Anti-CD5 antibodies and their use

Abstract

This disclosure relates to anti-CD5 antibodies and their uses, including ALK5 antibody conjugates and their use in treating cancer.

Description

[Technical Field]

[0001] 1. Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 507,751, filed June 13, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] 2. Sequence Listing This application is electronically filed in XML format and includes a sequence listing which is incorporated herein by reference in its entirety. The XML sequence listing was created on 30 May 2024, named SYN-003WO_SL.XML, and has a size of 121,893 bytes. [Background technology]

[0003] 3.Background CD5 is a cluster of differentiated proteins expressed on the surface of T cells. WO 2020 / 256751 describes the use of anti-CD5 antibodies conjugated to ALK5 inhibitors to direct ALK5 inhibitors to T cells while limiting the toxicity of ALK5 inhibitors in non-target tissues. Anti-CD5 antibody-ALK5 inhibitor conjugates are described in WO 2020 / 256751 as useful in the treatment of cancer. Anti-CD5 antibodies are also described as useful in treating CD5+ B or T cell-related diseases, e.g., B or T cell malignancies, autoimmune diseases, transplant diseases, and graft rejection (US8,679,500). [Overview of the project]

[0004] 4. Overview This disclosure provides an anti-CD5 antibody (e.g., a humanized anti-CD5 antibody) and its antigen-binding fragment.

[0005] This disclosure further provides a conjugate comprising an ALK5 inhibitor and an anti-CD5 antibody (e.g., a humanized anti-CD5 antibody) and its antigen-binding fragment, a nucleic acid encoding the anti-CD5 antibody and its antigen-binding fragment, and cells engineered to express the nucleic acid. For convenience, the conjugate comprising an ALK5 inhibitor and an anti-CD5 antibody or its antigen-binding fragment may be referred to simply as the “conjugate” herein.

[0006] This disclosure further provides methods for using anti-CD5 antibodies, antigen-binding fragments, and conjugates for cancer and cancer immunotherapy.

[0007] In certain embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises heavy-chain and / or light-chain variable sequences shown in Tables 1A to 1K.

[0008] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises heavy and / or light chain CDR sequences shown in Tables 1A to 1K. The CDR sequences shown in Tables 1A to 1K include CDR sequences defined according to the IMGT (Lefranc et al., 2003, Dev Comparat Immunol 27:55-77), Kabat (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.), and Chothia (Al-Lazikani et al., 1997, J. Mol. Biol 273:927-948) schemes for defining the CDR boundary. Tables 1A to 1K further include CDR sequences defined by combined overlapping regions of CDR sequences defined by the IMGT, Kabat, and Chothia schemes, and further include CDR sequences defined by common overlapping regions of CDR sequences defined by the IMGT, Kabat, and Chothia schemes. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8-1] [Table 8-2] [Table 9] [Table 10] [Table 11-1] [Table 11-2]

[0009] In certain embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 1, 6, and 13, and the light chain CDRs of SEQ ID NOs. 17, ATS, and 20.

[0010] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 11, and 14, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0011] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 3, 8, and 15, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0012] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 4, 8, and 15, and the light chain CDRs of SEQ ID NOs. 17, ATS, and 20.

[0013] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 11, and 13, and the light chain CDRs of SEQ ID NOs. 17, 19, and 21.

[0014] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 7, and 14, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0015] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 7, and 13, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0016] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 1, 6, and 16, and the light chain CDRs of SEQ ID NOs. 17, ATS, and 20.

[0017] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 9, and 14, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0018] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 9, and 16, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0019] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 10, and 14, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0020] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 10, and 13, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0021] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 12, and 14, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0022] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 12, and 13, and the light chain CDRs of SEQ ID NOs. 18, 19, and 21.

[0023] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 1, 88, and 89, and the light chain CDRs of SEQ ID NOs. 94, WT, and 95.

[0024] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 90, and 91, and the light chain CDRs of SEQ ID NOs. 96, 97, and 95.

[0025] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 90, and 91, and the light chain CDRs of SEQ ID NOs. 99, 97, and 95.

[0026] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDR of SEQ ID NOs. 3, 8, and 91, and the light chain CDR of SEQ ID NOs. 96, 97, and 95.

[0027] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDR of SEQ ID NOs. 3, 8, and 91, and the light chain CDR of SEQ ID NOs. 99, 97, and 95.

[0028] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 4, 8, and 91, and the light chain CDRs of SEQ ID NOs. 94, WT, and 95.

[0029] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 90, and 89, and the light chain CDRs of SEQ ID NOs. 96, 97, and 95.

[0030] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 90, and 89, and the light chain CDRs of SEQ ID NOs. 99, 97, and 95.

[0031] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 2, 102, and 91, and the light chain CDRs of SEQ ID NOs. 103, 97, and 95.

[0032] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 3, 8, and 91, and the light chain CDRs of SEQ ID NOs. 103, 97, and 95.

[0033] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 5, 102, and 89, and the light chain CDRs of SEQ ID NOs. 103, 97, and 95.

[0034] In other embodiments, the anti-CD5 antibody or antigen-binding fragment of the Disclosure (e.g., a humanized anti-CD5 antibody or its antigen-binding fragment) comprises the heavy chain CDRs of SEQ ID NOs. 104, 8, and 91, and the light chain CDRs of SEQ ID NOs. 94, 97, and 105.

[0035] As used herein, references to “heavy chain CDRs of sequence numbers X, Y, and Z” refer to the CDR-H1, CDR-H2, and CDR-H3 sequences, respectively. Similarly, references to “light chain CDRs of sequence numbers X, Y, and Z” refer to the CDR-L1, CDR-L2, and CDR-L3 sequences, respectively.

[0036] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 22 and 23, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 22 and 23, respectively.

[0037] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 24 and 25, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 24 and 25, respectively.

[0038] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 26 and 27, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 26 and 27, respectively.

[0039] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 28 and 29, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 28 and 29, respectively.

[0040] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 30 and 31, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 30 and 31, respectively.

[0041] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 32 and 33, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 32 and 33, respectively.

[0042] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 49 and 50, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 49 and 50, respectively.

[0043] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 84 and 92, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 92, respectively.

[0044] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 84 and 93, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 93, respectively.

[0045] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 84 and 98, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 98, respectively.

[0046] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 85 and 92, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 92, respectively.

[0047] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 85 and 93, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 93, respectively.

[0048] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 85 and 98, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 98, respectively.

[0049] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 86 and 92, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 92, respectively.

[0050] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 86 and 93, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 93, respectively.

[0051] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 86 and 98, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 98, respectively.

[0052] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 87 and 92, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 92, respectively.

[0053] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 87 and 93, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 93, respectively.

[0054] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 87 and 98, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 84 and 98, respectively.

[0055] In further embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure comprises the heavy chain and light chain variable regions of SEQ ID NOs. 100 and 101, respectively. In other embodiments, the present disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy chain and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NOs. 100 and 101, respectively.

[0056] In a further embodiment, the anti-CD5 antibody comprises one light chain and heavy chain from AB-1 to AB-10 shown in Table 1L. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4]

[0057] In one embodiment, the anti-CD5 antibody comprises the light and heavy chains of SEQ ID NOs. 69 and 70, respectively. In another embodiment, the anti-CD5 antibody comprises the light and heavy chains of SEQ ID NOs. 71 and 72, respectively. In yet another embodiment, the anti-CD5 antibody comprises the light and heavy chains of SEQ ID NOs. 73 and 74, respectively. In yet another embodiment, the anti-CD5 antibody comprises the light and heavy chains of SEQ ID NOs. 75 and 76, respectively. In yet another embodiment, the anti-CD5 antibody comprises the light and heavy chains of SEQ ID NOs. 77 and 78, respectively. In yet another embodiment, the anti-CD5 antibody comprises the light and heavy chains of SEQ ID NOs. 79 and 80, respectively.

[0058] In certain embodiments, the anti-CD5 antibody or antigen-binding fragment of the present disclosure is cross-reactive with human and cynomolgus monkey and / or rhesus monkey CD5.

[0059] Further exemplary features of the anti-CD5 antibody and its antigen-binding fragment of this disclosure are described in Section 6.1 and in specific embodiments 1 to 197 below.

[0060] Further exemplary features of the conjugates and conjugate components of the present disclosure are described in Sections 6.2 - 6.5 and Specific Embodiments 203 - 261 below. For example, exemplary ALK5 inhibitors that can be used in the conjugates of the present disclosure are described in Section 6.3, including Tables 2, 3A, 3B, and 4. In the conjugates of the present disclosure, the ALK5 inhibitor can be conjugated directly to the antibody component or linked to the antibody component by a linker. The linker can be a non-cleavable linker or, preferably, a cleavable linker (e.g., a protease-sensitive linker). Exemplary non-cleavable and cleavable linkers are described in Section 6.4. The average number of attached ALK5 inhibitor molecules per antibody or antigen-binding fragment can vary and generally ranges from 2 to 8 ALK5 inhibitor molecules per antibody or antigen-binding fragment. Drug loading is detailed in Section 6.5. Exemplary processes for making the conjugates and exemplary kits useful for making the conjugates are described in Specific Embodiments 474 - 482 below.

[0061] Yet another aspect of the present disclosure is a process for making an antibody-ALK5 inhibitor conjugate, wherein the antibody component is an anti-CD5 antibody of the present disclosure or an antigen-binding fragment thereof (e.g., a humanized anti-CD5 antibody or an antigen-binding fragment thereof).

[0062] Yet another aspect of the present disclosure is a kit comprising an anti-CD5 antibody of the present disclosure or an antigen-binding fragment thereof (e.g., a humanized anti-CD5 antibody or an antigen-binding fragment thereof) and an ALK5 inhibitor. The kit can be used, for example, to make the conjugates of the present disclosure.

[0063] Other aspects of the disclosure relate to nucleic acids encoding the anti-CD5 antibodies and antibody binding fragments of the disclosure. In some embodiments, the nucleic acid portion encoding the anti-CD5 antibody or antigen-binding fragment is codon-optimized for expression in human cells. Vectors (e.g., plasmids) containing the nucleic acid and host cells are also within the scope of the disclosure. The heavy chain coding sequence and the light chain coding sequence can be present on a single vector or on separate vectors.

[0064] Another aspect of the disclosure is a method of making an anti-CD5 antibody or an antigen-binding fragment thereof, comprising incubating a cell containing a nucleic acid or vector according to the disclosure under conditions suitable for expression of the coding region(s) and collecting the anti-CD5 antibody or an antigen-binding fragment thereof.

[0065] Nucleic acids, vectors, host cells, and their uses are further described in Section 6.6 below and in specific embodiments 198-202.

[0066] Yet another aspect of the disclosure is a pharmaceutical composition comprising an anti-CD5 antibody, antigen-binding fragment, conjugate, nucleic acid (or nucleic acid pair), vector (or vector pair), or host cell according to the disclosure and a physiologically suitable buffer, adjuvant, or diluent. Pharmaceutical compositions and exemplary pharmaceutical excipients that can be used to formulate exemplary pharmaceutical compositions are described in Section 6.7 below and in specific embodiments 262-291.

[0067] Yet another aspect of the disclosure is a method of treating cancer, comprising administering a prophylactically or therapeutically effective amount of an anti-CD5 antibody (e.g., a humanized anti-CD5 antibody), an antigen-binding fragment thereof, a conjugate, a nucleic acid, a vector, a host cell, or a pharmaceutical composition according to the disclosure to a subject that needs it.

[0068] In some embodiments, a method of treating cancer involves administering a conjugate or a pharmaceutical composition containing a conjugate of the present disclosure to a subject in need of it. The conjugates and pharmaceutical compositions may be administered as monotherapy or as part of a combination therapy, for example, in combination with an immune checkpoint modulator (e.g., a checkpoint inhibitor). Exemplary cancers that can be treated with the conjugates and pharmaceutical compositions of the present disclosure and exemplary combination therapies are described in Section 6.8 and in specific embodiments 292-473.

[0069] Another aspect of the present disclosure is an anti-CD5 antibody (e.g., a humanized anti-CD5 antibody), its antigen-binding fragment, conjugate, nucleic acid, vector, host cell, or pharmaceutical composition for use in the treatment of cancer.

[0070] Another aspect of this disclosure is the use of anti-CD5 antibodies (e.g., humanized anti-CD5 antibodies), their antigen-binding fragments, conjugates, nucleic acids, vectors, host cells, or pharmaceutical compositions according to this disclosure for the manufacture of pharmaceuticals for the treatment of cancer. [Brief explanation of the drawing]

[0071] 5. Brief description of the drawing [Figure 1A] This shows the amino acid sequence alignment between the parental mouse anti-CD5 antibody (Antibody B) and human germline Ig alleles. The alignment is between the parental mouse anti-CD5 antibody light chain and the Ig alleles: immunoglobulin kappa variable 3-11 allele 1 (IGKV3-11*01), immunoglobulin kappa variable 3-11 allele 2 (IGKV3-11*02), and immunoglobulin kappa variable 1-16 allele 1 (IGKV1-16*01). The figures disclose sequence numbers 107-110, in order of appearance. [Figure 1B]This shows the amino acid sequence alignment between the parental mouse anti-CD5 antibody (antibody B) and human germline Ig alleles. The diagram shows the amino acid sequence alignment between the parental mouse anti-CD5 antibody heavy chain and the Ig alleles IGKV3-11*01, IGKV3-11*02, and IGKV1-16*01. The diagram reveals sequence numbers 111-114, in order of appearance. [Figure 1C] This shows the amino acid sequence alignment between the parental mouse anti-CD5 antibody (Antibody B) and the human germline Ig allele. The table shows the mismatch rates between the human Ig allele and the light and heavy chains of the parental mouse anti-CD5 antibody. [Figure 2A] The diagram shows the amino acid sequence alignment between the parental mouse anti-CD5 antibody (antibody B), the humanized anti-CD5 antibody AB-5, the exemplary human antibody 4JLR.pdb, and three human germline Ig alleles. It also shows the light chain amino acid sequence alignment between the parental anti-CD5 antibody, AB-5, 4JLR.pdb, and the Ig alleles IGKV1-16*01, IGKV1-16*02, and IGKV1-39*01. The diagram discloses sequence numbers 115-120, respectively, in order of appearance. [Figure 2B] The diagram shows the amino acid sequence alignment between the parental mouse anti-CD5 antibody (antibody B), the humanized anti-CD5 antibody AB-5, the exemplary human antibody 4JLR.pdb, and three human germline Ig alleles. It also shows the heavy chain amino acid sequence alignment between the parental anti-CD5 antibody, AB-5, 4JLR.pdb, and the Ig alleles IGKV1-16*01, IGKV1-16*02, and IGKV1-39*01. The diagram discloses sequence numbers 121-126, in order of appearance. [Figure 3A] Exemplary SDS-PAGE and endotoxin analyses of purified negative controls and the anti-CD5 antibodies of this disclosure are shown. These are SDS-PAGE images of antibodies AB-4. Non-reducing antibody samples A-D show a single high MW band, while reducing antibody samples are associated with only two bands, 55 kDa and 25 kDa, corresponding to the IgG heavy chain and IgG light chain, respectively. [Figure 3B]Exemplary SDS-PAGE and endotoxin analyses of purified negative controls and the anti-CD5 antibodies of this disclosure are shown. The SDS-PAGE images of the negative control antibody NC-AB are shown. Non-reducing antibody samples A–D show a single high MW band, while reducing antibody samples are associated with only two bands, 55 kDa and 25 kDa, corresponding to the IgG heavy and light chains, respectively. [Figure 3C] Exemplary SDS-PAGE and endotoxin analyses of purified negative controls and the anti-CD5 antibodies of this disclosure are shown. These are SDS-PAGE images of antibodies AB-6. Non-reducing antibody samples A-D show a single high MW band, while reducing antibody samples are associated with only two bands, 55 kDa and 25 kDa, corresponding to the IgG heavy and IgG light chains, respectively. [Figure 3D] Exemplary SDS-PAGE and endotoxin analyses of purified negative controls and the anti-CD5 antibodies of this disclosure are shown. SDS-PAGE images of antibody AN-8 are shown. Non-reducing antibody samples A–D show a single high MW band, while reducing antibody samples are associated with only two bands, 55 kDa and 25 kDa, corresponding to the IgG heavy and light chains, respectively. [Figure 3E] Exemplary SDS-PAGE and endotoxin analyses of purified negative controls and the anti-CD5 antibodies of this disclosure are shown. Figures 3A to 3D are tables showing the purified antibody concentrations, their optical density (OD) values ​​at 545 nm, and endotoxin units (EU) per 1 mL and 1 mg of antibody sample. [Figure 4A] The results of the anti-CD5 antibody cell binding assay are shown. The table shows the antibody concentrations used in the cell binding assay. [Figure 4B] The results of the anti-CD5 antibody cell binding assay are shown. These are graphs of the Jurkat T cell binding concentration response for antibodies AB-1, AB-2, AB-3, AB-4, and the negative control antibody NC-AB. [Figure 4C] The results of the anti-CD5 antibody cell binding assay are shown. These are graphs of the Jurkat T cell binding concentration response for antibodies AB-1, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10. [Figure 4D] Shows the results of an anti-CD5 antibody cell binding assay. It is a concentration-response graph of CD3+ T cell binding for antibodies AB-1, AB-2, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10. [Figure 4E] Shows the results of an anti-CD5 antibody cell binding assay. It is a concentration-response graph of Jurkat T cell binding for the parental mouse anti-human CD5 (α-hCD5) antibody. [Figure 4F] Shows the results of an anti-CD5 antibody cell binding assay. It shows the raw data of the cell binding assay of α-hCD5 on mouse EL4 cells. [Figure 5A] Shows the internalization profile of exemplary humanized anti-CD5 antibodies of the present disclosure. It is a graph showing the change in signal intensity over 6 hours for antibodies AB-1, AB-2, AB-3, AB-4, and NC-AB. [Figure 5B] Shows the internalization profile of exemplary humanized anti-CD5 antibodies of the present disclosure. It is a graph showing the percentage of internalization values over time for the same antibodies as in Figure 5A. [Figure 5C] Shows the internalization profile of exemplary humanized anti-CD5 antibodies of the present disclosure. It is a graph showing the change in signal intensity over 6 hours for antibodies AB-1, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10. [Figure 5D] Shows the internalization profile of exemplary humanized anti-CD5 antibodies of the present disclosure. It is a graph showing the percentage of internalization values over time for the same antibodies as in Figure 5C. [Figure 5E] Shows the internalization profile of exemplary humanized anti-CD5 antibodies of the present disclosure. It is a bar graph showing the reduction rate of CD5 binding for antibody AB-4. [Figure 5F] Shows the internalization profile of exemplary humanized anti-CD5 antibodies of the present disclosure. It is a bar graph showing the reduction rate of CD5 binding for antibody AB-8. [Figure 6] It is a bar graph showing the percentage of cytotoxicity associated with control and exemplary humanized anti-CD5 antibodies of the present disclosure. [Figure 7A]The binding of parental CD5 antibodies, antibodies B and C, to HEK293 cells was analyzed by flow cytometry, as shown here. [Figure 7B] The binding of parental CD5 antibodies, antibodies B and C, to human CD5-transfected HEK293 cells was analyzed by flow cytometry. [Figure 7C] The binding of parental CD5 antibodies, antibodies B and C, to rhesus macaque CD5-transfected HEK293 cells is shown, analyzed by flow cytometry. [Figure 8A] This shows the internalization of AB-4 after CD5 binding on the surface of Jurkat cells, as measured by FACS. [Figure 8B] This shows the internalization of AB-6 after CD5 binding on the surface of Jurkat cells, as measured by FACS. [Figure 8C] This shows the internalization of AB-8 after CD5 binding on the surface of Jurkat cells, as measured by FACS. [Figure 9] The dose-response curves for the binding of various exemplary antibodies of this disclosure having an IgG4 Fc region to Jurkat cells are shown. [Figure 10A] The mean fluorescence intensity (MFI) of various exemplary antibodies of this disclosure after binding to Jurkat cells, as measured by FACS, is shown. [Figure 10B] The following are various exemplary internalization percentages of this disclosure after binding to Jurkat cells, as measured by FACS. [Figure 11A] The bar graph shows the percentage of SBE activity in HEK cells after exposure to exemplary antibody-TGFβ-antagonist-conjugates (ATACs) having the following antibody components: antibody B, AB-4, and AB-8. [Figure 11B] The percentage of SBE activity in HEK cells after exposure to exemplary antibody-TGFβ-antagonist-conjugates (ATACs) having the following antibody components is shown: antibody B, AB-4, and AB-8. Logarithmic plot. [Figure 12]The CDC activity of the exemplary antibodies and ATACs described herein is shown. [Modes for carrying out the invention]

[0072] 6. Detailed explanation This disclosure provides anti-CD5 antibodies (e.g., humanized anti-CD5 antibodies) and their antigen-binding fragments. The antibodies and antibody fragments of this disclosure are described in detail in Sections 4 and 6.1. This disclosure further provides conjugates useful for the treatment of cancer, comprising antibody components covalently bound to an ALK5 inhibitor, either directly or via a linker. An overview of the conjugates of this disclosure is presented in Section 6.2. The antibody component of the conjugate may be an intact antibody or a fragment thereof. ALK5 inhibitors that can be used in the conjugates of this disclosure are described in Section 6.3. The conjugates of this disclosure typically include a linker between the antibody and the ALK5 inhibitor. Exemplary linkers that can be used in the conjugates of this disclosure are described in Section 6.4. The conjugates of this disclosure may contain a varying number of ALK5 inhibitor portions per antibody. Drug loading is discussed in detail in Section 6.5. This disclosure further provides nucleic acids, vectors, and host cells useful for expressing the anti-CD5 antibodies and antigen-binding fragments of this disclosure. Nucleic acids, vectors, and host cells are described in Section 6.6. This disclosure further provides pharmaceutical formulations containing the conjugates of this disclosure. Pharmaceutical formulations containing the conjugates are described in Section 6.7. This disclosure further provides methods for treating various cancers using the conjugates of this disclosure. Methods for using the conjugates of this disclosure as monotherapy or as part of combination therapy for the treatment of cancer are described in Section 6.8.

[0073] 6.1. Anti-CD5 antibodies and antigen-binding fragments This disclosure provides anti-CD5 antibodies (e.g., humanized anti-CD5 antibodies) and their antigen-binding fragments. Unless otherwise indicated, the term “anti-CD5 antibody” (Ab) refers to an immunoglobulin molecule that specifically binds to human CD5 or is immunologically reactive with human CD5, and includes polyclonal, monoclonal, genetically engineered, and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bispecific antibodies, diabodies, triabodies, and tetrabodies), and antigen-binding fragments of antibodies, including, for example, Fab′, F(ab′)2, Fab, Fv, rIgG, and scFv fragments. Furthermore, unless otherwise indicated, the term “monoclonal antibody” (mAb) is intended to include both an intact molecule capable of specifically binding to a protein and an antibody fragment (e.g., Fab and F(ab′)2 fragments). Fab and F(ab′)2 fragments lack the Fc fragment of intact antibodies, disappear more rapidly from animal or plant circulation, and may exhibit less nonspecific tissue binding than intact antibodies (Wahl et al., 1983, J.Nucl.Med. 24:316).

[0074] The term "scFv" refers to a single-stranded Fv antibody in which the variable domains of the heavy and light chains from a conventional antibody are joined to form a single chain.

[0075] A reference to "VH" refers to the variable region of the immunoglobulin heavy chain of an antibody, including the Fv, scFv, or Fab heavy chains. A reference to "VL" refers to the variable region of the immunoglobulin light chain, including the Fv, scFv, dsFv, or Fab light chains. Antibodies (Ab) and immunoglobulins (Ig) are glycoproteins with the same structural characteristics. Antibodies exhibit binding specificity to specific targets, while immunoglobulins include both antibodies and other antibody-like molecules that lack target specificity. Natural antibodies and immunoglobulins are typically heterotetrameric glycoproteins of about 150,000 daltons, consisting of two identical light chains (L chains) and two identical heavy chains (H chains). Each heavy chain has a variable domain (VH) at the amino terminus, followed by a number of constant domains. Each light chain has a variable domain at the amino terminus (VL) and a constant domain at the carboxyl terminus.

