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 a neoplastic disease in a mammalian subject, wherein the neoplastic disease is non-small cell lung cancer that has (i) an intermediate tumor mutation burden of greater than 15 but less than 100 mutations per megabase sequenced, or a low tumor mutation burden of less than or equal to 15 mutations per megabase sequenced, and (ii) a low PD-L1 expression or an intermediate PD-L1 expression, the method 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,
wherein the immune checkpoint pathway modulator is a PD1 pathway inhibitor selected from monoclonal antibodies that interfere with the binding of PD1 and PDL1; and
wherein the IL-10 agent is a dimeric molecule having IL-10 activity and comprising two IL-10 polypeptides that bind to the IL-10 receptor and modulate the same signaling pathway as IL-10 and are capable of eliciting a biological response characteristic of IL-10.
2 . The method of claim 1 , wherein the neoplastic disease is a primary tumor.
3 . The method of claim 1 , wherein the mammalian subject is a human.
4 . The method of claim 1 , wherein the IL-10 agent comprises two IL-10polypeptides each having the amino acid sequence of SEQ ID NO: 25.
5 . The method of claim 1 , wherein the IL-10 agent comprises two IL-10polypeptides each having the amino acid sequence of SEQ ID NO: 26.
6 . The method of claim 1 , wherein the IL-10 agent comprises two IL-10polypeptides each having the amino acid sequence of SEQ ID NO: 27.
7 . 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.
8 . The method of claim 7 , wherein the modification comprises a linker.
9 . The method of claim 7 , wherein the modified IL-10 agent is a PEG-IL-10 agent.
10 . The method of claim 9 , 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.
11 . The method of claim 10 , wherein the PEG-IL-10 agent comprises a mixture of mono-pegylated and di-pegylated IL-10.
12 . The method of claim 9 , wherein the PEG component of the PEG-IL-10 agent has a molecular mass from about 5 kDa to about 50 kDa.
13 . The method of claim 9 , wherein the PEG component of the PEG-IL-10 agent has a molecular mass from about 20 kDa to about 40 kDa.
14 . The method of claim 1 , wherein the IL-10 agent is PEGylated.
15 . The method of claim 1 , wherein the IL-10 agent is an Fc fusion molecule.
16 . The method of claim 1 , wherein the IL-10 agent comprises a serum albumin or an albumin binding domain (ABD).
17 . The method of claim 1 , wherein the IL-10 agent is glycosylated or hesylated.
18 . The method of claim 1 , wherein the PD1 pathway inhibitor is selected from the group consisting of pembrolizumab and nivolumab.
19 . The method of claim 1 , further comprising the addition of a second immune checkpoint pathway modulator.
20 . 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.
21 . The method of claim 1 , wherein the administering of the immune checkpoint pathway modulator and the IL-10 agent is by parenteral injection.
22 . The method of claim 1 , wherein the administering of the IL-10 agent is by subcutaneous injection.
23 . The method of claim 1 , wherein the immune checkpoint pathway modulator and the IL-10 agent are administered simultaneously.
24 . The method of claim 1 , wherein the immune checkpoint pathway modulator and the IL-10 agent are administered sequentially.
25 . The method of claim 1 , further comprising administering at least one additional prophylactic or therapeutic agent.
26 . The method of claim 25 , wherein the prophylactic or therapeutic agent is a chemotherapeutic agent.