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EP-4735006-A1 - ENGINEERED CHIMERIC FUSION PROTEIN COMPOSITIONS AND METHODS OF USE THEREOF

EP4735006A1EP 4735006 A1EP4735006 A1EP 4735006A1EP-4735006-A1

Abstract

Compositions and methods for making and using engineered cells, such as, engineered myeloid cells that express a chimeric fusion protein that has a binding domain capable to binding surface molecules on target cells such as diseased cells.

Inventors

  • GETTS, DANIEL
  • WANG, Yuxiao
  • GERBER, Michele, Luise
  • MAURER, Matthew, Anthony

Assignees

  • CREATE Medicines, Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A pharmaceutical composition comprising a polynucleotide encoding a chimeric antigen receptor comprising: an anti-TROP2 binding scFv extracellular domain and a CD89 transmembrane domain, wherein the polynucleotide is formulated in an aqueous formulation for delivery systemically, at a therapeutically effective amount and time interval suitable for treating a cancer in a subject.
  2. 2. The pharmaceutical composition of claim 1, wherein the polynucleotide is an engineered RNA.
  3. 3. The pharmaceutical composition of claim 2, wherein the engineered RNA is an engineered mRNA.
  4. 4. The pharmaceutical composition of any one of claims 1 -3 , wherein the anti-TROP2 binding scFv comprises a heavy chain, and a light chain, wherein the heavy chain comprises a CDR3 having a sequence GGFGSSYWYFDV, and the light chain comprises a CDR3 having a sequence QQHYITPLT.
  5. 5. The pharmaceutical composition of claim 4, wherein the heavy chain further comprises a CDR1 sequence of NYGMN, and a CDR2 sequence of WINTYTGEPTYTDDFKG; and the light chain further comprises a CDR1 sequence of KASQDVSIAVA, and a CDR2 sequence of SASYRYT.
  6. 6. The pharmaceutical composition of any one of claims 1-5, wherein the CD89 transmembrane domain comprises a sequence LIRMAVAGLVLVALLAILV.
  7. 7. The pharmaceutical composition of any one of claims 1-6, further comprising a lipid nanoparticle delivery vehicle.
  8. 8. The pharmaceutical composition of claim 7, wherein the lipid nanoparticle delivery vehicle comprises a cationic lipid, a non-cationic lipid, a neutral lipid, a PEGylated lipid, or a combination thereof.
  9. 9. The pharmaceutical composition of any one of claims 1-8, wherein the subject is a human subject.
  10. 10. The pharmaceutical composition of any one of claims 1-9, wherein the cancer is an epithelial cancer.
  11. 11. The pharmaceutical composition of any one of claims 1-10, wherein the subj ect has an epithelial cancer.
  12. 12. The pharmaceutical composition of claim 1-11, wherein the cancer is selected from Urothelial, Cervical, Ovarian epithelial, Triple-negative breast, HR+/HER2- breast, Pancreatic ductal adenocarcinoma, Gastric adenocarcinoma, Esophageal carcinoma, Non-small cell lung and Colorectal cancer.
  13. 13. The pharmaceutical composition of claim 12, wherein the cancer is metastatic.
  14. 14. The pharmaceutical composition of any one of claims 1-13, wherein the pharmaceutical composition is formulated for systemic delivery.
  15. 15. The pharmaceutical composition of any one of claims 1-14, wherein the pharmaceutical composition is formulated for intravenous delivery.
  16. 16. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition is formulated for an intravenous injection or an infusion.
  17. 17. The pharmaceutical composition of any one of claim 1-16, wherein the therapeutically effective amount of a dose comprises 1-5000 microgram/microliter of the engineered RNA.
  18. 18. The pharmaceutical composition of any one of claims 1-17, comprising an amount of about 0.0005 to about 0.001, about 0.001 to about 0.005, about 0.005 to about 0.01, about 0.01 to about 0.05, about 0.05 to about 0.1, or about 0.1 to about 0.5 mg/kg of the engineered RNA per dose of the pharmaceutical composition.
  19. 19. The pharmaceutical composition of any one of claims 1-18, comprising an amount of about 0.001 to about 0.0015, about 0.0015 to about 0.002, about 0.002 to about 0.0025, about 0.0025 to about 0.003, about 0.003 to about 0.0035, about 0.0035 to about 0.004, about 0.004 to about 0.0045, about 0.0045 to about 0.005, about 0.005 to about 0.0055, about 0.0055 to about 0.006, about 0.006 to about 0.0065, about 0.0065 to about 0.007, about 0.007 to about 0.0075, about 0.0075 to about 0.008, about 0.008 to about 0.0085, about 0.0085 to about 0.009, about 0.009 to about 0.0095, or about 0.0095 to about 0.01 mg of the engineered RNA per kg of the subject’s body weight (mg/kg) per dose of the pharmaceutical composition.
  20. 20. The pharmaceutical composition of any one of claims 1-19, comprising an amount of about 0.01 to about 0.015, about 0.015 to about 0.02, about 0.02 to about 0.025, about 0.025 to about 0.03, about 0.03 to about 0.035, about 0.035 to about 0.04, about 0.04 to about 0.045, about 0.045 to about 0.05, about 0.05 to about 0.055, about 0.055 to about 0.06, about 0.06 to about 0.065, about 0.065 to about 0.07, about 0.07 to about 0.075, about 0.075 to about 0.08, about 0.08 to about 0.085, about 0.085 to about 0.09, about 0.09 to about 0.095, or about 0.095 to about 0.1 mg/kg of the engineered RNA per dose of the pharmaceutical composition.