[0076] For optimal delivery of ALK5 inhibitors conjugated to intracellular antibodies, the antibodies are preferably internalized. Internalized antibodies are internalized by the cell after binding to their target molecules on the cell surface. The effect of this is that the conjugate is taken up by the cell. Processes that enable the determination of whether an antibody has been internalized after binding to its antigen are known to those skilled in the art and are described, for example, on page 80 of PCT Publication WO2007 / 070538 and in section 6.11 of WO2020 / 256751. Once internalized, the ALK5 inhibitor can be released from the antibody by cleavage in lysosomes or by other cellular mechanisms, for example, if a cleavable linker is used to conjugate the ALK5 inhibitor to the antibody, as described in section 6.4.

[0077] The term "antibody fragment" refers to a portion of a full-length antibody, generally known as the target-binding or variable region. Examples of antibody fragments include Fab, Fab′, F(ab′)2, and Fv fragments. The "Fv" fragment is the smallest antibody fragment containing the complete target recognition and binding site. This region consists of a dimer (VH-VL dimer) of one heavy-chain variable domain and one light-chain variable domain in a close, non-covalent association. In this configuration, three CDRs of each variable domain interact to define the target-binding site on the surface of the VH-VL dimer. Often, six CDRs confer target-binding specificity to the antibody. However, in some examples, even a single variable domain (or half of an Fv containing only three target-specific CDRs) can have the ability to recognize and bind to a target. A "single-stranded Fv" or "scFv" antibody fragment contains the VH and VL domains of the antibody within a single polypeptide chain. Generally, Fv polypeptides further include a polypeptide linker between the VH domain and the VL domain, which allows the scFv to form a desired structure for target binding.

[0078] The Fab fragment contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab' fragment differs from the Fab fragment in that it has a few additional residues at the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. The F(ab') fragment is produced by cleaving the disulfide bond at the hinge cysteine ​​of the F(ab')2 pepsin digest product. Further chemical coupling of antibody fragments is known to those skilled in the art.

[0079] In certain embodiments, the antibodies of this disclosure are monoclonal antibodies. As used herein, the term “monoclonal antibody” is not limited to antibodies produced by hybridoma technology. The term “monoclonal antibody” refers to an antibody derived from a single clone, including any eukaryotic clone, prokaryotic clone, or phage clone, rather than the method by which it is produced. Monoclonal antibodies useful in connection with this disclosure can be prepared using a wide range of techniques known in the art, including the use of hybridoma, recombination, and phage display technologies, or combinations thereof.

[0080] The “humanized” form of a non-human (e.g., mouse) antibody is a chimeric immunoglobulin, immunoglobulin chain, or fragment thereof (Fv, Fab, Fab', F(ab')2, or other target-binding subdomain of the antibody) containing the smallest sequence derived from the non-human immunoglobulin. Generally, a humanized antibody contains substantially all of at least one, and typically two, variable domains, where all or substantially all of the CDR corresponds to that of the non-human immunoglobulin, and all or substantially all of the FR region is a human immunoglobulin sequence. A humanized antibody may also contain at least a portion of the immunoglobulin constant region (Fc), typically that of the human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art. For example, Riechmann et al., 1988, Nature 332:323-7, Queen et al.'s U.S. Patents No. 5,530,101, 5,585,089, 5,693,761, 5,693,762, and 6,180,370, European Patent Publication No. EP239400, PCT Publication No. WO91 / 09967, U.S. Patent No. 5,225,539, European Patent Publication No. EP592106, European Patent Publication No. EP519596, Padlan, 1991, Mol.Immunol., 28:489-498, Studnicka et al., 1994, Prot.Eng.7:805-814, Roguska et al. See al., 1994, Proc. Natl. Acad. Sci. 91:969-973, and U.S. Patent No. 5,565,332. All of these are incorporated herein by reference in their entirety.

[0081] The antibodies of this disclosure include derivatized antibodies. For example, but not limited to, derivatized antibodies are typically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, and conjugation to cellular ligands or other proteins (see Section 6.1 for consideration of antibody conjugates). Any of the numerous chemical modifications can be carried out by known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, and the metabolic synthesis of tunicamycin. In addition, derivatives can include one or more non-natural amino acids, for example, using ambrx technology (see, e.g., Wolfson, 2006, Chem. Biol. 13(10):1011-2).

[0082] In yet another embodiment of the present disclosure, the antibody or antibody fragment may be an antibody or antibody fragment whose sequence has been modified to alter at least one constant region-mediated biological effector function compared to the corresponding wild-type sequence. For example, in some embodiments, the antibody of the present disclosure may be modified to reduce at least one constant region-mediated biological effector function compared to an unmodified antibody (e.g., reduced binding to the Fc receptor (FcγR) or C1q). FcγR and C1q binding can be reduced by mutating the immunoglobulin constant region segment of the antibody in specific regions required for FcγR or C1q interaction (see, for example, Canfield and Morrison, 1991, J. Exp. Med. 173:1483-1491; Lund et al., 1991, J. Immunol. 147:2657-2662; Lo et al., 2017, J Biol Chem 292:3900-08; Wang et al., 2018, Protein Cell 9:63-73).

[0083] Reducing the FcγR binding ability of an antibody can also reduce other effector functions that depend on FcγR interaction, such as opsonization, phagocytosis, and antibody-dependent cytotoxicity ("ADCC"), while reducing C1q binding can reduce complement-dependent cytotoxicity ("CDCC"). Thus, by reducing or eliminating effector functions, it is possible to prevent T cells targeted by the conjugates of this disclosure from being destroyed via ADCC or CDC. Accordingly, in some embodiments, the effector function of the antibody is modified by selective mutation of the Fc portion of the antibody to eliminate ADCC / CDC function while maintaining antigen specificity and internalization ability.

[0084] Numerous mutations for reducing FcγR and C1q binding have been described in the art, and such mutations may be included in the antibodies of this disclosure. For example, U.S. Patent No. 6,737,056 discloses that single-position Fc region amino acid modifications at positions 238, 265, 269, 270, 292, 294, 295, 298, 303, 324, 327, 329, 333, 335, 338, 373, 376, 414, 416, 419, 435, 438, or 439 reduce binding to FcγRII and FcγRII. Unless otherwise specified herein, the numbering of amino acid residues in the Fc domain or constant region follows the EU numbering system, also known as the EU index, as described in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD. U.S. Patent No. 9,790,268 discloses that FcγR binding is reduced by an asparagine residue at amino acid position 298 and a serine or threonine residue at amino acid position 300.PCT Publication No. WO 2014 / 190441 is L234D / L235E:L234R / L235R / E233K, L234D / L235E / D265S:E233K / L234R / L235R / D265S, L234D / L235E / E269K:E233K / L234 R / L235R / E269K, L234D / L235E / K322A:E233K / L234R / L235R / K322A, L234D / L235E / P329W:E233K / L234R / L235R / P329W, L234D / L235E / E269K This describes modified Fc domains with reduced FcγR binding that have the / D265S / K322A:E233K / L234R / L235R / E269K / D265S / K322A and L234D / L235E / E269K / D265S / K322E / E333K:E233K / L234R / L235R / E269K / D265S / K322E / E333K mutations. Here, the set of mutations preceding the semicolon is present in the first Fc polypeptide of the Fc dimer, and the mutations following the semicolon are present in the second Fc polypeptide. Mutations that can reduce FcγR receptor binding and C1q binding include N297A, N297Q, N297G, D265A / N297A, D265A / N297G, L235E, L234A / L235A, and L234A / L235A / P329A (Lo. et al., 2017, J Biol Chem 292:3900-08, Wang et al., 2018, Protein Cell 9:63-73).

[0085] In some embodiments, the antibody or antigen-binding fragment of this disclosure comprises a first Fc region and a second Fc region that dimerize to form an Fc domain. For example, the Fc domain may include CH2 and CH3 domains derived from a human IgG1 domain (e.g., having one or more of the amino acid substitutions described in this section), or CH2 and CH3 domains derived from a human IgG2 domain or a human IgG4 domain. Exemplary sequences derived from human IgG1 that can be used include: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 51) (WT Sequence) APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 52) (Variant with L234A and L235A substitutions) APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 53) (Variant with N297A substitution)

[0086] In some embodiments, the anti-CD5 antibody of the present disclosure (e.g., a humanized anti-CD5 antibody) or its antigen-binding fragment has a first Fc region and / or a second Fc region containing a sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53.

[0087] The following are exemplary sequences derived from human IgG4 that can be used: APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 54)

[0088] In some embodiments, the anti-CD5 antibody of the present disclosure or its antigen-binding fragment has a first Fc region and / or a second Fc region comprising a sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100%) to SEQ ID NO: 54.

[0089] The following are example sequences derived from human IgG2 that can be used: APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 81)

[0090] In some embodiments, the anti-CD5 antibody of the present disclosure or its antigen-binding fragment has a first Fc region and / or a second Fc region containing a sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO: 81.

[0091] Anti-CD5 antibodies and antigen-binding fragments may include a hinge region that connects, for example, the CH1 domain to an Fc region containing the CH2 and CH3 domains. For example, human IgG1, IgG2, or IgG4 hinges can be used. Exemplary hinge sequences include EPKSCDKTHTCPPCP(SEQ ID NO: 66) (human IgG1), ESKYGPPCPSCP(SEQ ID NO: 67) (human IgG4), ESKYGPPCPPCP(SEQ ID NO: 68) (human IgG4 with S228P substitution), and ERKCCVECPPCP(SEQ ID NO: 83) (human IgG2).

[0092] Exemplary amino acid sequences including the CH1 domain (which may be C-terminus relative to VH), hinge, CH2 domain, and CH3 domain include the following: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 62) (Derived from Human IgG1) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 63) (Derived from human IgG1, with L234A and L235A substitutions) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 64) (Derived from human IgG1, with N297A substitution) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 65) (Derived from human IgG4, with S228P substitution) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 82) (Derived from Human IgG2)

[0093] As an alternative to mutating the constant region to reduce effector function, for example, by mutating the Fc domain as described above, the effector function can be eliminated by using antibody fragments (e.g., Fab, Fab', or F(ab')2 fragments).

[0094] In other embodiments of the present disclosure, an antibody or fragment thereof can be modified to acquire or improve at least one constant-region-mediated biological effector function compared to an unmodified antibody, for example, to enhance FcγR interactions (see, for example, US2006 / 0134709). For example, the antibodies of the present disclosure may have constant regions that bind to FcγRIIA, FcγRIIB, and / or FcγRIIIA with higher affinity than the corresponding wild-type constant regions.

[0095] Therefore, the antibodies of this disclosure may have modifications of biological activity that result in opsonization, phagocytosis, or reduction of ADCC. Such modifications are known in the art. For example, an antibody modification that reduces ADCC activity is described in U.S. Patent No. 5,834,597.

[0096] In another embodiment, the antibody or antibody fragment may be modified to increase or decrease its binding affinity to the fetal Fc receptor FcRn by, for example, mutating an immunoglobulin constant region segment in a specific region involved in FcRn interaction (see, for example, WO2005 / 123780). Such mutations can increase the binding of the antibody to FcRn, protecting the antibody from degradation and increasing its half-life.

[0097] In other embodiments, the antibody has one or more amino acids inserted into one or more of its hypervariable regions, as described, for example, in Jung and Plueckthun, 1997, Protein Engineering 10(9):959-966, Yazaki et al., 2004, Protein Eng. Des Sel. 17(5):481-9, and U.S. Patent Publication No. 2007 / 0280931.

[0098] 6.2. Antibody ALK5 Inhibitor Conjugates The conjugates of this disclosure generally consist of an ALK5 inhibitor covalently bound to an anti-CD5 antibody (e.g., humanized anti-CD5) or its antigen-binding fragment, typically via a linker, such that the covalent bond does not interfere with binding to CD5.

[0099] Techniques for conjugating drugs to antibodies are well known in the art (see, for example, Hellstrom et al., Controlled Drug Delivery, 2nd Ed., at pp.623-53 (Robinson et al., eds., 1987)), Thorpe et al., 1982, Immunol. Rev.62:119-58, Dubowchik et al., 1999, Pharmacology and Therapeutics 83:67-123, and Zhou, 2017, Biomedicines 5(4):E64). ALK5 inhibitors preferably bind to the antibody component in the conjugate of this disclosure via site-directed conjugation. For example, ALK5 inhibitors can be conjugated to antibody components via one or more natural or engineered cysteine, lysine, or glutamine residues, one or more non-natural amino acids (e.g., p-acetylphenylalanine (pAcF), p-azidomethyl-L-phenylalanine (pAMF), or selenocysteine ​​(Sec)), one or more glycans (e.g., fucose, 6-thiofucose, galactose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or sialic acid (SA)), or one or more short peptide tags of 4 to 6 amino acids. See, for example, Zhou, 2017, Biomedicines 5(4):E64, whose entire content is incorporated herein by reference.

[0100] In one example, an antibody or fragment thereof is fused to the amino acid sequence (or portion thereof; e.g., at least 10, 20, or 50 amino acid portions of a protein) of another protein via a covalent bond (e.g., a peptide bond) through or within the N-terminus or C-terminus of the antibody. The antibody, or fragment thereof, can be ligated to another protein at the N-terminus of the antibody's constant domain. Such fusions can be created using recombinant DNA procedures, for example, as described in WO86 / 01533 and EP0392745. In another example, the effector molecule can increase the in vivo half-life and / or enhance the delivery of the antibody across the epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumins, albumin-binding proteins, or albumin-binding compounds, such as those described in PCT Publication WO2005 / 117984.

[0101] The metabolic process or reaction may be a proteolytic cleavage of the conjugate's peptide linker, or an enzymatic process such as hydrolysis of a functional group such as a hydrazone, ester, or amide. Intracellular metabolites include, but are not limited to, antibodies and free drugs that have undergone intracellular cleavage after entry into, diffusion, uptake, or transport into cells.

[0102] The terms "intracellularly cleaved" and "intracellular cleavage" refer to intracellular metabolic processes or reactions on a conjugate that disrupt the covalent bond, or linker, between the drug portion (D) and the antibody (Ab), causing the drug to dissociate from the intracellular antibody. Therefore, the cleaved portion of the conjugate is an intracellular metabolite.

[0103] 6.3. ALK5 inhibitors The ALK5 inhibitors of this disclosure are preferably small molecules that competitively and reversibly bind to the ATP binding site within the cytoplasmic kinase domain of the ALK5 receptor and prevent downstream R-Smad phosphorylation.

[0104] ALK5 inhibitors may, but do not necessarily, be specific to or selective for ALK5 compared to other TGF-β family receptors such as ALK4 and / or ALK7 and / or TGF-β receptor II. In some embodiments, ALK5 inhibitors have activity against both ALK5 and TGF-β receptor II. It is preferable that ALK5 inhibitors have limited inhibitory activity against the BMP II receptor, but this is not necessary as the conjugates of this disclosure target T cells with minimal or no BMP II activity.

[0105] The ALK5 inhibitors of this disclosure, when measured in an in vitro cell assay using T cells from at least 3 subjects, at least 5 subjects, or at least 10 subjects, preferably have an IC5 level of 100 nM or less, more preferably 50 nM or less, and most preferably 20 nM or less. 50 It has. An exemplary cell assay is shown in Section 6.6 of WO2020 / 256751. Antibodies that recognize humans instead of mouse cells, and antibodies that recognize humans instead of mouse CD28 and CD3, can be used in conjugates that target humans instead of mouse CD5.

[0106] Examples of ALK5 inhibitors suitable for use in the antibody-drug conjugates of this disclosure include imidazole-benzodioxole compounds, imidazole-quinoxaline compounds, pyrazole-pyrrolo compounds, and thiazole compounds.

[0107] According to one aspect of this disclosure, an imidazole-benzodioxole type ALK5 inhibitor has the following formula: [ka]

[0108] In the formula, R 1 R is a lower alkyl group having hydrogen or 1 to about 5 carbon atoms. 2 R is a lower alkyl group having hydrogen or 1 to about 5 carbon atoms.3 is an amide, nitrile, alkynyl having 1 to about 3 carbon atoms, carboxyl or alkanol group having 1 to about 5 carbon atoms, A is a direct bond or alkyl having 1 to about 5 carbon atoms, and B is a direct bond or alkyl having 1 to about 5 carbon atoms. In a separate preferred embodiment of the present disclosure, R 2 is hydrogen or methyl, A has 1 carbon atom, B is a direct bond to a benzyl group, and R 3 is an amide. In a combined preferred embodiment of the present disclosure, R 2 is hydrogen or methyl, A has 1 carbon atom, and B is a direct bond to a benzyl group.

[0109] According to another aspect of the present disclosure, the imidazole - quinoxaline type ALK5 inhibitor has the following formula:

Chemical formula

[0110] In the formula, R 1 is hydrogen or lower alkyl having 1 to about 5 carbon atoms, R 2 is hydrogen, halogen, or lower alkyl having 1 to about 5 carbon atoms, R 3 is an amide, nitrile, alkynyl having 1 to about 3 carbon atoms, carboxyl or alkanol group having 1 to about 5 carbon atoms, A is a direct bond or alkyl having 1 to about 5 carbon atoms, and B is a direct bond or alkyl having 1 to about 5 carbon atoms. In a separate preferred embodiment of the present disclosure, R 2 is hydrogen or methyl, the halogen includes fluorine or chlorine, A has 1 carbon atom, B is a direct bond to a benzyl group, and R 3 is an amide. In a combined preferred embodiment of the present disclosure, R 2 is hydrogen or methyl, A has 1 carbon atom, and B is a direct bond to a benzyl group.

[0111] According to another aspect of this disclosure, a pyrazole-type ALK5 inhibitor has the following formula: [ka]

[0112] In the formula, R 2 R is a lower alkyl group having hydrogen, halogen, or 1 to about 5 carbon atoms. 4 This includes hydrogen, halogens, lower alkyl groups having 1 to about 5 carbon atoms, alkoxy groups having 1 to about 5 carbon atoms, haloalkyl groups, carboxyls, carboxyalkyl esters, nitriles, alkylamines, or groups having the following formulas: [ka]

[0113] In the formula, R 5 R is a lower alkyl, halogen, or morpholino having 1 to about 5 carbon atoms, 6 A is pyrrole, cyclohexyl, morpholino, pyrazole, pyran, imidazole, oxane, pyrrolidinyl, or alkylamine, where A is directly bonded or an alkyl having 1 to about 5 carbon atoms.

[0114] According to another aspect of this disclosure, a pyrazole-pyrrolo-type ALK5 inhibitor has the following formula: [ka]

[0115] In the formula, R 7 R is a hydrogen, halogen, lower alkyl, alkanol, morpholino, or alkylamine having 1 to about 5 carbon atoms, 2 R is a lower alkyl group having hydrogen, halogen, or 1 to about 5 carbon atoms. 8 is a group consisting of hydrogen, hydroxyl, amino, halogen, or a group having the following formula: [ka]

[0116] In the formula, R 5 It is piperazinyl, and R 6 A is a morpholino, piperidinyl, piperazinyl, alkoxy, hydroxyl, oxane, halogen, thioalkyl, or alkylamine, where A is a lower alkyl having 1 to about 5 carbon atoms.

[0117] According to another aspect of this disclosure, a thiazole-type ALK5 inhibitor has the following formula: [ka]

[0118] In the formula, R 9 R is a lower alkyl group having hydrogen, halogen, or 1 to about 5 carbon atoms. 10 These are hydrogen atoms or lower alkyl groups having 1 to about 5 carbon atoms.

[0119] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, in the formula, M 1 and M 2 Independently, [ka] Selected from, R 1 and R 2 Each time it appears, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 ,-C(O)N(R 10 )2, -N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 ,-S(O)R 10-S(O)2R 10 -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -N02, and -CN;-C1-C10 alkyl, -C2-C l0 Alkenyl and -C2-C l0 Alkinyl (each of them is a halogen, -OR) 10 , -SR 10 , -N(R 10 )2, -C(0)R 10 ,-C(O)N(R 10 )2, -N(R 10 )C(O)R 10 -C(0)OR 10 -OC(0)R 10 , -S(0)R 10 -S(0)2R 10 -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -N02, =0, =S, =N(R 10 ), -CN, C3-C 10 One or more substituents independently selected from carbon rings and 3- to 10-membered heterocycles, which are optionally substituted at each occurrence); and C3-C10 carbon rings and 3-10 membered heterocycles (each of which is a halogen, -OR) 10 , -SR 10 , -N(R 10 )2, -C(0)R 10 ,-C(O)N(R 10 )2,-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 ,-S(O)R 10 -S(O)2R 10 -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -NO2, =O, =S, =N(R 10)、-CN, -C1-C6 alkyl, -C2-C6 alkenyl, and -C2-C6 alkynyl, optionally substituted with one or more substituents independently selected therefrom); independently selected from, R 3 is hydrogen; and halogen, -NO2, =O, =S, =N(R 10 ), -CN, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 -C(O)OR 10 , and -OC(O)R 10 , optionally substituted with one or more substituents independently selected therefrom, -C1-C 10 alkyl selected from, n and m are independently selected from 0, 1, 2, 3, and 4, Q is a bond, -(CR 10 2) p -, -(CR 10 2) q C(=O)(CR 10 2) q -, -(CR 10 2) q C(=S)(CR 10 2) q -, -(CR 10 2) q C(=NR 10 )(CR 10 2) q , -(CR 10 2) q O(CR 10 2) q O(CR 10 2) q -, -(CR 10 2) q S(CR 10 2) q , -(CR 10 2) q N(R 10 )(CR 10 2) q , -(CR 10 2) qOC(=O)O(CR 10 2) q -,-(CR 10 2) q C(=O)N(R 10 )(CR 10 2) q -,-(CR 10 2) q N(R 10 )C(=O)(CR 10 2) q -, and -(CR 10 2) q N(R 10 )SO2(CR 10 2) q - Selected from, p is selected from 1, 2, 3, 4, and 5. q is independently selected from 0, 1, 2, 3, 4, and 5 at each occurrence. T is selected from optionally substituted saturated C3-C7 carbon rings, optionally substituted Cs-o bicyclic carbon rings, and optionally substituted 4-12 member heterocycles, where T is R 13 It is optionally replaced by one or more substituents that are independently selected at each occurrence, R 13 Each time it appears, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(0)R 10 ,-C(O)N(R 10 )2, -N(R 10 )C(O)R 10 -C(0)OR 10 -OC(0)R 10 , -S(0)R 10 -S(0)2R 10 -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -N02, =0, =S, =N(R 10 ), and -CN;-C1-C 10 Alkyl, -C2-C l0 Alkenyl and -C2-C l0Alkinyl (each of them is a halogen, -OR) 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 ,-C(O)N(R 10 )2, -N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 ,-S(O)R 10 -S(O)2R 10 -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C3-C 10 Each instance is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle); and C3-C 10 Carbon rings and 3- to 10-membered heterocycles (each of which is a halogen, -OR) 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 ,-C(O)N(R 10 )2, -N(R 10 )C(O)R 10 -C(O)OR 10 ,-OC(O)R 10 ,-S(O)R 10 -S(O)2R 10 -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -NO2, =O, =S, =N(R 10 (Optionally substituted with one or more substituents independently selected from -CN, -C1-C6 alkyl, -C2-C6 alkenyl, and -C2-C6 alkynyl) R 10 Each time it appears, Hydrogen;-C1-C 10 Alkyl, -C2-C l0 Alkenyl and -C2-C l0Alkynnyl (each of them is a halogen, -OH, -CN, -NH2, =O, =S, -O-C1-C) 10 Alkyl, C3-C 12 Each occurrence is optionally substituted with one or more substituents independently selected from carbon rings and 3- to 12-membered heterocycles; and C3-C 12 Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C1-C) 10 Alkyl, -O-C1-C 10 Alkyl and -C1-C 10 One or more substituents independently selected from the haloalkyl group (which are optionally substituted at each occurrence). The example compounds of the aforementioned formula are described in WO2019 / 195278.

