Conjugates for targeted cell surface editing
Provided are conjugates including a targeting moiety that binds to a cell surface molecule of a target cell and a target cell surface-editing enzyme. Also provided are compositions and kits that include the conjugates, as well as methods of using the conjugates. Methods of making conjugates are also provided.
1. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a conjugate comprising (a) an antibody that binds to a cell surface molecule of a cancer cell and (b) a sialidase conjugated to the antibody, whereupon, after administration to the individual, the sialidase cleaves a sialic acid from the surface of the cancer cell, wherein:
the sialic acid is a ligand for a sialic acid-binding Ig-like lectin (Siglec) receptor;
the Siglec receptor is an immune inhibitory receptor present on an immune cell selected from the group consisting of: a natural killer (NK) cell, a macrophage, a monocyte, a neutrophil, a dendritic cell, a T cell, a B cell, a mast cell, a basophil, and an eosinophil;
the sialidase is conjugated to the antibody via a linker; and
the cell surface molecule is a tumor-associated cell surface molecule on the surface of the cancer cell.
2. The method of claim 1 , wherein the conjugate, when administered to the individual, modulates an immune pathway in the individual.
3. The method of claim 1 , wherein the conjugate, when administered to the individual, cleaves all or a portion of the sialic acid from the surface of the cancer cell.
4. The method of claim 1 , wherein the Siglec receptor is Siglec 7.
5. The method of claim 1 , wherein the Siglec receptor is Siglec 9.
6. The method of claim 1 , wherein the sialidase is a bacterial sialidase or a mammalian neuraminidase.
7. The method of claim 6 , wherein the sialidase is a bacterial sialidase.
8. The method of claim 7 , wherein the bacterial sialidase is a Salmonella typhimurium sialidase or a Vibrio cholerae sialidase.
9. The method of claim 8 , wherein the sialidase is a Vibrio cholerae sialidase.
10. The method of claim 6 , wherein the sialidase is a mammalian neuraminidase.
11. The method of claim 10 , wherein the mammalian neuraminidase is a human neuraminidase.
12. The method of claim 11 , wherein the sialidase is a human neuraminidase selected from the group consisting of: human neuraminidase 1, human neuraminidase 2, human neuraminidase 3, and human neuraminidase 4.
13. The method of claim 1 , wherein the antibody is an IgG, a single chain Fv (scFv), Fab, (Fab) 2 , or (scFv′) 2 .
14. The method of claim 1 , wherein the antibody comprises a fragment crystallizable (Fc) region.
15. The method of claim 14 , wherein the sialidase is conjugated to the Fc region of the antibody.
16. The method of claim 1 , wherein the sialidase is conjugated to a heavy chain of the antibody.
17. The method of claim 16 , wherein the sialidase is conjugated to the C-terminus of the heavy chain.
18. The method of claim 1 , wherein the conjugate is a fusion protein.
19. The method of claim 1 , wherein cleavage of sialic acid on the surface of the cancer cell enhances natural killer (NK) cell activation by increasing natural-killer group 2 member D protein (NKG2D) binding to a NKG2D ligand on the cancer cell surface.
20. The method of claim 1 , wherein the cancer cell is a carcinoma cell.
21. The method of claim 1 , wherein the cancer cell is selected from the group consisting of: a breast cancer cell, an ovarian cancer cell, a gastric cancer cell, and a colon cancer cell.
22. The method of claim 1 , wherein the cell surface molecule is human epidermal growth factor receptor 2 (HER2).
23. The method of claim 1 , wherein the antibody is trastuzumab.
24. The method of claim 1 , wherein the antibody is selected from the group consisting of: cetuximab, daratumumab, girentuximab, panitumumab, ofatumumab, and rituximab.