Granted Patent
B2
US 12,673,088 · App. 17/929,888 · Granted Jul 7, 2026
Combined preparations for the treatment of cancer or infection
Assignee:
IMMUTEP S.A.S.
A61K38/1774A61K38/177A61K39/3955A61P31/16A61P31/22A61P35/04C07K16/2818A61K39/39558A61K2300/00C07K2317/70C07K2317/76C07K2319/30C07K2319/32Y02A50/30
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Abstract
Combined preparations, and pharmaceutical compositions, comprising: (a) LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; and (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, are described. The PD-1 pathway inhibitor, such as an anti-PD-1 antibody or an anti-PD-L1 antibody, and a soluble derivative of LAG-3, acting as an APC activator, together synergistically activate T cells (in particular, CD8 + T cells). Use of the combined preparations and compositions as medicaments, in particular for the treatment of cancer or infection, and to methods for the treatment of cancer or infection, is described.
Claims (327)
1 . A method of treating or ameliorating a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of:
a human LAG-3 protein, or a derivative thereof which is a soluble fragment, variant, or mutant of human LAG-3 protein that is able to bind to MHC class II molecules, wherein the derivative comprises domain D1 and domain D2 of human LAG3 protein, and wherein the derivative is fused to an Immunoglobulin Fc sequence; and
a programmed cell death protein-1 (PD-1) pathway inhibitor, wherein the PD-1 pathway inhibitor is (i) an anti-PD-1 antibody, or a fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2; or (ii) an anti-PD-L1 antibody, or a fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1;
wherein the LAG-3 protein or the derivative of LAG-3 protein binds to MHC class II molecules on antigen-presenting cells (APCs), thereby activating APCs and further activating T cells.
2 . The method according to claim 1 , wherein the LAG-3 protein, or derivative thereof, and the PD-1 pathway inhibitor are administered sequentially or co-administered to the subject.
3 . The method according to claim 2 , wherein the LAG-3 protein, or derivative thereof, and the PD-1 pathway inhibitor are administered to the subject within 96 hours of each other.
4 . The method according to claim 1 , wherein the LAG-3 protein, or derivative thereof, is administered after the PD-1 pathway inhibitor.
5 . The method according to claim 1 , wherein the LAG-3 protein, or derivative thereof, is administered to the subject at a dose which is a molar equivalent of 0.25-30 mg of LAG-3Ig fusion protein IMP321.
6 . The method according to claim 1 , wherein a plurality of doses of the LAG-3 protein, or derivative thereof, is administered to the subject and/or a plurality of doses of the PD-1 pathway inhibitor is administered to the subject.
7 . The method according to claim 6 , wherein a dose of the LAG-3 protein, or derivative thereof, is administered before, with, or after each administration of two or more doses of the PD-1 pathway inhibitor.
8 . The method according to claim 1 , wherein the PD-1 pathway inhibitor is pembrolizumab or nivolumab or pidilizumab.
9 . The method according to claim 1 , wherein the PD-1 pathway inhibitor is BMS-936559, MEDI4736, MPDL3280A, or MSB0010718C.
10 . The method according to claim 1 , wherein the LAG-3 protein or derivative thereof, and the PD-1 pathway inhibitor, are administered in any of the combinations of dosage amounts shown in the Table below:
Human dose of LAG-3
protein or derivative
Dose of PD-1 pathway
thereof (given as a mg
Type of PD-1
inhibitor: mg/kg [mg
dose of IMP321, or a
pathway inhibitor
dose for 70 kg human]
molar equivalent thereof)
Pembrolizumab
0.001-5 mg/kg
[0.07-350 mg]
0.25-30
mg
0.001-2.5 mg/kg
[0.07-175 mg]
0.25-30
mg
0.001-1 mg/kg
[0.07-70 mg]
0.25-30
mg
0.001-<1 mg/kg
[0.07-<70 mg]
0.25-30
mg
0.001-0.5 mg/kg
[0.07-35 mg]
0.25-30
mg
0.001-0.1 mg/kg
[0.07-7 mg]
0.25-30
mg
0.002-5 mg/kg
[0.14-350 mg]
0.25-30
mg
0.002-2.5 mg/kg
[0.14-175 mg]
0.25-30
mg
0.002-1 mg/kg
[0.14-70 mg]
0.25-30
mg
0.002-<1 mg/kg
[0.14-<70 mg]
0.25-30
mg
0.002-0.5 mg/kg
[0.14-35 mg]
0.25-30
mg
0.002-0.1 mg/kg
[0.14-7 mg]
0.25-30
mg
Pembrolizumab
0.001-5 mg/kg
[0.07-350 mg]
1-30
mg
0.001-2.5 mg/kg
[0.07-175 mg]
1-30
mg
