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US-20260125471-A1 - SUBCUTANEOUS ADMINISTRATION OF ANTIBODIES FOR THE TREATMENT OF DISEASE

US20260125471A1US 20260125471 A1US20260125471 A1US 20260125471A1US-20260125471-A1

Abstract

This invention provides methods of subcutaneous administration of anti-CD3 monoclonal antibodies (mAbs) either alone or in combination with monoclonal antibodies, that recognize the Interleukin-6 (IL-6) and IL-6 receptor (IL-6R) complex for the treatment, prevention or alleviating a symptom of a disease.

Inventors

  • Kunwar Shailubhai
  • Vaseem A. PALEJWALA
  • Jules S. Jacob

Assignees

  • TIZIANA LIFE SCIENCES PLC

Dates

Publication Date
20260507
Application Date
20250902

Claims (20)

  1. 1 . A method of treating or alleviating a symptom of a pulmonary disease in a subject in need thereof comprising administering to the subject a first and a second dose of an antibody that recognizes the Interleukin-6 (IL-6) and IL-6 receptor (IL-6R) complex (IL-6Rc), wherein the antibody that recognizes IL-6Rc (anti-IL-6Rc antibody) comprises a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 35, a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 24, a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 25, and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 26.
  2. 2 . The method of claim 1 , wherein the first administration is by inhalation and the second administration is by subcutaneous injection.
  3. 3 . The method of claim 1 , wherein the first administration is by subcutaneous injection and the second administration is by inhalation.
  4. 4 . The method of claim 1 , wherein the pulmonary disease is a pulmonary inflammatory disease.
  5. 5 . The method of claim 4 , wherein the pulmonary inflammatory disease is acute respiratory distress syndrome idiopathic pulmonary fibrosis (IPF), or systemic pulmonary sclerosis.
  6. 6 . The method of claim 1 , wherein the subject has a disease or pathology associated with coronavirus infection.
  7. 7 . The method of claim 1 , wherein the method further comprises subcutaneously administering to the subject a first dose of a composition comprising an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYGMH (SEQ ID NO: 42), a heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence VIWYDGSKKYYVDSVKG (SEQ ID NO: 43), a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence QMGYWHFDL (SEQ ID NO: 44), a light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSYLA (SEQ ID NO: 45), a light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence DASNRAT (SEQ ID NO: 46), and a light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQRSNWPPLT (SEQ ID NO: 47).
  8. 8 . The method of claim 7 , wherein the anti-CD3 antibody is a monoclonal antibody.
  9. 9 . The method of claim 7 , wherein the anti-CD3 antibody is fully human or humanized.
  10. 10 . The method of claim 7 , wherein (a) the anti-CD3 antibody comprises a variable heavy chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 48 and a variable light chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 49 or (b) the anti-CD3 antibody comprises a heavy chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 51.
  11. 11 . The method of claim 1 , wherein the antibody that recognizes IL-6Rc is a monoclonal antibody.
  12. 12 . The method of claim 1 , wherein the antibody that recognizes IL-6Rc is fully human.
  13. 13 . The method of claim 7 , wherein the anti-CD3 antibody is administered at a daily dose of 1 mg to 5 mg.
  14. 14 . The method of claim 13 , wherein the daily dose is administered for at least 5 consecutive days.
  15. 15 . The method of claim 1 , wherein the anti-IL-6Rc is administered at a daily dose of 50 mg to 300 mg.
  16. 16 . The method of claim 15 , wherein the daily dose is administered once daily.
  17. 17 . The method of claim 15 , wherein the daily dose is administered once every 14 days.
  18. 18 . The method of claim 1 , wherein the anti-IL-6Rc antibody is administered subcutaneously.
  19. 19 . The method of claim 7 , further comprising administering to the subject a second dose of the anti-CD3 antibody, wherein the second administration is intranasal.
  20. 20 . The method of claim 7 , further comprising a second administration of the anti-CD3 antibody, wherein the second administration is subcutaneous and to a different site of the body than the first administration.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of U.S. patent application Ser. No. 17/723,098, filed Apr. 18, 2022, which claims priority to and the benefit of U.S. Provisional Application No. 63/175,674, filed Apr. 16, 2021, which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING This application is being filed electronically via EFS-Web and includes an electronically submitted sequence listing in .xml format. The .xml file contains a sequence listing entitled “TIZI-029_D01US_SeqList_ST26-updated.xml” created on Oct. 15, 2025 and having a size of 73,845 bytes. The sequence listing contained in this .xml file is part of the specification and is incorporated herein by reference in its entirety. TECHNICAL FIELD This invention relates generally to methods and use of subcutaneous administration of anti-CD3 monoclonal antibodies (mAbs) either alone or in combination with monoclonal antibodies, that recognize the Interleukin-6 (IL-6) and IL-6 receptor (IL-6R) complex. These mAbs are administered by subcutaneous injection and/or intravenously to patients with an inflammatory, autoimmune or oncological disease such as for example, diabetes, non-alcoholic steatohepatitis (NASH), cancer, and rheumatoid arthritis BACKGROUND Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for maintaining sugar homeostasis in blood. However, decreases in insulin sensitivity due to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH). Although the exact underlying cause of IR has not been fully elucidated, several major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. Accordingly, there exists a need for therapies that neutralize the biological activities CD3 to treat and prevent inflammatory, autoimmune and oncological disease such as for example, diabetes, non-alcoholic steatohepatitis (NASH), cancers and rheumatoid arthritis. SUMMARY The disclosure provides a method of treating, preventing or alleviating a symptom of an inflammatory disease, an autoimmune disease or an oncological disease in a subject in need thereof comprising subcutaneously administering to the subject a composition comprising an anti-CD3 antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is fully human or humanized. In some embodiments, the anti-CD3 antibody comprises a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYGMH (SEQ ID NO: 42), a heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence VIWYDGSKKYYVDSVKG (SEQ ID NO: 43), a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence QMGYWHFDL (SEQ ID NO: 44), a light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSYLA (SEQ ID NO: 45), a light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence DASNRAT (SEQ ID NO: 46), and a light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQRSNWPPLT (SEQ ID NO: 47). In some embodiments, the anti-CD3 antibody comprises a variable heavy chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 48 and a variable light chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 49. In some embodiments, the anti-CD3 antibody comprises a heavy chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the autoimmune disease is diabetes or rheumatoid arthritis. In some embodiments, the diabetes is Type 1 diabetes. In some embodiments, the autoimmune disease is lupus. In some embodiments, the autoimmune disease is multiple sclerosis. In some embodiments, the inflammatory disease is Type II diabetes, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the oncological disease is hematological cancer. In some embodiments, the hematological cancers is multiple myeloma. In some embodiments, the method further comprises a second administration of the anti-CD3 antibody, wherein the second administration is intranasal. In some embodiments, the method further comprises a second administration of the anti-CD3 antibody, wherein the second administration is subcutaneous and to a different site of the body than the first administration. In some embodiments, the methods provided further comprise administering an antibody that