TGF-βRII binding protein

Abstract

To provide a new pharmaceutical agent for the treatment of human disease, in particular for the treatment of cancer.SOLUTION: The present invention relates to an antibody or antibody fragment thereof that specifically binds to the extracellular domain of human TGF-βRII. The present invention further relates to a vector comprising a polynucleotide encoding the antibody or antibody fragment of the invention, an isolated cell producing the antibody or antibody fragment of the invention, and a pharmaceutical composition comprising the antibody or antibody fragment of the invention. The antibody or antibody fragment of the invention can be used to treat cancer.SELECTED DRAWING: None

Description

[Technical Field] 【0001】 This invention relates to the medical field. More specifically, it relates to proteins that bind to transforming growth factor-beta receptor II (TGF-βRII), and their use in the treatment of humans, particularly in the treatment of cancer. [Background technology] 【0002】 Transforming growth factor β (TGF-β) is the signaling molecule of the TGF-β superfamily. There are three TGF-β ligands (TGF-β1, 2, and 3) that regulate various cellular functions. TGF-β signaling plays a tumor suppressor role in normal cells, but can also play a tumor-promoting role in malignant cells. These are involved in processes such as proliferation, migration, differentiation, apoptosis, angiogenesis, and epithelial-mesenchymal metastasis (Bierie and Moses, 2006; Siegel and Massague, 2003). These signals are mediated by binding to TGF-β receptor type 2 (TGF-βRII), leading to dimerization with TGF-βRII and its phosphorylation. Subsequently, this heterotetramer complex, consisting of two TGF-βRII and two TGF-βRI, recruits SMAD2 and SMAD3 for phosphorylation, and then recruits SMAD4 to bind to the co-SMAD molecule to form a SMAD / co-SMAD complex, which then translocates to the nucleus that regulates the transcription of TGF-β target genes (Hata and Chen, 2016; Vander Ark, Cao et al., 2018). 【0003】 High levels of TGF-β expression have been shown to be associated with poor prognosis in cancer. TGF-β may induce epithelial-mesenchymal metastasis, which promotes the migration and metastasis of cancer cells. Gene expression profiles indicate that TGF-β signaling is a significant pathway in liver metastasis of colorectal cancer (Jung, Staudacher et al., 2017). Furthermore, stroma-epithelium interactions have been reported to be involved in cancer progression. The abundant stromal cell component found in solid tumors is cancer-associated fibroblasts (CAFs), which contribute to immune evasion in addition to constructing and reconstructing the extracellular matrix that can serve as a scaffold for tumors, and also promote tumorigenesis and growth (Quail and Joyce, 2013). Tumor-derived TGF-β1 induces the trans-differentiation of fibroblasts into "activated" CAFs by binding to TGFβRII, which can promote a protumoric stromal environment. 【0004】 Existing methods targeting the TGF-β signaling pathway to inhibit CAF and abnormal TGF-β signaling characteristics of tumors have so far had suboptimal efficacy and / or development obligations. One anti-TGF-βRII monoclonal antibody, LY3022859, disclosed in WO2010 / 053814, has been reported to block the extracellular domain of TGF-βRII. However, a Phase I dose-escalation study caused cytokine release syndrome and was deemed unsafe in patients with progressive solid tumors. Another agent disclosed in WO2012 / 093125 is an anti-TGF-βRII monovariable domain with a shorter half-life, and the precise mechanism of action or binding domain of this molecule has not been established. To date, no anti-TGF-βRII antibodies have successfully reached clinical trials, due to the complexity and multifaceted nature of TGF-β tumor modulation making drug development difficult (Hao, Baker et al., 2019). In this specification, we describe novel heavy chain variable regions, heavy chains, Fab, and full-length IgG monospecific antibodies capable of binding to TGF-βRII. These antibodies, or antibodies containing these heavy chains or heavy chain variable regions, target novel sites on TGF-βRII and block the interaction between the receptor and its ligand, which represents an improvement over existing antibodies. [Overview of the Initiative] 【0005】 The object of the present invention is to provide a novel pharmaceutical for the treatment of human diseases, specifically cancer. This object is satisfied by providing an antibody or antibody fragment, as described herein and claimed, that specifically binds to the extracellular domain of human TGF-βRII, and a specific binding domain. 【0006】 In a first aspect, the present invention relates to an antibody or antibody fragment that specifically binds to the extracellular domain of human TGF-βRII, wherein the antibody or antibody fragment binds to an epitope of the extracellular domain of human TGF-βRII, and phenylalanine (F) at position 25 of isoform A of human TGF-βRII or position 50 of isoform B of human TGF-βRII is an essential residue for binding. 【0007】 Preferably, such antibody or antibody fragment binds to TGF-βRII, blocking or inhibiting the binding of human TGF-β to human TGF-βRII, thereby inhibiting signal transduction to cells and blocking or inhibiting the heterodimerization of TGF-βRII. 【0008】 In a second aspect, the present invention relates to a vector comprising a polynucleotide encoding either or both of the heavy and light chains of an antibody or antibody fragment described herein. 【0009】 In a third aspect, the present invention relates to cells that produce antibodies or antibody fragments as described herein. 【0010】 In a fourth aspect, the present invention relates to a pharmaceutical composition comprising an antibody or antibody fragment described herein and a pharmaceutically acceptable carrier, diluent, or excipient. 