METHODS AND COMPOSITIONS FOR TREATING SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) WITH MOSUNETUZUMAB
Disclosed herein are compositions and methods for the treatment of systemic lupus erythematosus using anti-CD20/anti-CD3 bispecific antibodies, such as mosunetuzumab.
1 . A method of treating a patient, comprising administering to the patient an effective amount of mosunetuzumab, wherein the patient has systemic lupus erythematosus.
2 . The method of claim 1 , wherein the patient is being administered before being administered the effective amount of mosunetuzumab an oral corticosteroid, an antimalarial agent, or an immunosuppressant.
3 . The method of claim 2 , wherein the patient has been administered a stable dose of at least 40 mg/day prednisone (or equivalent) for at least 7 days prior to being administered an effective amount of mosunetuzumab.
4 . The method of claim 2 , wherein the patient has been administered the antimalarial agent at a stable dose for at least 4 weeks prior to being administered an effective amount of mosunetuzumab.
5 . The method of claim 2 , wherein the patient has been administered an immunosuppressant at a stable dose for at least 4 weeks prior to being administered an effective amount of mosunetuzumab.
6 . The method of claim 5 , wherein the immunosuppressant is azathioprine, mycophenolate mofetil, mycophenolic acid, or methotrexate.
7 . The method of claim 1 , wherein the patient does not have a lupus-associated neuropsychiatric disease.
8 . The method of claim 7 , wherein the lupus-associated neuropsychiatric disease is meningitis, retinitis, cerebral vasculitis, myelopathy, demyelination syndromes, acute confusional state, psychosis, acute stroke or stroke syndrome, cranial neuropathy, status epilepticus or seizures, cerebellar ataxia, or mononeuritis multiplex.
9 . The method of claim 1 , wherein the patient does not have active overlap syndrome with mixed connective tissue disease or systemic sclerosis within a year of being administered the effective amount of mosunetuzumab.
10 . The method of claim 1 , wherein the patient does not have catastrophic or severe antiphospholipid syndrome within a year of being administered the effective amount of mosunetuzumab, unless the severe antiphospholipid syndrome has been adequately controlled by administering anticoagulant therapy to the patient at least 3 months of being administered the effective amount of mosunetuzumab.
11 . The method of claim 1 , wherein the patient has not been administered:
(a) at least 12 months before being administered the effective amount of mosunetuzumab:
(i) anti-CD19 antibody therapy, or
(ii) anti-CD20 monoclonal antibody therapy;
or
(b) at least 30 days before being administered the effective amount of mosunetuzumab:
(i) kinase inhibitors of Janus Kinase (JAK) kinase, Bruton tyrosine kinase, or tyrosine kinase 2, or
(ii) tacrolimus, ciclosporin, or voclosporin;
or
(c) at least 2 months before being administered the effective amount of mosunetuzumab:
(i) cyclophosphamide, or
(ii) biologic therapy.
12 . The method of claim 11 , wherein:
(a) the anti-CD19 therapy is blinatumomab;
(b) the anti-CD20 therapy is obinutuzumab, rituximab, ocrelizumab, or ofatumumab;
(c) the kinase inhibitors are baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib;
or
(d) the biologic therapy is belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept.
13 . The method of claim 1 , wherein the patient does not have significant lupus-associated renal disease or significant renal impairment.
14 . The method of claim 1 , wherein the patient does not have one laboratory parameter selected from the group consisting of:
total
bilirubin
>
1.5
×
ULN
,
(
a
)
ANC
<
1.5
×
10
9
/
L
(
<
1500
/
mm
3
)
,
(
b
)
platelet
count
<
100
×
10
9
/
L
(
100
,
000
/
mm
3
)
,
(
c
)
hemoglobin
<
100
g
/
L
,
(
d
)
(e) estimated glomulerular filtration rate (eGFR)<30 ml/min/1.73 m 2 calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation, and
(f) positive serum human chorionic gonadotropin.
15 . The method of claim 1 , wherein at least one symptom of SLE is reduced.
16 . The method of claim 15 , wherein the at least one reduced symptom of SLE is measured using a Patient Global Impression of Severity (PGI-S), a Physician Global Assessment (PGA), a decrease in titer of antinuclear antibody (ANA), a decrease in titer of anti-double stranded DNA (dsDNA) antibody (IgG) titer, an increase in complement C3 levels, or an increase in complement C4 levels.
