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US-12624120-B2 - Anti-transferrin receptor (TfR) antibody and uses thereof

US12624120B2US 12624120 B2US12624120 B2US 12624120B2US-12624120-B2

Abstract

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.

Inventors

  • Romesh R. Subramanian
  • Mohammed T. Qatanani
  • Timothy Weeden
  • Cody A. Desjardins
  • Brendan Quinn

Assignees

  • DYNE THERAPEUTICS, INC.

Dates

Publication Date
20260512
Application Date
20210108

Claims (20)

  1. 1 . An antibody that binds to human transferrin receptor (TfR), wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and the VL comprise: (i) a heavy chain complementarity determining region 1 (CDR-H1) as set forth in SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) as set forth in SEQ ID NO: 2, a heavy chain complementarity determining region 3 (CDR-H3) as set forth in SEQ ID NO: 3, a light chain complementarity determining region 1 (CDR-L1) as set forth in SEQ ID NO: 4, a light chain complementarity determining region 2 (CDR-L2) as set forth in SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) as set forth in SEQ ID NO: 6; or (ii) a CDR-H1 as set forth in SEQ ID NO: 7, a CDR-H2 as set forth in SEQ ID NO: 8, a CDR-H3 as set forth in SEQ ID NO: 9, a CDR-L1 as set forth in SEQ ID NO: 10, a CDR-L2 as set forth in SEQ ID NO: 11, and a CDR-L3 as set forth in SEQ ID NO: 6; or (iii) a CDR-H1 as set forth in SEQ ID NO: 12, a CDR-H2 as set forth in SEQ ID NO:13, a CDR-H3 as set forth in SEQ ID NO: 14, a CDR-L1 as set forth in SEQ ID NO: 15, a CDR-L2 as set forth in SEQ ID NO: 5, and a CDR-L3 as set forth in SEQ ID NO: 16.
  2. 2 . The antibody of claim 1 , wherein the VH comprises an amino acid sequence at least 85% identical to SEQ ID NO: 17, and the VL comprises an amino acid sequence at least 85% identical to SEQ ID NO: 18.
  3. 3 . The antibody of claim 2 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 17, and the VL comprises the amino acid sequence of SEQ ID NO: 18.
  4. 4 . 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, an scFv, and an Fv.
  5. 5 . The antibody of claim 4 , wherein the antibody is an scFv.
  6. 6 . The antibody of claim 5 , wherein the scFv comprises the amino acid sequence of SEQ ID NO: 19.
  7. 7 . The antibody of claim 5 , wherein the scFv is fused to an Fc.
  8. 8 . The antibody of claim 7 , wherein the antibody comprises the amino acid sequence of SEQ ID NO: 21 or SEQ ID NO: 22.
  9. 9 . The antibody of claim 4 , wherein the antibody is a full-length IgG.
  10. 10 . The antibody of claim 9 , wherein the antibody comprises a heavy chain constant region of isotype IgG1 as set forth in SEQ ID NO: 23 or SEQ ID NO: 24.
  11. 11 . The antibody of claim 10 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27, and a light chain comprising the amino acid sequence of SEQ ID NO: 28.
  12. 12 . The antibody of claim 4 , wherein the antibody is a F(ab′) fragment.
  13. 13 . The antibody of claim 12 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 28.
  14. 14 . The antibody of claim 12 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 28.
  15. 15 . The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising an N-terminal pyroglutamate.
  16. 16 . The antibody of claim 1 , wherein the antibody binds transferrin receptor 1 (TfR1) with a K D in a range of 10 −11 M to 10 −7 M.
  17. 17 . A complex comprising the antibody of claim 1 covalently linked to a molecular payload.
  18. 18 . 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.
  19. 19 . A method of delivering a molecular payload to the brain or the muscle of a subject, comprising administering to the subject the complex of claim 17 .
  20. 20 . A method of treating a disease, comprising administering to the subject the complex of claim 17 , wherein the molecular payload is a therapeutic agent.