【0011】 In a fifth aspect, the present invention relates to a pharmaceutical product for preventing cancer, suppressing the progression or recurrence of cancer symptoms, and / or treating cancer, comprising an antibody or antibody fragment described herein as an active ingredient. 【0012】 In a sixth aspect, the present invention relates to a method for treating cancer in a subject, comprising administering to the subject an effective amount of an antibody or antibody fragment described herein, or a pharmaceutical composition described herein. 【0013】 In a seventh aspect, the present invention relates to a method for blocking the binding of human TGF-β to human TGF-βRII in cells, comprising: providing cells with an antibody or antibody fragment described herein; and enabling the antibody or antibody fragment to bind to human TGF-βRII in cells, thereby blocking the binding of human TGF-β to human TGF-βRII in cells. 【0014】 In an eighth aspect, the present invention relates to a method for inhibiting signal transduction to cells induced by the binding of human TGF-β to human TGF-βRII, comprising: providing cells with an antibody or antibody fragment described herein; and enabling the antibody or antibody fragment to bind to human TGF-βRII in cells, thereby inhibiting signal transduction to cells. 【0015】 In a ninth aspect, the present invention relates to a method for preventing or inhibiting metastasis, comprising administering to a subject an effective amount of an antibody or antibody fragment described herein, or a pharmaceutical composition described herein. [Modes for carrying out the invention] 【0016】 In general, the present invention relates to proteins, specifically antibodies or antibody fragments, that specifically bind to the extracellular domain of human TGF-βRII. Preferably, the antibody is isolated. Preferably, the antibody is a monoclonal antibody. More preferably, the antibody is an isolated monoclonal antibody. 【0017】 "Isolated monoclonal antibodies" refer to antibodies produced by cloned cells. Examples of isolated antibodies include, but are not limited to, affinity-purified antibodies, antibodies produced in vitro in hybridomas or other cell lines, and human antibodies derived from transgenic non-human animals. 【0018】 The term "antibody" refers to an immunoglobulin molecule containing four polypeptide chains: two heavy chains (H) and two light chains (L). Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain variable region contains three heavy chain complementarity-determining regions (HCDR) and four framework regions (FR), and is preferably human or humanized. The heavy chain constant region consists of three domains, CH1, CH2, and CH3, and may originate from any organism, preferably human. The CH1 and CH2 domains of the heavy chain constant region are connected via a movable hinge region. Each light chain contains a light chain variable region (VL) and a light chain constant region (CL). The light chain variable region can be of two types: kappa (K) or lambda (λ), and, like the VH, contains three light chain complementarity-determining regions (LCDR) and four framework regions. The light chain variable region is preferably human or humanized. The light chain constant region consists of one domain, CL, and can originate from any organism, preferably human. These two heavy chains are linked to each other by a disulfide bond between two hinge regions, and each of these heavy chains is paired with a light chain by a disulfide bond between the CH1 region and the CL region. In conventional antibodies, the two heavy chains and two light chains are identical, providing the antibody with two identical antigen-binding sites. 【0019】 Antibody binding possesses distinct characteristics, including specificity and affinity. Specificity determines which antigen or epitope is specifically bound by the antibody-binding domain. Affinity is a measure of the strength of binding to a particular antigen or epitope. 【0020】 A "human" antibody refers to an antibody in which all antibody domains are derived from human germline immunoglobulin sequences. The human antibodies used in this invention can be produced by methods using mice transformed to produce human antibodies, such as Humab mice, KM mice, Xeno mice, Tc mice, or MeMo® mice (WO2009 / 157771). Human antibodies can also be prepared using SCID mice in which human immune cells have been reconstituted to produce a human antibody response during immunization. 【0021】 The "humanized" antibody region refers to an antibody prepared, for example, by transplanting the complementarity-determining region (CDR) sequence of an antibody derived from the germline of a non-human animal such as a mouse or chicken into the human framework sequence of a human antibody. Also, a humanized antibody can be produced by ligating a nucleic acid encoding the CDR region of an antibody isolated from an antibody-producing hybridoma to a nucleic acid encoding the framework region of a human-derived antibody using well-known methods. 【0022】 An antibody can bind to an antigen through its heavy and / or light chain variable regions, specifically through its specific CDRs. The CDRs of the heavy and / or light chain variable regions of an antibody bind to the "epitope" (also referred to as "antigen determinant") of an antigen. An epitope can be formed by non-adjacent amino acids or non-adjacent amino acids juxtaposed by the tertiary folding of a protein, namely, so-called linear epitopes and conformational epitopes, respectively. An epitope formed from adjacent linear amino acids is typically retained upon exposure to a denaturing solvent, while an epitope formed by tertiary folding typically loses its conformation upon treatment with a denaturing solvent. An epitope can typically contain 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids within its unique spatial conformation. 