTHRC1 is also implicated as a positive regulator of bone formation and thus has a preventive effect against osteoporosis (Chen et al., Bone Research, 2019; Kimura et al., PloS One, 2008). Overall, research on CTHRC1 to date has indicated that it plays a role in bone development, wound repair, cancer, fibrosis, arthritis, and osteoporosis. However, despite these findings, the lack of disclosed inhibitors of CTHRC1 has made further investigation into the