17 . The method of claim 16 , wherein the at least one reduced symptom is a change in response of at least one step on the PGI-S from a previous response, wherein the change is one change of from “very severe” to “severe,” “severe” to “moderate,” “moderate” to “mild,” or “mild” to “none.”
18 . The method of claim 16 , wherein the at least one reduced symptom is a change in rating by a healthcare provider using the PGA, wherein the change is a decrease from a previous rating using the PGA.
19 . The method of claim 18 , wherein the decrease from a previous rating using the PGA is ≥0.3 points from baseline.
20 . The method of claim 1 , wherein the administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein the C1D1 is less than C1D2, and wherein the C1D1 is between about 1.6 mg to about 5 mg and the C1D2 is between about 15 mg to about 60 mg.
21 . The method of claim 20 , wherein the C1D2 is 15 mg, 45 mg, or 60 mg.
22 . The method of claim 20 , wherein the first dose cycle is about 8 days.
23 . The method of claim 22 , wherein the C1D1 dose of mosunetuzumab is administered on about day 1 of the cycle.
24 . The method of claim 22 , wherein the C1D2 dose of mosunetuzumab is administered on about day 8 of the cycle.
25 . The method of claim 1 , wherein mosunetuzumab is administered subcutaneously.
26 . The method of claim 1 , wherein the patient is further administered tocilizumab if the patient experiences cytokine release syndrome (CRS).
27 . The method of claim 1 , further comprising administering to the patient a corticosteroid, cyclophosphamide, a B-cell-depleting therapy, or calcineurin inhibitor.
28 . The method of claim 27 , wherein the corticosteroid comprises hydrocortisone, cortisone acetate, prednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, methylprednisolone or prednisone; wherein the B-cell-depleting therapy comprises administering rituximab, ocrelizumab, ofatumumab, or obinutuzumab, or wherein the calcineurin inhibitor comprises ciclosporin, tacrolimus, or vocolosporin.
29 . The method of claim 16 , wherein the ANA are at an initial titer that is greater than or equal to 1:80 on HEp-2 cells or equivalent positive test.
30 . The method of claim 16 , wherein the ANA are at a titer that is less than 1:80 on HEp-2 cells or equivalent positive test.
31 . A method of treating a patient, comprising administering to the patient an effective amount of mosunetuzumab, wherein:
(a) the patient has systemic lupus erythematosus;
(b) mosunetuzumab is administered according to a dosing regimen comprising at least a first dosing cycle of about 8 days, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein C1D1 is between about 1.6 mg to about 5 mg on day 1 of the cycle and the C1D2 is between about 15 mg to about 60 mg on day 8 of the cycle; and
(c) mosunetuzumab is administered subcutaneously.
32 . The method of claim 31 , wherein C1D1 is 1.6 mg.
33 . The method of claim 31 , wherein C1D1 is 5 mg.
34 . The method of claim 31 , wherein C1D2 is 15 mg.
35 . The method of claim 31 , wherein C1D2 is 45 mg.
36 . The method of claim 31 , wherein C1D2 is 60 mg.
37 . The method of claim 31 , wherein C1D1 is 1.6 mg and C1D2 is 15 mg.
38 . The method of claim 31 , wherein C1D1 is 1.6 mg and C1D2 is 45 mg.
39 . The method of claim 31 , wherein C1D1 is 1.6 mg and C1D2 is 60 mg.
40 . The method of claim 31 , wherein C1D1 is 5 mg and C1D2 is 15 mg.
41 . The method of claim 31 , wherein C1D1 is 5 mg and C1D2 is 45 mg.
42 . The method of claim 31 , wherein C1D1 is 5 mg and C1D2 is 60 mg.
43 . The method of claim 31 , wherein at least one symptom of SLE is reduced.
44 . The method of claim 43 , wherein the at least one reduced symptom of SLE is measured using a Patient Global Impression of Severity (PGI-S), a Physician Global Assessment (PGA), a decrease in titer of antinuclear antibody (ANA), a decrease in titer of anti-double stranded DNA (dsDNA) antibody (IgG) titer, an increase in complement C3 levels, or an increase in complement C4 levels.
45 . The method of claim 44 , wherein the at least one reduced symptom is a change in response of at least one step on the PGI-S from a previous response, wherein the change is one change of from “very severe” to “severe,” “severe” to “moderate,” “moderate” to “mild,” or “mild” to “none.”
46 . The method of claim 44 , wherein the at least one reduced symptom is a change in rating by a healthcare provider using the PGA, wherein the change is a decrease from a previous rating using the PGA.
