Antisense compounds and uses thereof
The present disclosure provides compounds comprising modified oligonucleotides and anti-CD22 antibodies. Certain such modified oligonucleotides conjugated to anti-CD22 antibodies are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.
1. A compound comprising one or more modified oligonucleotides and an anti-CD22 antibody, wherein the one or more modified oligonucleotides comprise:
16 linked nucleosides having a nucleobase sequence of the sequence recited in SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17;
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of three linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a (S)-cEt sugar modification; wherein each nucleoside of the 3 40 wing segment comprises a (S)-cEt sugar modification; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.
2. The compound of claim 1 , wherein the one or more modified oligonucleotides consist of:
16 linked nucleosides having a nucleobase sequence of the sequence recited in SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17;
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of three linked nucleosides;
wherein the gap segment is positioned between the 5 ′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a (S)-cEt sugar modification; wherein each nucleoside of the 3′ wing segment comprises a (S)-cEt sugar modification; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.
3. The compound of claim 1 , wherein the one or more modified oligonucleotides consist of ISIS 632407, ISIS 632407, ISIS 632417, ISIS 632424, ISIS 632460, ISIS 632461, ISIS 632527, ISIS 632528, ISIS 632634, ISIS 632640, ISIS 632669, ISIS 632672, ISIS 632673 or ISIS 632682.
4. The compound of claim 1 , wherein the one or more modified oligonucleotides consist of ISIS 632461.
5. The compound of claim 1 , wherein the compound comprises the anti-CD22 antibody and 2-4 modified oligonucleotides.
6. The compound of claim 1 , wherein the compound consists of the anti-CD22 antibody conjugated to 2-4 modified oligonucleotides.
7. The compound of claim 1 , wherein the one or more modified oligonucleotides are conjugated to the anti-CD22 antibody at a 5′ end.
8. The compound of claim 1 , wherein the one or more modified oligonucleotides are conjugated to the anti-CD22 antibody through a linker comprising an oligoethyleneglycol moiety.
9. The compound of claim 1 , wherein the one or more modified oligonucleotides are conjugated to the anti-CD22 antibody through a linker comprising a triethyleneglycol moiety.
10. A method of treating a B-cell disease, comprising contacting a cell with the compound of claim 1 .
11. The method of claim 10 , wherein the B-cell disease is leukemia, precursor B-cell acute lymphoblastic leukemia, or lymphoma.
12. The method of claim 10 , wherein the B-cell disease is a B-cell mediated autoimmune disease.
13. The method of claim 10 , wherein the method comprises contacting the cell with one or more chemotherapy agents.
14. The method of claim 13 , wherein one of the one or more chemotherapy agents comprises vincristine.
15. The method of claim 13 , wherein one of the one or more chemotherapy agents comprises doxorubicin.
16. The method of claim 13 , wherein the one or more chemotherapy agents comprise vincristine and doxorubicin.