0.001-1 mg/kg
[0.07-70 mg]
1-30
mg
0.001-<1 mg/kg
[0.07-<70 mg]
1-30
mg
0.001-0.5 mg/kg
[0.07-35 mg]
1-30
mg
0.001-0.1 mg/kg
[0.07-7 mg]
1-30
mg
0.002-5 mg/kg
[0.14-350 mg]
1-30
mg
0.002-2.5 mg/kg
[0.14-175 mg]
1-30
mg
0.002-1 mg/kg
[0.14-70 mg]
1-30
mg
0.002-1 mg/kg
[0.14-70 mg]
1-30
mg
0.002-<1 mg/kg
[0.14-<70 mg]
1-30
mg
0.002-0.5 mg/kg
[0.14-35 mg]
1-30
mg
Pembrolizumab
0.001-5 mg/kg
[0.07-350 mg]
6-30
mg
0.001-2.5 mg/kg
[0.07-175 mg]
6-30
mg
0.001-1 mg/kg
[0.07-70 mg]
6-30
mg
0.001-<1 mg/kg
[0.07-<70 mg]
6-30
mg
0.001-0.5 mg/kg
[0.07-35 mg]
6-30
mg
0.001-0.1 mg/kg
[0.07-7 mg]
6-30
mg
0.002-5 mg/kg
[0.14-350 mg]
6-30
mg
0.002-2.5 mg/kg
[0.14-175 mg]
6-30
mg
0.002-1 mg/kg
[0.14-70 mg]
6-30
mg
0.002-<1 mg/kg
[0.14-<70 mg]
6-30
mg
0.002-0.5 mg/kg
[0.14-35 mg]
6-30
mg
0.002-0.1 mg/kg
[0.14-7 mg]
6-30
mg
Nivolumab
0.001-5 mg/kg
[0.07-350 mg]
0.25-30
mg
0.001-2.5 mg/kg
[0.07-175 mg]
0.25-30
mg
0.001-1 mg/kg
[0.07-70 mg]
0.25-30
mg
0.001-<1 mg/kg
[0.07-<70 mg]
0.25-30
mg
0.001-0.5 mg/kg
[0.07-35 mg]
0.25-30
mg
0.001-0.1 mg/kg
[0.07-7 mg]
0.25-30
mg
0.002-5 mg/kg
[0.14-350 mg]
0.25-30
mg
0.002-2.5 mg/kg
[0.14-175 mg]
0.25-30
mg
0.002-1 mg/kg
[0.14-70 mg]
0.25-30
mg
0.002-<1 mg/kg
[0.14-<70 mg]
0.25-30
mg
0.002-0.5 mg/kg
[0.14-35 mg]
0.25-30
mg
0.002-0.1 mg/kg
[0.14-7 mg]
0.25-30
mg
Nivolumab
0.001-5 mg/kg
[0.07-350 mg]
1-30
mg
0.001-2.5 mg/kg
[0.07-175 mg]
1-30
mg
0.001-1 mg/kg
[0.07-70 mg]
1-30
mg
0.001-<1 mg/kg
[0.07-<70 mg]
1-30
mg
0.001-0.5 mg/kg
[0.07-35 mg]
1-30
mg
0.001-0.1 mg/kg
[0.07-7 mg]
1-30
mg
0.002-5 mg/kg
[0.14-350 mg]
1-30
mg
0.002-2.5 mg/kg
[0.14-175 mg]
1-30
mg
0.002-1 mg/kg
[0.14-70 mg]
1-30
mg
0.002-<1 mg/kg
[0.14-<70 mg]
1-30
mg
0.002-0.5 mg/kg
[0.14-35 mg]
1-30
mg
0.002-0.1 mg/kg
[0.14-7 mg]
1-30
mg
Nivolumab
0.001-5 mg/kg
[0.07-350 mg]
6-30
mg
0.001-2.5 mg/kg
[0.07-175 mg]
6-30
mg
0.001-1 mg/kg
[0.07-70 mg]
6-30
mg
0.001-<1 mg/kg
[0.07-<70 mg]
6-30
mg
0.001-0.5 mg/kg
[0.07-35 mg]
6-30
mg
0.001-0.1 mg/kg
[0.07-7 mg]
6-30
mg
0.002-5 mg/kg
[0.14-350 mg]
6-30
mg
0.002-2.5 mg/kg
[0.14-175 mg]
6-30
mg
0.002-1 mg/kg
[0.14-70 mg]
6-30
mg
0.002-<1 mg/kg
[0.14-<70 mg]
6-30
mg
0.002-0.5 mg/kg
[0.14-35 mg]
6-30
mg
0.002-0.1 mg/kg
[0.14-7 mg]
6-30
mg.
11 . The method according to claim 1 , wherein the derivative of LAG-3 protein comprises domains D1, D2, D3, and optionally D4, of human LAG-3 protein.
12 . The method according to claim 1 , wherein the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321.
13 . The method according to claim 1 , wherein the cancer is a PD-L1-positive or a PD-L2-positive cancer.
14 . The method according to claim 1 , wherein the cancer is skin, lung, ovarian, renal, colon, colorectal, breast, gastric, esophageal, pancreatic, bladder, urothelial, or liver cancer, or a melanoma a prostate cancer, a head and neck cancer, a cervical cancer, a thyroid cancer, a glioblastoma, a glioma, leukemia, a lymphoma, an adrenal gland cancer, an AIDS-associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a carotid body tumor, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, a gestational trophoblastic disease, a germ cell tumor, a haematological malignancy, hepatocellular carcinoma, an islet cell tumor, a Kaposi's sarcoma, a kidney cancer, a lipoma/benign lipomatous tumor, a liposarcoma/malignant lipomatous tumor, a medulloblastoma, a meningioma, a Merkel cell carcinoma, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplasia syndrome, a neuroblastoma, a neuroendocrine tumor, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterior uveal melanoma, a rare hematologic disorder, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a soft-tissue sarcoma, a squamous cell cancer, a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid metastatic cancer, or a uterine cancer.
15 . The method of claim 14 , wherein
(i) the lung cancer is squamous or nonsquamous non-small-cell lung carcinoma (NSCLC),
(ii) the melanoma is metastatic malignant melanoma;
(iii) the prostate cancer is hormone refractory prostate adenocarcinoma;
(iv) the head and neck cancer is squamous cell carcinoma of the head and neck; or
(v) the lymphoma is a B cell lymphoma.
Priority Claims (1)
GB 1500374
· Jan 9, 2015
· national
Continuity (3)
Division
15542466
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