47 . The method of claim 46 , wherein the decrease from a previous rating using the PGA is ≥0.3 points from baseline.
48 . The method of claim 31 , wherein mosunetuzumab is administered subcutaneously.
49 . The method of claim 31 , wherein the patient is further administered tocilizumab if the patient experiences cytokine release syndrome (CRS).
50 . The method of claim 31 , further comprising administering to the patient a corticosteroid, cyclophosphamide, a B-cell-depleting therapy, or calcineurin inhibitor.
51 . The method of claim 50 , wherein the corticosteroid comprises hydrocortisone, cortisone acetate, prednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, methylprednisolone or prednisone; wherein the B-cell-depleting therapy comprises administering rituximab, ocrelizumab, ofatumumab, or obinutuzumab, or wherein the calcineurin inhibitor comprises ciclosporin, tacrolimus, or vocolosporin.
52 . The method of claim 44 , wherein the ANA are at an initial titer that is greater than or equal to 1:80 on HEp-2 cells or equivalent positive test.
53 . The method of claim 44 , wherein the ANA are at a titer that is less than the titer of 1:80 on HEp-2 cells or equivalent positive test.
54 . A method of treating a patient who is part of a population of patients, comprising administering to the patients an effective amount of mosunetuzumab, wherein each patient of the population of patients has systemic lupus erythematosus.
55 . The method of claim 54 , wherein the patient is being administered before being administered the effective amount of mosunetuzumab an oral corticosteroid, an antimalarial agent, or an immunosuppressant.
56 . The method of claim 55 , wherein the patient has been administered a stable dose of at least 40 mg/day prednisone (or equivalent) for at least 7 days prior to being administered an effective amount of mosunetuzumab.
57 . The method of claim 55 , wherein the patient has been administered the antimalarial agent at a stable dose for at least 4 weeks prior to being administered an effective amount of mosunetuzumab.
58 . The method of claim 55 , wherein the patient has been administered an immunosuppressant at a stable dose for at least 4 weeks prior to being administered an effective amount of mosunetuzumab.
59 . The method of claim 58 , wherein the immunosuppressant is azathioprine, mycophenolate mofetil, mycophenolic acid, or methotrexate.
60 . The method of claim 54 , wherein the patient does not have a lupus-associated neuropsychiatric disease.
61 . The method of claim 60 , wherein the lupus-associated neuropsychiatric disease is meningitis, retinitis, cerebral vasculitis, myelopathy, demyelination syndromes, acute confusional state, psychosis, acute stroke or stroke syndrome, cranial neuropathy, status epilepticus or seizures, cerebellar ataxia, or mononeuritis multiplex.
62 . The method of claim 54 , wherein the patient does not have active overlap syndrome with mixed connective tissue disease or systemic sclerosis within a year of being administered the effective amount of mosunetuzumab.
63 . The method of claim 54 , wherein the patient does not have catastrophic or severe antiphospholipid syndrome within a year of being administered the effective amount of mosunetuzumab, unless the severe antiphospholipid syndrome has been adequately controlled by administering anticoagulant therapy to the patient at least 3 months of being administered the effective amount of mosunetuzumab.
64 . The method of claim 54 , wherein the patient has not been administered:
(a) at least 12 months before being administered the effective amount of mosunetuzumab:
(i) anti-CD19 antibody therapy, or
(ii) anti-CD20 monoclonal antibody therapy;
or
(b) at least 30 days before being administered the effective amount of mosunetuzumab:
(i) kinase inhibitors of Janus Kinase (JAK) kinase, Bruton tyrosine kinase, or tyrosine kinase 2, or
(ii) tacrolimus, ciclosporin, or voclosporin;
or
(c) at least 2 months before being administered the effective amount of mosunetuzumab:
(i) cyclophosphamide, or
(ii) biologic therapy.
65 . The method of claim 64 , wherein:
(a) the anti-CD19 therapy is blinatumomab;
(b) the anti-CD20 therapy is obinutuzumab, rituximab, ocrelizumab, or ofatumumab;
(c) the kinase inhibitors are baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib;
or
(d) the biologic therapy is belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept.
66 . The method of claim 54 , wherein the patient does not have significant lupus-associated renal disease or significant renal impairment.
