KR-20260067384-A - TLR3 Targeting for the Treatment of Hematopoietic Stem Cell Proliferation-Related Diseases or Disorders

Abstract

The technology described herein relates to compositions and methods for treating diseases or disorders associated with hematopoietic stem cell and progenitor cell (HSPC) proliferation, including the use of Toll-like receptor 3 (TLR3) inhibitors.

Inventors

• 존 레오나드
• 페소아 로드리게스 세실리아

Assignees

• 더 칠드런스 메디칼 센터 코포레이션

Dates

Publication Date

20260512

Application Date

20240801

Priority Date

20230802

Claims (20)

1. A method for treating a disease or disorder associated with the proliferation of hematopoietic stem cells and progenitor cells (HSPCs), wherein the method comprises the step of administering an effective amount of a Toll-like receptor 3 (TLR3) inhibitor to a subject in need thereof.
2. The method of claim 1, wherein the TLR3 inhibitor is selected from the group consisting of CUCPT4a (Formula I), T5260630 (Formula II), T5626448 (Formula III), Formula IV, Formula V, SMU-CX1 (Formula VI), TLR3 Morpolino (e.g., SEQ ID NO. 26), TLR3 CRISPR Guide RNA (e.g., SEQ ID NO. 62), Enpatoran (Formula VII), and TLR7-IN-1 (Formula VIII).
3. A method according to claim 1 or 2, wherein the TLR3 inhibitor is CUCPT4a.
4. A method according to claim 1 or 2, wherein the disease or disorder associated with increased HSPC proliferation is selected from the group consisting of clonal hematopoiesis, myelodysplastic syndrome (MDS), multiple myeloma, and leukemia.
5. A method according to claim 4, wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell prolymphocyte leukemia (B-PLL), blastocystic plasmacytic dendritic neoplasm (BPDCN), chronic myelomonocytic leukemia (CMML), hairy cell leukemia, pediatric myelomonocytic leukemia (JMML), large granulocyte leukemia (LGLL), and T-cell prolymphocyte leukemia (T-PLL).
6. A method according to any one of claims 1 to 5, wherein the TLR3 inhibitor reduces or inhibits TLR3 interaction with double-stranded RNA (dsRNA).
7. A method according to any one of claims 1 to 6, wherein the TLR3 inhibitor reduces or inhibits TLR3-induced interferon regulatory factor 3 (Irf3) cell signaling in hematopoietic stem cells (HSPC).
8. In claim 7, the method wherein the reduced or inhibited TLR3-induced cell signaling reduces or inhibits the expression of beta 2 microglobulin (B2M) on the cell surface of the HSPC.
9. In claim 8, the method wherein the reduced or suppressed B2M expression increases the macrophage phagocytosis of the HSPC.
10. In claim 9, the increased macrophage phagocytosis of the HSPC reduces the proliferating HSPC.
11. A method according to any one of claims 1 to 10, wherein the TLR3 inhibitor reduces or inhibits the expression of beta 2 microglobulin (B2M) on the cell surface of the HSPC.
12. A method according to any one of claims 1 to 11, wherein the TLR3 inhibitor increases the phagocytic activity of the HSPC on macrophages.
13. A method according to any one of claims 1 to 12, wherein the TLR3 inhibitor reduces the proliferation of the HSPC.
14. A method for treating clonal hematopoiesis, myelodysplastic syndrome (MDS), multiple myeloma, or leukemia, wherein the method comprises the step of administering an effective amount of a Toll-like receptor 3 (TLR3) inhibitor to a subject requiring it.
15. In claim 14, the method wherein the TLR3 inhibitor is selected from the group consisting of CUCPT4a (Formula I), T5260630 (Formula II), T5626448 (Formula III), Formula IV, Formula V, SMU-CX1 (Formula VI), TLR3 morpholino (e.g., SEQ ID NO. 26), TLR3 CRISPR guide RNA (e.g., SEQ ID NO. 62), enfatoran (Formula VII), and TLR7-IN-1 (Formula VIII).
16. Method according to claim 14 or 15, wherein the TLR3 inhibitor is CUCPT4a.
17. A method according to any one of claims 14 to 16, wherein the disease or disorder associated with increased HSPC proliferation is selected from the group consisting of clonal hematopoiesis, myelodysplastic syndrome (MDS), multiple myeloma, and leukemia.
18. In claim 17, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell prolymphocyte leukemia (B-PLL), blastocystic plasmacytic dendritic neoplasm (BPDCN), chronic myelomonocytic leukemia (CMML), hairy cell leukemia, pediatric myelomonocytic leukemia (JMML), large granulocyte leukemia (LGLL), and T-cell prolymphocyte leukemia (T-PLL).
19. A method for treating clonal hematopoiesis, myelodysplastic syndrome (MDS), multiple myeloma, or leukemia, wherein the method comprises the step of administering an effective amount of CUCPT4a to a subject requiring it.
20. In claim 19, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell prolymphocyte leukemia (B-PLL), blastocystic plasmacytic dendritic neoplasm (BPDCN), chronic myelomonocytic leukemia (CMML), hairy cell leukemia, pediatric myelomonocytic leukemia (JMML), large granulocyte leukemia (LGLL), and T-cell prolymphocyte leukemia (T-PLL).

