COMPOSITIONS AND METHODS OF USE OF INTERLEUKIN-10 IN COMBINATION WITH IMMUNE CHECK-POINT PATHWAY INHIBITORS
The present disclosure provides a method for the treatment of neoplastic disease in a mammalian subject the method comprising the administration of an IL-10 agent in combination with the administration of at least one modulator of at least one immune checkpoint pathway. The present disclosure further provides a method for the treatment of neoplastic disease wherein the neoplasm has a low or intermediate tumor mutation burden, low or intermediate level of expression of the immune checkpoint molecule, or metastatic neoplastic disease.
1 . A method of treating or preventing a neoplastic disease in a mammalian subject, comprising administering to the subject:
a) a therapeutically effective amount of an immune checkpoint pathway modulator, and
b) a therapeutically effective amount of an IL-10 agent.
2 . The method of claim 1 , wherein the neoplastic disease is a neoplastic disease having an intermediate tumor mutation burden or low tumor mutation burden.
3 . The method of claim 2 , wherein the neoplastic disease is a primary tumor.
4 . The method of claim 1 , wherein the IL-10 agent is administered sufficient to maintain a mean IL-10 agent serum trough concentration of at least 1.0 ng/mL over the course of treatment.
5 . The method of claim 1 , wherein the IL-10 agent comprises two IL-10 polypeptides each having the amino acid sequence of SEQ ID 25.
6 . The method of claim 1 , wherein the IL-10 agent comprises two IL-10 polypeptides each having the amino acid sequence of SEQ ID 26.
7 . The method of claim 1 , wherein the IL-10 agent comprises two IL-10 polypeptides each having the amino acid sequence of SEQ ID 27.
8 . The method of claim 1 , wherein the IL-10 agent is PEGylated.
9 . The method of claim 1 , wherein the immune checkpoint pathway modulator is selected from the group consisting of antagonist antibodies to CTLA4, PD1, PDL1, BTLA, TIM3, LAG3, A2aR and a Killer Inhibitory Receptor.
10 . The method of claim 1 , wherein the immune checkpoint pathway modulator is selected from the group consisting of antagonist antibodies to CTLA4, PD1, PDL1 and BTLA.
11 . The method claim 14 , wherein the immune checkpoint pathway modulator is a PD1 immune checkpoint pathway inhibitor.
12 . The method of claim 14 , wherein cell surface expression of PD-L1 is intermediate or low in the neoplastic disease.
13 . The method of claim 12 , wherein the PD1 immune checkpoint pathway inhibitor is selected from the group consisting of pembrolizumab, nivolumab, and AM0001.
14 . The method of claim 13 , wherein the PD1 immune checkpoint pathway inhibitor is a small molecule.
15 . The method claim 14 , wherein the immune checkpoint pathway modulator is and CTLA4 immune checkpoint pathway inhibitor.
16 . The method of claim 15 , wherein the CTLA4 immune checkpoint pathway inhibitor is ipilumumab.
17 . The method of claim 1 , wherein the neoplastic disease, disorder or condition is a cancer.
18 . The method of claim 17 , wherein the cancer is a solid tumor or a hematological disorder.
19 . The method of claim 18 , wherein the cancer is selected from the group consisting of melanoma, lung cancer, kidney cancer and breast cancer.
20 . The method of claim 14 , the method comprising the addition of a second immune checkpoint pathway modulator.
21 . The method of claim 1 , wherein the IL-10 agent comprises at least one modification to form a modified IL-10 agent, wherein the modification does not alter the amino acid sequence of the IL-10 agent.
22 . The method of claim 21 , wherein the modified IL-10 agent is a PEG-IL-10 agent.
23 . The method of claim 22 , wherein the PEG-IL-10 agent comprises at least one PEG molecule covalently attached to at least one amino acid residue of at least one subunit of IL-10.
24 . The method of claim 21 , wherein the PEG-IL-10 agent comprises a mixture of mono-pegylated and di-pegylated IL-10.
25 . The method of claim 22 , wherein the PEG component of the PEG-IL-10 agent has a molecular mass from about 5 kDa to about 50 kDa.
26 . The method of claim 22 , wherein the PEG component of the PEG-IL-10 agent has a molecular mass from about 20 kDa to about 40 kDa.
27 . The method of claim 21 , wherein the modification comprises a linker.
28 . (canceled)
29 . (canceled)
30 . (canceled)
31 . The method of claim 22 , wherein the administering of the immune checkpoint pathway modulator and the IL-10 agent is by parenteral injection.
32 . The method of claim 31 , wherein the administering of the IL-10 agent is by subcutaneous injection.
33 . The method of claim 22 , wherein the immune checkpoint pathway modulator and the IL-10 agent are administered simultaneously.
34 . The method of claim 22 , wherein the immune checkpoint pathway modulator and the IL-10 agent are administered sequentially.
35 . The method of claim 22 , further comprising administering at least one additional prophylactic or therapeutic agent.
36 . The method of claim 35 , wherein the prophylactic or therapeutic agent is a chemotherapeutic agent.
37 . The method of claim 22 , wherein the subject is a human.
38 - 46 . (canceled)