METHODS, COMPOSITIONS AND DOSING REGIMENS FOR TREATING OR PREVENTING INTERFERON-GAMMA RELATED INDICATIONS
The disclosure relates generally to methods compositions and dosing regimens for treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with elevated IFN-γ levels.
1 . A method of treating a symptom of Macrophage Activation Syndrome (MAS) in a subject comprising administering an antibody that binds interferon gamma (IFNγ),
wherein the antibody is administered at
i) a first dose of 6.0 mg/kg of the subject's body weight, and
ii) a second dose of 3.0 mg/kg of the subject's body weight, and
wherein the antibody comprises:
a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); and a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable light chain complementarity determining region 2 (VL CDR2) region comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable light chain complementarity determining region 3 (VL CDR3) region comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6),
wherein the subject has Adult-Onset Still's Disease (AOSD) or Systemic Lupus Erythematosus (SLE).
2 . The method of claim 1 , wherein the antibody comprises the heavy chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 47, and the light chain variable amino acid sequence to the amino acid sequence of SEQ ID NO: 48.
3 . The method of claim 1 , wherein the first dose of the antibody is administered over a period of 1 hour.
4 . The method of claim 1 , wherein the first dose of the antibody is administered over a period of at least 2 hours.
5 . The method of claim 1 , wherein the second dose is administered for a first treatment period, wherein the second dose is administered of every three days after the first dose during the first treatment period.
6 . The method of claim 5 , wherein the first treatment period is about two weeks.
7 . The method of claim 5 , wherein the second dose is administered for a second treatment period after completion of the first treatment period.
8 . The method of claim 7 , wherein the second dose is administered twice weekly during the second treatment period.
9 . The method of claim 7 , wherein the second treatment period is about 2 weeks.
10 . The method of claim 1 , wherein the first dose and the second dose is administered intravenously.
11 . The method of claim 1 , wherein the antibody is in a pharmaceutical composition at a concentration of 5 mg/mL.
12 . The method of claim 1 , wherein the antibody is administered as a pharmaceutical formulation and wherein the pharmaceutical formulation comprises L-histidine, L-histidine monohydrochloride, monohydrate, sodium chloride (NaCl), and Polysorbate 80, wherein the pH of the formulation is between pH 5.8 and pH 6.2.
13 . The method of claim 1 , wherein the subject has Adult-Onset Still's Disease (AOSD).
14 . The method of claim 1 , wherein the subject has Systemic Lupus Erythematosus (SLE).
15 . The method of claim 1 , wherein the subject is an adult subject.
16 . The method of claim 1 , wherein the subject is a pediatric subject.
17 . A method of alleviating a symptom of macrophage activation syndrome (MAS), the method comprising detecting a level of C-X-C motif Chemokine Ligand 9 (CXCL9), alone or in conjunction with one or more other biomarkers in a biological sample from a subject, comparing the detected level of CXCL9 to a control level of expression, and when the detected level is elevated, administering an antagonistic anti-interferon gamma (IFNγ) antibody in an amount sufficient to alleviate the symptom of MAS in the subject.
18 . The method of claim 17 , wherein the one or more other biomarkers is selected from the group consisting of total IFNγ level, CXCL10, CXCL11, and combinations thereof.
19 . The method of claim 17 , wherein the biological sample is or is derived from blood.
20 . The method of claim 17 , wherein the biological sample is serum.
21 . The method of claim 17 , wherein the anti-IFNγ antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) region comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable heavy chain complementarity determining region 2 (VL CDR2) comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable heavy chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6).
22 . The method of claim 17 , wherein the anti-IFNγ antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO: 47 and the light chain variable amino acid sequence of SEQ ID NO: 48).
23 . The method of claim 17 , wherein the symptom of MAS is in the context of Adult Onset Still's Disease (AOSD).
24 . The method of claim 17 , wherein the symptom of MAS is in the context of systemic lupus erythematosus (SLE).
25 . The method of claim 17 , wherein the symptom of MAS is in the context of autoimmune disease or inflammatory disorder.
26 . The method of claim 17 , wherein the subject is an adult subject.
27 . The method of claim 17 , wherein the subject is a pediatric subject.
28 . A method diagnosing MAS in a subject comprising:
a. detecting if CXCL9 is present in a blood sample obtained from the subject;
b. diagnosing the subject with MAS when CXCL9 is elevated in comparison to a control sample; and
c. administering a antagonistic anti-Interferon Gamma (IFNγ) antibody to the subject.
29 . The method of claim 28 , wherein the biological sample is or is derived from blood.
30 . The method of claim 28 , wherein the biological sample is serum.
31 . The method of claim 28 , wherein the anti-IFNγ antibody comprises a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO: 1); a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of AISGSGGSTYYADSVKG (SEQ ID NO: 2); a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of DGSSGWYVPHWFDP (SEQ ID NO: 3); a variable light chain complementarity determining region 1 (VL CDR1) region comprising the amino acid sequence of TRSSGSIASNYVQ (SEQ ID NO: 4); a variable heavy chain complementarity determining region 2 (VL CDR2) comprising the amino acid sequence of EDNQRPS (SEQ ID NO: 5); and a variable heavy chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of QSYDGSNRWM (SEQ ID NO: 6).
32 . The method of claim 28 , wherein the anti-IFNγ antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO: 47 and the light chain variable amino acid sequence of SEQ ID NO: 48).