[0120] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, In the formula, M 1 and M 2 One of them is, [ka] And M 1 and M 2 The other of the two is, [ka] And, R 1 and R 2 Each instance independently involves hydrogen, halogen, and -OR. 11 , -SR 11 , -N(R 11 )2, -NO2, -CN, phenyl, or -C1-C6 alkyl, wherein the -C1-C6 alkyl is a halogen, -OR 11 , -SR 11 ,-S(O)R 10 -S(O)2R11 -S(O)2N(R 11 )2-N(R 11 )2, -C(O)R 10 ,-C(O)N(R 11 )2, -N(R 11 )C(O)R 10 , -C(O)OR 11 -OC(O)R 10 Optionally substituted with one or more substituents independently selected from -NO2 and -CN, R 3 Each instance independently consists of a halogen, a -C1-C3 alkyl, a -C1-C3 haloalkyl, -OH, -NO2, -CN, -O-C1-C3 alkyl, or -O-C1-C3 haloalkyl. R 4 Each instance independently consists of hydrogen or a C1-C3 alkyl group, or two R groups. 4 They bond together with the atoms to which they are bonded to form a 5 or 6-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogens, -C1-C3 alkyl, -OH, -O-C1-C3 alkyl, and -O-C1-C3 haloalkyl. R 5 is hydrogen, halogen, -OR 61 , -SR 61 , -N(R 61 )2, -NO2, -CN, and -C1-C6 alkyl, where the -C1-C6 alkyl is a halogen, -OR 61 , -SR 61 , -N(R 61 )Optionally substituted with one or more substituents independently selected from -NO2 and -CN, R 6 Each occurrence is independently determined by halogen, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 20 ,-C(O)N(R 21 )2, -N(R 21 )C(O)R 20 , -C(O)OR 21 -OC(O)R 21 ,-S(O)R 20-S(O)2R 21 -S(O)2N(R 21 )2, -OC(O)OR 21 ,-OC(O)N(R 21 )2, -NR 21 C(=O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -NO2, -CN;C1-C 10 Alkyl, C2-C 10 Alkenyl and C2-C 10 Alkinyl (each of them is a halogen, -OR) 21 , -SR 21 , -N(R 21 )2, -C(O)R 20 ,-C(O)N(R 21 )2, -N(R 21 )C(O)R 20 , -C(O)OR 21 -OC(O)R 21 ,-S(O)R 20 -S(O)2R 21 -S(O)2N(R 21 )2, -OC(O)OR 21 ,-OC(O)N(R 21 )2, -NR 21 C(=O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -CN, C3-C 10 The carbon ring and the C3-C are optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycles. 10 A carbon ring and a 3- to 10-membered heterocycle may have one or more R X ; and C3-C 10 Carbon rings and 3- to 10-membered heterocycles (each of which is a halogen, -OR) 20 -OH, -SR 20 -SH, -N(R 21 )2, -C(O)R 20 ,-C(O)N(R 21 )2, -N(R 21 )C(O)R 20 , -C(O)OR 21-OC(O)R 21 ,-S(O)R 20 -S(O)2R 21 -S(O)2N(R 21 )2, -OC(O)OR 21 ,-OC(O)N(R 21 )2, -NR 21 C(=O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -CN, -C2-C6 alkenyl, -C2-C6 alkynyl, and C 1- The C1-C6 alkyl group is optionally substituted with one or more substituents independently selected from the C6 alkyl group, and the C1-C6 alkyl group is R Y (Optionally substituted with one or more substituents independently selected from) R 7 and R 8 The elements are independently selected from hydrogen, halogen, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, and -O-C1-C3 haloalkyl, or R 7 and R 8 These are bonded together with the atoms they are bonded to, forming a C5-C6 carbon ring or a 5 or 6-membered heterocycle (each of which is a halogen, -OR 31 , -SR 31 , -N(R 31 ) Optionally substituted with one or more substituents independently selected from -NO2, -CN, and -C1-C6 alkyl, wherein the C1-C6 alkyl is a halogen, -OR 31 , -SR 31 , -N(R 31 ) which are optionally substituted with one or more substituents independently selected from -NO2 and -CN, Y is -O- and -N(R 9 )- Selected from, R 9 Each instance of occurrence is independent of the others. Hydrogen; as well as halogens, -OR 41 , -SR 41 ,-S(O)R 40 -S(O)2R 41-S(O)2N(R 41 )2 -N(R 41 )2, -C(O)R 40 ,-C(O)N(R 41 )2, -N(R 41 )C(O)R 40 , -C(O)OR 41 -OC(O)R 40 Selected from -C1-C6 alkyl groups, each R is optionally substituted with one or more substituents independently selected from -NO2 and -CN. 10 , R 20 , and R 40 teeth, -C1-C 10 Alkyl, -C2-C 10 Alkenyl and -C2-C 10 Alkinyl (each of them is R Y ; and C3-C 12 Carbon rings and 3- to 12-membered heterocycles (each of which is R X (Optionally substituted with one or more substituents independently selected from) (Optionally substituted with one or more substituents independently selected from) (Independently selected from at each occurrence, Each R 11 , R 21 , R 31 , R 41 , and R 61 teeth, Hydrogen;-C1-C 10 Alkyl, -C2-C 10 Alkenyl and -C2-C 10 Alkinyl (each of them is R Y ; and C3-C 12 Carbon rings and 3- to 12-membered heterocycles (each of which is R X (Optionally substituted with one or more substituents independently selected from) (Optionally substituted with one or more substituents independently selected from) or (Independently selected from at each occurrence, Or two R atoms on the same N atom 11 , R 21 , R 31 , R 41 , or R 61 Together with the N atom to which they bond, RX This forms an N-containing heterocycle that is optionally substituted, Each R X teeth, Halogen, -OR 51 , -SR 51 , -N(R 51 )2, -C(O)R 50 ,-C(O)N(R 51 )2, -N(R 51 )C(O)R 50 , -C(O)OR 51 -OC(O)R 51 ,-S(O)R 50 -S(O)2R 51 -S(O)2N(R 51 )2, -OC(O)OR 51 ,-OC(O)N(R 51 )2, -NR 51 C(=O)OR 51 , -N(R 51 )C(O)N(R 51 )2, -NO2, =O, =S, =N(R 51 ), -CN, -C2-C6 alkenyl, -C2-C6 alkynyl, and C1-C6 alkyl are independently selected at each occurrence, and the C1-C6 alkyl is -OR 51 , -SR 51 , -N(R 51 )2, -C(O)R 50 ,-C(O)N(R 51 )2, -N(R 51 )C(O)R 50 , -C(O)OR 51 -OC(O)R 51 ,-S(O)R 50 -S(O)2R 51 -S(O)2N(R 51 )2, -OC(O)OR 51 ,-OC(O)N(R 51 )2, -NR 51 C(=O)OR 51 , -N(R 51 )C(O)N(R 51 )2, and are optionally substituted with one or more substituents independently selected from =O, Each R Y teeth, Halogen, -OR 51 , -SR 51 , -N(R 51 )2, -C(O)R 50 ,-C(O)N(R 51 )2, -N(R 51 )C(O)R 50 , -C(O)OR 51 -OC(O)R 51 ,-S(O)R 50 -S(O)2R 51 -S(O)2N(R 51 )2, -OC(O)OR 51 ,-OC(O)N(R 51 )2, -NR 51 C(=O)OR 51 , -N(R 51 )C(O)N(R 51 )2, -NO2, =O, =S, =N(R 51 ), and -CN are independently selected at each occurrence, Each R 50 teeth, -C1-C 10 Alkyl, -C2-C 10 Alkenyl and -C2-C 10 Alkynnyl (each of them is a halogen, -OH, -CN, -NO2, -NH2, =O, =S, -O-C1-C) 10 Alkyl, C3-C 12 The carbon ring is optionally substituted with one or more substituents independently selected from 3- to 12-membered heterocycles; as well as C3-C 12 Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C1-C) 10 Alkyl, -O-C1-C 10 Alkyl and -C1-C 10 (Optionally substituted with one or more substituents independently selected from the haloalkyl) and independently selected at each occurrence, Each R 51 teeth, Hydrogen;-C1-C 10 Alkyl, -C2-C 10 Alkenyl and -C2-C 10Alkynnyl (each of them is a halogen, -OH, -CN, -NO2, -NH2, =O, =S, -O-C1-C) 10 Alkyl, C3-C 12 The carbon ring is optionally substituted with one or more substituents independently selected from 3- to 12-membered heterocycles; as well as C3-C 12 Carbon rings and 3- to 12-membered heterocycles (each of which is a halogen, -OH, -CN, -NO2, -NH2, =O, =S, -C1-C) 10 Alkyl, -O-C1-C 10 Alkyl and -C1-C 10 (Optionally substituted with one or more substituents independently selected from the haloalkyl) and independently selected at each occurrence, Z 1 , Z 2 , Z 3 , and Z 4 It is selected independently of N or C(H), n is selected from 1, 2, and 3. m is 0, 1, or 2. s is selected from 0 and 1. w is selected from 0, 1, 2, 3, 4, and 5. Exemplary compounds of the aforementioned formula are described in WO2021 / 011834. In some embodiments, the ALK5 inhibitor is an ALK5 inhibitor listed in Table 16 of WO2021 / 011834.

[0121] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, in the formula, L is -[CR′2]p-L'-[CH2]q-, L' is either nonexistent or -S-, -O-, or -NH-. A either does not exist, or is a carbon ring or heteroring. Q 3 is N or CR 3 And, Q 4 is N or CR4 And, Q 5 is N or CR 5 And, Q 6 is N or CR 6 And, Q 7 is C or N, R 1 is hydrogen, halo, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R 2 Each time it appears, independently, Halo and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 3 H, Halo, C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 It is an alkoxy, R 4 H, Halo, C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 It is an alkoxy, R 5 H, Halo, C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 It is an alkoxy, R 6 H, Halo, C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 It is an alkoxy, R 7 This is a reactive portion that can bind to a linker or a reactive portion that can bind to an antibody. R 9 Each instance of these appears independently as follows: Haro, -OR', -SR', -N(R')2, -C(O)R', -C(O)OC 1-6Hydroxylalkyl, -C(O)N(R′)N(R′)C(O)R′, -C(O)OR′, -OC(O)R′, -S(O)R′, -S(O)2R′, -S(O)2OR′, -C(O)NHS(O)2-C 1-6 Alkyl, -C(O)NHS(O)2-C 3-8 Cycloalkyl, -P(O)(OR′)2, -OP(O)(OR′)2, -NO2, =O, -CN, C 1-4 Alkyl, C 2-5 Alkenil, C 2-5 Alkinyl, C 1-4 Haloalkyl, C 2-5 Haloalkenil, C 2-5 Haloalkynyl, carbon ring, or heterocycle, In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 Each of these has 0 to 3 R 10 Replaced by, R 10 Each occurrence is independently C 1-3 Alkoxy or C 1-3 It is a haloalkoxy, R' is independently composed of hydrogen and C at each occurrence. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, or C 1-6 It is a haloalkyl, m is between 0 and 3. n is between 0 and 5. p is 1 to 3, q is between 0 and 3. Exemplary compounds of the above formula are described in WO2022 / 006340. In some embodiments, the ALK5 inhibitor is an ALK5 inhibitor listed in Tables 15, 16, 17, 18, or 19 of WO2022 / 006340.

[0122] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, in the formula, Q 3 is N or CR 3 And, Q 4 is N or CR 4 And, Q 5 is N or CR 5 And, Q 6 is N or CR 6 And, R a and R b Each of these is either H or R a and R b Together with the atoms to which they bond, they form a heterocyclic ring. R 1 H, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R 2 Each time it appears, independently, Halo and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 3 H, Halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 4 H, Halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 5 H, Halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 6 H, Halo, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, where R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each occurrence independently generates 0 to 3 R 10 Replaced by, R 7 This is a reactive portion that can bind to a linker or a reactive portion that can bind to an antibody, an antibody construct, or a targeting portion. R 10 Each occurrence is independently C 1-3 Alkoxy or C 1-3 It is a haloalkoxy, m is between 0 and 3. In the formula, Q 6 R 1 When methyl, CR 6 And R a and R b These atoms, together with the atoms to which they bond, form a heterocyclic ring. Examples of compounds that fit the aforementioned formula are described in WO2022 / 076905.

[0123] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, in the formula, Q 6 is N or CR 6 And, R 1 H, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R 2 Each time it appears, independently, Halo and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 6H, Halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, where R 1 , R 2 , and R 6 Each occurrence independently generates 0 to 3 R 10 Replaced by, R 7 This is a reactive portion that can bind to a linker or a reactive portion that can bind to an antibody. R 10 Each occurrence is independently C 1-3 Alkoxy or C 1-3 It is a haloalkoxy, and m is between 0 and 3. In the formula, Q 6 R 1 When methyl, CR 6 That is the case. Examples of compounds that fit the aforementioned formula are described in WO2022 / 076905.

[0124] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, in the formula, Q 6 is N or CR 6 And, R 1 H, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R 2 Each time it appears, independently, Halo and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, R 6 H, Halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, where R1 , R 2 , and R 6 Each of these has 0 to 3 R 10 Replaced by, R 7 This is a reactive portion that can bind to a linker or a reactive portion that can bind to an antibody, an antibody construct, or a targeting portion. R 10 Each occurrence is independently C 1-3 Alkoxy or C 1-3 It is a haloalkoxy, m is between 0 and 3. Examples of compounds that fit the aforementioned formula are described in WO2022 / 076905.

[0125] According to another aspect of this disclosure, an ALK5 inhibitor is a formula [ka] It has, in the formula, Q A CR A or N, R A H, Halo, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, Ring B is a carbon ring or a heterocycle, R 1 H, C 1-3 Alkyl, or C 1-3 It is a haloalkyl, R 2 Each time it appears, independently, Halo and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 It is a haloalkoxy, where R 1 and R 2 Each occurrence independently generates 0 to 3 R 10 Replaced by, R 7 This is a reactive portion that can bind to a linker or a reactive portion that can bind to an antibody, an antibody construct, or a targeting portion. R 9 Each time it appears, independently, Halo and C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, or C 1-3 It is a haloalkoxy, R 10 Each occurrence is independently C 1-3 Alkoxy or C 1-3 It is a haloalkoxy, m is between 0 and 3, and n is between 0 and 5. Examples of compounds that fit the aforementioned formula are described in WO2022 / 076905.

[0126] In some embodiments, the ALK5 inhibitor is an ALK5 inhibitor listed in Table 17, Table 18, Table 19, or Table 20 of WO2022 / 076905.

[0127] In a particular embodiment, the ALK5 inhibitor is selected from any of the compounds referred to as A to N in Table 2 below. [Table 13-1] [Table 13-2] [Table 13-3]

[0128] In further specific embodiments, the ALK5 inhibitor is selected from any of the compounds designated 1 to 283 in Table 3A below. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] [Table 14-11] [Table 14-12] [Table 14-13]

[0129] In further specific embodiments, the ALK5 inhibitor is selected from any of the compounds designated 1 to 463 in Table 3B below. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16 Table 15-17 Table 15-18 Table 15-19 Table 15-20 Table 15-21 Table 15-22 Table 15-23 Table 15-24 Table 15-25

[0130] The preparation and use of ALK5 inhibitors are well known and well documented in the scientific and patent literature. PCT Publication WO2000 / 61576 and U.S. Patent Publication US2003 / 0149277 disclose triarylimidazole derivatives and their use as ALK5 inhibitors. PCT Publication WO2001 / 62756 discloses pyridinylimidazole derivatives and their use as ALK5 inhibitors. PCT Publication WO2002 / 055077 discloses the use of imidazolyl acetal derivatives as ALK5 inhibitors. PCT Publication WO2003 / 087304 discloses trisubstituted heteroaryl derivatives and their use as ALK5 and / or ALK4 inhibitors. WO2005 / 103028, U.S. Patent Publication US2008 / 0319012, and U.S. Patent No. 7,407,958 disclose 2-pyridyl-substituted imidazoles as ALK5 and / or ALK4 inhibitors. One representative compound, IN-1130, exhibits ALK5 and / or ALK4 inhibitory activity in several animal models.The following patents and publications provide additional examples of ALK5 inhibitors and provide exemplary synthetic schemes and methods using ALK5 inhibitors: U.S. Patents No. 6,465,493, 6,906,089, 7,365,066, 7,087,626, 7,368,445, 7,265,225, 7,405,299, 7,407,958, 7,511,056, 7,612,094, 7,691,865, 7,863,288, 8,410,146, 8,410,146, 8,420,685, 8,513,222, and Nos. 8,614,226, 8,791,113, 8,815,893, 8,846,931, 8,912,216, 8,987,301, 9,051,307, 9,051,318, 9,073,918, and PCT Publication No. WO2004 / 065392, Patents Nos. WO2009 / 050183, WO2009 / 133070, WO2011 / 146287, WO2013 / 009140, WO2019 / 195278, WO2021 / 011834, WO2022 / 006340, and WO2022 / 076905. The aforementioned patents and patent publications are incorporated in their entirety by reference.

[0131] Several ALK5 inhibitors are commercially available, including SB-525334 (CAS 356559-20-1), SB-505124 (CAS 694433-59-5), SB-431542 (CAS 301836-41-9), SB-202474 (EMD4 Biosciences Merck KGaA, Darmstadt, Germany), LY-364947 (CAS 396129-53-6), IN-1130, GW-788388, and D4476 (EMD4 Biosciences Merck KGaA, Darmstadt, Germany).

[0132] The structures and names of ALK5 inhibitors described herein refer to the molecules before they bind to the antibody and / or linker.

[0133] Preferred ALK5 inhibitors are those that can be linked to the linker via a free NH or NH2 group, preferably an NH or NH2 group bonded to or part of an alkyl, heteroaryl, or aryl group (for example, in compounds 1-23, 26-29, 31, 35, 37, 39, 40, 42, 43, 45-48, 50-85, 87-90, 93, 96, 98-104, 106, 108, 109, 111, 112, 114, 116-120, 132, 146, 149, 156, 184, 187, 193, 218, 260-277, 282, and 283 shown in Table 3A). ALK5 inhibitors can be derivatized to add a free NH or NH2 group. The design of derivatized ALK5 inhibitors should preferably take into account the structure-activity relationship (SAR) of the inhibitor to reduce the possibility of losing inhibitory activity when adding an NH or NH2 group, although the activity may be determined empirically. Exemplary derivatized counterparts of some compounds shown in Table 2 are shown in Table 4 below. [Table 16-1] [Table 16-2]

[0134] 6.4. Linker Typically, a conjugate contains a linker between the ALK5 inhibitor and the antibody. The linker is a portion containing a covalent bond or atomic chain that covalently binds the antibody to the drug portion. In various embodiments, the linker is a divalent radical such as alkyldiyl, aryldiyl, heteroaryldiyl, or a portion such as:-(CR2) n O(CR2) n- Repeating units of alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine®); as well as diacid esters and amides including succinates, succinamides, diglycolates, malonates, and caproamides. For example, various PEG-containing linkers are known and commercially available in the art (e.g., from BroadPharm (broadpharm.com)). Examples of PEG-containing linkers include Mal-PEG2-Val-Cit-PAB-OH (BroadPharm catalog number BP-23203), Mal-PEG4-Val-Cit-PAB-OH (BroadPharm catalog number BP-23204), Mal-PEG4-Val-Cit-PAB-PNP (BroadPharm catalog number BP-23668), Mal-amide-PEG2-Val-Cit-PAB-PNP (BroadPharm catalog number BP-23675), azid-PEG3-Val-Cit-PAB-OH (BroadPharm catalog number BP-23206), and azid-PEG4-Val-Cit-PAB-OH (BroadPharm catalog number BP-23207). This includes azid-PEG3-Val-Cit-PAB-PNP (BroadPharm catalog number BP-23368), Fmoc-PEG4-Ala-Ala-Asn-PAB (BP-23328), azid-PEG5-Ala-Ala-Asn-PAB (BroadPharm catalog number BP-23329), Fmoc-PEG3-Ala-Ala-Asn(Trt)-PAB (BroadPharm catalog number BP-23285), azid-PEG4-Ala-Ala-Asn(Trt)-PAB (BroadPharm catalog number BP-23284), and Fmoc-PEG3-Ala-Ala-Asn(Trt)-PAB-PNP (BroadPharm catalog number BP-23297).

[0135] A linker may include one or more linker components, such as stretcher and spacer portions. For example, a peptidyl linker may include two or more amino acid peptidyl components and optionally one or more stretcher and / or spacer portions. Various linker components are known in the art, some of which are described below.

[0136] The linker may be a "cleavable linker" that facilitates the release of the drug into the cell. For example, an acid-unstable linker (e.g., hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linker, a photo-unstable linker, a dimethyl linker, or a disulfide-containing linker (Chari et al., 1992, Cancer Research 52:127-131, U.S. Patent No. 5,208,020) may be used.

[0137] Examples of linkers and linker components known in the art include aleimidocaproyl (mc); maleimidocaproyl-p-aminobenzylcarbamate; maleimidocaproyl-peptide-aminobenzylcarbamate linker, e.g., maleimidocaproyl-L-phenylalanine-L-lysine-p-aminobenzylcarbamate and maleimidocaproyl-L-valine-L-citrulline-p-aminobenzylcarbamate (vc); and 3-(2-pyridyldithio)propionic acid N-sucrose. Synimidyl (also known as N-succinimidyl 4-(2-pyridyldithio)pentanoate or SPP); 4-succinimidyl-oxycarbonyl-2-methyl-2-(2-pyridyldithio)-toluene (SMPT); 3-(2-pyridyldithio)propionic acid N-succinimidyl (SPDP); 4-(2-pyridyldithio)butyrate N-succinimidyl (SPDB); 2-iminothiolane; S-acetylsuccinate anhydride; disulfide benzylcarbamic acid; carbonate; hydrazone linker; N-(α-maleimideacetoxy ) succinimide ester; N-[4-(p-azidosalicylamide)butyl]-3'-(2'-pyridyldithio)propionamide (AMAS); N[β-maleimidopropyloxy]succinimide ester (BMPS); [N-ε-maleimidocaproyloxy]succinimide ester (EMCS); N-[γ-maleimidobutyryloxy]succinimide ester (GMBS); succinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxy-[6-amidecaproate](LC-SMCC); 6-(3-[ 2-Pyridyldithio]-propionamide)succinimidyl hexanoate (LC-SPDP); m-maleimidobenzoyl-N-hydroxysuccinimidate (MBS); [4-iodoacetyl]aminobenzoate N-succinimidyl (SIAB); 4-[N-maleimidomethyl]cyclohexane-1-carboxylic acid succinimidyl (SMCC); 3-[2-pyridyldithio]-propionamide N-succinimidyl (SPDP); [N-ε-maleimidocaproyloxy]sulfosuccinimidate (Sulfo-EMCS);N-[γ-maleimidobutyryloxy]sulfosuccinimidate (Sulfo-GMBS); 4-sulfosuccinimidyl-6-methyl-α-(2-pyridyldithio)toluamide]hexanoate-) (Sulfo-LC-SMPT); 6-(3'-[2-pyridyldithio]-propionamide)sulfosuccinimidyl hexanoate (Sulfo-LC-SPDP); m-maleimidobenzoyl-N-hydroxysulfosuccinimidate (Sulfo-MBS); [4-iodoacetyl]aminobenzoate N-sulfosuccinimidyl (Sulfo- Examples include SIAB; 4-[N-maleimidomethyl]cyclohexane-1-carboxylic acid sulfosuccinimidyl (Sulfo-SMCC); 4-[p-maleimidophenyl]butyrate sulfosuccinimidyl (Sulfo-SMPB); ethylene glycol-bis(succinate N-hydroxysuccinimid) (EGS); disuccinimidyl tartrate (DST); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); diethylenetriamine-pentaacetic acid (DTPA); thiourea linkers; and oxime-containing linkers.

