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JP-2026514435-A - Methods and compositions for treating autoimmune diseases

JP2026514435AJP 2026514435 AJP2026514435 AJP 2026514435AJP-2026514435-A

Abstract

The present invention relates, in general terms, to a method for treating autoimmune diseases with immunotherapy. The present invention also relates, in general terms, to a method for treating autoimmune diseases comprising administering a cyclophosphamide preconditioning regimen and subsequently administering immunotherapy.

Inventors

  • ビンダー グウェンドリン ノールトン
  • チャン デビッド ジフン
  • バス サミク
  • ニヒトバーガー スティーヴン アラン

Assignees

  • カバレッタ バイオ インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20240329
Priority Date
20230330

Claims (20)

  1. A method for treating autoimmune diseases in subjects who require treatment for autoimmune diseases, (a) Administering to the subject a preconditioning regimen consisting of one or more doses of cyclophosphamide between 100 and 1,500 mg/ m² /day, (b) The method comprising administering a therapeutically effective amount of genetically modified CAR immune cells to the subject, wherein the subject receives cyclophosphamide at least three days prior to step (b).
  2. The method according to claim 1, wherein the preconditioning regimen includes administering cyclophosphamide to the subject in a total dose of less than 1,000 mg/ m² .
  3. The method according to claim 1 or claim 2, wherein the one or more doses of cyclophosphamide are 100 to 800 mg/ m² /day.
  4. A method for treating autoimmune diseases in subjects who require treatment for autoimmune diseases, (a) Administering the subject a preconditioning regimen including one or more doses of cyclophosphamide at a dose of 100-800 mg/ m² /day, (b) The method comprising administering a therapeutically effective amount of genetically modified CAR immune cells to the subject, wherein the preconditioning regimen comprises administering cyclophosphamide to the subject in a total dose of less than 1,000 mg/ m² .
  5. The method according to claim 4, wherein the subject receives the cyclophosphamide at least three days before step (b).
  6. A method for treating autoimmune diseases in subjects who require treatment for autoimmune diseases, (a) Administering the subject a preconditioning regimen including one or more doses of cyclophosphamide at a dose of 100 to 1,500 mg/ m² /day, (b) The method comprising administering a therapeutically effective amount of genetically modified CAR immune cells to the subject, wherein the genetically modified CAR immune cells comprise a nucleic acid encoding CAR, and the CAR comprises an extracellular antigen-binding site comprising a heavy chain variable domain ( VH ) comprising complementarity-determining regions CDR H1 , CDR H2 , and CDR H3 , and a light chain variable domain ( VL ) comprising complementarity-determining regions CDR L1 , CDR L2 , and CDR L3 , wherein CDR H1 , CDR H2 , and CDR H3 each comprise the amino acid sequences of SEQ ID NOs. 1, 2, and 3, and CDR L1 , CDR L2 , and CDR L3 each comprise the amino acid sequences of SEQ ID NOs. 5, 6, and 7.
  7. The method according to claim 6, wherein the subject receives the cyclophosphamide at least three days before step (b).
  8. The method according to claim 6 or 7, wherein the preconditioning regimen comprises administering cyclophosphamide to the subject in a total dose of less than 1,000 mg/ m² .
  9. The method according to any one of claims 6 to 8, wherein the dose of cyclophosphamide is 100 to 800 mg/ m² /day.
  10. The method according to any one of claims 1, 6, or 7, wherein the one or more doses of cyclophosphamide are 1,000 mg/ m² /day.
  11. The method according to any one of claims 1 to 9, wherein the one or more doses of cyclophosphamide are 750 mg/ m² /day.
  12. The method according to any one of claims 1 to 9, wherein the one or more doses of cyclophosphamide are 500 mg/ m² /day.
  13. The method according to any one of claims 1 to 9, wherein the one or more doses of cyclophosphamide are 375 mg/ m² /day.
  14. The method according to any one of claims 1 to 9, wherein the one or more doses of cyclophosphamide are 250 mg/ m² /day.
  15. The method according to any one of claims 1 to 14, wherein the subject is administered cyclophosphamide 3 to 7 days prior to step (b).
  16. The method according to any one of claims 1 to 15, wherein the subject is administered cyclophosphamide three days prior to step (b).
  17. The method according to any one of claims 1 to 9, wherein the preconditioning regimen includes administering cyclophosphamide to the subject three and four days prior to step (b).
  18. The method according to any one of claims 1 to 9 or 17, wherein the preconditioning regimen essentially comprises administering cyclophosphamide to the subject three and four days prior to step (b).
  19. The method according to claim 17 or claim 18, wherein the one or more doses of cyclophosphamide are 250 mg/ m² /day, 375 mg/ m² /day, or 500 mg/ m² /day.
  20. The method according to any one of claims 1 to 9 or 17, wherein the preconditioning regimen includes administering cyclophosphamide to the subject 3, 4, and 5 days prior to step (b).