Description

ENGINEERED CHIMERIC FUSION PROTEIN COMPOSITIONS AND METHODS OF USE THEREOF CROSS REFERNCE [0001] This application claims the benefit of U.S. Provisional Application No. 63/511,274, filed on 6/30/23; and U.S. Provisional Application No. 63/579,422, filed on 8/29/23; each of which is incorporated herein by reference in its entirety. BACKGROUND [0002] Cellular immunotherapy is a promising new technology for fighting difficult to treat diseases, such as cancer, and persistent infections and also certain diseases that are refractory to other forms of treatment. A major breakthrough has come across with the discovery of CAR-T cell and their potential use in immunotherapy. CAR-T cells are T lymphocytes expressing a chimeric antigen receptor which helps target the T cell to specific diseased cells such as cancer cells, and can induce cytotoxic responses intended to kill the target cancer cell or immunosuppression and/or tolerance depending on the intracellular domain employed and co-expressed immunosuppressive cytokines. Although CAR-T cells continue to remain prospective tools for cancer therapy, several limitations along the way has slowed the progress on CAR-T cells and dampened its promise in clinical trials. [0003] Understanding the limitations of CAR-T cells is the key to leveraging the technology and continue innovations towards better immunotherapy models. Specifically, in T cell malignancies, CAR-T cells appear to have faced a major problem. CAR-T cells and malignant T cells share surface antigen in most T cell lymphomas (TCL), therefore, CAR-T cells are subject to cytotoxicity in the same way as cancer cells. In some instances, the CAR-T products may be contaminated by malignant T cells. Additionally, T cell aplasia is a potential problem due to prolonged persistence of the CAR-T cells. Other limitations include the poor ability for CAR-T cells to penetrate into solid tumors and the potent tumor microenvironment which acts to downregulate their anti-tumor potential. CAR-T cell function is also negatively influenced by the immunosuppressive tumor microenvironment (TME) that leads to endogenous T cell inactivation and exhaustion. [0004] Myeloid cells, including macrophages, are cells derived from the myeloid lineage and belong to the innate immune system. They are derived from bone marrow stem cells which egress into the blood and can migrate into tissues. Some of their main functions include phagocytosis, the activation of T cell responses, and clearance of cellular debris and extracellular matrices. They also play an important role in maintaining homeostasis, and initiating and resolving inflammation. Moreover, myeloid cells can differentiate into numerous downstream cells, including macrophages, which can display different responses ranging from pro-inflammatory to anti-inflammatory depending on the type of stimuli they receive from the surrounding microenvironment. Furthermore, tissue macrophages have been shown to play a broad regulatory and activating role on other immune cell types including CD8+ and CD4+ T effector cells, NK cells and T regulatory cells. Macrophages have been shown to be a main immune infiltrate in malignant tumors and have been shown to have a broad immunosuppressive influence on effector immune infiltration and function. SUMMARY [0005] The diverse functionality of myeloid cells makes them an ideal cell therapy candidate that can be engineered to have numerous therapeutic effects. The present disclosure is related to immunotherapy using myeloid cells (e.g., CD14+ cells) of the immune system, particularly phagocytic cells. A number of therapeutic indications could be contemplated using myeloid cells. For example, myeloid cell immunotherapy could be exceedingly important in treating cancer, autoimmunity, fibrotic diseases and infections. The present disclosure is related to immunotherapy using myeloid cells, including phagocytic cells of the immune system, particularly monocytes. It is an object of the invention disclosed herein to harness one or more of these functions of myeloid cells for therapeutic uses. For example, it is an object of the invention disclosed herein to harness the phagocytic activity of myeloid cells, including engineered myeloid cells, for therapeutic uses. For example, it is an object of the invention disclosed herein to harness the ability of myeloid cells, including engineered myeloid cells, to promote T cell activation. For example, it is an object of the invention disclosed herein to harness the ability of myeloid cells, including engineered myeloid cells, to promote secretion of tumoricidal molecules. For example, it is an object of the invention disclosed herein to harness the ability of myeloid cells, including engineered myeloid cells, to promote recruitment and trafficking of immune cells and molecules. In one aspect the disclosure provides new and useful chimeric constructs that, when expressed in a myeloid cell, the myeloid cell can drive targeted