[0138] In some embodiments, the linker is cleavable under intracellular or extracellular conditions so that, in a suitable environment, cleavage of the linker releases the ALK5 inhibitor from the antibody. In other embodiments, the linker is not cleavable, and the drug is released, for example, by antibody degradation in lysosomes (see U.S. Patent Publication 2005 / 0238649, which is incorporated herein by reference in its entirety).

[0139] Examples of non-cleavable linkers that can be used in the conjugates of this disclosure include 1-carboxylic acid N-maleimidomethylcyclohexane linkers, maleimidocaproyl linkers, or mercaptoacetamidecaproyl linkers.

[0140] In some embodiments, the linker can be cleaved by cleavage agents present in the intracellular environment (e.g., within lysosomes, endosomes, or caveoleas). The linker may be a peptidyl linker cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, lysosomal or endosomal proteases. In some embodiments, the peptidyl linker comprises peptidyl components having a length of at least two amino acids or at least three amino acids.

[0141] The cleavage agents may include, but are not limited to, cathepsins B and D, as well as plasmin, all of which are known to hydrolyze dipeptide drug derivatives that result in the release of active drugs within target cells (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). For example, peptidyl linkers cleavable by the thiol-dependent protease cathepsin-B (e.g., Phe-Leu or Gly-Phe-Leu-Gly linkers (SEQ ID NO: 106)). Other examples of such linkers are described, for example, in U.S. Patent No. 6,214,345, which is incorporated herein by reference in its entirety.

[0142] In some embodiments, the peptidyl linker cleavable by intracellular proteases is either a Val-Cit linker or a Phe-Lys linker (see, for example, U.S. Patent No. 6,214,345 describing the synthesis of doxorubicin using a val-cit linker).

[0143] In other embodiments, the cleavable linker is pH-sensitive, i.e., susceptible to hydrolysis at a specific pH value. Typically, it is a pH-sensitive linker that can be hydrolyzed under acidic conditions. For example, acid-unstable linkers that can be hydrolyzed in lysosomes (e.g., hydrazones, semicarbazones, thiosemicarbazones, cis-aconitamides, orthoesters, acetals, ketals, etc.). (See, for example, U.S. Patents 5,122,368, 5,824,805, 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661.) Such linkers are relatively stable under neutral pH conditions, such as those in blood, but unstable below pH 5.5 or pH 5.0, which is the approximate pH of lysosomes. In certain embodiments, the hydrolyzable linker is a thioether linker (e.g., a thioether bonded to the therapeutic agent via an acylhydrazone linkage) (see, for example, U.S. Patent No. 5,622,929).

[0144] In other embodiments, the linker is cleavable under reducing conditions (e.g., a disulfide linker). Various disulfide linkers are known in the art, including those that can be formed using SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)toluene), SPDB, and SMPT. (For example, see Thorpe et al., 1987, Cancer Res. 47:5924-5931, and Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (CWVogel ed., Oxford U. Press, 1987), and also see U.S. Patent No. 4,880,935.)

[0145] In other embodiments, the linker is a malonic acid linker (Johnson et al., 1995, Anticancer Res. 15: 1387-93), a maleimide benzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10): 1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10): 1305-12).

[0146] In some embodiments, the linker is a multivalent linker that can be used to link multiple drug molecules to a single antibody molecule. For example, the Fleximer linker technology developed by Mersana is based on incorporating drug molecules into a solubilized polyacetal backbone via a sequence of ester bonds. This methodology allows for highly loaded conjugates (e.g., with drug-antibody ratios (DARs) up to 20) while maintaining good physicochemical properties. Exemplary polyvalent linkers are described, for example, in WO2009 / 073445, WO2010 / 068795, WO2010 / 138719, WO2011 / 120053, WO2011 / 171020, WO2013 / 096901, WO2014 / 008375, WO2014 / 093379, WO2014 / 093394, and WO2014 / 093640, the contents of which are incorporated herein by reference in their entirety.

[0147] In many cases, linkers are substantially insensitive to the extracellular environment. As used herein, “substantially insensitive to the extracellular environment” means that, in relation to linkers, about 20%, 15%, 10%, 5%, 3%, or less than about 1% of the linkers in a sample of the conjugate are cleaved when the conjugate is present in an extracellular environment (e.g., plasma).

[0148] Whether the linker is substantially unsensitive to the extracellular environment can be determined, for example, by incubating the conjugate with plasma for a predetermined period (e.g., 2, 4, 8, 16, or 24 hours) and then quantifying the amount of free drug present in the plasma.

[0149] In other non-mutually exclusive embodiments, the linker can promote intracellular integration. In certain embodiments, the linker promotes intracellular integration when conjugated to a therapeutic agent (i.e., in the environment of the linker-therapeutic portion of the conjugate described herein). In other embodiments, the linker promotes intracellular integration when conjugated to both an ALK5 inhibitor and an antibody.

[0150] In many embodiments, the linker is self-immolative. As used herein, the term “self-immolative” refers to a bifunctional chemical moiety capable of covalently linking two separate chemical moieties into a stable, triplicate molecule. This spontaneously separates from the second chemical moiety when the bond to the first moiety is cleaved. See, for example, PCT Publications WO2007 / 059404, WO2006 / 110476, WO2005 / 112919, WO2010 / 062171, WO2009 / 017394, WO2007 / 089149, WO2007 / 018431, WO2004 / 043493, and WO2002 / 083180. These relate to drug-cleavable substrate conjugates, in which a drug and a cleavable substrate are optionally linked through a self-destructing linker, all of which are explicitly incorporated by reference. An example of a self-destructing spacer unit that can be used in the generated self-destructing linker is illustrated by Equation I below.

[0151] Various exemplary linkers that can be used in the present composition and method are described in PCT Publication WO2004 / 010957, U.S. Patent Publication US2006 / 0074008, U.S. Patent Publication US2005 / 0238649, and U.S. Patent Publication US2006 / 0024317 (each of which is incorporated herein by reference in whole for the entire purpose).

[0152] The conjugate of this disclosure may be of the following formula I, where an antibody (Ab) is conjugated to one or more ALK5 inhibitor drug moieties (D) via an optional linker (L). [ka]

[0153] Therefore, the antibody may be conjugated to the drug directly or via a linker. In Formula I, p is the average number of drug (i.e., ALK5 inhibitor) portions per antibody, which can range, for example, from about 1 to about 20 drug portions per antibody, and in certain embodiments, from about 2 to about 8 drug portions per antibody. Further details of the drug loading are described in Section 6.5 below.

[0154] In some embodiments, the linker component may include a “stretcher” that links the antibody to another linker component or drug moiety, for example, via a cysteine ​​residue. An example stretcher is shown below (where the left wavy line indicates the site of covalent binding to the antibody, and the right wavy line indicates the site of covalent binding to another linker component or drug moiety). [ka] See U.S. Patent No. 9,109,035, Ducry et al., 2010, Bioconjugate Chem. 21:5-13.

[0155] In some embodiments, the linker components may include amino acid units. In one such embodiment, the amino acid units facilitate the release of the drug from the conjugate upon exposure to intracellular proteases such as lysosomal enzymes by enabling the cleavage of the linker by proteases. See, for example, Doronina et al., 2003, Nat. Biotechnol. 21:778-784. Exemplary amino acid units include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include valine-citrulline (VC or val-cit), alanine-phenylalanine (AF or ala-phe), phenylalanine-lysine (FK or phe-lys), or N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). The amino acid units may include naturally occurring amino acid residues, and similarly, minor amino acids and naturally occurring amino acid analogs, such as citrulline amino acid units, can be designed and optimized for selectivity to enzymatic cleavage by specific enzymes, such as cathepsins B, C, and D, or plasmin proteases.

[0156] In some embodiments, the linker components may include “spacer” units that link the antibody to the drug moiety directly or by stretcher and / or amino acid units. The spacer units may be “self-destructive” or “non-self-destructive.” A “non-self-destructive” spacer unit is one in which some or all of the spacer unit remains bound to the drug moiety when the conjugate is enzymatically (e.g., proteolytically) cleaved. Examples of non-self-destructive spacer units include, but are not limited to, glycine spacer units and glycine-glycine spacer units. A “self-destructive” spacer unit allows for the release of the drug moiety without a separate hydrolysis step. In certain embodiments, the linker spacer units include p-aminobenzyl units. In such embodiments, p-aminobenzyl alcohol is bound to the amino acid units via an amide bond, and a carbamate, methylcarbamate, or carbonate is created between the benzyl alcohol and the cytotoxic agent. For example, see Hamann et al., 2005, Expert Opin. Ther. Patents 15:1087-1103. In one embodiment, the spacer unit is p-aminobenzyloxycarbonyl (PAB). In a particular embodiment, the phenylene portion of the p-aminobenzyl unit is Q mSubstituting with, where Q is --C1-C8 alkyl, --O--(C1-C8 alkyl), -halogen, -nitro, or -cyano, and m is an integer in the range of 0 to 4. Further examples of self-destructing spacer units include, but are not limited to, aromatic compounds that are electronically similar to p-aminobenzyl alcohol (see, for example, U.S. Patent Publication 2005 / 0256030), e.g., 2-aminoimidazole-5-methanol derivatives (Hay et al., 1999, Bioorg. Med. Chem. Lett. 9:2237), and ortho or para-aminobenzyl acetals. Spacers that undergo cyclization during amide bond hydrolysis can be used, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., 1995, Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al., 1972, Amer. Chem. Soc. 94:5815), and 2-aminophenylpropionic acid amide (Amsberry et al., 1990, J. Org. Chem. 55:5867). Removal of amine-containing drugs substituted at the α-position of glycine (Kingsbury et al., 1984, J. Med. Chem. 27:1447) is also an example of a self-destructing spacer useful for conjugates.

[0157] In one embodiment, the spacer unit is a branched bis(hydroxymethyl)styrene (BHMS) unit as shown below, which can be used to incorporate and release multiple drugs. [ka] Ab and D are defined as above for Formula I, where A is the stretcher, a is an integer between 0 and 1, W is the amino acid unit, w is an integer between 0 and 12, Q is --C1-C8 alkyl, --O--(C1-C8 alkyl), -halogen, -nitro, or -cyano, m is an integer in the range of 0 to 4, n is 0 or 1, and p is in the range of 1 to approximately 20.

[0158] The linker may include one or more of the linker components described above. In a particular embodiment, the linker is as shown in parentheses in the following conjugate expression: [ka] In the formula, Ab, A, a, W, w, D, and p are as defined in the previous paragraph, Y is a spacer unit, and y is 0, 1, or 2. An exemplary embodiment of such a linker is described in U.S. Patent Publication 2005 / 0238649 A1, which is incorporated herein by reference.

[0159] Exemplary linker components and their combinations are shown below in relation to the conjugate of Equation II. [ka] [ka]

[0160] The linker components, including stretchers, spacers, and amino acid units, may be synthesized by methods known in the art, such as those described in U.S. Patent Publication No. 2005 / 0238649.

[0161] 6.5. Drug Loading The drug load is denoted by p and is the average number of ALK5 inhibitor moieties per antibody in the molecule. The drug load ("p") may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more moieties (D) per antibody, but the average number is often a fraction or decimal. Generally, the ALK5 inhibitor load is, on average, 2 to 8 drug moieties per antibody, more preferably 2 to 4 drug moieties per antibody, or 5 to 7 drug moieties per antibody.

[0162] As those skilled in the art will understand, in many cases, a reference to a conjugate is an abbreviated notation for a group or collection of conjugate molecules (sometimes in relation to a pharmaceutical composition), each molecule consisting of an antibody covalently bound to one or more ALK5 inhibitor moieties, and the drug loading ratio represents the average drug loading in the group or collection, although the ratio based on individual molecules may vary from one conjugate molecule to another in the group. In some embodiments, the group or collection includes a conjugate molecule containing antibodies covalently bound to drug moieties between 1 and 30, in some embodiments between 1 and 20, between 1 and 15, between 2 and 12, between 2 and 8, between 4 and 15, or between 6 and 12. Preferably, the average within the group is as described in the previous paragraph, for example, 2 to 8 drug moieties per antibody, more preferably 4 to 8 drug moieties per antibody, or 5 to 7 drug moieties per antibody.

[0163] Some conjugate populations may be in the form of compositions comprising the conjugates described herein and antibody molecules lacking a drug moiety, such as antibodies that failed to conjugate to ALK5 antibody.

[0164] The average number of ALK5 inhibitor moieties per antibody in the conjugate preparation from the conjugation reaction may be characterized by conventional means such as mass spectrometry and ELISA assays.

[0165] Furthermore, the quantitative distribution of the conjugate with respect to p may be determined. In some cases, the separation, purification, and characterization of homogeneous conjugates, where p is a specific value from conjugates with other ALK5 inhibitor loads, may be achieved by means such as electrophoresis.

[0166] For some antibody-drug conjugates, p may be limited by the number of binding sites on the antibody. For example, if the binding is cysteinethiol, the antibody may have one or several cysteinethiol groups, or one or several sufficiently reactive thiol groups (through which a linker may be bound), as in the exemplary embodiments above. In certain embodiments, a higher drug load, e.g., p > 5, may cause aggregation, insolubility, toxicity, or loss of cell permeability in certain antibody-drug conjugates. In certain embodiments, the drug loads of the conjugates of this disclosure are in the range of 1 to about 8, about 2 to about 6, about 3 to about 5, about 3 to about 4, about 3.1 to about 3.9, about 3.2 to about 3.8, about 3.2 to about 3.7, about 3.2 to about 3.6, about 3.3 to about 3.8, or about 3.3 to about 3.7. In fact, for certain conjugates, the optimal ratio of drug portion to antibody may be less than 8, and may range from approximately 2 to approximately 5. See U.S. Patent Publication 2005 / 0238649, which is incorporated herein by reference in its entirety.

[0167] In certain embodiments, a drug moiety less than the theoretical maximum value is conjugated to the antibody during the conjugation reaction. The antibody may contain lysine residues that do not react with the drug-linker intermediate or linker reagent, as discussed below. Generally, the antibody contains few free reactive cysteinethiol groups that may be linked to the drug moiety; in fact, most cysteinethiol residues in the antibody exist as disulfide crosslinks. In certain embodiments, the antibody may be reduced under partially or completely reducing conditions with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP) to generate reactive cysteinethiol groups. In certain embodiments, the antibody is exposed to denaturing conditions to expose reactive nucleophiles such as lysine or cysteine.

[0168] The conjugate load (drug / antibody ratio) may be controlled in various ways, for example, by (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to the antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limited reducing conditions for cysteine ​​thiol modification, or (iv) manipulating the amino acid sequence of the antibody by recombinant techniques so that the number and position of cysteine ​​residues are modified to control the number and / or position of linker-drug binding (such as thioMab or thioFab prepared as disclosed in PCT Publication WO2006 / 034488, which is incorporated herein by reference in its entirety).

[0169] It should be understood that when two or more nucleophiles react with a drug-linker intermediate or linker reagent, followed by a drug moiety reagent, the resulting product is a mixture of conjugate compounds having a distribution of one or more drug moieties bound to the antibody. The average number of drugs per antibody may be calculated from the mixture by a dual ELISA antibody assay, which is antibody-specific and drug-specific. Individual conjugate molecules may be identified in the mixture by mass spectrometry and separated by HPLC, for example, hydrophobic interaction chromatography.

[0170] In some embodiments, a homogeneous conjugate having a single load value may be isolated from the conjugate mixture by electrophoresis or chromatography.

[0171] 6.6. Nucleic acids, recombinant vectors, and host cells This disclosure provides nucleic acid molecules encoding immunoglobulin light chain and heavy chain genes (e.g., VL and VL pairs) for an anti-CD5 antibody and its antigen-binding fragment, vectors containing such nucleic acids, and host cells capable of producing the anti-CD5 antibody and its antigen-binding fragment of this disclosure. In certain embodiments, the nucleic acid molecules encode the anti-CD5 antibody and antibody-binding fragment of this disclosure, and the host cells are capable of expressing the anti-CD5 antibody and antibody-binding fragment of this disclosure.

[0172] The anti-CD5 antibodies described herein can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in host cells. To recombinantly express the antibody, host cells are transfected with one or more recombinant expression vectors containing DNA fragments encoding the antibody's immunoglobulin light and heavy chains, resulting in the expression of the light and heavy chains within the host cells. Optionally, these chains can be secreted into the culture medium from which the host cells are cultured, and the antibody can be recovered from that medium. Antibody heavy and light chain genes are obtained using standard recombinant DNA methodologies, such as those described in Molecular Cloning; A Laboratory Manual, Second Edition (Sambrook, Fritsch and Maniatis (eds), Cold Spring Harbor, NY, 1989), Current Protocols in Molecular Biology (Ausubel, FM et al., eds., Greene Publishing Associates, 1989), and U.S. Patent No. 4,816,397. These genes are incorporated into a recombinant expression vector, and the vector is introduced into host cells.

[0173] V H The DNA encoding the region, V HThe coding DNA can be converted into a full-length heavy chain gene by operably ligating it to another DNA molecule (CH1, CH2, CH3, and optionally CH4) that codes for the heavy chain constant region. The sequences of human heavy chain constant region genes are known in the art (see, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242), and DNA fragments containing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be the IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, or IgD constant region, but in certain embodiments it is the IgG1 or IgG4 constant region.

[0174] V L The DNA encoding the region, V L The coding DNA can be converted into a full-length light chain gene (and Fab light chain gene) by operably ligating it to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242), and DNA fragments containing these regions can be obtained by standard PCR amplification. The light chain constant region can be either a kappa constant region or a lambda constant region, but in certain embodiments, it is a kappa constant region.

[0175] To express the anti-CD5 antibody of this disclosure, the partial or full-length light chain and heavy chain encoding DNA obtained as described above is inserted into an expression vector such that the genes are operably ligated to transcriptional and translational regulatory sequences. In this context, the term “operably ligated” is intended to mean that the antibody gene is ligated to the vector such that the transcriptional and translational regulatory sequences in the vector perform their intended functions of regulating the transcription and translation of the antibody gene. The expression vector and expression regulatory sequences are selected to be compatible with the expression host cell used. The antibody light chain gene and antibody heavy chain gene can be inserted into separate vectors, but more typically, both genes are inserted into the same expression vector.

[0176] The antibody gene is inserted into the expression vector by standard methods (e.g., ligation of the antibody gene fragment and complementary restriction sites on the vector, or blunt-end ligation if no restriction sites exist). Prior to insertion of the anti-CD5 antibody-related light or heavy chain sequence, the expression vector may already contain the antibody constant region sequence. For example, anti-CD5 monoclonal antibody-related V H and V L One approach to converting a sequence into a full-length antibody gene is V H The segment is operably connected to the CH segment(s) within the vector, V LThe process involves inserting the segments into an expression vector that already encodes the heavy chain constant region and the light chain constant region, respectively, so that the segments are operably linked to the CL segment within the vector. In addition, or alternatively, the recombinant expression vector can encode a signal peptide that facilitates the secretion of the antibody chain from host cells. The antibody chain gene can be cloned into the vector so that the signal peptide is linked in a frame to the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein). Exemplary signal peptides include MGSTAILGLLLAVLQGGRA (SEQ ID NO: 60) and METDTLLLWVLLLWVPGSTGAS (SEQ ID NO: 61).

[0177] In addition to the antibody chain gene, the recombinant expression vectors of this disclosure possess regulatory sequences that control the expression of the antibody chain gene in host cells. The term “regulatory sequences” is intended to include promoters, enhancers, and other expression regulatory elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain gene. Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif., 1990. Those skilled in the art will understand that the design of the expression vector, including the selection of regulatory sequences, may depend on factors such as the selection of host cells to be transformed and the desired level of protein expression. Suitable regulatory sequences for mammalian host cell expression include viral elements that lead to high levels of protein expression in mammalian cells, such as cytomegalovirus (CMV)-derived promoters and / or enhancers (e.g., CMV promoter / enhancer), simian virus 40 (SV40) (e.g., SV40 promoter / enhancer), adenoviruses (e.g., adenovirus major late promoter (AdMLP)), and polyomas. For further descriptions of viral regulatory elements and their sequences, see, for example, U.S. Patent No. 5,168,062 by Stinski, U.S. Patent No. 4,510,245 by Bell et al., and U.S. Patent No. 4,968,615 by Schaffner et al.

[0178] The antibodies of this disclosure can be expressed in either prokaryotic or eukaryotic host cells. In certain embodiments, antibody expression is carried out in eukaryotic cells, e.g., mammalian host cells, that have optimal secretion of appropriately folded immunologically active antibodies. Exemplary mammalian host cells for expressing the recombinant antibodies of this disclosure include Chinese hamster ovary (CHO cells) (used with a DHFR-selectable marker, e.g., as described in Kaufman and Sharp, 1982, Mol. Biol. 159:601-621, and as described in Urlaub and Chasin, 1980, Proc. Natl. Acad. Sci. USA 77:4216-4220) - This includes CHO cells, NSO myeloma cells, COS cells, and SP2 cells. When a recombinant expression vector encoding an antibody gene is introduced into mammalian host cells, the antibody is produced by culturing the host cells for a period sufficient to allow antibody expression in the host cells or secretion of the antibody into the culture medium in which the host cells grow. The antibody can be recovered from the culture medium using standard protein purification methods. Host cells can also be used to produce intact antibody portions, such as Fab fragments or scFv molecules. It should be understood that variations of the above procedure are within the scope of this disclosure. For example, it may be desirable to transfect host cells with DNA encoding either the light chain or heavy chain (but not both) of the anti-CD5 antibody of this disclosure.

[0179] For recombinant expression of the anti-CD5 antibody of this disclosure, host cells can be co-transfected with two expression vectors of this disclosure: a first vector encoding a heavy-chain polypeptide and a second vector encoding a light-chain polypeptide. The two vectors may contain the same selectable marker, or each may contain a different selectable marker. Alternatively, a single vector encoding both the heavy-chain polypeptide and the light-chain polypeptide can be used.

[0180] Once nucleic acids encoding one or more portions of an anti-CD5 antibody have been introduced, further modifications or mutations can be introduced into the encoding sequence to produce nucleic acids encoding antibodies with different CDR sequences, antibodies with reduced affinity for the Fc receptor, or antibodies of a different subclass.

[0181] The anti-CD5 antibodies of this disclosure can also be produced by chemical synthesis (e.g., by the method described in Solid Phase Peptide Synthesis, 2nd ed., 1984 The Pierce Chemical Co., Rockford, Ill.). Variant antibodies can also be generated using a cell-free platform (see, for example, Chu et al., Biochemia No. 2, 2001 (Roche Molecular Biologicals) and Murray et al., 2013, Current Opinion in Chemical Biology, 17:420-426).

[0182] Once the anti-CD5 antibody or its antigen-binding fragment of the present disclosure is produced by recombinant expression, it can be purified by any method known in the art for the purification of immunoglobulin molecules, for example, by chromatography (e.g., ion-exchange, affinity, and size column chromatography), centrifugation, differential solubility, or any other standard technique for protein purification. Furthermore, the anti-CD5 antibody and / or binding fragment of the present disclosure can be fused to a heterologous polypeptide sequence, either as described herein or otherwise known in the art, to facilitate purification.

[0183] Once isolated, the anti-CD5 antibody or antigen-binding fragment can be further purified, if desired, by high-performance liquid chromatography (e.g., Fisher, Laboratory Techniques In Biochemistry And Molecular Biology, Work and Burdon, eds., Elsevier, 1980) or by gel filtration chromatography on a Superdex® 75 column (Pharmacia Biotech AB, Uppsala, Sweden).

[0184] 6.7. Formulation and Administration Preferred routes of administration for the conjugates, antibodies, and antigen-binding fragments of this disclosure include, but are not limited to, oral, parenteral, rectal, transmucosal, intestinal, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreous, intracavitary, intraperitoneal, or intratumoral injection. Preferred routes of administration are parenteral, more preferably intravenous. Alternatively, the conjugates, antibodies, or antibody fragments may be administered locally rather than systemically, for example, by direct injection of the conjugate, antibody, or antibody fragment into a solid tumor or hematological malignancy.