Description

RELATED APPLICATIONS This application is a national stage filing under 35 U.S.C. § 371 of International Application No. PCT/US2021/012681, filed Jan. 8, 2021 which claims the benefit under 35 U.S.C § 119 (e) of the filing date of U.S. Provisional Application No. 63/069,062, entitled “ANTI-TRANSFERRIN RECEPTOR (TFR) ANTIBODY AND USES THEREOF”, filed Aug. 23, 2020; U.S. Provisional Application No. 63/055,412, entitled “ANTI-TRANSFERRIN RECEPTOR (TFR) ANTIBODY AND USES THEREOF”, filed Jul. 23, 2020; and U.S. Provisional Application No. 62/968,271, entitled “ANTI-TRANSFERRIN RECEPTOR (TFR) ANTIBODY AND USES THEREOF”, filed Jan. 31, 2020; the contents of each of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION The present application relates to novel anti-transferrin receptor (TfR) antibodies and the use of the antibodies. REFERENCE TO SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB The instant application contains a sequence listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jul. 29, 2022, is named D082470024US03-SEQ-ZJG and is 69,626 bytes in size. BACKGROUND Transferrin Receptor (TfR) is a dimeric transmembrane glycoprotein receptor involved in iron transport. Two transferrin receptors have been characterized in humans, transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2). It has been shown that TfR is overexpressed in cancer cells with higher metastatic potential. TfR1 has been shown to express on the endothelial cells of the blood brain barrier can be used to allow the delivery of large molecules into the brain. SUMMARY The present disclosure is based, at least in part, on the development of new antibodies that bind transferrin receptor 1 (anti-TfR antibodies). In some embodiments, anti-TfR antibodies described herein selectively bind to human or non-human primate (NHP) transferrin receptor with high specificity and affinity. In some embodiments, the anti-TfR antibodies described herein are useful for targeting tissues and/or (e.g., and) cells that express TfR. In some embodiments, the anti-TfR antibodies provided herein are used for detection of TfR in a cell or a tissue. In some embodiments, the anti-TfR antibodies provided herein are used in diagnostic, therapeutic, or research applications. In some embodiments, the anti-TfR antibodies described herein are used to deliver a molecular payload to a target cell or tissue (e.g., a cell or tissue that expresses TfR). As such, in some aspects, complexes comprising the anti-TfR antibodies conjugated (e.g., covalently conjugated) to a molecular payload (e.g., a diagnostic agent or a therapeutic agent) are provided. In some embodiments, the anti-TfR antibodies is used to deliver the conjugated molecular payload to a cell or a tissue that expresses TfR1 (e.g., muscle or the brain) for diagnosing and/or (e.g., and) treating a disease (e.g., a muscle disease or a neurological disease). In some aspects, the present disclosure provides data demonstrating that the anti-TfR antibodies described herein has superior activity in delivering molecular payload into a target cell (e.g., a muscle cell), compared with other known anti-TfR antibodies. Some aspects of the present disclosure provide antibodies that bind to human transferrin receptor (TfR), wherein the antibody comprises: (i) a heavy chain complementary determining region 1 (CDR-H1), a heavy chain complementary determining region 2 (CDR-H2), and a heavy chain complementary determining region 3 (CDR-H3) of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 17; and/or (e.g., and) (ii) a light chain complementary determining region 1 (CDR-L1), a light chain complementary determining region 2 (CDR-L2), and a light chain complementary determining region 3 (CDR-L3) of a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the antibody comprises: a CDR-H1 as set forth in SEQ ID NO: 1, a CDR-H2 as set forth in SEQ ID NO: 2, a CDR-H3 as set forth in SEQ ID NO: 3; and/or (e.g., and) a CDR-L1 as set forth in SEQ ID NO: 4, a CDR-L2 as set forth in SEQ ID NO: 5, and a CDR-L3 as set forth in SEQ ID NO: 6. In some embodiments, the antibody comprises: a CDR-H1 as set forth in SEQ ID NO: 7, a CDR-H2 as set forth in SEQ ID NO: 8, a CDR-H3 as set forth in SEQ ID NO: 9 and/or (e.g., and) a CDR-L1 as set forth in SEQ ID NO: 10, a CDR-L2 as set forth in SEQ ID NO: 11, and a CDR-L3 as set forth in SEQ ID NO: 6. In some embodiments, the antibody comprises: a CDR-H1 as set forth in SEQ ID NO: 12, a CDR-H2 as set forth in SEQ ID NO:13, a CDR-H3 as set forth in SEQ ID NO: 14; and/or (e.g., and) a CDR-L1 as set forth in SEQ ID NO: 15, a CDR-L2 as set forth in SEQ ID NO: 5, and a CDR-L3 as set forth in SEQ ID NO: 16. In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 85% id