Aptamers to 4-1BB and their use in treating diseases and disorders
The present disclosure relates generally to the field of nucleic acids and, more particularly, to aptamers capable of binding to 4-1BB; pharmaceutical compositions comprising such 4-1BB aptamers; and methods of making and using the same.
1. An aptamer comprising the sequence of SEQ ID NO: 14:
5′-CCCWCWAGX-L1 (n) -YCGGAWGZ-3′
wherein,
X is a G or a C;
Y is a G or a C;
Z is a C or a W;
wherein,
each W is independently a modified pyrimidine; and
each C is independently a modified cytidine;
wherein
L1 is independently selected from a nucleotide, a spacer sequence, or a combination thereof; and
n is an integer from 0 to 14.
2. The aptamer of claim 1 , wherein said modified pyrimidine is a C-5 modified pyrimidine and said modified cytidine is a C-5 modified cytidine.
3. The aptamer of claim 2 , wherein said C-5 modified pyrimidine is selected from the group consisting of the C-5 modified pyrimidines of FIG. 3 .
4. The aptamer of claim 2 , wherein said C-5 modified pyrimidine is selected from the group consisting of 5-(N-benzylcarboxyamide)-2′-deoxyuridine (BndU), 5-(N-isobutylcarboxyamide)-2′-deoxyuridine (iBudU), 5-(N-tryptaminocarboxyamide)-2′-deoxyuridine (TrpdU) and 5-(N-naphthylmethylcarboxyamide)-2′-deoxyuridine (NapdU).
5. The aptamer of claim 2 , wherein said C-5 modified pyrimidine is 5-(N-tryptaminocarboxyamide)-2′-deoxyuridine (TrpdU).
6. The aptamer of claim 2 , wherein said C-5 modified cytidine is 5-methylcytidine.
7. The aptamer of claim 1 , wherein the aptamer binds to a 4-1BB protein.
8. The aptamer of claim 7 , wherein the Kd of said aptamer-4-1BB protein interaction is 50 nM or less.
9. The aptamer of claim 7 , wherein said aptamer has the ability to inhibit the binding of a 4-1BB protein to a 4-1BB receptor ligand (4-1BBL).
10. An aptamer that binds to a 4-1BB protein, the aptamer comprising a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID NOS: 4-13.
11. The aptamer of claim 10 , wherein said aptamer has the ability to inhibit the binding of a 4-1BB to a 4-1BB receptor ligand (4-1BBL).
12. The aptamer of claim 10 , wherein the sequence has at least about 91%, 92%, 93%, 94% or 95% identity to a sequence selected from the group consisting of SEQ ID NOS: 4-13.
13. A pharmaceutical composition comprising an aptamer having a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID NOS: 4-13, or a pharmaceutically acceptable salt thereof.
14. The pharmaceutical composition of claim 13 , wherein the sequence has at least about 91%, 92%, 93%, 94% or 95% identity to a sequence selected from the group consisting of SEQ ID NOS: 4-13.
15. A pharmaceutical composition comprising an aptamer having the sequence of CCTGCACCCAGTGTCCCCGACGGGGCCCTCTAGCCGTACTCTGTAATGG CGGATGCTGACGGAGAGGAGGACGG (SEQ ID NO:6); or a pharmaceutically acceptable salt thereof.