[0185] The compositions of this disclosure can be formulated by known methods for preparing pharmaceutically useful compositions, for example, by combining a conjugate with a pharmaceutically suitable excipient in a mixture. Sterile phosphate-buffered saline is an example of a pharmaceutically suitable excipient. Other suitable excipients are well known to those skilled in the art. See, for example, Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company 1990), and their revised editions.

[0186] In preferred embodiments, the conjugate is formulated in Good's biological buffer (pH 6-7) using a buffer selected from the group consisting of N-(2-acetamide)-2-aminoethanesulfonic acid (ACES), N-(2-acetamide)iminodiacetic acid (ADA), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), 3-(N-morpholinyl)-2-hydroxypropanesulfonic acid (MOPSO), and piperazine-N,N'-bis(2-ethanesulfonic acid) [Pipes]. A more preferred buffer is MES or MOPS in a concentration range of preferably 20-100 mM, more preferably about 25 mM. A 25 mM MES with a pH of 6.5 is most preferred. The formulation may further contain 25 mM trehalose and 0.01% v / v polysorbate 80 as excipients, and the final buffer concentration may be changed to 22.25 mM as a result of the added excipients. The preferred storage method is as a lyophilized formulation of the conjugate stored at a temperature range of -20°C to 2°C, with storage at 2°C to 8°C being most preferred.

[0187] The conjugate can be formulated for intravenous administration, for example, via bolus injection, slow infusion, or continuous infusion. Preferably, the conjugate is infused over a period of less than about 4 hours, and more preferably over a period of less than about 3 hours. For example, the first 25-50 mg can be infused within 30 minutes, preferably within another 15 minutes, and the remainder can be infused over the next 2-3 hours. The formulation for injection can be provided in unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for use in a suitable vehicle, for example, sterile, pyrogen-free water.

[0188] Additional pharmaceutical methods may be used to control the duration of action of the conjugate. Controlled-release preparations can be prepared by using polymers to composite or adsorb the conjugate. For example, biocompatible polymers include poly(ethylene-co-vinyl acetate) matrices and polyacid anhydride copolymer matrices of stearic acid dimer and sebacic acid. Sherwood et al., 1992, Bio / Technology 10:1446. The release rate of the conjugate from such matrices depends on the molecular weight of the conjugate, the amount of conjugate in the matrix, and the size of the dispersed particles. Saltzman et al., 1989, Biophys.J.55:163, Sherwood et al., above. Other solid dosage forms are described in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company 1990), and their revised editions.

[0189] Generally, the dosage of conjugate administered to humans will vary depending on factors such as the patient's age, weight, height, sex, general medical condition, and prior medical history. While it may be desirable to provide the recipient with a dose of conjugate ranging from approximately 0.3 mg / kg to 5 mg / kg as a single intravenous infusion, lower or higher doses may be administered depending on the situation. For example, a dose of 0.3–5 mg / kg for a 70 kg patient is equivalent to 21–350 mg or 12–20 mg for a 1.7 m patient. 6The dosage is mg / m2. The dosage may be repeated as needed, for example, once a week for 2 to 10 weeks, once a week for 8 weeks, or once a week for 4 weeks. Alternatively, as needed in maintenance therapy, it may be administered at a lower frequency, for example, every other week for several months, or monthly or quarterly for several months. Preferred dosages may include, but are not limited to, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, and 5.0 mg / kg. More preferred dosages are 0.6 mg / kg when administered weekly and 1.2 mg / kg when administered less frequently. Any amount in the range of 0.3 to 5 mg / kg may be used. The dosage is preferably administered once a week, multiple times. A minimum dosing schedule of 4 weeks, more preferably 8 weeks, and more preferably 16 weeks or more may be used, and the frequency of dosing depends on toxic side effects and recovery therefrom, mainly related to hematological toxicity. The dosing schedule may include administration once or twice a week in cycles selected from the following groups: (i) weekly, (ii) every other week, (iii) 1 week of treatment followed by 2, 3, or 4 weeks of rest, (iv) 2 weeks of treatment followed by 1, 2, 3, or 4 weeks of rest, (v) 3 weeks of treatment followed by 1, 2, 3, 4, or 5 weeks of rest, (vi) 4 weeks of treatment followed by 1, 2, 3, 4, or 5 weeks of rest, (vii) 5 weeks of treatment followed by 1, 2, 3, 4, or 5 weeks of rest, and (viii) monthly. The cycle may be repeated 2, 4, 6, 8, 10, or 12 or more times.

[0190] Alternatively, the conjugate may be administered as a single dose every two or three weeks, repeated until a total of at least three doses have been received. Or, twice a week for four to six weeks. To allow the patient to recover from any drug-related toxicity, the dose may be administered every other week or even less frequently. Alternatively, the dosing schedule may be reduced, i.e., every two or three weeks for two to three months. The dosing schedule may be optionally repeated at other intervals, and the dose may be administered via various parenteral routes with appropriate adjustments to the dose and schedule.

[0191] 6.8. Treatment methods using the conjugates of this disclosure The conjugates of this disclosure can be used to treat a variety of cancers. The conjugates can be used as monotherapy or as part of a combination therapy regimen, for example, with standard treatment agents or regimens. In some embodiments, the combination therapy involves administering the conjugate in combination with immunotherapy, such as checkpoint modulator (e.g., checkpoint inhibitor) therapy, chimeric antigen receptor (CAR) therapy, adoptive T-cell therapy (e.g., autologous T-cell therapy), oncolytic virus therapy, dendritic cell vaccine therapy, interferon gene stimulator (STING) agonist therapy, Toll-like receptor (TLR) agonist therapy, intratumor CpG therapy, cytokine therapy (e.g., IL2, IL12, IFN-α, or INF-γ therapy), or a combination thereof. In some embodiments, combination therapy involves administering a conjugate in combination with immunoconservative chemotherapy (e.g., antimetabolites such as 5-fluorouracil, gemcitabine, or methotrexate; alkylating agents such as cyclophosphamide, dacarbazine, mechloretamine, diaziquan, or temozolomide; anthracyclines such as doxorubicin or epirubicin; antimicrotubule agents such as vinblastine; platinum compounds such as cisplatin or oxaliplatin; taxanes such as paclitaxel or docetaxel; topoisomerase inhibitors such as etoposide or mitoxantrone; or vinca alkaloids such as vincristine).

[0192] Examples of cancers that can be treated using the conjugates of this disclosure include, but are not limited to, pancreatic cancer, glioblastoma, myelodysplastic syndrome, prostate cancer (e.g., castration-resistant prostate cancer), liver cancer (e.g., hepatocellular carcinoma), melanoma, breast cancer, urothelial carcinoma (e.g., bladder cancer, urethral cancer, and ureteral cancer), kidney cancer (e.g., renal cell carcinoma and urothelial carcinoma), lung cancer (e.g., non-small cell lung cancer (NSCLC) such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, as well as small cell lung cancer), and colorectal cancer (e.g., adenocarcinoma, cancerous tumors, gastrointestinal stromal tumors, and colorectal lymphoma). Additional examples of cancers that can be treated using the conjugates of this disclosure include head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)) and ovarian cancer.

[0193] The conjugates of this disclosure can be used in combination with checkpoint modulators (e.g., checkpoint inhibitors), such as drugs targeting PD1, PDL1, CTLA4, TIGIT, LAG3, OX40, ICOS, GITR, CD40, or VISTA. Checkpoint modulators include antibodies and small molecules, and include, for example, inhibitors targeting PD1, PDL1, CTLA4, TIGIT, LAG3, ICOS, or VISTA (e.g., inhibitory antibodies), as well as agonists targeting, for example, OX40, GITR, or CD40 (e.g., agonist antibodies).

[0194] Exemplary checkpoint modulators targeting PD1 include pembrolizumab, nivolumab, semiprimab, and dostallimab. Exemplary checkpoint modulators targeting PD1 include atezolizumab, avelumab, durvalumab, BMS-1001, and BMS-1166. Exemplary checkpoint modulators targeting CTLA4 are ipilimumab. Exemplary checkpoint modulators targeting TIGIT include etigirimab, tilagorumab, and AB154. Exemplary checkpoint modulators targeting LAG3 include LAG525, Sym022, relatrimab, and TSR-033. Exemplary checkpoint modulators targeting OX40 include MEDI6469, PF-04518600, and BMS 986178. Exemplary checkpoint modulators targeting ICOS include MEDI-570, ferazirimab, and BMS 986226. Exemplary checkpoint modulators targeting GITR include TRX-518, AMG 228, MK-4166, MEDI1873, INCAGN01876, and GWN323. Exemplary checkpoint modulators targeting CD40 include sericrelumab, CP-870, CP-893, and APX005M. An exemplary checkpoint modulator targeting VISTA is HMBD-002.

[0195] For the treatment of melanoma carrying BRAF mutations, the conjugates of this disclosure can be used in combination with drugs that specifically target BRAF mutations, such as venurafenib, dabrafenib, and trametinib.

[0196] For the treatment of malignant melanoma, the conjugate of this disclosure may be used in combination with checkpoint modulators (e.g., inhibitors) such as ipilimumab, nivolumab, pembrolizumab, cemiprimab, or avelumab.

[0197] For the treatment of non-small cell lung cancer (NSCLC), the conjugate of this disclosure can be used in combination with standard therapeutic chemotherapy such as cisplatin, carboplatin, paclitaxel, gemcitabine, vinorelbine, irinotecan, etoposide, or vinblastine. In addition, the conjugate can be used in combination with targeted therapies such as bevacizumab or elbitux. Furthermore, the conjugate can be used in combination with checkpoint modulators (e.g., inhibitors) such as pembrolizumab, nivolumab, semiprimab, dostallimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

[0198] For the treatment of bladder cancer, the conjugates of this disclosure can be used in combination with standard treatments, including but not limited to cisplatin, mitomycin-C, carboplatin, docetaxel, paclitaxel, doxorubicin, 5-FU, methotrexate, vinblastine, ifosfamide, and pemetrexed. In addition, the conjugates can be used in combination with checkpoint modifiers (e.g., inhibitors) such as ipilimumab.

[0199] For the treatment of renal cancer, the conjugates of this disclosure can be used in combination with standard treatment measures, such as angiogenic and / or specific tyrosine kinase-blocking agents, including sorafenib, sunitinib, temsirolimus, everolimus, pazopanib, and axitinib. In addition, the conjugates can be used in combination with checkpoint modifiers (e.g., inhibitors), such as nivolumab.

[0200] For the treatment of breast cancer, the conjugates of this disclosure can be used in combination with anthracyclines (doxorubicin or epirubicin) and taxanes (paclitaxel or docetaxel), as well as standard chemotherapy agents such as fluorouracil, cyclophosphamide, and carboplatin. In addition, the conjugates of this disclosure can be used in combination with targeted therapies. Targeted therapies for HER2 / neu-positive tumors include trastuzumab and pertuzumab, and those for estrogen receptor (ER)-positive tumors include tamoxifen, toremifene, and fulvestrant. In addition, the conjugates can be used in combination with checkpoint modulators (e.g., inhibitors) such as atezolizumab.

[0201] In the case of pancreatic cancer, the conjugates of this disclosure can be used in combination with standard chemotherapy agents such as gemcitabine, 5-fluouracil, irinotecan, oxaliplatin, paclitaxel, capecitabine, cisplatin, or docetaxel. In addition, the conjugates can be used in combination with targeted therapies such as erlotinib, which inhibits EGFR.

[0202] In the case of glioblastoma, the conjugates of this disclosure can be used in combination with standard chemotherapy agents such as carboplatin, cyclophosphamide, etoposide, lomustine, methotrexate, or procarbazine.

[0203] In the case of prostate cancer, the conjugate of this disclosure can be used in combination with standard chemotherapy agents including docetaxel, optionally with steroid prednisone, or with cabazitaxel. In addition, the conjugate can be used in combination with checkpoint modifiers (e.g., inhibitors) such as ipilimumab.

[0204] The use of the conjugates of this disclosure in combination with one or more therapies does not restrict the order in which the therapies are administered. For example, the conjugates of this disclosure may be administered before, during, or after a subject is treated with one or more therapies. In some embodiments, the conjugates of this disclosure are administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or concurrently with or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the treatment of a patient with another therapy (e.g., the second therapeutic agent described above). In some embodiments, the conjugate of the present disclosure is incorporated into the same regimen as the second therapeutic agent. [Examples]

[0205] 7. Examples 7.1. Example 1: Production of humanized anti-CD5 antibody having a human IgG skeleton 7.1.1. Overview Antibodies against human proteins or peptides isolated from non-human animal cells (e.g., mouse anti-human CD5 antibodies) often induce immune responses when used as therapeutic agents. Although humanized antibodies are generally considered less immunogenic than their parental counterparts, they may still be associated with antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) caused by the interaction between the constant Fc region of these antibodies and Fc receptors on immune cells.

[0206] Two parent antibodies were used to manipulate humanized CD5 antibodies with low ADCC and CDC. The first parent antibody was a humanized anti-CD5 antibody (referred to herein as “Antibody A”), and the second parent antibody was a mouse anti-human CD5 antibody (referred to herein as “Antibody B”).

[0207] 7.1.2. Method 7.1.2.1. Design of constructs AB-1 to AB-4 using antibody A The variable region sequences (VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50) of the first parent antibody (Antibody A) were incorporated into the human IgG backbone. More specifically, the heavy chain of the parent antibody was incorporated into either wild-type human IgG1, IgG1 with mutations L234A and L235A (IgG1(LALA)), IgG1 with the N297A mutation (IgG1(N297A)), or IgG4 with the S228P mutation (IgG4(S228P)). The heavy chain with the human IgG backbone was then combined with the light chain incorporated into human Ig kappa. The complete light and heavy chain sequences of the antibodies are referred to as AB-1 to AB-4 and are shown in Table 1L.

[0208] 7.1.2.2. Humanization of Antibody B The parental mouse anti-human CD5 antibody (Antibody B) was humanized as follows. The amino acid sequences of the parental light and heavy chains were aligned with the human germline Ig alleles IGKV3-11*01, IGKV3-11*02, and IGKV1-16*01. Figures 1A to 1C show the amino acid residue alignment mismatch between the parental mouse antibody and the germline Ig framework. Next, the amino acid sequences of the light and heavy chain complementarity-determining regions (CDRs) of the parental antibody were transplanted into the human Ig framework sequence. The resulting sequence was further modified by introducing various reverse mutations in residues to preserve the antigen-binding activity of the parental antibody. Figures 2A and 2B illustrate the humanization of the parental mouse anti-human CD5 antibody VH and VL amino acid sequences to the AB-5 VH and VL amino acid sequences, using antibody 4JLR.pdb as the reference framework.

[0209] The obtained sequences were checked for confounding issues such as N-glycosylation, interface changes, and potentially problematic proline residues. Six humanized anti-CD5 antibody VH-VL sequences were selected for further analysis. The complete light and heavy chain sequences of the humanized antibodies, designated AB-5 to AB-10, are shown in Table 1L. Subsequently, VH and VL were cloned into the human IgG1(LALA)Fc backbone.

[0210] 7.1.2.3. Production and Purification of Humanized Anti-CD5 Antibodies All antibody constructs were expressed in Expi293 cells by transient transfection. The supernatant was collected from the transfected cells, centrifuged at 8,500 rpm for 20 minutes at 4°C, and filtered through a 0.22 μm filter membrane.

[0211] Antibodies in the filtered protein suspension were purified using the Protein A resin system. Briefly, each resin column was pre-equilibrated with Buffer A (PBS, pH 7.4). The sample was packed into the column and washed with Buffer D (1% Triton 114 in PBS, pH 7.4). Next, the column was washed with Buffer A, and the target antibody was eluted with Buffer B (0.1M glycine, pH 3.0). The column was neutralized with Buffer C (1M Tris-HCl, pH 8.0). A small portion of the antibody-containing solution was run on a 12% SDS-PAGE. The antibody in the remaining portion was dialyzed overnight against Buffer A. The following day, the antibody was concentrated by ultrafiltration at 4°C with a molecular cutoff of 30 kDa.

[0212] The endotoxin levels of the purified protein were analyzed using antibodies diluted 5- to 250-fold with the ToxinSensor® Chromogenic LAL Endotoxin Assay Kit (Genescript, catalog number L00350).

[0213] 7.1.3.Results A total of four anti-CD5 antibody constructs were generated using the humanized parental antibody (Antibody A), and six anti-CD5 humanized antibody constructs were generated using the mouse anti-human CD5 parental antibody (Antibody B), as described in Sections 7.1.2.1 and 7.1.2.2. In addition, the negative control antibody NC-AB was designed and generated by incorporating its VH and VL sequences into human IgG1 (LALA) and human Ig kappa, respectively. All anti-CD5 antibody constructs generated in this example are shown in Table 5 below. [Table 17]

[0214] The antibody constructs were cloned into Expi293 cells, and the antibodies were produced and purified as described in Section 7.1.2.3. Exemplary SDS-PAGE images of the three anti-CD5 antibodies, AB-4, AB-6, and AB-8, as well as the negative control antibody NC-AB, are shown in Figures 3A to 3D. Furthermore, the purified antibodies had low endotoxin levels, less than 1 EU / mg for all samples at the highest concentration evaluated (Figure 3E).

[0215] 7.2. Example 2: Target cell binding of a humanized anti-CD5 antibody having a human IgG skeleton. 7.2.1. Overview CD5 is a surface glycoprotein expressed on T cells. To evaluate the antibody-binding efficacy of humanized anti-CD5 antibodies, a cell-binding assay using Jurkat T cells was employed.

[0216] 7.2.2. Method 7.2.2.1. Cell Culture and Maintenance Jurkat T cells were maintained in RPMI medium supplemented with 10% FBS. EL4 cells were maintained in DMEM medium supplemented with 10% FBS. CD3+ T cells were maintained in K5 medium supplemented with 10% FBS, 1× non-essential amino acids, 1 mM sodium pyruvate, 2 mM L-glutamine, and 55 μM 2-mercaptoethanol.

[0217] All cell culture media were supplemented with 1× streptomycin-penicillin (100 μg / mL streptomycin-100 units / penicillin 1 mL), and the cells were cultured at 37°C and 5% CO2 in a humidified incubator, and subcultured 2-3 times per week.

[0218] 7.2.2.2. Flow Cytometry Analysis Jurkat T cells were washed twice in FACS buffer (PBS + 1% BSA) and incubated on ice for 30 minutes with humanized anti-CD5 antibody or isotype control NC-AB diluted according to the table shown in Figure 4A. After washing twice in FACS buffer, the samples were further incubated on ice for 30 minutes with a secondary antibody conjugated with a fluorophore, washed, and captured by flow cytometry. The data were analyzed to evaluate the EC of each antibody. 50 The value was obtained.

[0219] 7.2.3.Results In the first evaluation, humanized anti-CD5 antibodies (AB-1, AB-2, AB-3, and AB-4) derived from the first parent antibody A were evaluated against the isotype control antibody (NC-AB). Humanized anti-CD5 antibodies AB-1, AB-2, and AB-3 showed overlapping concentration-response curves, indicating comparable target binding velocities (Figure 4B). The maximum MFI of AB-4 was lower than that of the other three anti-CD5 antibodies, but the EC50 values ​​of all four antibodies were similar (Figure 4B and Table 6). [Table 18]

[0220] Next, the binding of humanized anti-CD5 antibodies derived from antibody B, a parental mouse anti-hCD5 antibody, to Jurkat T cells was compared with that of AB-1. The concentration-response curves of antibodies AB-5 to AB-10 showed that they exhibited higher target binding than AB-1 (Figure 4C).

[0221] Repeated evaluations in CD3+ T cells, comparing the binding of AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10 with that of AB-1 and AB-2, yielded similar results (Figure 4D). In summary, humanized anti-CD5 antibodies (AB-5 to AB-10) derived from antibody B exhibited EC50 values ​​approximately an order of magnitude lower than those of AB-1 and AB-2 (Table 7). [Table 19]

[0222] Next, the specificity of antibody B, a parental mouse anti-CD5 antibody, was evaluated using Jurkat T cells and mouse EL4 cells. The parental antibody bound to Jurkat T cells with an EC50 value of 0.08 but not to mouse EL4 cells (Figures 4E and 4F), demonstrating high specificity for human CD5.

[0223] 7.3. Example 3: Internalization of a humanized anti-CD5 antibody having a human IgG skeleton 7.3.1. Overview Identifying antibodies that efficiently internalize into cells, rather than simply binding to antigens on the cell surface, is essential for developing therapeutic antibodies that can mediate receptor endocytosis.

[0224] 7.3.2. Method Antibody endocytosis was evaluated using a flow cytometry-based antibody internalization assay. Briefly, Jurkat cells were incubated with 1 μg / mL of antibody, washed, and incubated with the secondary antibody R-phycoerythrin AffiniPure F(ab')2 fragment goat anti-human IgG (Jackson). Fluorescence intensity was measured at the start of the evaluation (0 hours), as well as at 4 and 6 hours.

[0225] 7.3.3.Results In the first evaluation, the internalization of humanized anti-CD5 antibodies AB-1, AB-2, AB-3, and AB-4 was assessed against the isotype control antibody NC-AB. All four anti-CD5 antibodies showed a similar decrease in signal intensity (Figure 5A), which was associated with comparable internalization rates (Figure 5B).

[0226] Next, the internalization of humanized anti-CD5 antibodies AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, and AB-1 was evaluated. Changes in signal intensity and internalization rate were similar for AB-1 in both evaluations (Figures 5A and 5C, and Figures 5B and 5D, respectively), allowing for a comparison of the internalization dynamics of antibodies derived from the first parental antibody (antibody A) with those derived from the parental mouse anti-hCD5 antibody (antibody B). Similar to the findings in the first evaluation, most antibodies showed similar changes in signal intensity (Figure 5C) and internalization rate (Figure 5D). Overall, the humanized anti-CD5 antibodies exhibited a median internalization of 38% (Table 8). [Table 20]

[0227] Antibody internalization was repeatedly evaluated for AB-4 and AB-8, and this time, fluorescence signal intensity was assessed at 0, 2, and 6 hours. In this study, AB-4 was associated with 44% and AB-8 with a 53% reduction in surface CD5 binding at 6 hours, further supporting the efficient internalization of humanized anti-CD5 antibodies derived from both parent antibodies.

[0228] 7.4. Example 4: ADCC evaluation of humanized anti-CD5 antibody having a human IgG skeleton 7.4.1. Overview The Fc region of humanized antibodies is often associated with antibody-dependent cytotoxicity (ADCC). Therefore, humanized anti-CD5 antibodies containing human IgG chains with low ADCC activity, such as IgG1-LALA, can help overcome this limitation.

[0229] 7.4.2. Method To evaluate the ADCC effect of anti-CD5 antibodies, we developed an ADCC assay. Briefly, NK cells were isolated from PBMCs and used to target Jurkat T cells (4 × 10⁶ cells) with an effector:target cell ratio (E:T) of 5:1. 4Cells were co-cultured with the cells (per well). Humanized anti-CD5 antibody, as well as parental mouse anti-hCD5 antibody, positive control antibody (anti-human MHC class I antibody), and negative control antibody (NC-AB) were diluted to a concentration of 30 μg / mL and added to the wells. The plates were incubated at 37°C and 5% CO2 for 4 hours. After incubating the cells with CytoTox 96® reagent at room temperature for 30 minutes, data was collected using a 490 nm plate reader.

[0230] 7.4.3.Results As expected, the positive control antibody, an anti-human MHC class I antibody, was associated with strong cytotoxicity (Figure 6). AB-3 was the only antibody with a wild-type IgG1 skeleton included in this evaluation, and none of the other humanized anti-CD5 antibodies exhibited measurable ADCC. This is because the percentage of cytotoxicity levels associated with these antibodies was indistinguishable from the cell death rate in the no-antibody control (Figure 6). These results indicate that the IgG1-LALA, IgG1-N297A, and IgG4 skeletons provided protection against ADCC compared to the wild-type IgG1 skeleton.

[0231] 7.5. Example 5: Conjugation of anti-CD5 antibody to human or rhesus monkey CD5-HEK293 cells 7.5.1. Overview The binding of anti-CD5 antibodies, antibody B and antibody C (mouse parental antibodies against the AB-11 antibody sequence), to human or rhesus monkey CD5-expressing HEK cells was evaluated.

