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US 2026/0274997 A1Published application
Transferrin receptor binding molecule conjugates for delivery of oligonucleotides to cells
AssigneeDenali Therapeutics Inc.
InventorsHai L. TRAN, Robert C. WELLS, Sarah L. DEVOS, Mark S. DENNIS
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Abstract
Provided herein are conjugates comprising: an anti-TfR antibody antigen binding domain that binds to a transferrin receptor and an oligonucleotide(s). The conjugates can be used to deliver an oligonucleotide to a cell that expresses the transferrin receptor. Delivering the oligonucleotide to a cell can be used to modulate expression of a target gene or sequence in the cell.
Claims54
A TfR binder-oligonucleotide conjugate comprising:
- wherein
- P comprises an anti-TfR antibody antigen binding domain,
- F is present or absent, and if present comprises a peptide, a Fc polypeptide, a Fc dimer, or albumin;
- L is present or absent, and if present comprises a linking group;
- P′ is present or absent, and if present comprises an anti-TfR antibody antigen binding domain or a non-binding Fab or a non-binding variable region (NBVR);
- O comprises an oligonucleotide;
- y is an integer greater than or equal to 1 (e.g., 1, 2, 3, or 4);
- and
- n is an integer greater than or equal to 1 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8).
6 more elements
An TfR binder-oligonucleotide conjugate comprising:
- an antibody that specifically binds to TfR, wherein the antibody comprises three heavy chain CDRs and three light chain CDRs wherein:
- a) CDR-H1 comprises SEQ ID NO:
- 12,
- CDR-H2 comprises SEQ ID NO:
- 13,
- CDR-H3 comprises SEQ ID NO:
- 14,
- CDR-L1 comprises SEQ ID NO:
- 15,
- CDR-L2 comprises SEQ ID NO:
- 16, and
- CDR-L3 comprises SEQ ID NO:
- 17;
- b) CDR-H1 comprises SEQ ID NO:
- 21,
- CDR-H2 comprises SEQ ID NO:
- 22,
- CDR-H3 comprises SEQ ID NO:
- 23,
- CDR-L1 comprises SEQ ID NO:
- 24,
- CDR-L2 comprises SEQ ID NO:
- 25, and
- CDR-L3 comprises SEQ ID NO:
- 26;
- (c) CDR-H1 comprises SEQ ID NO:
- 114,
- CDR-H2 comprises SEQ ID NO:
- 115,
- CDR-H3 comprises SEQ ID NO:
- 116,
- CDR-L1 comprises SEQ ID NO:
- 117,
- CDR-L2 comprises SEQ ID NO:
- 118, and
- CDR-L3 comprises SEQ ID NO:
- 119;
- (d) CDR-H1 comprises SEQ ID NO:
- 126,
- CDR-H2 comprises SEQ ID NO:
- 127,
- CDR-H3 comprises SEQ ID NO:
- 128,
- CDR-L1 comprises SEQ ID NO:
- 129,
- CDR-L2 comprises SEQ ID NO:
- 130, and
- CDR-L3 comprises SEQ ID NO:
- 131;
- (e) CDR-H1 comprises SEQ ID NO:
- 134,
- CDR-H2 comprises SEQ ID NO:
- 135,
- CDR-H3 comprises SEQ ID NO:
- 136,
- CDR-L1 comprises SEQ ID NO:
- 137,
- CDR-L2 comprises SEQ ID NO:
- 138, and
- CDR-L3 comprises SEQ ID NO:
- 139;
- (f) CDR-H1 comprises SEQ ID NO:
- 154,
- CDR-H2 comprises SEQ ID NO:
- 155,
- CDR-H3 comprises SEQ ID NO:
- 156,
- CDR-L1 comprises SEQ ID NO:
- 157,
- CDR-L2 comprises SEQ ID NO:
- 158, and
- CDR-L3 comprises SEQ ID NO:
- 159;
- or
- (g) CDR-H1 comprises SEQ ID NO:
- 161,
- CDR-H2 comprises SEQ ID NO:
- 162,
- CDR-H3 comprises SEQ ID NO:
- 163,
- CDR-L1 comprises SEQ ID NO:
- 164,
- CDR-L2 comprises SEQ ID NO:
- 165, and
- CDR-L3 comprises SEQ ID NO:
- 166;
- and
- an oligonucleotide conjugated to a cysteine modification on the constant domain of the antibody.
85 more elements
The TfR binder-oligonucleotide conjugate comprising:
- an antibody that specifically binds TfR, wherein the antibody comprises three heavy chain CDRs and three light chain CDRs wherein
- a) CDR-H1 comprises SEQ ID NO:
- 12,
- CDR-H2 comprises SEQ ID NO:
- 13,
- CDR-H3 comprises SEQ ID NO:
- 14,
- CDR-L1 comprises SEQ ID NO:
- 15,
- CDR-L2 comprises SEQ ID NO:
- 16, and
- CDR-L3 comprises SEQ ID NO:
- 17;
- b) CDR-H1 comprises SEQ ID NO:
- 21,
- CDR-H2 comprises SEQ ID NO:
- 22,
- CDR-H3 comprises SEQ ID NO:
- 23,
- CDR-L1 comprises SEQ ID NO:
- 24,
- CDR-L2 comprises SEQ ID NO:
- 25, and
- CDR-L3 comprises SEQ ID NO:
- 26;
- (c) CDR-H1 comprises SEQ ID NO:
- 114,
- CDR-H2 comprises SEQ ID NO:
- 115,
- CDR-H3 comprises SEQ ID NO:
- 116,
- CDR-L1 comprises SEQ ID NO:
- 117,
- CDR-L2 comprises SEQ ID NO:
- 118, and
- CDR-L3 comprises SEQ ID NO:
- 119;
- (d) CDR-H1 comprises SEQ ID NO:
- 126,
- CDR-H2 comprises SEQ ID NO:
- 127,
- CDR-H3 comprises SEQ ID NO:
- 128,
- CDR-L1 comprises SEQ ID NO:
- 129,
- CDR-L2 comprises SEQ ID NO:
- 130, and
- CDR-L3 comprises SEQ ID NO:
- 131;
- (e) CDR-H1 comprises SEQ ID NO:
- 134,
- CDR-H2 comprises SEQ ID NO:
- 135,
- CDR-H3 comprises SEQ ID NO:
- 136,
- CDR-L1 comprises SEQ ID NO:
- 137,
- CDR-L2 comprises SEQ ID NO:
- 138, and
- CDR-L3 comprises SEQ ID NO:
- 139;
- (f) CDR-H1 comprises SEQ ID NO:
- 154,
- CDR-H2 comprises SEQ ID NO:
- 155,
- CDR-H3 comprises SEQ ID NO:
- 156,
- CDR-L1 comprises SEQ ID NO:
- 157,
- CDR-L2 comprises SEQ ID NO:
- 158, and
- CDR-L3 comprises SEQ ID NO:
- 159;
- or
- (g) CDR-H1 comprises SEQ ID NO:
- 161,
- CDR-H2 comprises SEQ ID NO:
- 162,
- CDR-H3 comprises SEQ ID NO:
- 163,
- CDR-L1 comprises SEQ ID NO:
- 164,
- CDR-L2 comprises SEQ ID NO:
- 165, and
- CDR-L3 comprises SEQ ID NO:
- 166;
- and
- an oligonucleotide conjugated through a linker to S239C substitution on the constant domain of the antibody, wherein the position is according to EU numbering.
85 more elements
Dependencies are inferred from the claim text.