JPWO2021154476A5 - - Google Patents

Claims (21)

An antibody that binds to human transferrin receptor (TfR), wherein the antibody has a heavy chain complementarity determining region 1 (CDR-H1) of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 15, a heavy chain complementarity determining region 2 (CDR-H2), and heavy chain complementarity determining region 3 (CDR-H3); and light chain complementarity determining region 1 of the light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 16. (CDR-L1), light chain complementarity determining region 2 (CDR-L2), and light chain complementarity determining region 3 (CDR-L3). Antibodies are as follows:
(i) CDR-H1 as represented by SEQ ID NO: 155, CDR-H2 as represented by SEQ ID NO: 156, CDR-H3 as represented by SEQ ID NO: 157; and SEQ ID NO: 158; CDR-L1 as represented by SEQ ID NO: 159, CDR-L2 as represented by SEQ ID NO: 14, and CDR-L3 as represented by SEQ ID NO: 14;
(ii) CDR-H1 as represented by SEQ ID NO: 9, CDR-H2 as represented by SEQ ID NO: 10, CDR-H3 as represented by SEQ ID NO: 11; and SEQ ID NO: 12; CDR-L1 as represented by SEQ ID NO: 13, CDR-L2 as represented by SEQ ID NO: 14; or
(iii) CDR-H1 as represented by SEQ ID NO: 160, CDR-H2 as represented by SEQ ID NO: 161, CDR-H3 as represented by SEQ ID NO: 162; and SEQ ID NO: 163; CDR-L1 as represented by SEQ ID NO: 13, CDR-L2 as represented by SEQ ID NO: 164, and CDR-L3 as represented by SEQ ID NO: 164.
The antibody according to claim 1, comprising: The antibody combines human or humanized framework regions with CDR-H1, CDR-H2, CDR-H3 of VH as represented by SEQ ID NO: 15, and CDR-H2, CDR-H3 of VL as represented by SEQ ID NO: 16. The antibody according to claim 1 or claim 2, comprising together with CDR-L1, CDR-L2, CDR-L3. The antibody of any one of claims 1 to 3, wherein the antibody comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15, and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO: 16. . 5. The antibody according to any one of claims 1 to 4, wherein the antibody is selected from the group consisting of full-length IgG, Fab fragment, F(ab') fragment, F(ab')2 fragment, scFv, and Fv. antibody. 6. The antibody of claim 5, wherein the antibody is a full-length IgG, optionally comprising a heavy chain constant region of isotype IgG1 represented by SEQ ID NO: 175 or SEQ ID NO: 176. 7. The antibody of claim 6, wherein the antibody comprises 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. Claims that the antibody is a Fab fragment and optionally that the antibody comprises 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. The antibody according to item 5. A nucleic acid encoding an antibody according to any one of claims 1 to 8. A method for producing an anti-TfR1 antibody, comprising culturing a cell containing the nucleic acid according to claim 9 under conditions suitable for antibody expression. 9. A conjugate comprising an antibody according to any one of claims 1 to 8 covalently linked to a molecular payload, comprising:
Optionally, the antibody and the molecular payload are linked via a linker, optionally the molecular payload is a diagnostic or therapeutic agent, and further optionally the therapeutic agent is an oligonucleotide, protein, peptide, nucleic acid. , polypeptides, or small molecules,
Said complex. 12. The conjugate of claim 11, wherein the molecular payload is a diagnostic or therapeutic agent. 13. The conjugate of claim 11 or 12, wherein the molecular payload comprises an oligonucleotide, protein, peptide, nucleic acid, polypeptide, or small molecule. Anti-transferrin receptor antibodies
(i) a cleavable linker (optionally, the cleavable linker comprises a valine-citrulline sequence); or
(ii) a non-cleavable linker (optionally, the non-cleavable linker is an alkane linker)
is covalently linked to the molecular payload via
Optionally, the molecular payload is linked to the antibody via conjugation to a lysine or cysteine residue of the antibody.
A complex according to any one of claims 11 to 13. Any of claims 11 to 14, wherein the anti-transferrin receptor antibody is covalently linked to the molecular payload via a cleavable linker, optionally the cleavable linker comprising a valine-citrulline sequence. Complex according to paragraph 1. A method for detecting a transferrin receptor in an in vitro biological sample, the method comprising: contacting the antibody according to any one of claims 1 to 8 with a biological sample; and measuring binding of the antibody to the biological sample. optionally wherein the antibody is covalently linked to a diagnostic agent. A conjugate according to any one of claims 11 to 15 for use in a method of in vivo diagnosis, the method comprising delivering the conjugate to a target cell or tissue expressing a transferrin receptor. wherein the molecular payload is a diagnostic agent. (a) The target cell is a muscle cell;
(b) the target tissue is muscle tissue or brain tissue; or
(c) target cells or tissues cross the blood-brain barrier;
Complex for use according to claim 17. A conjugate according to any one of claims 11 to 15 for use in a method of treating a disease, the method comprising administering to a subject an effective amount of the conjugate, wherein the molecule The conjugate wherein the payload is a therapeutic agent. (a) the disease is a neurological disease and the molecular payload is a drug for treating a neurological disease; or
(b) the disease is a muscle disease and the molecular payload is a drug for treating a muscle disease, further optionally wherein the muscle disease is a rare muscle disease or muscular atrophy;
A complex according to claim 19. 21. The complex according to claim 19 or claim 20, wherein the subject is a human.