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US-12624111-B2 - Methods for treating metastatic colon cancer with leronlimab

US12624111B2US 12624111 B2US12624111 B2US 12624111B2US-12624111-B2

Abstract

The present disclosure relates to the use of competitive inhibitors of the CCR5 receptor, such as the monoclonal antibody leronlimab, or binding fragments thereof, in the treatment or prevention of cancer.

Inventors

  • Denis BURGER
  • Scott Kelly

Assignees

  • CYTODYN INC.

Dates

Publication Date
20260512
Application Date
20200731

Claims (20)

  1. 1 . A method of treating or, inhibiting, metastatic colon cancer comprising administering to a subject in need thereof an anti-CCR5 cell receptor binding agent comprising a leronlimab antibody, or binding fragment thereof in an injected amount of 5.8 mg/kg/week.
  2. 2 . The method of claim 1 , wherein said administration results in reduced metastasis of the cancer to at least one of the lungs or the liver.
  3. 3 . The method of claim 2 , wherein metastasis to the lung is reduced by more than 50%, by 50% to 60%, by 60% to 70%, by 70% to 80%, by 80% to 90%, or by more than 85%.
  4. 4 . The method of claim 2 , wherein metastasis to the liver is reduced by more than 40%, by 40% to 50%, by 50% to 60%, or by more than 50%.
  5. 5 . The method of claim 1 , wherein total vessel area of vessels feeding a tumor is reduced by more than 40%, by 40% to 50%, by 50% to 60%, by 60% to 70%, or by more than 60%.
  6. 6 . The method of claim 1 , wherein vessel length density of vessels feeding a tumor is reduced by more than 40%, by 40% to 50%, by 50% to 60%, or by more than 50%.
  7. 7 . The method of claim 1 , wherein the number of vessels feeding a tumor is reduced by more than 40%, by 40% to 50%, by 50% to 60%, by 60% to 70%, by 70% to 80%, or by more than 70%.
  8. 8 . The method of claim 7 , wherein the number of larger vessels is reduced by more than 40%, by 40% to 50%, by 50% to 60%, or by more than 50%.
  9. 9 . The method of claim 7 , wherein the number of smaller vessels is reduced by more than 40%, by 40% to 50%, by 50% to 60%, by 60% to 70%, by 70% to 80%, or by more than 70%.
  10. 10 . The method of claim 1 , wherein said administration results in one of increased levels of CD4+CD25+ cells or decreased levels of CD4+CD25− cells in the peripheral blood of the subject; or wherein, the anti-CCR5 cell receptor binding agent does not alter tyrosine kinase phosphorylation in CD4+ cells.
  11. 11 . A method of reducing metastatic burden in a subject having colon cancer, comprising administering to a subject in need thereof an anti-CCR5 cell receptor binding agent comprising a leronlimab antibody, or binding fragment thereof in an injected amount of 5.8 mg/kg/week.
  12. 12 . The method of claim 11 , wherein metastatic burden in a lung is reduced by more than 50%, by 50% to 60%, by 60% to 70%, by 70% to 80%, by 80% to 90%, or by more than 85%.
  13. 13 . The method of claim 11 , wherein metastatic burden in a liver is reduced by more than 40%, by 40% to 50%, by 50% to 60%, or by more than 50%.
  14. 14 . A method of reducing tumor-associated angiogenesis in a subject having colon cancer, comprising administering to a subject in need thereof an anti-CCR5 cell receptor binding agent comprising a leronlimab antibody, or binding fragment thereof in an injected amount of 5.8 mg/kg/week.
  15. 15 . The method of claim 14 , wherein total vessel area of vessels feeding a tumor is reduced by more than 40%, by 40% to 50%, by 50% to 60%, by 60% to 70%, or by more than 60%.
  16. 16 . The method of claim 14 , wherein vessel length density of vessels feeding a tumor is reduced by more than 40%, by 40% to 50%, by 50% to 60%, or by more than 50%.
  17. 17 . The method of claim 14 , wherein the number of vessels feeding a tumor is reduced by more than 40%, by 40% to 50%, by 50% to 60%, by 60% to 70%, by 70% to 80%, or by more than 70%.
  18. 18 . The method of claim 17 , wherein the number of larger vessels is reduced by more than 40%, by 40% to 50%, by 50% to 60%, or by more than 50%.
  19. 19 . The method of claim 17 , wherein the number of smaller vessels is reduced by more than 40%, by 40% to 50%, by 50% to 60%, by 60% to 70%, by 70% to 80%, or by more than 70%.
  20. 20 . The method according to claim 1 , wherein preventing the cancer comprises slowing the growth of the cancer.

