Induced internalization of surface receptors
View Patent ↗Disclosed is a hetero-bifunctional ligand for use in inducing internalization of a target receptor. The hetero-bifunctional ligand includes a target receptor-binding agent that specifically binds the target receptor linked to an internalizing receptor-binding agent that specifically binds to an internalizing receptor, where the two binding agents are non-identical. Also disclosed is a method of inducing the internalization of a target receptor on a cell. The method includes contacting a cell with a hetero-bifunctional ligand, where binding of the hetero-bifunctional ligand induces internalization of a target receptor of the cell. Also disclosed a method of treating a disease or condition associated with a target receptor using the disclosed hetero-bifunctional ligand and pharmaceutical compositions including a hetero-bifunctional ligand.
1. A hetero-bifunctional ligand for use in inducing internalization of a target receptor, comprising:
a target receptor-binding agent that specifically binds the target receptor on a cell, wherein the target receptor-binding agent is polyguanosine or oligodeoxyguanosine and the target receptor is neuropilin-1;
a heterologous internalizing receptor-binding agent that specifically binds to an internalizing receptor on the same cell, wherein the internalizing receptor-binding agent is Fucoidan or sulfated dextran and the internalizing receptor is a scavenger receptor; and
a linker linking the target receptor-binding agent to the internalizing receptor-binding agent, wherein the linker has a length sufficient to allow the hetero-bifunctional ligand to bind to the target receptor and the internalizing receptor on the same cell, wherein binding of the hetero-bifunctional ligand to the internalizing receptor and the target receptor induces internalization of both the internalizing receptor and the target receptor on the same cell.
2. The hetero-bifunctional ligand of claim 1 , wherein the linker is a heterologous linker.
3. The hetero-bifunctional ligand of claim 1 , wherein the sulfated dextran has a molecular weight average of 500 kilodaltons.
4. The hetero-bifunctional ligand of claim 1 , wherein the polyguanosine or oligodeoxyguanosine is between about 6 nucleotides in length and about 100 nucleotides in length.
5. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 18 nucleotides in length.
6. A pharmaceutical composition, comprising a therapeutically effective amount of the hetero-bifunctional ligand of claim 1 and a pharmaceutically acceptable carrier.
7. The hetero-bifunctional ligand of claim 1 , wherein the scavenger receptor is SREC-1 (scavenger receptor expressed by endothelial cells I).
8. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 19 nucleotides in length.
9. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 20 nucleotides in length.
10. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 30 nucleotides in length.
11. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 40 nucleotides in length.
12. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 50 nucleotides in length.
13. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 60 nucleotides in length.
14. The hetero-bifunctional ligand of claim 4 , wherein the polyguanosine or oligodeoxyguanosine is about 100 nucleotides in length.