[0232] 7.5.2. Method Human embryonic kidney cells (HEK-293, ATCC) were placed in a 10cm space. 2The cells were plated in tissue culture dishes. When the cells reached 70% confluence, they were transiently transfected with either human or rhesus monkey CD5-containing DNA plasmids. Briefly, Mirus Transit®-LT1, a broad-spectrum, low-toxicity transfection reagent, was combined with 1 μg of plasmid DNA in low-serum cell culture medium (Opti-MEM®). The mixture was incubated at room temperature for 30 minutes and then added dropwise to HEK-293 cells. After 48 hours, the transfected cells were gently detached from the plate with Accutase® cell detachment solution, washed twice in ice-cold staining buffer (1×dPBS, 1% FBS, 0.05% sodium azide), and counted. 1.5×10 5 Cells were incubated with either 7.5 μg / mL of antibody C-PE (phycoerythrin) conjugate or antibody B-PE in 100 μL of staining buffer. After 60 minutes on ice, the cells were washed twice in staining buffer to completely remove any unbound antibody. Cells were captured using an Attune® NxT acoustic cytometer, and analysis was completed using FlowJo® software.

[0233] 7.5.3.Results Flow cytometry plots are shown in Figures 7A and 7C, while the percentage of positive CD5+ cells, measured by antibody binding and mean fluorescence intensity, is shown in Tables 9A and 9B, respectively. [Table 21] [Table 22]

[0234] Antibody B bound to human CD5-expressing HEK293 cells, while antibody C bound to CD5-expressing cells of both human and rhesus monkeys.

[0235] 7.6. Example 6: Internalization of AB-4, AB-6, and AB-8 We studied the internalization of humanized antibodies AB-4, AB-6, and AB-8 after binding to CD5-expressing Jurkat cells. Briefly, the antibodies were incubated with Jurkat cells for 2–6 hours, and antibody internalization was measured by FACS staining.

[0236] The results are shown in Figures 8A to 8C. AB-4, AB-6, and AB-8 were internalized, respectively.

[0237] 7.7. Example 7: Humanized antibody having human IgG4 Fc 7.7.1. Overview The Fc regions of humanized anti-human CD5 antibodies AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10, as well as the mouse anti-human CD5 antibody B, were substituted with the human IgG4 Fc region containing the S228P substitution. Binding to Jurkat cells was evaluated.

[0238] 7.7.2. Method Serial dilutions of anti-CD5 antibody and isotype control antibody were prepared and incubated with Jurkat cells at 4°C for 60 minutes. The cells were then washed three times. PE-goat anti-human IgG secondary antibody was added to the cells and incubated at 4°C for 30 minutes. The cells were washed and analyzed by FACS.

[0239] 7.7.3.Results The dose-response curve of the antibody that binds to Jurkat cells is shown in Figure 9. The EC50 values ​​are shown in Table 10. [Table 23]

[0240] 7.8. Example 8: Internalization of humanized antibodies containing human IgG1 or IgG4 Fc 7.8.1. Overview After binding to Jurkat cells, we evaluated the internalization of (1) mouse anti-human CD5 antibody B having human IgG4 Fc regions with AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, and (2) AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, and S228P substitution.

[0241] 7.8.2. Method Logarithmic phase Jurkat cells (2E5 / sample) were washed in cell culture medium and plated in a 96-well U-bottom plate in cell culture medium. 1 μg / mL antibody was incubated with the cells at 4°C for 60 minutes. The cells were then washed twice and resuspended in growth medium (RPMI1640 + 10% FBS). The cells were incubated at 37°C for 0, 4, or 6 hours. The cells were then washed twice in staining buffer. Secondary antibody (PE-goat anti-human IgG) in staining buffer was added and incubated at 4°C for 30 minutes. The cells were washed twice, resuspended in staining buffer, and analyzed by FACS.

[0242] 7.8.3.Results The results are shown in Figures 10A and 10B. All antibodies showed internalization at 4 and 6 hours. The internalization rates at 4 and 6 hours are summarized in Table 11. [Table 24]

[0243] 7.9. Example 9: In vitro characterization of antibody-TGFβ-antagonist conjugate (ATAC) Antibodies AB-4, AB-8, and B were conjugated with ALK5 inhibitor compound C (see Table 2), and the activity of the TGFβ / SMAD signaling pathway after exposure to the antibody-ALK5 inhibitor conjugate was monitored by the HEK-CD5 SBE luciferase assay.

[0244] 7.9.1. Method HEK-CD5 cells were plated in triples in 96-well plates. After cell binding, the conjugated antibody was titrated and incubated for 18 hours in a 37°C / 5% CO2 incubator. TGFβ was added to the plates and incubated for a further 3 hours. The assay was developed using a commercially available luciferase detection reagent, data were captured with a luminometer, and plotted using GraphPad Prism® software.

[0245] 7.9.2.Results The results are shown in Figures 11A and 11B. Each conjugate was active in the assay. The EC50 values ​​are reported in Table 12. [Table 25]

[0246] 7.10. Example 10: CDC activity of the antibody of this disclosure 7.10.1. Overview The complement-dependent cytotoxicity (CDC) of the antibodies and antibody-ALK5 inhibitor conjugates described herein was evaluated.

[0247] 7.10.2. Method T cells were isolated from human PBMCs and plated in triples in a round-bottom 96-well plate. Antibodies were added to the cells and incubated on ice for 0.5 hours. Then, rabbit serum complement was added to a final concentration of 5%. The cells were incubated in a 37°C / 5% CO2 incubator for 2 hours. Propidium iodide was added to the cells, data were captured using a FACS instrument, analyzed using FlowJo® software, and plotted using GraphPad Prism®.

[0248] 7.10.3.Results The results are shown in Figure 12. CDC was observed only in AB-3, which possesses the wild-type IgG1 Fc domain.

