Compositions and methods of use of interleukin-10 in combination with immune check-point pathway inhibitors

Abstract

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)