Compositions and methods for treating cancer and promoting wound healing
Protein complex variants, compositions, and methods of use thereof are provided. The protein complex variant includes a cholera toxin B subunit variant having one or more modifications thereto. The method of use thereof includes treating a disease by administering an effective amount of a composition including a cholera toxin B subunit variant to a subject in need thereof.
1. A method of reducing colon cancer risk in chronic colitis patients, comprising administering to a subject in need thereof an effective amount of a cholera toxin B subunit variant comprising an endoplasmic reticulum (ER) retention sequence attached to its C-terminus.
2. The method of claim 1 , wherein the cholera toxin B subunit variant further comprises an Asn4 to Ser mutation.
3. The method of claim 1 , wherein the C-terminal ER retention sequence comprises SEKDEL (SEQ ID NO: 30), KDEL (SEQ ID NO: 31), or HDEL (SEQ ID NO: 32).
4. The method of claim 1 , wherein the C-terminal ER retention sequence comprises a hexapeptide sequence.
5. The method of claim 1 , wherein the C-terminal ER retention sequence comprises KDEL (SEQ ID NO: 31).
6. The method of claim 1 , wherein the cholera toxin B subunit variant is substantially immunologically identical to a cholera toxin B subunit.
7. The method of claim 1 , wherein the composition is administered to the subject without significantly changing a fecal microbiome of the subject.
8. The method of claim 1 , wherein the administering of the composition comprises oral administration.
9. The method of claim 1 , wherein the administering of the composition decreases protein levels of tumor promoting cytokines.
10. The method of claim 1 , wherein the administering of the composition increases innate immune cell populations in the subject's colon.
11. The method of claim 10 , wherein the administering of the composition increases the innate immune cell populations without producing a substantial effect on adaptive immune cell populations.
12. The method of claim 1 , wherein the administering of the composition provides an increased effect on colon gene expression as compared to small intestine gene expression.
13. The method of claim 1 , wherein the cholera toxin B subunit variant comprises the sequence of SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 25.
14. The method of claim 1 , wherein the cholera toxin B subunit variant further comprises a secretory signal peptide selected from a rice alpha-amylase secretory signal peptide, a Nicotiana plumbagenifolia calreticulin secretory signal peptide, an apple pectinase secretory signal peptide, or a barley alpha-amylase secretory signal peptide.
15. The method of claim 14 , wherein the secretory signal peptide has an amino acid sequence selected from SEQ ID NO: 18, 20, 22, or 24.
16. The method of claim 14 , wherein the secretory signal peptide comprises the rice alpha-amylase secretory signal peptide.
17. The method of claim 1 , wherein the cholera toxin B subunit variant comprises an amino acid sequence selected from SEQ ID NO: 26, 27, 28, or 29.
18. The method of claim 1 , wherein the cholera toxin B subunit variant comprises two or more N-linked glycosylation sequons.
19. The method of claim 18 , wherein the cholera toxin B subunit variant comprises the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14.
20. A method of promoting wound healing from an intestinal injury, comprising administering to a subject in need thereof an effective amount of a cholera toxin B subunit variant comprising an endoplasmic reticulum (ER) retention sequence attached to its C-terminus.
21. The method of claim 20 , wherein the cholera toxin B subunit variant further comprises an Asn4 to Ser mutation.
22. The method of claim 20 , wherein the C-terminal ER retention sequence comprises SEKDEL (SEQ ID NO: 30), KDEL (SEQ ID NO: 31), or HDEL (SEQ ID NO: 32).
23. The method of claim 20 , wherein the C-terminal ER retention sequence comprises a hexapeptide sequence.
24. The method of claim 20 , wherein the C-terminal ER retention sequence comprises KDEL (SEQ ID NO: 31).
25. The method of claim 20 , wherein the cholera toxin B subunit variant is substantially immunologically identical to a cholera toxin B subunit.
26. The method of claim 20 , wherein the wound healing comprises mucosal wound healing.
27. The method of claim 1 , wherein the cholera toxin B subunit variant comprises the amino acid sequence of SEQ ID NO: 4.
28. The method of claim 20 , wherein the intestinal injury is acute.
29. The method of claim 20 , wherein the intestinal injury is chronic.
30. The method of claim 20 , wherein the cholera toxin B subunit variant further comprises a secretory signal peptide selected from a rice alpha-amylase secretory signal peptide, a Nicotiana plumbagenifolia calreticulin secretory signal peptide, an apple pectinase secretory signal peptide, or a barley alpha-amylase secretory signal peptide.
31. The method of claim 30 , wherein the secretory signal peptide has an amino acid sequence selected from SEQ ID NO: 18, 20, 22, or 24.
32. The method of claim 30 , wherein the secretory signal peptide comprises the rice alpha-amylase secretory signal peptide.
33. The method of claim 20 , wherein the cholera toxin B subunit variant comprises an amino acid sequence selected from SEQ ID NO: 26, 27, 28, or 29.
34. The method of claim 20 , wherein the cholera toxin B subunit variant comprises two or more N-linked glycosylation sequons.
35. The method of claim 34 , wherein the cholera toxin B subunit variant comprises the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14.
36. The method of claim 20 , wherein the cholera toxin B subunit variant comprises the sequence of SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 25.
37. The method of claim 20 , wherein the cholera toxin B subunit variant comprises the amino acid sequence of SEQ ID NO: 4.