[0249] 8. Specific Embodiments This disclosure is illustrated by the following specific embodiments. 1. An anti-CD5 antibody or its antigen-binding fragment, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 6, and 13, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 11, and 14, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 15, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (d) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 4, 8, and 15, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. (e) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 11, and 13, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, 19, and 21, respectively. (f) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 7, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (g) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 7, and 13, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (h) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 6, and 16, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. (i) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 9, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively, (j) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 9, and 16, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (k) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 10, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (l) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 10, and 13 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (m) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 12, and 14 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively, or (n) An anti-CD5 antibody or its antigen-binding fragment, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 12, and 13, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 2. An anti-CD5 antibody or its antigen-binding fragment, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 7, and 14, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 7, and 13, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (c) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 6, and 13, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. (d) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 9, and 14, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (e) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 9, and 16, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (f) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 10, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (g) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 10, and 13, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (h) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 12, and 14 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively, or (i) an anti-CD5 antibody or antigen-binding fragment, optionally the anti-CD5 antibody or antigen-binding fragment described in Embodiment 1, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 12, and 13, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 3. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 6, and 13, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. 4. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 11, and 14, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 5. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 15, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 6. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 4, 8, and 15, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. 7. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 11, and 13, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, 19, and 21, respectively. 8. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 7, and 14, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 9. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 7, and 13, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 10. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 6, and 16, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, ATS, and 20, respectively. 11. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 9, and 14, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 12. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 9, and 16, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 13. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 10, and 14, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 14. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 10, and 13, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 15. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 12, and 14, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 16. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 12, and 13, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 17. An anti-CD5 antibody or antigen-binding fragment thereof according to any one of Embodiments 1 to 16, which is a humanized anti-CD5 antibody or an antigen-binding fragment thereof. 18. Anti-CD5 antibody or antigen-binding fragment thereof, (a) VH having a sequence that is at least 90% identical to sequence number 22 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 23 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (b) VH having a sequence that is at least 90% identical to sequence number 24 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 25 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (c) VH having a sequence that is at least 90% identical to sequence number 26 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 27 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (d) VH having a sequence that is at least 90% identical to sequence number 28 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 29 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (e) VH having a sequence that is at least 90% identical to sequence number 30 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 31 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (f) An anti-CD5 antibody or antigen-binding fragment thereof, optionally comprising a VH having a sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) of sequence SEQ ID NO: 32, and a VL having a sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) of sequence SEQ ID NO: 33, wherein the antibody or antigen-binding fragment is optionally described in any one of Embodiments 1 to 17. 19. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 18, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 22 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 23 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 20. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 19, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 22, and VL has a sequence that is at least 95% identical to SEQ ID NO: 23. 21. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 19, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 22, and VL has a sequence that is at least 97% identical to SEQ ID NO: 23. 22. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 19, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 22, and VL has a sequence that is at least 99% identical to SEQ ID NO: 23. 23. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 19, wherein VH has a sequence identical to SEQ ID NO: 22, and VL has a sequence identical to SEQ ID NO: 23. 24. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 18, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 24 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 25 (for example, at least 95%, at least 97%, at least 99%, or 100% identical). 25. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 24, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 24, and VL has a sequence that is at least 95% identical to SEQ ID NO: 25. 26. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 24, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 24, and VL has a sequence that is at least 97% identical to SEQ ID NO: 25. 27. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 24, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 24, and VL has a sequence that is at least 99% identical to SEQ ID NO: 25. 28. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 24, wherein VH has a sequence identical to SEQ ID NO: 24, and VL has a sequence identical to SEQ ID NO: 25. 29. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 18, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 26 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 27 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 30. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 29, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 26, and VL has a sequence that is at least 95% identical to SEQ ID NO: 27. 31. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 29, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 26, and VL has a sequence that is at least 97% identical to SEQ ID NO: 27. 32. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 29, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 26, and VL has a sequence that is at least 99% identical to SEQ ID NO: 27. 33. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 29, wherein VH has a sequence identical to SEQ ID NO: 26, and VL has a sequence identical to SEQ ID NO: 27. 34. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 18, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 28 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 29 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 35. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 34, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 28, and VL has a sequence that is at least 95% identical to SEQ ID NO: 29. 36. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 34, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 28, and VL has a sequence that is at least 97% identical to SEQ ID NO: 29. 37. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 34, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 28, and VL has a sequence that is at least 99% identical to SEQ ID NO: 29. 38. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 34, wherein VH has the same sequence as SEQ ID NO: 28 and VL has the same sequence as SEQ ID NO: 29. 39. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 18, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 30 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 31 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 40. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 39, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 30, and VL has a sequence that is at least 95% identical to SEQ ID NO: 31. 41. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 39, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 30, and VL has a sequence that is at least 97% identical to SEQ ID NO: 31. 42. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 39, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 30, and VL has a sequence that is at least 99% identical to SEQ ID NO: 31. 43. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 39, wherein VH has the same sequence as SEQ ID NO: 30 and VL has the same sequence as SEQ ID NO: 31. 44. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 18, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 32 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 33 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 45. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 44, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 32, and VL has a sequence that is at least 95% identical to SEQ ID NO: 33. 46. ​​The anti-CD5 antibody or antigen-binding fragment according to Embodiment 44, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 32, and VL has a sequence that is at least 97% identical to SEQ ID NO: 33. 47. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 44, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 32, and VL has a sequence that is at least 99% identical to SEQ ID NO: 33. 48. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 44, wherein VH has the same sequence as SEQ ID NO: 32 and VL has the same sequence as SEQ ID NO: 33. 49. Anti-CD5 antibody or antigen-binding fragment thereof, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 34, 39, and 43, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 45, RAN, and 48, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 35, 40, and 44, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48, respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 36, 41, and 44, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (d) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of NYG, SEQ ID NO: 41, and SEQ ID NO: 44, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 45, RAN, and SEQ ID NO: 48, respectively, or (e) An anti-CD5 antibody or its antigen-binding fragment, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 38, 42, and 43, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48, respectively. 50. The anti-CD5 antibody or antigen-binding fragment thereof according to Embodiment 49, which is a humanized anti-CD5 antibody or an antigen-binding fragment thereof. 51. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49 or Embodiment 50, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 34, 39, and 43, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 45, RAN, and 48, respectively. 52. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49 or Embodiment 50, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 35, 40, and 44, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48, respectively. 53. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49 or Embodiment 50, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 36, 41, and 44, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. 54. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49 or Embodiment 50, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of NYG, SEQ ID NO: 3741, and SEQ ID NO: 44, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 45, RAN, and SEQ ID NO: 48, respectively. 55. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49 or Embodiment 50, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 38, 42, and 43, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48, respectively. 56. An anti-CD5 antibody or antigen-binding fragment thereof, optionally comprising a VH having a sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) of SEQ ID NO: 49, and a VL having a sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) of SEQ ID NO: 50, which is either an antibody or antigen-binding fragment according to any one of embodiments 49 to 55. 57. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 56, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 49, and VL has a sequence that is at least 95% identical to SEQ ID NO: 50. 58. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 56, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 49, and VL has a sequence that is at least 97% identical to SEQ ID NO: 50. 59. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 56, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 49, and VL has a sequence that is at least 99% identical to SEQ ID NO: 50. 60. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 56, wherein VH has the same sequence as SEQ ID NO: 49 and VL has the same sequence as SEQ ID NO: 50. 61. Anti-CD5 antibody or antigen-binding fragment thereof, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 88, and 89, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, WT, and 95, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 90, and 91, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95, respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 90, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95 respectively. (d) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95 respectively. (e) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95 respectively. (f) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 4, 8, and 91, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, WT, and 95, respectively. (g) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 90, and 89, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95, respectively. (h) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 90, and 89 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95 respectively. (i) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 102, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95 respectively, (j) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95, respectively. (k) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 102, and 89 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95 respectively, or (l) An anti-CD5 antibody or its antigen-binding fragment, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 104, 8, and 91, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, 97, and 105, respectively. 62. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 1, 88, and 89, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, WT, and 95, respectively. 63. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 90, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95, respectively. 64. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 90, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95, respectively. 65. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95, respectively. 66. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95, respectively. 67. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 4, 8, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, WT, and 95, respectively. 68. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 90, and 89, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95, respectively. 69. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 90, and 89, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95, respectively. 70. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 102, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95, respectively. 71. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95, respectively. 72. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 102, and 89, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95, respectively. 73. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 61, wherein VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 104, 8, and 91, respectively, and VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, 97, and 105, respectively. 74. An anti-CD5 antibody or antigen-binding fragment thereof according to any one of embodiments 61 to 73, which is a humanized anti-CD5 antibody or an antigen-binding fragment thereof. 75. Anti-CD5 antibody or antigen-binding fragment thereof, (a) VH having a sequence that is at least 90% identical to sequence number 84 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (b) VH having a sequence that is at least 90% identical to sequence number 84 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (c) VH having a sequence that is at least 90% identical to sequence number 84 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (d) VH having a sequence that is at least 90% identical to sequence number 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (e) VH having a sequence that is at least 90% identical to sequence number 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (f) VH having a sequence that is at least 90% identical to sequence number 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (g) VH having a sequence that is at least 90% identical to sequence number 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (h) VH having a sequence that is at least 90% identical to sequence number 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (i) VH having a sequence that is at least 90% identical to sequence number 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (j) VH having a sequence that is at least 90% identical to sequence number 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (k) VH having a sequence that is at least 90% identical to sequence number 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (l) VH having a sequence that is at least 90% identical to sequence number 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), An anti-CD5 antibody or antigen-binding fragment thereof, optionally comprising (m) VH having a sequence that is at least 90% identical to SEQ ID NO: 100 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to SEQ ID NO: 101 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), wherein the antibody or antigen-binding fragment is optionally described in any one of embodiments 61 to 74. 76. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 84 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 92 (for example, at least 95%, at least 97%, at least 99%, or 100% identical). 77. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 76, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 84, and VL has a sequence that is at least 95% identical to SEQ ID NO: 92. 78. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 76, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 84, and VL has a sequence that is at least 97% identical to SEQ ID NO: 92. 79. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 76, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 84, and VL has a sequence that is at least 99% identical to SEQ ID NO: 92. 80. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 76, wherein VH has the same sequence as SEQ ID NO: 84 and VL has the same sequence as SEQ ID NO: 92. 81. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 84 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 93 (for example, at least 95%, at least 97%, at least 99%, or 100% identical). 82. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 81, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 84, and VL has a sequence that is at least 95% identical to SEQ ID NO: 93. 83. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 81, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 84, and VL has a sequence that is at least 97% identical to SEQ ID NO: 93. 84. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 81, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 84, and VL has a sequence that is at least 99% identical to SEQ ID NO: 93. 85. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 81, wherein VH has the same sequence as SEQ ID NO: 84 and VL has the same sequence as SEQ ID NO: 93. 86. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 84 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 98 (for example, at least 95%, at least 97%, at least 99%, or 100% identical). 87. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 86, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 98, and VL has a sequence that is at least 95% identical to SEQ ID NO: 98. 88. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 86, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 84, and VL has a sequence that is at least 97% identical to SEQ ID NO: 98. 89. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 86, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 84, and VL has a sequence that is at least 99% identical to SEQ ID NO: 98. 90. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 86, wherein VH has the same sequence as SEQ ID NO: 84 and VL has the same sequence as SEQ ID NO: 98. 91. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 92. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 91, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 85, and VL has a sequence that is at least 95% identical to SEQ ID NO: 92. 93. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 91, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 85, and VL has a sequence that is at least 97% identical to SEQ ID NO: 92. 94. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 91, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 85, and VL has a sequence that is at least 99% identical to SEQ ID NO: 92. 95. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 91, wherein VH has the same sequence as SEQ ID NO: 85 and VL has the same sequence as SEQ ID NO: 92. 96. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 85 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 93 (for example, at least 95%, at least 97%, at least 99%, or 100% identical). 97. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 96, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 85, and VL has a sequence that is at least 95% identical to SEQ ID NO: 93. 98. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 96, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 85, and VL has a sequence that is at least 97% identical to SEQ ID NO: 93. 99. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 96, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 85, and VL has a sequence that is at least 99% identical to SEQ ID NO: 93. 100. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 96, wherein VH has the same sequence as SEQ ID NO: 85 and VL has the same sequence as SEQ ID NO: 93. 101. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 102. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 101, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 85, and VL has a sequence that is at least 95% identical to SEQ ID NO: 98. 103. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 101, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 85, and VL has a sequence that is at least 97% identical to SEQ ID NO: 98. 104. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 101, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 85, and VL has a sequence that is at least 99% identical to SEQ ID NO: 98. 105. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 101, wherein VH has the same sequence as SEQ ID NO: 85 and VL has the same sequence as SEQ ID NO: 98. 106. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 107. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 106, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 86, and VL has a sequence that is at least 95% identical to SEQ ID NO: 92. 108. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 106, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 86, and VL has a sequence that is at least 97% identical to SEQ ID NO: 92. 109. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 106, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 86, and VL has a sequence that is at least 99% identical to SEQ ID NO: 92. 110. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 106, wherein VH has the same sequence as SEQ ID NO: 86 and VL has the same sequence as SEQ ID NO: 92. 111. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 112. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 111, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 86, and VL has a sequence that is at least 95% identical to SEQ ID NO: 83. 113. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 111, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 86, and VL has a sequence that is at least 97% identical to SEQ ID NO: 93. 114. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 111, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 86, and VL has a sequence that is at least 99% identical to SEQ ID NO: 93. 115. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 111, wherein VH has the same sequence as SEQ ID NO: 86 and VL has the same sequence as SEQ ID NO: 93. 116. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 117. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 116, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 86, and VL has a sequence that is at least 95% identical to SEQ ID NO: 98. 118. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 116, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 86, and VL has a sequence that is at least 97% identical to SEQ ID NO: 98. 119. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 116, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 86, and VL has a sequence that is at least 99% identical to SEQ ID NO: 98. 120. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 116, wherein VH has the same sequence as SEQ ID NO: 86 and VL has the same sequence as SEQ ID NO: 98. 121. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 122. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 121, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 87, and VL has a sequence that is at least 95% identical to SEQ ID NO: 92. 123. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 121, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 87, and VL has a sequence that is at least 97% identical to SEQ ID NO: 92. 124. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 121, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 87, and VL has a sequence that is at least 99% identical to SEQ ID NO: 92. 125. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 121, wherein VH has the same sequence as SEQ ID NO: 87 and VL has the same sequence as SEQ ID NO: 92. 126. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 127. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 126, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 87, and VL has a sequence that is at least 95% identical to SEQ ID NO: 93. 128. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 126, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 87, and VL has a sequence that is at least 97% identical to SEQ ID NO: 93. 129. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 126, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 87, and VL has a sequence that is at least 99% identical to SEQ ID NO: 93. 130. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 126, wherein VH has the same sequence as SEQ ID NO: 87 and VL has the same sequence as SEQ ID NO: 93. 131. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical). 132. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 131, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 87, and VL has a sequence that is at least 95% identical to SEQ ID NO: 98. 133. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 131, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 87, and VL has a sequence that is at least 97% identical to SEQ ID NO: 98. 134. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 131, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 87, and VL has a sequence that is at least 99% identical to SEQ ID NO: 98. 135. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 131, wherein VH has the same sequence as SEQ ID NO: 87 and VL has the same sequence as SEQ ID NO: 98. 136. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 75, wherein VH has a sequence that is at least 90% identical to SEQ ID NO: 100 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL has a sequence that is at least 90% identical to SEQ ID NO: 101 (for example, at least 95%, at least 97%, at least 99%, or 100% identical). 137. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 136, wherein VH has a sequence that is at least 95% identical to SEQ ID NO: 100, and VL has a sequence that is at least 95% identical to SEQ ID NO: 101. 138. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 136, wherein VH has a sequence that is at least 97% identical to SEQ ID NO: 100, and VL has a sequence that is at least 97% identical to SEQ ID NO: 101. 139. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 136, wherein VH has a sequence that is at least 99% identical to SEQ ID NO: 100, and VL has a sequence that is at least 99% identical to SEQ ID NO: 101. 140. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 136, wherein VH has the same sequence as SEQ ID NO: 100 and VL has the same sequence as SEQ ID NO: 101. 141. An anti-CD5 antibody or its antigen-binding fragment according to any one of Embodiments 1 to 140, wherein the antigen-binding fragment is Fab, Fab', F(ab')2, scFv, or Fv fragment. 142. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 141, wherein the antigen-binding fragment is Fab. 143. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 141, wherein the antigen-binding fragment is Fab'. 144. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 141, wherein the antigen-binding fragment is F(ab')2. 145. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 141, wherein the antigen-binding fragment is scFv. 146. The anti-CD5 antibody or its antigen-binding fragment according to Embodiment 141, wherein the antigen-binding fragment is an Fv fragment. 147. An anti-CD5 antibody or antigen-binding fragment thereof according to any one of Embodiments 1 to 146, comprising an antibody. 148. An anti-CD5 antibody or antigen-binding fragment according to any one of Embodiments 1 to 146, comprising an antigen-binding fragment. 149. An anti-CD5 antibody or antigen-binding fragment according to any one of Embodiments 1 to 148, comprising a first Fc region and a second Fc region forming an Fc domain, wherein the Fc domain is optionally a human Fc domain. 150. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 149, wherein the first Fc region and / or the second Fc region comprises one or more amino acid substitutions that reduce effector function. 151. The one or more substitutions are N297A, N297Q, N297G, D265A / N297A, D265A / N297G, L235E, L234A / L235A, L234A / L235A / P329A, L234D / L235E:L234R / L235R / E233K, L234D / L235E / D265S:E233K / L234R / L235R / D265S, L234D / L235E / E269K:E233K / L234R / L235R / E269K, L234D / L235E / K322A:E233K / L234 An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150, comprising R / L235R / K322A, L234D / L235E / P329W:E233K / L234R / L235R / P329W, L234D / L235E / E269K / D265S / K322A:E233K / L234R / L235R / E269K / D265S / K322A, or L234D / L235E / E269K / D265S / K322E / E333K:E233K / L234R / L235R / E269K / D265S / K322E / E333K. 152. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include N297A. 153. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include N297Q. 154. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include N297G. 155. An anti-CD5 antibody or antigen-binding fragment thereof according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include D265A / N297A. 156. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include D265A / N297G. 157. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L235E. 158. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234A / L235A. 159. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234A / L235A / P329A. 160. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E:L234R / L235R / E233K. 161. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E / D265S:E233K / L234R / L235R / D265S. 162. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E / E269K:E233K / L234R / L235R / E269K. 163. An anti-CD5 antibody or antigen-binding fragment thereof according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E / K322A:E233K / L234R / L235R / K322A. 164. An anti-CD5 antibody or antigen-binding fragment thereof according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E / P329W:E233K / L234R / L235R / P329W. 165. An anti-CD5 antibody or antigen-binding fragment thereof according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E / E269K / D265S / K322A:E233K / L234R / L235R / E269K / D265S / K322A. 166. An anti-CD5 antibody or antigen-binding fragment thereof according to Embodiment 150 or Embodiment 151, wherein one or more of the substitutions include L234D / L235E / E269K / D265S / K322E / E333K. 167. An anti-CD5 antibody or antigen-binding fragment according to any one of embodiments 150 to 166, wherein the first Fc region and / or the second Fc region include L234A and L235A substitutions. 168. An anti-CD5 antibody or antigen-binding fragment according to any one of embodiments 150 to 167, wherein the first Fc region and / or the second Fc region comprises an N297A substitution. 169. An anti-CD5 antibody or antigen-binding fragment according to any one of embodiments 149 to 168, wherein the Fc domain comprises a human IgG1 Fc domain or a variant thereof. 170. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 169, wherein the first Fc region and / or the second Fc region comprises an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53. 171. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 170, wherein the first Fc region and / or the second Fc region comprises an amino acid sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) that of SEQ ID NO: 51. 172. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 170, wherein the first Fc region and / or the second Fc region comprises an amino acid sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) that of SEQ ID NO: 52. 173. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 170, wherein the first Fc region and / or the second Fc region comprises an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO: 53. 174. An anti-CD5 antibody or antigen-binding fragment according to any one of Embodiments 149 to 168, wherein the Fc domain comprises a human IgG2 Fc domain or a variant thereof. 175. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 174, wherein the first Fc region and / or the second Fc region comprises an amino acid sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) that of SEQ ID NO: 81. 176. An anti-CD5 antibody or antigen-binding fragment according to any one of Embodiments 149 to 168, wherein the Fc domain comprises a human IgG4 Fc domain or a variant thereof. 177. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 176, wherein the first Fc region and / or the second Fc region comprises an amino acid sequence that is at least 90% identical to (e.g., at least 95%, at least 97%, at least 99%, or 100%) that of SEQ ID NO: 54. 178. An anti-CD5 antibody or antigen-binding fragment according to any one of embodiments 149 to 177, wherein the Fc domain includes a hinge region. 179. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 178, wherein the hinge region comprises one or more amino acid substitutions that reduce half-antibody exchange. 180. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 179, wherein the Fc domain is an IgG4 Fc domain or a variant thereof, and the hinge region includes an S228P substitution. 181. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 178, wherein the hinge region includes an IgG1 hinge region. 182. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 181, wherein the hinge region comprises the amino acid sequence of SEQ ID NO: 66. 183. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 178, wherein the hinge region includes an IgG2 hinge region. 184. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 183, wherein the hinge region comprises the amino acid sequence of SEQ ID NO: 83. 185. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 178, wherein the hinge region includes an IgG4 hinge region. 186. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 185, wherein the hinge region comprises the amino acid sequence of SEQ ID NO: 67. 187. The anti-CD5 antibody or antigen-binding fragment according to Embodiment 185, wherein the hinge region comprises the amino acid sequence of SEQ ID NO: 68. 188. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 69 and a heavy chain having the amino acid sequence of SEQ ID NO: 70. 189. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 71 and a heavy chain having the amino acid sequence of SEQ ID NO: 72. 190. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 73 and a heavy chain having the amino acid sequence of SEQ ID NO: 74. 191. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 75 and a heavy chain having the amino acid sequence of SEQ ID NO: 76. 192. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 77 and a heavy chain having the amino acid sequence of SEQ ID NO: 78. 193. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 79 and a heavy chain having the amino acid sequence of SEQ ID NO: 80. 194. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49, comprising a light chain having the amino acid sequence of SEQ ID NO: 55 and a heavy chain having the amino acid sequence of SEQ ID NO: 56. 195. An anti-CD5 antibody or its antigen-binding fragment according to Embodiment 49, comprising a light chain having the amino acid sequence of SEQ ID NO: 55 and a heavy chain having the amino acid sequence of SEQ ID NO: 57. 196. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49, comprising a light chain having the amino acid sequence of SEQ ID NO: 55 and a heavy chain having the amino acid sequence of SEQ ID NO: 58. 197. An anti-CD5 antibody or antigen-binding fragment according to Embodiment 49, comprising a light chain having the amino acid sequence of SEQ ID NO: 55 and a heavy chain having the amino acid sequence of SEQ ID NO: 59. 198. A nucleic acid comprising the coding region of any one anti-CD5 antibody or its antigen-binding fragment, as described in Embodiments 1 to 197. 199. The nucleic acid according to Embodiment 198, which is codon-optimized for expression in mammalian cells, wherein the mammalian cells are, optionally, human cells. 200. A vector comprising the nucleic acid described in Embodiment 198 or Embodiment 199, which is optionally a plasmid. 201. Cells manipulated to express the nucleic acid described in any one of Embodiments 198 to 199, or containing the vector described in Embodiment 200. 202. A method for producing an anti-CD5 antibody or an antigen-binding fragment thereof, comprising culturing the cells described in Embodiment 201 under conditions in which the anti-CD5 antibody or its antigen-binding fragment is expressed, and recovering the anti-CD5 antibody or its antigen-binding fragment from the cell culture. 203. An antibody-ALK5 inhibitor conjugate comprising an anti-CD5 antibody or its antigen-binding fragment as described in any one of Embodiments 1 to 197, conjugated to an ALK5 inhibitor. 204. The ALK5 inhibitor is IC 50 The antibody-ALK5 inhibitor conjugate according to Embodiment 203, wherein the concentration is 20 nM or less. 205. The antibody-ALK5 inhibitor conjugate according to Embodiment 203 or Embodiment 204, wherein the ALK5 inhibitor is an imidazole-type compound, a pyrazole-type compound, or a thiazole-type compound. 206. The antibody-ALK5 inhibitor conjugate according to Embodiment 205, wherein the ALK5 inhibitor is an imidazole-type compound. 207. The antibody-ALK5 inhibitor conjugate according to Embodiment 205, wherein the ALK5 inhibitor is a pyrazole compound. 208. The antibody-ALK5 inhibitor conjugate according to Embodiment 205, wherein the ALK5 inhibitor is a thiazole compound. 209. The antibody-ALK5 inhibitor conjugate according to Embodiment 205, wherein the ALK5 inhibitor is an imidazole-type compound that is an imidazole-benzodioxole compound or an imidazole-quinoxaline compound. 210. The antibody-ALK5 inhibitor conjugate according to Embodiment 209, wherein the ALK5 inhibitor is an imidazole-benzodioxole compound. 211. The antibody-ALK5 inhibitor conjugate according to Embodiment 209, wherein the ALK5 inhibitor is an imidazole-quinoxaline compound. 212. The antibody-ALK5 inhibitor conjugate according to Embodiment 205, wherein the ALK5 inhibitor is a pyrazole-pyrrolo compound. 213. The antibody-ALK5 inhibitor conjugate according to Embodiment 205, wherein the ALK5 inhibitor is an imidazole-benzodioxole compound, an imidazole-quinoxaline compound, a pyrazole-pyrrolo compound, or a thiazole-type compound. 214. The antibody-ALK5 inhibitor conjugate according to Embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Section 6.3. 215. The antibody-ALK5 inhibitor conjugate according to Embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 2. 216. The antibody-ALK5 inhibitor conjugate according to Embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 3A. 217. The antibody-ALK5 inhibitor conjugate according to Embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 3B. 218. The antibody-ALK5 inhibitor conjugate according to Embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 4. 219. The ALK5 inhibitor has a structure [ka] The antibody-ALK5 inhibitor conjugate according to Embodiment 203, having the following characteristics. 220. The ALK5 inhibitor has a structure [ka] The antibody-ALK5 inhibitor conjugate according to Embodiment 203, having the following characteristics. 221. The ALK5 inhibitor has a structure [ka] The antibody-ALK5 inhibitor conjugate according to Embodiment 203, having the following characteristics. 222. The ALK5 inhibitor has a structure [ka] The antibody-ALK5 inhibitor conjugate according to Embodiment 203, having the following characteristics. 223. The antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 222, wherein the ALK5 inhibitor is linked to the antibody or antigen-binding fragment via a linker. 224. The antibody-ALK5 inhibitor conjugate according to Embodiment 223, wherein the linker is a PEG-containing linker. 225. The antibody-ALK5 inhibitor conjugate according to Embodiment 223 or Embodiment 224, wherein the linker is a polyvalent linker. 226. The antibody-ALK5 inhibitor conjugate according to any one of embodiments 223 to 225, wherein the linker is a linker that cannot be cleaved. 227. The antibody-ALK5 inhibitor conjugate according to Embodiment 226, wherein the non-cleavable linker is an N-maleimidomethylcyclohexane 1-carboxylate linker, a maleimidocaproyl linker, or a mercaptoacetamidecaproyl linker. 228. The antibody-ALK5 inhibitor conjugate according to Embodiment 227, wherein the non-cleavable linker is an N-maleimidomethylcyclohexane 1-carboxylate linker. 229. The antibody-ALK5 inhibitor conjugate according to Embodiment 227, wherein the non-cleavable linker is a maleimidocaproyl linker. 230. The antibody-ALK5 inhibitor conjugate according to Embodiment 227, wherein the non-cleavable linker is a mercaptoacetamide caproyl linker. 231. The antibody-ALK5 inhibitor conjugate according to any one of embodiments 223 to 225, wherein the linker is a cleavable linker. 232. The antibody-ALK5 inhibitor conjugate according to Embodiment 231, wherein the cleavable linker is a dipeptide linker, a disulfide linker, or a hydrazone linker. 233. The antibody-ALK5 inhibitor conjugate according to Embodiment 232, wherein the cleavable linker is a dipeptide linker. 234. The antibody-ALK5 inhibitor conjugate according to Embodiment 232, wherein the cleavable linker is a disulfide linker. 235. The antibody-ALK5 inhibitor conjugate according to Embodiment 232, wherein the cleavable linker is a hydrazone linker. 236. The antibody-ALK5 inhibitor conjugate of Embodiment 232, wherein the linker is a protease-sensitive linker, for example, a valine-citrulline dipeptide linker. 237. The antibody-ALK5 inhibitor conjugate according to Embodiment 232, wherein the linker is a glutathione-sensitive disulfide linker. 238. The antibody-ALK5 inhibitor conjugate according to Embodiment 232, wherein the linker is an acid-sensitive disulfide linker. 239. The antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 238, wherein the ALK5 inhibitor conjugates to the antigen or antigen-binding fragment via site-specific conjugation. 240. The antibody-ALK5 inhibitor conjugate according to Embodiment 239, wherein the ALK5 inhibitor is conjugated via one or more cysteine ​​residues, lysine residues, or glutamine residues on the antibody or antigen-binding fragment. 241. The antibody-ALK5 inhibitor conjugate according to Embodiment 240, wherein the ALK5 inhibitor is conjugated via one or more cysteine ​​residues on the antibody or antigen-binding fragment. 242. The antibody-ALK5 inhibitor conjugate according to Embodiment 240, wherein the ALK5 inhibitor is conjugated via one or more lysine residues on the antibody or antigen-binding fragment. 243. The antibody-ALK5 inhibitor conjugate according to Embodiment 240, wherein the ALK5 inhibitor is conjugated via one or more glutamine residues on the antibody or antigen-binding fragment. 244. The antibody-ALK5 inhibitor conjugate according to Embodiment 239, wherein the ALK5 inhibitor is conjugated via one or more non-natural amino acid residues on the antibody or antigen-binding fragment. 245. The antibody-ALK5 inhibitor conjugate according to Embodiment 244, wherein one or more non-natural amino acid residues include p-acetylphenylalanine (pAcF). 246. The antibody-ALK5 inhibitor conjugate according to Embodiment 244, wherein one or more non-natural amino acid residues include p-azidomethyl-L-phenylalanine (pAMF). 247. The antibody-ALK5 inhibitor conjugate according to Embodiment 244, wherein one or more non-natural amino acid residues contain selenocysteine ​​(Sec). 248. The antibody-ALK5 inhibitor conjugate according to Embodiment 239, wherein the ALK5 inhibitor is conjugated via one or more glycans on the antibody or antigen-binding fragment. 249. The antibody-ALK5 inhibitor conjugate according to Embodiment 248, wherein one or more glycans contain fucose. 250. The antibody-ALK5 inhibitor conjugate according to Embodiment 248, wherein one or more glycans include 6-thiophtholose. 251. The antibody-ALK5 inhibitor conjugate according to Embodiment 248, wherein one or more glycans contain galactose. 252. The antibody-ALK5 inhibitor conjugate according to Embodiment 248, wherein one or more glycans contain N-acetylgalactosamine (GalNAc). 253. The antibody-ALK5 inhibitor conjugate according to Embodiment 248, wherein one or more glycans contain N-acetylglucosamine (GlcNAc). 254. The antibody-ALK5 inhibitor conjugate according to Embodiment 248, wherein one or more glycans contain sialic acid (SA). 255. An antibody-ALK5 inhibitor conjugate according to any one of Embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 1 to 30. 256. An antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 1 to 20. 257. An antibody-ALK5 inhibitor conjugate according to any one of Embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 1 to 15. 258. An antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 2 to 12. 259. An antibody-ALK5 inhibitor conjugate according to any one of Embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 4 to 15. 260. An antibody-ALK5 inhibitor conjugate according to any one of Embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 6 to 12. 261. An antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 254, wherein the average number of ALK5 inhibitor molecules per antibody or antigen-binding fragment molecule is in the range of 2 to 8. 262. An antibody-ALK5 inhibitor conjugate comprising an anti-CD5 antibody or its antigen-binding fragment as described in any one of Embodiments 1 to 197, conjugated to means for inhibiting ALK5, wherein the conjugate optionally further comprises means for linking the anti-CD5 antibody or its antigen-binding fragment to means for inhibiting ALK5. 263. A pharmaceutical composition comprising an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 262 and a pharmaceutically acceptable carrier. 264. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a drug-antibody ratio (DAR) of 1 to 30. 265. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 20. 266. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 15. 267. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 12. 268. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 4 to 15. 269. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 6 to 12. 270. The pharmaceutical composition according to Embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 8. 271. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 30. 272. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 20. 273. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 15. 274. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 12. 275. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 4 to 15. 276. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 6 to 12. 277. The pharmaceutical composition according to Embodiment 263, wherein at least 40% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 8. 278. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 30. 279. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 20. 280. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 15. 281. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 12. 282. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 4 to 15. 283. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 6 to 12. 284. The pharmaceutical composition according to Embodiment 263, wherein at least 50% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 8. 285. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 30. 286. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 20. 287. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 1 to 15. 288. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 12. 289. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 4 to 15. 290. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 6 to 12. 291. The pharmaceutical composition according to Embodiment 263, wherein at least 60% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR of 2 to 8. 292. A method for treating cancer, comprising administering to a subject in need thereof an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 262 or a pharmaceutical composition according to any one of embodiments 263 to 291. 293. The method according to Embodiment 292, wherein the cancer is an immunogenic cancer. 294. The method according to Embodiment 293, wherein the cancer is a solid tumor expressing a tumor antigen. 295. The method according to Embodiment 294, wherein the tumor antigen is gp100, melanA, or MAGE A1. 296. The method according to Embodiment 295, wherein the tumor antigen is gp100. 297. The method according to Embodiment 295, wherein the tumor antigen is melanA. 298. The method according to Embodiment 295, wherein the tumor antigen is MAGE A1. 299. The method according to Embodiment 292, wherein the cancer is a solid tumor containing immune infiltrates. 300. The method according to any one of embodiments 292 to 299, wherein the cancer is treatable by immunotherapy. 301. The method according to Embodiment 300, wherein the immunotherapy is cytokine therapy, adoptive T-cell therapy, chimeric antigen receptor (CAR) therapy, checkpoint modulator (e.g., checkpoint inhibitor) therapy, oncolytic virus therapy, dendritic cell vaccine therapy, STING agonist therapy, TLR agonist therapy, or intratumor CpG therapy. 302. The method according to Embodiment 300, wherein the immunotherapy is cytokine therapy, adoptive T-cell therapy, chimeric antigen receptor (CAR) therapy, or checkpoint modulator (e.g., checkpoint inhibitor) therapy. 303. The method according to Embodiment 302, wherein the immunotherapy is cytokine therapy. 304. The method according to Embodiment 303, wherein the cytokine therapy is IL2 therapy. 305. The method according to Embodiment 303, wherein the cytokine therapy is IL12 therapy. 306. The method according to Embodiment 303, wherein the cytokine therapy is IFN-α therapy. 307. The method according to Embodiment 303, wherein the cytokine therapy is IFN-γ therapy. 308. The method according to Embodiment 302, wherein the immunotherapy is adoptive T-cell therapy. 309. The method according to Embodiment 308, wherein the adoptive T-cell therapy is autologous T-cell therapy. 310. The method according to Embodiment 302, wherein the immunotherapy is chimeric antigen receptor (CAR) therapy. 311. The method according to Embodiment 302, wherein the immunotherapy is a checkpoint modulator (e.g., checkpoint inhibitor) therapy. 312. The method according to Embodiment 311, wherein the checkpoint modifier is an antibody. 313. The method according to Embodiment 302, Embodiment 311, or Embodiment 312, wherein the checkpoint modifier is an inhibitor of PD1, PDL1, or CTLA4. 314. The method according to Embodiment 313, wherein the checkpoint modifier is a PD1 inhibitor. 315. The method according to Embodiment 314, wherein the inhibitor of PD1 is an antibody. 316. The method according to Embodiment 315, wherein the PD1 inhibitor is pembrolizumab, nivolumab, semiprimab, or dostallimab. 317. The method according to Embodiment 316, wherein the PD1 inhibitor is pembrolizumab. 318. The method according to Embodiment 316, wherein the PD1 inhibitor is nivolumab. 319. The method according to Embodiment 316, wherein the PD1 inhibitor is semiprimab. 320. The method according to Embodiment 316, wherein the PD1 inhibitor is dostallimab. 321. The method according to Embodiment 313, wherein the checkpoint modifier is a PDL1 inhibitor. 322. The method according to Embodiment 321, wherein the inhibitor of PDL1 is an antibody. 323. The method according to Embodiment 322, wherein the inhibitor of PDL1 is atezolizumab, avelumab, or durvalumab. 324. The method according to Embodiment 323, wherein the inhibitor of PDL1 is atezolizumab. 325. The method according to Embodiment 323, wherein the inhibitor of PDL1 is avelumab. 326. The method according to Embodiment 323, wherein the inhibitor of PDL1 is durvalumab. 327. The method according to Embodiment 313, wherein the checkpoint modifier is a CTLA4 inhibitor. 328. The method according to Embodiment 327, wherein the inhibitor of CTLA4 is an antibody. 329. The method according to Embodiment 328, wherein the inhibitor of CTLA4 is ipilimumab. 330. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets TIGIT. 331. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets LAG3. 332. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets OX40. 333. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets ICOS. 334. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets GITR. 335. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets CD40. 336. The method according to Embodiment 311 or 312, wherein the checkpoint modifier targets VISTA. 337. The method according to any one of Embodiments 292 to 336, wherein the cancer is lung cancer, liver cancer, urothelial carcinoma, kidney cancer, breast cancer, melanoma, pancreatic cancer, glioblastoma, myelodysplastic syndrome, prostate cancer, or colorectal cancer. 338. The method according to any one of embodiments 292 to 336, wherein the cancer is head and neck cancer. 339. The method according to Embodiment 338, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). 340. The method according to any one of embodiments 292 to 336, wherein the cancer is ovarian cancer. 341. The method according to Embodiment 337, wherein the cancer is non-small cell lung cancer (NSCLC), liver cancer, urothelial carcinoma, kidney cancer, breast cancer, or melanoma. 342. The method according to Embodiment 337, wherein the cancer is lung cancer. 343. The method according to Embodiment 342, wherein the cancer is NSCLC. 344. The method according to embodiment 343, wherein the NSCLC is an adenocarcinoma. 345. The method according to embodiment 343, wherein the NSCLC is squamous cell carcinoma. 346. The method according to Embodiment 343, wherein the NSCLC is a large cell carcinoma. 347. The method according to Embodiment 342, wherein the cancer is small cell lung cancer. 348. The method according to embodiment 337, wherein the cancer is liver cancer. 349. The method according to Embodiment 348, wherein the liver cancer is hepatocellular carcinoma. 350. The method according to Embodiment 337, wherein the cancer is urothelial carcinoma. 351. The method according to Embodiment 350, wherein the cancer is bladder cancer. 352. The method according to Embodiment 350, wherein the cancer is urethral cancer. 353. The method according to Embodiment 350, wherein the cancer is ureteral cancer. 354. The method according to Embodiment 337, wherein the cancer is kidney cancer. 355. The method according to Embodiment 354, wherein the kidney cancer is renal cell carcinoma. 356. The method according to embodiment 354, wherein the kidney cancer is urothelial carcinoma. 357. The method according to embodiment 337, wherein the cancer is breast cancer. 358. The method according to Embodiment 337, wherein the cancer is melanoma. 359. The method according to Embodiment 337, wherein the cancer is pancreatic cancer. 360. The method according to Embodiment 337, wherein the cancer is glioblastoma. 361. The method according to embodiment 337, wherein the cancer is myelodysplastic syndrome. 362. The method according to embodiment 337, wherein the cancer is prostate cancer. 363. The method according to Embodiment 337, wherein the cancer is colorectal cancer. 364. The method according to embodiment 363, wherein the colorectal cancer is an adenocarcinoma. 365. The method according to embodiment 363, wherein the colorectal cancer is a carcinoid tumor. 366. The method according to embodiment 363, wherein the colorectal cancer is a gastrointestinal stromal tumor. 367. The method according to embodiment 363, wherein the colorectal cancer is colorectal lymphoma. 368. The method according to any one of embodiments 292 to 367, wherein the cancer is treatable with an ALK5 inhibitor. 369. The method according to any one of embodiments 292 to 368, wherein the cancer is treatable by chemotherapy. 370. The method according to any one of Embodiments 292 to 369, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered as monotherapy. 371. The method according to any one of Embodiments 292 to 369, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered as part of a combination therapy regimen comprising, optionally, the administration of one or more agents (each a "second therapeutic agent") that are not antibody-ALK5 inhibitor conjugates according to any one of Embodiments 203 to 261. 372. The method according to Embodiment 371, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered in combination with a standard treatment or therapeutic regimen. 373. The method according to Embodiment 371 or 372, wherein the combination therapy comprises administering at least one second therapeutic agent to the subject. 374. The method according to any one of Embodiments 371 to 373, wherein the combination therapy regimen comprises immunotherapy, optionally wherein the immunotherapy is checkpoint modulator (e.g., checkpoint inhibitor) therapy, chimeric antigen receptor (CAR) therapy, adoptive T-cell therapy, oncolytic virus therapy, dendritic cell vaccine therapy, STING agonist therapy, TLR agonist therapy, intratumor CpG therapy, or cytokine therapy. 375. The method according to any one of Embodiments 371 to 374, wherein the combination therapy includes checkpoint modulator (e.g., checkpoint inhibitor) therapy. 376. The method according to Embodiment 375, wherein the checkpoint modulator therapy includes T cell checkpoint modulator (e.g., checkpoint inhibitor) therapy. 377. The method according to Embodiment 376, wherein the T-cell checkpoint modulator therapy comprises an antibody or an antigen-binding fragment thereof. 378. The method according to any one of embodiments 375 to 377, wherein the checkpoint modulator therapy targets PD1, PDL1, CTLA4, TIGIT, LAG3, OX40, ICOS, GITR, CD40, VISTA, or a combination thereof. 379. The method according to Embodiment 378, wherein the checkpoint modulator therapy targets PD1. 380. The method according to any one of embodiments 371 to 379, wherein the second therapeutic agent includes means for targeting PD1. 381. The method according to any one of embodiments 371 to 379, wherein the second therapeutic agent is pembrolizumab. 382. The method according to any one of embodiments 371 to 379, wherein the second therapeutic agent is nivolumab. 383. The method according to any one of embodiments 371 to 379, wherein the second therapeutic agent is semiprimab. 384. The method according to any one of embodiments 371 to 379, wherein the second therapeutic agent is dostallimab. 385. The method according to any one of embodiments 378 to 384, wherein the checkpoint modulating agent therapy targets PDL1. 386. The method according to any one of embodiments 371 to 385, wherein the second therapeutic agent includes means for targeting PDL1. 387. The method according to any one of embodiments 371 to 385, wherein the second therapeutic agent is atezolizumab. 388. The method according to any one of embodiments 371 to 385, wherein the second therapeutic agent is avelumab. 389. The method according to any one of embodiments 371 to 385, wherein the second therapeutic agent is durvalumab. 390. The method according to any one of embodiments 378 to 389, wherein the checkpoint modulating agent therapy targets CTLA4. 391. The method according to any one of embodiments 371 to 390, wherein the second therapeutic agent includes means for targeting CTLA4. 392. The method according to any one of embodiments 371 to 390, wherein the second therapeutic agent is ipilimumab. 393. The method according to any one of embodiments 378 to 391, wherein the checkpoint modulator therapy targets TIGIT. 394. The method according to any one of embodiments 371 to 393, wherein the second therapeutic agent includes means for targeting TIGIT. 395. The method according to any one of embodiments 371 to 393, wherein the second therapeutic agent is etigirimab. 396. The method according to any one of embodiments 371 to 393, wherein the second therapeutic agent is tiragolumab. 397. The method according to any one of embodiments 371 to 393, wherein the second therapeutic agent is AB154. 398. The method according to any one of embodiments 378 to 397, wherein the checkpoint modulator therapy targets LAG3. 399. The method according to any one of embodiments 371 to 398, wherein the second therapeutic agent includes means for targeting LAG3. 400. The method according to any one of embodiments 371 to 398, wherein the second therapeutic agent is LAG525. 401. The method according to any one of embodiments 371 to 398, wherein the second therapeutic agent is Sym022. 402. The method according to any one of embodiments 371 to 398, wherein the second therapeutic agent is relatrimab. 403. The method according to any one of embodiments 371 to 398, wherein the second therapeutic agent is TSR-033. 404. The method according to any one of embodiments 378 to 403, wherein the checkpoint modulating agent therapy targets OX40. 405. The method according to any one of embodiments 371 to 404, wherein the second therapeutic agent is a means for targeting OX40. 406. The method according to any one of embodiments 371 to 404, wherein the second therapeutic agent is MEDI6469. 407. The method according to any one of embodiments 371 to 404, wherein the second therapeutic agent is PF-04518600. 408. The method according to any one of embodiments 371 to 404, wherein the second therapeutic agent is BMS 986178. 409. The method according to any one of embodiments 378 to 408, wherein the checkpoint modulator therapy targets CD40. 410. The method according to any one of embodiments 371 to 409, wherein the second therapeutic agent includes means for targeting CD40. 411. The method according to any one of embodiments 371 to 409, wherein the second therapeutic agent is sericrelmab. 412. The method according to any one of embodiments 371 to 409, wherein the second therapeutic agent is CP-870,893. 413. The method according to any one of embodiments 371 to 409, wherein the second therapeutic agent is APX005M. 414. The method according to any one of embodiments 378 to 413, wherein the checkpoint modulator therapy targets ICOS. 415. The method according to any one of embodiments 371 to 414, wherein the second therapeutic agent includes means for targeting ICOS. 416. The method according to any one of embodiments 371 to 414, wherein the second therapeutic agent is MEDI-570. 417. The method according to any one of embodiments 371 to 414, wherein the second therapeutic agent is ferazirimab. 418. The method according to any one of embodiments 371 to 414, wherein the second therapeutic agent is BMS 986226. 419. The method according to any one of embodiments 378 to 418, wherein the checkpoint modulator therapy targets GITR. 420. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent includes means for targeting GITR. 421. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent is TRX-518. 422. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent is AMG 228. 423. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent is MK-4166. 424. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent is MEDI1873. 425. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent is INCAGN01876. 426. The method according to any one of embodiments 371 to 419, wherein the second therapeutic agent is GWN323. 427. The method according to any one of embodiments 378 to 426, wherein the checkpoint modulating agent therapy targets VISTA. 428. The method according to any one of embodiments 371 to 427, wherein the second therapeutic agent includes means for targeting VISTA. 429. The method according to any one of embodiments 371 to 427, wherein the second therapeutic agent is HMBD-002. 430. The method according to any one of embodiments 371 to 428, wherein the second therapeutic agent is a chimeric antigen receptor (CAR). 431. The method according to any one of Embodiments 371 to 430, wherein the combination therapy includes adoptive T-cell therapy. 432. The method according to Embodiment 431, wherein the adoptive T-cell therapy is autologous T-cell therapy. 433. The method according to any one of Embodiments 371 to 432, wherein the combination therapy includes oncolytic virus therapy. 434. The method according to any one of Embodiments 371 to 433, wherein the combination therapy includes dendritic cell vaccine therapy. 435. The method according to any one of Embodiments 371 to 434, wherein the combination therapy includes STING agonist therapy. 436. The method according to any one of embodiments 371 to 435, wherein the combination therapy includes TLR agonist therapy. 437. The method according to any one of embodiments 371 to 436, wherein the combination therapy includes chemotherapy. 438. The method according to Embodiment 437, wherein the second therapeutic agent is an antimetabolite, an alkylating agent, anthracycline, a microtubule inhibitor, a platinum compound, a taxane, a topoisomerase inhibitor, or a vinca alkaloid. 439. The method according to Embodiment 438, wherein the second therapeutic agent is an antimetabolite. 440. The method according to Embodiment 439, wherein the antimetabolite is 5-fluorouracil. 441. The method according to Embodiment 439, wherein the antimetabolite is gemcitabine. 442. The method according to Embodiment 439, wherein the antimetabolite is methotrexate. 443. The method according to Embodiment 438, wherein the second therapeutic agent is an alkylating agent. 444. The method according to Embodiment 443, wherein the alkylating agent is cyclophosphamide. 445. The method according to Embodiment 443, wherein the alkylating agent is dacarbazine. 446. The method according to Embodiment 443, wherein the alkylating agent is mechloretamine. 447. The method according to Embodiment 443, wherein the alkylating agent is diaziquan. 448. The method according to Embodiment 443, wherein the alkylating agent is temozolomide. 449. The method according to Embodiment 438, wherein the second therapeutic agent is an anthracycline. 450. The method according to Embodiment 449, wherein the anthracycline is doxorubicin. 451. The method according to Embodiment 449, wherein the anthracycline is epirubicin. 452. The method according to Embodiment 438, wherein the second therapeutic agent is a microtubule inhibitor. 453. The method according to Embodiment 452, wherein the microtubule inhibitor is vinblastine. 454. The method according to Embodiment 438, wherein the second therapeutic agent is a platinum compound. 455. The method according to Embodiment 454, wherein the platinum compound is cisplatin. 456. The method according to Embodiment 454, wherein the platinum compound is oxaliplatin. 457. The method according to Embodiment 438, wherein the second therapeutic agent is a taxane. 458. The method according to Embodiment 457, wherein the taxane is paclitaxel. 459. The method according to Embodiment 457, wherein the taxane is docetaxel. 460. The method according to Embodiment 438, wherein the second therapeutic agent is a topoisomerase inhibitor. 461. The method according to Embodiment 460, wherein the topoisomerase inhibitor is etoposide. 462. The method according to Embodiment 460, wherein the topoisomerase inhibitor is mitoxantrone. 463. The method according to Embodiment 438, wherein the second therapeutic agent is a vinca alkaloid. 464. The method according to embodiment 463, wherein the vinca alkaloid is vincristine. 465. The method according to any one of embodiments 371 to 464, wherein the combination therapy includes intratumor CpG therapy. 466. The method according to any one of embodiments 371 to 465, wherein the second therapeutic agent is a cytokine. 467. The method according to Embodiment 466, wherein the cytokine is IL2. 468. The method according to embodiment 466, wherein the cytokine is IL12. 469. The method according to Embodiment 466, wherein the cytokine is IFN-α. 470. The method according to Embodiment 466, wherein the cytokine is IFN-γ. 471. The method according to any one of embodiments 371 to 470, comprising treating the subject with the combination therapy. 472. The method according to any one of embodiments 371 to 471, comprising administering the second therapeutic agent(s) to the subject. 473. A method for treating a subject having a disease or disorder associated with elevated CD5 expression, comprising administering to the subject an anti-CD5 antibody or antigen-binding fragment described in any one of Embodiments 1 to 197, wherein the disease or disorder is optionally a B-cell or T-cell malignancy, an autoimmune disease, a transplant disease, or a graft rejection. 474. A process for producing an antibody-ALK5 inhibitor conjugate, comprising conjugating an antibody or antigen-binding fragment described in any one of Embodiments 1 to 197 to an ALK5 inhibitor, wherein the antibody or antigen-binding fragment is conjugated to the ALK5 inhibitor via a linker. 475. The process according to Embodiment 474, wherein the ALK5 inhibitor is the ALK5 inhibitor described in any one of Embodiments 203 to 261. 476. The process according to Embodiment 474 or Embodiment 475, wherein the linker is the linker described in any one of Embodiments 223 to 238. 477. The process according to any one of embodiments 474 to 476, wherein the antibody or its antigen-binding fragment is conjugated to the ALK5 inhibitor via a linker, and the process further comprises the step of causing the ALK5 inhibitor to be conjugated to the linker. 478. A kit comprising an antibody or antigen-binding fragment described in any one of Embodiments 1 to 197, and an ALK5 inhibitor. 479. The kit according to Embodiment 478, wherein the ALK5 inhibitor is the ALK5 inhibitor described in any one of Embodiments 203 to 261. 480. The kit according to embodiment 478 or embodiment 479, further comprising a linker. 481. The kit according to Embodiment 478 or Embodiment 479, wherein the ALK5 inhibitor is conjugated to the linker. 482. The kit according to Embodiment 480 or Embodiment 481, wherein the linker is the linker described in any one of Embodiments 223 to 238. 483. A method for delivering an ALK5 inhibitor to T cells, comprising administering an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 262 to a subject, for example, a subject according to any one of embodiments 292 to 472. 484. A method for inducing an immune response in a subject, comprising administering an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 262 to the subject, for example, a subject according to any one of embodiments 292 to 472. 485. A method for stimulating T cells in a subject, comprising administering an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 262 to the subject, for example, a subject according to any one of embodiments 292 to 472.

