IL-10 variant molecules and methods of treating inflammatory disease
The application relates to compositions or formulations comprising variant IL-10 molecules, fusion proteins, and chimeric proteins thereof useful for the treatment of cancer, inflammatory diseases or disorders, and autoimmune diseases or disorders.
1. A method of treating inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a fusion protein of formula (I, II, III, IV, V, VI, or VII)
IL10-L 1 -X 1 -L 1 -X 2 -L 1 -IL10 (Formula I);
(Z) n —X 1 -L 2 -Y 2 -L 1 -IL10 (Formula II);
IL10-L 1 -Y 1 -L 2 -X 2 —(Z) n (Formula III);
X 1 -L 2 -X 2 -L 1 -IL10 (Formula IV); or
IL10-L 1 -X 1 -L 2 -X 2 (Formula V);
wherein
“IL-10” is a monomer sequence selected from SEQ ID No 57;
“L 1 ” is a linker of SEQ ID No: 31 or 54;
“L 2 ” is a linker of SEQ ID No: 30;
“X 1 ” is a VH region obtained from a first antibody specific for epidermal growth factor receptor (EGFR); CD3α; MAdCAM α 4 β7 integrin; HIV, or Ebola;
“X 2 ” is a VL region obtained from the same antibody as X 1 ;
“Y 1 ” is a VH region obtained from a second antibody specific for EGFR, CD3α, MAdCAM, α4β7 integrin, HIV, or Ebola;
“Y 2 ” is a VL region obtained from the same second antibody as Y 1 ; and
“Z” is a cytokine other than IL-10, wherein “n” is an integer of zero;
wherein the effective amount of the composition comprising the fusion protein reduces inflammation.
2. The method according to claim 1 , wherein the fusion protein is SEQ ID Nos: 48, or 49.
3. The method according to claim 1 , wherein the fusion protein forms a protein complex and the protein complex is formed between SEQ ID Nos: 48 and 49.
4. The method according to claim 1 , wherein the composition comprises a fusion protein of SEQ ID Nos: 37, 40, or 43.
5. The method according to claim 1 , wherein the VH region and the VL region are from an anti-Ebola antibody; and wherein the VH region and VL region comprise a framework region with 6 CDRs.
6. The method according to claim 5 , wherein the VH region and the VL region comprises the framework region from an anti-Ebola antibody that is engrafted with 6 CDR regions from an anti MAdCAM antibody.
7. The method according to claim 1 , wherein the VH region and the VL region comprise modifications that reduce the antigenicity in a subject.
8. The method according to claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, preservative, stabilizers, or any combination thereof.
9. The method according to claim 1 , wherein the inflammatory disease is inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or any combination thereof.