67 . The method of claim 54 , wherein the patient does not have one laboratory parameter selected from the group consisting of:
total
bilirubin
>
1.5
×
ULN
,
(
a
)
ANC
<
1.5
×
10
9
/
L
(
<
1500
/
mm
3
)
,
(
b
)
platelet
count
<
100
×
10
9
/
L
(
100
,
000
/
mm
3
)
,
(
c
)
hemoglobin
<
100
g
/
L
,
(
d
)
(e) estimated glomulerular filtration rate (eGFR)<30 ml/min/1.73 m 2 calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation, and
(f) positive serum human chorionic gonadotropin.
68 . The method of claim 54 , wherein at least one symptom of SLE is reduced in at least one patient in the population of patients.
69 . The method of claim 68 , wherein the at least one reduced symptom of SLE is measured using a Patient Global Impression of Severity (PGI-S), a Physician Global Assessment (PGA), a decrease in titer of antinuclear antibody (ANA), a decrease in titer of anti-double stranded DNA (dsDNA) antibody (IgG) titer, an increase in complement C3 levels, or an increase in complement C4 levels.
70 . The method of claim 69 , wherein the at least one reduced symptom is a change in response of at least one step on the PGI-S from a previous response, wherein the change is one change of from “very severe” to “severe,” “severe” to “moderate,” “moderate” to “mild,” or “mild” to “none.”
71 . The method of claim 69 , wherein the at least one reduced symptom is a change in rating by a healthcare provider using the PGA, wherein the change is a decrease from a previous rating using the PGA.
72 . The method of claim 71 , wherein the decrease from a previous rating using the PGA is ≥0.3 points from baseline.
73 . The method of claim 54 , wherein the administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein the C1D1 is less than C1D2, and wherein the C1D1 is between about 1.6 mg to about 5 mg and the C1D2 is between about 15 mg to about 60 mg.
74 . The method of claim 73 , wherein the C1D2 is 15 mg, 45 mg, or 60 mg.
75 . The method of claim 73 , wherein the first dose cycle is about 8 days.
76 . The method of claim 75 , wherein the C1D1 dose of mosunetuzumab is administered on about day 1 of the cycle.
77 . The method of claim 75 , wherein the C1D2 dose of mosunetuzumab is administered on about day 8 of the cycle.
78 . The method of claim 54 , wherein mosunetuzumab is administered subcutaneously.
79 . The method of claim 54 , wherein the patient is further administered tocilizumab if the patient experiences cytokine release syndrome (CRS).
80 . The method of claim 54 , further comprising administering to the patient a corticosteroid, cyclophosphamide, a B-cell-depleting therapy, or calcineurin inhibitor.
81 . The method of claim 80 , wherein the corticosteroid comprises hydrocortisone, cortisone acetate, prednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, methylprednisolone or prednisone; wherein the B-cell-depleting therapy comprises administering rituximab, ocrelizumab, ofatumumab, or obinutuzumab, or wherein the calcineurin inhibitor comprises ciclosporin, tacrolimus, or vocolosporin.
82 . The method of claim 69 , wherein the ANA are at an initial titer that is greater than or equal to 1:80 on HEp-2 cells or equivalent positive test.
83 . The method of claim 69 , wherein the ANA are at a titer that is less than 1:80 on HEp-2 cells or equivalent positive test.
84 . A method of treating a patient of a population of patients, comprising administering to the patient an effective amount of mosunetuzumab, wherein:
(a) the population of patients has systemic lupus erythematosus;
(b) mosunetuzumab is administered according to a dosing regimen comprising at least a first dosing cycle of about 8 days, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein C1D1 is between about 1.6 mg to about 5 mg on day 1 of the cycle and the C1D2 is between about 15 mg to about 60 mg on day 8 of the cycle; and
(c) mosunetuzumab is administered subcutaneously.
85 . The method of claim 84 , wherein C1D1 is 1.6 mg.
86 . The method of claim 84 , wherein C1D1 is 5 mg.
87 . The method of claim 84 , wherein C1D2 is 15 mg.
88 . The method of claim 84 , wherein C1D2 is 45 mg.
89 . The method of claim 84 , wherein C1D2 is 60 mg.
90 . The method of claim 84 , wherein C1D1 is 1.6 mg and C1D2 is 15 mg.
91 . The method of claim 84 , wherein C1D1 is 1.6 mg and C1D2 is 45 mg.
92 . The method of claim 84 , wherein C1D1 is 1.6 mg and C1D2 is 60 mg.
93 . The method of claim 84 , wherein C1D1 is 5 mg and C1D2 is 15 mg.