Description

Cross-reference of related applications: This application claims the benefit and priority of U.S. Provisional Application No. 63/493,133, filed on 30 March 2023, all of which disclosures are incorporated herein by reference in their entirety for all purposes. Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy, created on 28 March 2024, is named CBB-203WO_SL.xml and is 57.9 kilobytes in size. Field of Invention The present invention relates, in general terms, to a method of using immunotherapy to treat autoimmune diseases. The present invention also relates, in general terms, to lymphocyte depletion preconditioning regimens that can be administered to a subject prior to immunotherapy. Background: According to the U.S. National Institutes of Health, more than 23.5 million people in the United States suffer from autoimmune diseases. Autoimmune diseases are a group of diseases in which the body's immune system attacks healthy cells or tissues. In autoimmune diseases in which B cells are involved in the onset or maintenance of the disease, a specific population of a patient's B cells differentiates into antibody-secreting cells that produce antibodies targeted against normal tissues and cells. These autoantibodies are the effectors of the disease, but the underlying cause is the defective B cells that mistakenly differentiate into cells that secrete these pathogenic antibodies. Current treatment options for autoimmune-mediated diseases involve systemic immunosuppression achieved through corticosteroids, immunosuppressive drugs, and biological agents. Most commonly, corticosteroids are used chronically and short-term to control the disease, acting through various mechanisms that control or downmodulate multiple inflammatory pathways. In many cases, systemic immunosuppressants, such as mycophenolates, azathioprine, and methotrexate, are added to minimize patient symptoms and manage anticipated relapses. Most treatments for autoimmune diseases are not curative and often require lifelong chronic administration. Furthermore, patients undergoing chronic immunosuppressive therapy are at risk of serious and life-threatening infections. Therefore, there is a significant unmet medical need for these patients. Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has become an established treatment method for various cancers. This method has been particularly successful in hematological malignancies, such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Generally, CAR T-cell therapy for cancer treatment involves isolating T cells from human blood, genetically engineering the cells to express a CAR for a target antigen of interest, administering a preconditioning regimen of lymphocyte depletion chemotherapy to the patient, and subsequently administering the genetically engineered CAR T cells to the patient, thereby enabling the CAR T cells to target and destroy cancer cells expressing this antigen. Lymphocyte depletion preconditioning is considered an essential element of CAR T-cell therapy for cancer patients. Such preconditioning regimens have been demonstrated to enhance the viability, persistence, and efficacy of administered CAR T-cells by increasing levels of homeostatic cytokines such as IL-7 and IL-15, eliminating endogenous immune cells that compete for these cytokines, thereby creating a more favorable environment for the proliferation of injected cells (Nissani et al. (2021) J. Immunother. Cancer 9:e001743 (Non-Patent Literature 1)). Recently, CAR T-cell therapy has also been investigated as a treatment for treatment-resistant systemic lupus erythematosus (SLE), a B-cell-mediated autoimmune disease. Researchers reported that administration of CAR T-cell therapy induced clinical remission in 5 out of 5 patients with moderate to severe treatment-resistant SLE (Mackensen et al. (2022) Nat.Med. 28:2124-2132 (Non-Patent Literature 2)). In this study, patients received a lymphocyte depletion preconditioning regimen including a total dose of 75 mg/ m² of fludarabine (25 mg/ m² on days -5, -4, and -3) and a total dose of 1,000 mg/ m² of cyclophosphamide (1,000 mg/ m² on day -3; Mackensen (ibid.)) prior to CAR T-cell therapy. Similar findings have been reported in case studies of patients with antisynthesis syndrome (myositis) (Müller et al. (2022) Lancet 401:815-818 (Non-patent Literature 3)). In neither study was the need for preconditioning regimens to achieve favorable treatment outcomes examined. While lymphocyte depletion preconditioning is understood to be a crucial step in genetically engineered T-cell therapy for cancer treatment, the degree and intensity of lymphocyte depletion preconditioning required to enable successful treatment of autoimmune diseases with T-cell therapy remain unclear. Therefore, despite the advances made to date, novel and