Combined preparations for the treatment of cancer or infection
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.
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 LAG-3 protein, or a derivative of LAG-3 protein that is able to bind to MHC class II molecules, wherein the derivative of LAG-3 protein comprises recombinant soluble human LAG-3Ig fusion protein IMP321, wherein the LAG-3 protein or the derivative of LAG-3 protein is an APC activator that binds to MHC class II molecules, thereby activating APCs; and
a programmed cell death protein-1 (PD-1) pathway inhibitor, wherein the PD-1 pathway inhibitor is selected from the group consisting of BMS-936559, MEDI4736, MPDL3280A, and MSB0010718C;
wherein the LAG-3 protein or the derivative of LAG-3 protein, and the PD-1 pathway inhibitor cause a synergistic activation of T cells in the subject, the synergistic activation of T cells in the subject being more than a sum of activation of T cells in the subject caused by administration to the subject of the LAG-3 protein or the derivative of LAG-3 protein alone and administration to the subject of the PD-1 pathway inhibitor alone.
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, is administered after the PD-1 pathway inhibitor.
4. 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.
5. 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.
6. 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 thereof
Type of PD-1
Dose of PD-1 pathway
(given as a mg dose of
pathway
inhibitor: mg/kg [mg
IMP321, or a molar
inhibitor
dose for 70 kg human]
equivalent thereof)
BMS-936559
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
BMS-936559
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
BMS-936559
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
MPDL3280A
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-<l 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
MPDL3280A
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
MPDL3280A
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.
7. The method according to claim 1 , wherein:
the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321, and the PD-1 pathway inhibitor is BMS-936559;
the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321, and the PD-1 pathway inhibitor is MEDI4736;
the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321, and the PD-1 pathway inhibitor is MPDL3280A; or
the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321, and the PD-1 pathway inhibitor is MSB0010718C.
8. The method according to claim 1 , wherein the cancer is skin, lung (especially squamous or nonsquamous non-small-cell lung carcinoma, NSCLC), ovarian, renal, colon, colorectal, breast, gastric, esophageal, pancreatic, bladder, urothelial, or liver cancer, or a melanoma (for example, metastatic malignant melanoma), a prostate cancer (for example hormone refractory prostate adenocarcinoma), a head and neck cancer (for example, squamous cell carcinoma of the head and neck), a cervical cancer, a thyroid cancer, a glioblastoma, a glioma, leukemia, a lymphoma (for example, a B cell 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.
9. The method according to claim 1 , wherein the subject is a human subject.
10. The method according to claim 1 , wherein the T cells are CD8+T cells.