Description

TLR3 Targeting for the Treatment of Hematopoietic Stem Cell Proliferation-Related Diseases or Disorders Cross-reference regarding related applications This application claims the benefit pursuant to 35 U.S.C. §119(e) of U.S. Provisional Application No. 63/530,358 filed August 2, 2023, the entirety of which is incorporated herein by reference. Government support The present invention was made with government support under Project Nos. 5T32HL007574-41 and 5T32HL007574-40 awarded by the National Institutes of Health. The government retains specific rights to the present invention. See sequence list The present application contains a list of sequences submitted in XML format through the patent center, the entirety of which is incorporated herein by reference. An XML copy created on July 31, 2024, is named 701039-000129WOPT_SL.xml and has a size of 62,124 bytes. Technical field of invention The technology described herein relates to Toll-like receptor 3 (TLR3) targeting for the treatment of hematopoietic stem cell proliferation-associated diseases or disorders. Development, tissue integrity, and defense against immunogenic stimuli require the effective removal of damaged and defective cells. Innate immune cells, such as macrophages and neutrophils, coordinate the removal or phagocytosis of these dying cells by identifying molecules expressed on their surfaces. Therefore, the phagocytosis process needs to be carefully regulated to avoid the unnecessary removal of healthy cells. Surface molecules, such as complement opsonins, exposed phosphatidylserine (PS), caleticulin (Calr), and annexin I, function as signals to initiate phagocytosis ("eat me" signals). These surface molecules are not present at high levels on the surface of living, healthy cells, except during specific physiological cases. On the other hand, surface molecules, such as B2m, function as "don't eat me" signals to prevent the unnecessary removal of healthy cells that simultaneously present "eat me" molecules on their surfaces. Hematopoietic stem cells generated during embryonic development maintain lifelong tissue homeostasis, and phagocytosis by macrophages plays a pivotal role in ensuring the quality of newly formed hematopoietic stem and progenitor cells (HSPCs) within the embryonic microenvironment; see, for example, Arandjelovic et al. Nat. Immunol. 16, 907-917 (2015); Kelley et al. EMBO Rep. 22, e52564 (2021); Arosa et al. Journal of Biological 274(24):16917-22 (1999); Bertrand et al. Nature 464, 108-111 (2010); Wattrus et al. Science 377, 1413-1419 (2022); the entire contents of each of which are incorporated herein by reference. Hematopoietic stem cells and progenitor cells (HSPCs) present surface caleticulin (Calr) as a "eat me" signal that induces macrophage interactions. During their interactions, macrophages may completely phagocytize ("dooming") HSPCs or sample a small portion of HSPC cellular material without killing them ("grooming"). While HSPC dooming eliminates selected stem cell clones, HSPC grooming regulates HSPC proliferation by activating Il-1b-dependent signaling. Grooming and dooming are critical quality control steps for eliminating stressed HSPCs during development. Despite the importance of these processes, the mechanism by which macrophages distinguish which HSPCs to doom and which to groom remains unclear. There is a significant need for compositions and methods to regulate the dooming and grooming of HSPCs by macrophages. The technology described herein relates to compositions and methods for treating diseases or disorders associated with hematopoietic stem cell and progenitor cell (HSPC) proliferation, including the use of Toll-like receptor 3 (TLR3) inhibitors. Accordingly, in one embodiment, the present invention describes a method for treating a disease or disorder related to the proliferation of hematopoietic stem cells and progenitor cells (HSPCs), and the method comprises the step of administering an effective amount of a Toll-like receptor 3 (TLR3) inhibitor to a subject who requires it. In some embodiments of any aspect, the TLR3 inhibitor is selected from the group consisting of CUCPT4a (Formula I), T5260630 (Formula II), T5626448 (Formula III), Formula IV, Formula V, SMU-CX1 (Formula VI), TLR3 morpholino (e.g., SEQ ID NO. 26), TLR3 CRISPR guide RNA (e.g., SEQ ID NO. 62), enfatoran (Formula VII), and TLR7-IN-1 (Formula VIII). In some embodiments of any aspect, the TLR3 inhibitor is CUCPT4a. In some embodiments of any aspect, the disease or disorder associated with increased HSPC proliferation is selected from the group consisting of clonal hematopoiesis, myelodysplastic syndrome (MDS), multiple myeloma, and leukemia. In some embodiments of any aspect, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), B-cell prolymphocyte leukemia (B-PLL), blastocystic plasmacytic dendritic neoplasm (BPDCN), chronic myelomon