Description

STATEMENT REGARDING SEQUENCE LISTING The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 230042_429USPC_SEQUENCE_LISTING.txt. The text file is 16 KB, was created on Jan. 20, 2022, and is being submitted electronically via EFS-Web. BACKGROUND Technical Field The present disclosure relates to the use of competitive inhibitors of the CCR5 receptor, such as the monoclonal antibody leronlimab, in the treatment or prevention of cancer. Background Inflammation may occur in response to trauma, chemical or physical injury, autoimmune responses, infectious agents, cancer, etc. Inflammation is an important component of innate immunity and is necessary for priming adaptive immunity and for the effector phase of the immune response. Soluble mediators, such as chemokines, are shown to play an important role in driving the various components of inflammation, especially leukocyte influx. Chemokines bind to their receptors which are expressed on many cell types, including, for example, leukocytes, endothelial cells, fibroblasts, epithelial, smooth muscle, and parenchymal cells. Chemokines play an important role in leukocyte biology, by controlling cell recruitment and activation in basal and in inflammatory circumstances. In addition, because chemokine receptors are expressed on other cell types, chemokines have multiple other roles, including angiogenesis, tissue and vascular remodeling, pathogen elimination, antigen presentation, leukocyte activation and survival, chronic inflammation, tissue repair/healing, fibrosis, embryogenesis, tumorigenesis, etc. CCL5 (C-C chemokine ligand 5), an inflammatory chemokine also known as regulated upon activation and normal T cell expressed and secreted (RANTES), plays an important role in these immunologic mechanisms. CCL5 acts as a key regulator of T cell migration to inflammatory sites, directing migration of T cells to damaged or infected sites. CCL5 also regulates T cell differentiation. Many biologic effects of chemokines are mediated by their interaction with chemokine receptors on cell surfaces. In the present invention, the most relevant known receptor for CCL5 is the CCR5 receptor; however, CCR1 and CCR3 are also known CCL5 receptors and CCR4 and CD44 are auxiliary receptors. Tamamis et al., Elucidating a KeyAnti-HIV-1 and Cancer-Associated Axis: The Structure of CCL5 (Rantes) in Complex with CCR5, SCIENTIFIC REPORTS, 4: 5447 (2014). Inflammatory chemokines have long been viewed mainly as indispensable “gate keepers” of immunity and inflammation. However, recent research indicates that, for example, cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. While the CCR5 receptor and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, extensive studies on the role of the CCL5 ligand/CCR5 receptor axis have only been performed in only a limited number of cancers. Aldinucci et al., The Inflammatory chemokine CCL5 and Cancer Progression, MEDIATORS OF INFLAMMATION, vol. 2014, article ID 292376, 12 pages. The CCR5 receptor is a C-C chemokine G-coupled protein receptor expressed on lymphocytes (e.g., NK cells, B cells), monocytes, macrophages, dendritic cells, a subset of T cells, etc. The CCR5 receptor spans the cellular plasma membrane seven times in a serpentine manner. The extracellular portions represent potential targets for antibodies targeting CCR5, and comprise an amino-terminal domain (Nt) and three extracellular loops (ECL1, ECL2, and ECL3). The extracellular portions of CCR5 comprise just 90 amino acids distributed over four domains. The largest of these domains are at the Nt and ECL2 at approximately 30 amino acids each. Olson et al., CCR5 Monoclonal Antibodies for HIV-1 Therapy, CURR. OPIN. HIV AIDS, March, 4(2): 104-111 (2009). The formation of the CCL5 ligand and CCR5 receptor complex causes a conformational change in the receptor that activates the subunits of the G-protein, inducing signaling and leading to changed levels of cyclic AMP (cAMP), inositol triphosphate, intracellular calcium, and tyrosine kinase activation. These signaling events cause cell polarization and translocation of the transcription factor NF-kB, which results in the increase of phagocytic ability, cell survival, and transcription of proinflammatory genes. Once G-protein dependent signaling occurs, the CCL5/CCR5 receptor complex is internalized via endocytosis. A complete complex structure of CCL5 in complex with CCR5 has been computationally derived. It is reported that the 1-15 residue moiety of CCL5 is inserted into the CCR5 binding pocket; the 1-6 N-terminal domain of CCL5 is buried within the transmembra