ANTI-TRANSFERRIN RECEPTOR (TFR) ANTIBODY AND USES THEREOF
Aspects of the disclosure relate to antibodies that bind to transferrin receptor (e.g., transferrin receptor 1) and complexes comprising the antibody covalently linked to a molecular payload. Methods of making and using the antibodies are also provided.
1 . An antibody that binds to human transferrin receptor (TfR), wherein the antibody comprises the antibody comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDR-H3) of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, and a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3) of a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 55.
2 . The antibody of claim 1 , wherein the antibody comprises a CDR-H1 of SEQ ID NO: 49, a CDR-H2 of SEQ ID NO: 50, a CDR-H3 of SEQ ID NO: 51, a CDR-L1 of SEQ ID NO: 52, a CDR-L2 of SEQ ID NO: 29, and a CDR-L3 of SEQ ID NO: 53.
3 . The antibody of claim 1 , wherein the antibody comprises human or humanized framework regions with the CDR-H1, the CDR-H2, the CDR-H3 of a VH as set forth in SEQ ID NO: 54, and the CDR-L1, the CDR-L2, the CDR-L3 of a VL as set forth in SEQ ID NO: 55.
4 . The antibody of claim 1 , wherein the antibody comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 54, and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO: 55.
5 . The antibody of claim 1 , wherein the antibody is selected from the group consisting of a full-length IgG, a Fab fragment, a F(ab′) fragment, a F(ab′)2 fragment, a scFv, and a Fv.
6 . The antibody of claim 5 , wherein the antibody is a full-length IgG.
7 . The antibody of claim 6 , wherein the antibody comprises a heavy chain constant region of the isotype IgG1 set forth in SEQ ID NO: 175 or SEQ ID NO: 176.
8 . The antibody of claim 6 , wherein the antibody comprises:
(i) a heavy chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 180, and a light chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 181;
(ii) a heavy chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 178, and a light chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 179; or
(iii) a heavy chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 182, and a light chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 183.
9 . The antibody of claim 5 , wherein the antibody is a F(ab′) fragment.
10 . The antibody of claim 9 , wherein the antibody comprises:
(i) a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 186, and a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 181;
(ii) a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 185, and a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 179; or
(iii) a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 187, and a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 183.
11 . The antibody of claim 1 , wherein the antibody binds transferrin receptor 1 (TfR1) with a K D of less than 10 −8 M.
12 . A nucleic acid encoding the antibody of claim 1 .
13 . A method of producing an anti-TfR1 antibody, comprising culturing cells comprising the nucleic acid of claim 12 under conditions suitable for the expression of the antibody.
14 . A complex comprising the antibody of claim 1 covalently linked to a molecular payload.
15 . A method of detecting a transferrin receptor in a biological sample, comprising contacting the antibody of claim 1 with the biological sample and measuring binding of the antibody to the biological sample.
16 . A method of delivering a molecular payload to a cell, comprising contacting the cell with the complex of claim 14 .
17 . The method of claim 16 , wherein the cell is a muscle cell.
18 . A method of delivering a molecular payload to the brain or the muscle of a subject, comprising administering to the subject an effective amount of the complex of claim 14 .
19 . A method of treating a disease, comprising administering to the subject an effective amount of the complex of claim 14 , wherein the molecular payload is a therapeutic agent.
20 . The method of claim 19 , wherein the disease is a neurological disease and the molecular payload is a drug for treating a neurological disease, or wherein the disease is a muscle disease and the molecular payload is a drug for treating a muscle disease.