[0250] While various specific embodiments have been illustrated and described, it will be understood that various modifications can be made without departing from the spirit and scope of this disclosure.

[0251] 9. Citation of References All publications, patents, patent applications, and other documents referenced herein are incorporated herein by reference in whole for all purposes to the same extent as if each individual publication, patent, patent application, or other document were individually indicated as being incorporated herein by reference for all purposes. In the event of any conflict between one or more teachings of the references incorporated herein and the present disclosure, the teachings herein shall prevail.

Claims

1. An anti-CD5 antibody or its antigen-binding fragment, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 1, 6, and 13, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 17, ATS, and 20, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 11, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 3, 8, and 15, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 18, 19, and 21, respectively. (d) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 4, 8, and 15, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 17, ATS, and 20, respectively. (e) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 11, and 13 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 17, 19, and 21 respectively. (f) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 7, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (g) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 7, and 13 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (h) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 1, 6, and 16, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 17, ATS, and 20, respectively. (i) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 9, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively, (j) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 9, and 16 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (k) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 10, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (l) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 10, and 13 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (m) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 12, and 14 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively, or (n) An anti-CD5 antibody or its antigen-binding fragment, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 12, and 13, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively.

2. An anti-CD5 antibody or its antigen-binding fragment, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 2, 7, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 18, 19, and 21 respectively, (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 7, and 13, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 1, 6, and 13, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 17, ATS, and 20, respectively. (d) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 9, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (e) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 9, and 16, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (f) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 10, and 14 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (g) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 10, and 13 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively. (h) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 12, and 14 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21 respectively, or (i) an anti-CD5 antibody or antigen-binding fragment according to claim 1, optionally comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 12, and 13, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively.

3. The anti-CD5 antibody or antigen-binding fragment according to claim 1 or 2, wherein the anti-CD5 antibody or antigen-binding fragment thereof is a humanized anti-CD5 antibody or an antigen-binding fragment thereof.

4. An anti-CD5 antibody or its antigen-binding fragment, (a) VH having a sequence that is at least 90% identical to sequence number 22 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 23 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), (b) VH having a sequence that is at least 90% identical to sequence number 24 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 25 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (c) VH having a sequence that is at least 90% identical to sequence number 26 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 27 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), (d) VH having a sequence that is at least 90% identical to sequence number 28 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 29 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (e) VH having a sequence that is at least 90% identical to sequence number 30 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 31 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (f) an anti-CD5 antibody or antigen-binding fragment according to any one of claims 1 to 3, comprising VH having a sequence that is at least 90% identical to SEQ ID NO: 32 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) and VL having a sequence that is at least 90% identical to SEQ ID NO: 33 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical).

5. An anti-CD5 antibody or its antigen-binding fragment, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 34, 39, and 43, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 45, RAN, and 48, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 35, 40, and 44 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48 respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 36, 41, and 44, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 18, 19, and 21, respectively. (d) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of NYG, SEQ ID NO: 41, and SEQ ID NO: 44, respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 45, RAN, and SEQ ID NO: 48, respectively, or (e) An anti-CD5 antibody or its antigen-binding fragment, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 38, 42, and 43, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48, respectively.

6. The anti-CD5 antibody or antigen-binding fragment according to claim 5, which is a humanized anti-CD5 antibody or an antigen-binding fragment thereof.

7. An anti-CD5 antibody or antigen-binding fragment thereof, optionally comprising VH having a sequence that is at least 90% identical to SEQ ID NO: 49 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to SEQ ID NO: 50 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), wherein the antibody or antigen-binding fragment is optionally the one described in claim 5 or 6.

8. An anti-CD5 antibody or its antigen-binding fragment, (a) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 1, 88, and 89, respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 94, WT, and 95, respectively. (b) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 90, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95 respectively. (c) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 90, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95 respectively. (d) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs: 3, 8, and 91 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs: 96, 97, and 95 respectively, (e) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95 respectively. (f) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 4, 8, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, WT, and 95 respectively. (g) VH containing CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 90, and 89 respectively, and VL containing CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 96, 97, and 95 respectively. (h) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 90, and 89 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 99, 97, and 95 respectively. (i) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 2, 102, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95 respectively, (j) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 3, 8, and 91 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95 respectively. (k) VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 5, 102, and 89 respectively, and VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 103, 97, and 95 respectively, or (l) An anti-CD5 antibody or its antigen-binding fragment, comprising VH, which includes CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs. 104, 8, and 91, respectively, and VL, which includes CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs. 94, 97, and 105, respectively.

9. The anti-CD5 antibody or antigen-binding fragment according to claim 8, which is a humanized anti-CD5 antibody or an antigen-binding fragment thereof.

10. An anti-CD5 antibody or its antigen-binding fragment, (a) VH having a sequence that is at least 90% identical to sequence number 84 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), (b) VH having a sequence that is at least 90% identical to sequence number 84 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (c) VH having a sequence that is at least 90% identical to sequence number 84 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (for example, at least 95%, at least 97%, at least 99%, or 100% identical), (d) VH having a sequence that is at least 90% identical to sequence number 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (e) VH having a sequence that is at least 90% identical to sequence number 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (f) VH having a sequence that is at least 90% identical to sequence number 85 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (g) VH having a sequence that is at least 90% identical to sequence number 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (h) VH having a sequence that is at least 90% identical to sequence number 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (i) VH having a sequence that is at least 90% identical to sequence number 86 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (j) VH having a sequence that is at least 90% identical to sequence number 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 92 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (k) VH having a sequence that is at least 90% identical to sequence number 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 93 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), (l) VH having a sequence that is at least 90% identical to sequence number 87 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to sequence number 98 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), An anti-CD5 antibody or antigen-binding fragment thereof, optionally comprising (m) VH having a sequence that is at least 90% identical to SEQ ID NO: 100 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), and VL having a sequence that is at least 90% identical to SEQ ID NO: 101 (e.g., at least 95%, at least 97%, at least 99%, or 100% identical), wherein the antibody or antigen-binding fragment is as described in claim 8 or 9.

11. The antigen-binding fragments are Fab, Fab', and F(ab'). ２ An anti-CD5 antibody or its antigen-binding fragment according to any one of claims 1 to 10, which is an scFv or Fv fragment.

12. It comprises a first Fc region and a second Fc region forming an Fc domain, optionally the Fc domain being a human Fc domain, optionally the first Fc region and / or the second Fc region comprising one or more amino acid substitutions that reduce effector function, optionally the one or more substitutions being N297A, N297Q, N297G, D265A / N297A, D265A / N297G, L235E, L234A / L235A, L234A / L235A / P329A, L234D / L235E:L234R / L235R / E233K, L234D / L235E / D265S:E233K / L234R / L235R / D265S, L234D / L235E / E269K: E233K / L234R / L235R / E269K, L234D / L235E / K322A: E233K / L234R / L235R / K322A, L23 4D / L235E / P329W: E233K / L234R / L235R / P329W, L234D / L235E / E269K / D265S / K322A: E233K / An anti-CD5 antibody or its antigen-binding fragment according to any one of claims 1 to 11, comprising L234R / L235R / E269K / D265S / K322A, or L234D / L235E / E269K / D265S / K322E / E333K:E233K / L234R / L235R / E269K / D265S / K322E / E333K.

13. The Fc domain is (a) a human IgG1 Fc domain or a variant thereof, wherein the first Fc region and / or the second Fc region optionally contain an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO: 51, SEQ ID NO: 52, or SEQ ID NO: 53; (b) a human IgG2 Fc domain or a variant thereof, wherein the first Fc region and / or the second Fc region optionally contain an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO: 81; or (c) a human IgG4 The anti-CD5 antibody or antigen-binding fragment according to claim 12, comprising a human IgG4 Fc domain or variant thereof, wherein the Fc domain or variant thereof optionally includes an amino acid sequence in which the first Fc region and / or the second Fc region are at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:

54.

14. (a) A light chain having the amino acid sequence of SEQ ID NO: 69, and a heavy chain having the amino acid sequence of SEQ ID NO: 70, (b) A light chain having the amino acid sequence of SEQ ID NO: 71, and a heavy chain having the amino acid sequence of SEQ ID NO: 72 (c) A light chain having the amino acid sequence of SEQ ID NO: 73, and a heavy chain having the amino acid sequence of SEQ ID NO: 74 (d) A light chain having the amino acid sequence of SEQ ID NO: 75, and a heavy chain having the amino acid sequence of SEQ ID NO: 76, (e) A light chain having the amino acid sequence of SEQ ID NO: 77, and a heavy chain having the amino acid sequence of SEQ ID NO: 78, or (f) The anti-CD5 antibody or antigen-binding fragment according to claim 1, comprising a light chain having the amino acid sequence of SEQ ID NO: 79 and a heavy chain having the amino acid sequence of SEQ ID NO:

80.

15. (a) A light chain having the amino acid sequence of SEQ ID NO: 55, and a heavy chain having the amino acid sequence of SEQ ID NO: 56, (b) A light chain having the amino acid sequence of SEQ ID NO: 55, and a heavy chain having the amino acid sequence of SEQ ID NO: 57 (c) A light chain having the amino acid sequence of SEQ ID NO: 55, and a heavy chain having the amino acid sequence of SEQ ID NO: 58, or (d) The anti-CD5 antibody or antigen-binding fragment according to claim 5, comprising a light chain having the amino acid sequence of SEQ ID NO: 55 and a heavy chain having the amino acid sequence of SEQ ID NO:

59.

16. A nucleic acid comprising the coding region of an anti-CD5 antibody or its antigen-binding fragment according to any one of claims 1 to 15, wherein the nucleic acid is optionally codon-optimized for expression in mammalian cells, and optionally the mammalian cells are human cells.

17. A vector comprising the nucleic acid according to claim 16, which is optionally a plasmid.

18. A cell manipulated to express the nucleic acid described in claim 16, or comprising the vector described in claim 17.

19. A method for producing an anti-CD5 antibody or its antigen-binding fragment, comprising: culturing the cells described in claim 18 under conditions in which the anti-CD5 antibody or its antigen-binding fragment is expressed; and recovering the anti-CD5 antibody or its antigen-binding fragment from the cell culture.

20. An antibody-ALK5 inhibitor conjugate comprising an anti-CD5 antibody or its antigen-binding fragment according to any one of claims 1 to 15, conjugated to an ALK5 inhibitor.

21. The ALK5 inhibitor has a structure 【Chemistry 1】 The antibody-ALK5 inhibitor conjugate according to claim 20, comprising:

22. The antibody-ALK5 inhibitor conjugate according to claim 20 or 21, wherein the ALK5 inhibitor is linked to the antibody or antigen-binding fragment via a linker.

23. A pharmaceutical composition comprising an antibody-ALK5 inhibitor conjugate according to any one of claims 20 to 22 and a pharmaceutically acceptable carrier.

24. A method for treating cancer, comprising administering to a subject in need of such treatment an antibody-ALK5 inhibitor conjugate according to any one of claims 20 to 22 or a pharmaceutical composition according to claim 23.

25. The method according to claim 24, wherein the cancer is lung cancer, liver cancer, urothelial carcinoma, kidney cancer, breast cancer, melanoma, pancreatic cancer, glioblastoma, myelodysplastic syndrome, prostate cancer, or colorectal cancer.

26. The method according to claim 24 or 25, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered as monotherapy.

27. The method according to claim 24 or 25, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered as part of a combination therapy regimen that optionally includes administering one or more agents other than the antibody-ALK5 inhibitor conjugate (each a "second therapeutic agent").

28. The method according to claim 27, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered in combination with a standard therapy or treatment regimen.

29. The method according to claim 27 or 28, wherein the combination therapy comprises administering at least one second therapeutic agent to the subject.

30. The method according to any one of claims 27 to 29, wherein the combination therapy regimen comprises immunotherapy, optionally wherein the immunotherapy is checkpoint modulator (e.g., checkpoint inhibitor) therapy, chimeric antigen receptor (CAR) therapy, adoptive T cell therapy, oncolytic virus therapy, dendritic cell vaccine therapy, STING agonist therapy, TLR agonist therapy, intratumor CpG therapy, or cytokine therapy.

31. A method for treating a subject having a disease or disorder associated with elevated CD5 expression, comprising administering to the subject an anti-CD5 antibody or antigen-binding fragment according to any one of claims 1 to 15, wherein the disease or disorder is optionally a B-cell or T-cell malignancy, an autoimmune disease, a transplant disease, or a graft rejection.

32. A process for producing an antibody-ALK5 inhibitor conjugate, comprising conjugating an antibody or antigen-binding fragment thereof according to any one of claims 1 to 15 to an ALK5 inhibitor, wherein optionally the antibody or antigen-binding fragment is conjugated to the ALK5 inhibitor via a linker.

33. The process according to claim 32, wherein the antibody or antigen-binding fragment is conjugated to the ALK5 inhibitor via a linker, and the process further comprises the step of conjugating the ALK5 inhibitor to the linker.

34. A kit comprising an antibody or antigen-binding fragment according to any one of claims 1 to 15, and an ALK5 inhibitor.

35. The kit according to claim 34, further comprising a linker.

36. The kit according to claim 34, wherein the ALK5 inhibitor is conjugated to the linker.

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