Polysialic acid derivatives, methods of production, and uses in enhancing cancer antigen production and targeting
View Patent ↗The present invention relates to compositions and methods of their production and use, including use in increasing de-N-acetyl sialic acid antigen of a mammalian cell and methods that exploit the increase in deNAc sialic acid antigen on such cells.
1. A method of increasing a de-N-acetylated antigen of a cancer cell, said method comprising:
contacting a cancer cell having a de-N-acetyl sialic acid antigen with an effective amount of a composition comprising a polysialic acid derivative to increase the amount of the de-N-acetyl sialic acid antigen of said cell, wherein said polysialic acid derivative is substantially unoxidized and purified and comprises (i) a mixture of N-acetyl sialic acid and de-N-acetyl sialic acid residues, and (ii) a non-reducing end de-N-acetyl sialic acid residue that is resistant to degradation by exoneuraminidase.
2. The method of claim 1 , wherein said cancer cell is a neuroblastoma cell, a leukemia cell, or a melanoma cell.
3. The method of claim 1 , wherein said cell is in a subject, and said contacting comprises administering to said subject an effective amount of said composition.
4. The method of claim 3 , wherein said administering is by infusion or by local injection.
5. The method of claim 3 , wherein said administering is prior to surgical intervention to remove cancerous cells.
6. The method of claim 3 , wherein said administering is at the time of or after surgical intervention to remove cancerous cells.
7. The method of claim 3 , further comprising:
administering at least one of an immunotherapy, a cancer chemotherapy or a radiation therapy to the subject.
8. A method of facilitating binding of an antibody to a cell having a de-N-acetyl sialic acid antigen, said method comprising:
contacting a cell having a de-N-acetyl sialic acid antigen with an effective amount of a composition comprising a polysialic acid derivative so as to increase the amount of said antigen on said cell, wherein said polysialic acid derivative is substantially unoxidized and purified and comprises (i) a mixture of N-acetyl sialic acid and de-N-acetyl sialic acid residues, and (ii) a non-reducing end de-N-acetyl sialic acid residue that is resistant to degradation by exoneuraminidase; and
contacting said cell with an antibody specific for said antigen to facilitate binding of said antibody to said cell.
9. The method of claim 8 , wherein binding of said antibody to said cell is cytotoxic to the cell.
10. The method of claim 8 , wherein said antibody comprises a conjugate.
11. The method of claim 10 , wherein said conjugate comprises a detectable label or a cytotoxic drug.
12. The method of claim 8 , wherein said cell is a cancer cell.
13. A method of reducing the viability of a cancer cell, said method comprising:
contacting a cancer cell having a de-N-acetyl sialic acid antigen with an effective amount of a composition comprising a polysialic acid derivative so as to reduce the viability of said cell, wherein said polysialic acid derivative has a reducing end and a non-reducing end, and wherein said polysialic acid derivative is a substantially unoxidized and purified oligosaccharide comprising (i) a mixture of N-acetyl sialic acid and de-N-acetyl sialic acid residues, and (ii) a de-N-acetyl sialic acid residue at said non-reducing end that is resistant to degradation by exoneuraminidase.
14. The method of claim 13 , wherein said cancer cell is a neuroblastoma cell, a leukemia cell, or a melanoma cell.
15. The method of claim 13 , wherein said polysialic derivative comprises at least one dimer of de-N-acetyl sialic acid and N-acetyl sialic acid linked through a glycosidic bond selected from α(2→8) and α(2→9).
16. The method of claim 15 , wherein said polysialic derivative has a degree of polymerization of about 2-10.
17. The method of claim 13 , wherein said mixture comprises de-N-acetyl sialic residues in an amount of about 10%-60%.
18. The method of claim 13 , wherein said polysialic acid derivative comprises a conjugate.
19. The method of claim 13 , wherein said cell is in a subject, and said contacting comprises administering to said subject an effective amount of said composition.