94 . The method of claim 84 , wherein C1D1 is 5 mg and C1D2 is 45 mg.
95 . The method of claim 84 , wherein C1D1 is 5 mg and C1D2 is 60 mg.
96 . The method of claim 84 , wherein at least one symptom of SLE is reduced.
97 . The method of claim 96 , wherein the at least one reduced symptom of SLE is measured using a Patient Global Impression of Severity (PGI-S), a Physician Global Assessment (PGA), a decrease in titer of antinuclear antibody (ANA), a decrease in titer of anti-double stranded DNA (dsDNA) antibody (IgG) titer, an increase in complement C3 levels, or an increase in complement C4 levels.
98 . The method of claim 97 , wherein the at least one reduced symptom is a change in response of at least one step on the PGI-S from a previous response, wherein the change is one change of from “very severe” to “severe,” “severe” to “moderate,” “moderate” to “mild,” or “mild” to “none.”
99 . The method of claim 97 , wherein the at least one reduced symptom is a change in rating by a healthcare provider using the PGA, wherein the change is a decrease from a previous rating using the PGA.
100 . The method of claim 99 , wherein the decrease from a previous rating using the PGA is ≥0.3 points from baseline.
101 . The method of claim 84 , wherein mosunetuzumab is administered subcutaneously.
102 . The method of claim 84 , wherein the patient is further administered tocilizumab if the patient experiences cytokine release syndrome (CRS).
103 . The method of claim 84 , further comprising administering to the patient a corticosteroid, cyclophosphamide, a B-cell-depleting therapy, or calcineurin inhibitor.
104 . The method of claim 103 , wherein the corticosteroid comprises hydrocortisone, cortisone acetate, prednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, methylprednisolone or prednisone; wherein the B-cell-depleting therapy comprises administering rituximab, ocrelizumab, ofatumumab, or obinutuzumab, or wherein the calcineurin inhibitor comprises ciclosporin, tacrolimus, or vocolosporin.
105 . The method of claim 97 , wherein the ANA are at an initial titer that is greater than or equal to 1:80 on HEp-2 cells or equivalent positive test.
106 . The method of claim 97 , wherein the ANA are at a titer that is less than the titer of 1:80 on HEp-2 cells or equivalent positive test.
107 . A kit, comprising:
(a) a first container comprising mosunetuzumab; and
(b) a package insert with instructions for providing a therapy to in a patient who has Systemic lupus erythematosus wherein the mosunetuzumab is administered subcutaneously and according to a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein C1D1 is between about 1.6 mg to about 5 mg and administered on day 1 of the cycle and the C1D2 is between about 15 mg to about 60 mg and administered on day 8 of the cycle.
108 . The kit of claim 107 , wherein C1D1 is 1.6 mg, and C1D2 is 15 mg.
109 . The kit of claim 107 , wherein C1D1 is 1.6 mg, and C1D2 is 45 mg.
110 . The kit of claim 107 , wherein C1D1 is 1.6 mg, and C1D2 is 60 mg.
111 . The kit of claim 107 , wherein C1D1 is 5 mg, and C1D2 is 15 mg.
112 . The kit of claim 107 , wherein C1D1 is 5 mg, and C1D2 is 45 mg.
113 . The kit of claim 107 , wherein C1D1 is 5 mg, and C1D2 is 60 mg.
114 . The kit of claim 107 , wherein the mosunetuzumab is contained within an injection device.
115 . The kit of claim 114 , wherein the injection device is a syringe or an autoinjector.
116 . The kit of claim 107 , further comprising a second container.
117 . The kit of claim 116 , wherein the first container comprises an injection device comprising sufficient mosunetuzumab to deliver the first dose and the second container comprises an injection device comprising sufficient mosunetuzumab to deliver the second dose.
118 . The kit of claim 116 , further comprising at least a third container.
119 . The kit of claim 118 , wherein the third container comprises a medicament, and the instructions further provide instructions for administering the medicament.
120 . The kit of claim 119 , wherein the medicament comprises a corticosteroid, cyclophosphamide, a B-cell-depleting therapy, or a calcineurin inhibitor.
121 . The kit of claim 120 , wherein the corticosteroid comprises hydrocortisone, cortisone acetate, prednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, methylprednisolone or prednisone; wherein the B-cell-depleting therapy comprises rituximab, ocrelizumab, ofatumumab, or obinutuzumab, and wherein the calcineurin inhibitor comprises ciclosporin, tacrolimus, or vocolosporin.