【0023】 An "antigen" is typically a molecule that can induce an immune response in a host organism and thereby produce antibodies having specificity for the antigen. At the molecular level, an antigen is characterized by its ability to be bound by the antigen-binding site of an antibody. As described above, the antigen-binding site of an antibody is formed by its heavy and / or light chain variable regions, specifically by its CDRs. An antigen contains at least one epitope, but often contains more than one epitope. 【0024】 In addition, a mixture of antigens can be regarded as an "antigen", and those skilled in the art will understand that while tumor cell lysates or virus particles may sometimes be designated as "antigens", such tumor cell lysate or virus particle preparations contain many antigenic determinants. 【0025】 In the present invention, the antigen is human TGF-βRII. Human TGF-βRII is a transmembrane protein that exists in different isoforms. The amino acid sequence of human TGF-βRII isoform A is provided as SEQ ID NO: 101, and the amino acid sequence of the extracellular domain of human TGF-βRII isoform A is provided as SEQ ID NO: 102. Human TGF-βRII isoform B is a splice variant that encodes a longer isoform due to an insertion into the extracellular domain. The amino acid sequence of human TGF-βRII isoform B is provided as SEQ ID NO: 103, and the amino acid sequence of the extracellular domain of human TGF-βRII isoform B is as described in SEQ ID NO: 104. 【0026】 TGF-βRII is a member of the serine / threonine protein kinase family and the TGFB receptor subfamily. It is known by various synonyms including TGFBR2, AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2, RIIC, TAAD2, TGFR-2, TGFβ-RII, transforming growth factor beta receptor 2, and TBR-ii, TBRII. TGF-βRII forms a heterodimeric complex with another receptor protein and binds to TGF-β. This receptor / ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of a subset of genes related to cell proliferation. 【0027】 An antibody binds to an antigen with a specific binding affinity. "Binding affinity" is determined by the dissociation constant (K off / k on ) calculated by the formula: k D and refers to the strength of the antibody-antigen interaction. Depending on the desired biological activity, an antibody has a high k onSpeed ​​and / or low k off You can choose based on speed. 【0028】 "Antibody fragment" includes, but is not limited to, functional fragments of the heavy chain and / or light chain. Such functional fragment comprises at least one CDR derived from or synthesized therefrom from an antibody heavy chain or light chain, and is capable of specifically recognizing an antigen. The antibody fragment may be, for example, Fab,F(ab')2, scFv, minibody, or sdAb. "Antibody fragment" further refers to the proteinaceous portion containing the functional part of the antibody. In this case, it is at least one of the heavy chain variable regions or HCDRs described herein. The antibody fragment may include, but is not limited to, any binder such as single-stranded Fv, single-stranded or tandem diabody (TandAb®), VHH, Anticalins®, Nanobodies®, BiTE®, Fab, Ankyrin repeat protein or DARPIN®, Avimer®, DART, TCR-like antibody, Adnectin®, Affilin®, Trans-Body®, Affibody®, TrimerX®, MicroProtein, Fynomer®, Centyrin®, or KALBITOR®. 【0029】 "Fab" typically refers to a binding domain that includes the heavy chain variable region, light chain variable region, CH1, and CL region. 【0030】 "F(ab')2" typically refers to a binding domain containing two Fab domains linked together by a hinge region. 【0031】 A "single-stranded variable fragment" (scFv) typically refers to a binding domain containing VH and VL domains linked via a linker, such as a peptide linker approximately 10 to 25 amino acids in length. 【0032】 A "minibody" typically refers to a binding domain containing two scFv and CH3 domains. 【0033】 A "single-domain antibody" (sdAb) typically refers to a binding domain containing only the VH or VL domain of an antibody, usually fused to or otherwise linked to a portion of the Fc region. Like whole antibodies, this antibody can selectively bind to a specific antigen. Single-domain antibody fragments can be engineered from heavy-chain antibodies found in camelids, which are sometimes called VHH fragments (Nanobody®). Some fish also possess heavy-chain-only antibodies (IgNAR, "novel immunoglobulin antigen receptor"), from which single-domain antibody fragments called VNAR fragments can be obtained. An alternative approach is to split dimeric variable domains derived from common immunoglobulin G (IgG) from humans or mice into monomers. While most single-domain antibody research currently relies on heavy-chain variable domains, it has also been shown that nanobodies derived from light chains can bind to target epitopes. Therefore, nanobodies are also included in this invention. 【0034】 The “antibody fragment” also refers to at least one CDR, which is part of a protein construct exhibiting binding specificity to the antigen. Preferably, at least one CDR is HCDR3. In one embodiment, the protein construct comprises HCDR1, HCDR2, and HCDR3. In another embodiment, the protein construct comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3. The protein construct may further comprise a portion of the Fc region containing CH2 and / or CH3. The protein construct may also comprise a CH1 region. The CH1, CH2, and / or CH3 regions may be manipulated to obtain any desired properties with respect to antigen binding and / or effector function. 【0035】 The present invention also includes variants of the antibody or antibody fragment of the present invention. A “variant” of the antibody or antibody fragment of the present invention comprises at least a functional portion of the antibody or antibody fragment described herein, or a derivative or analog thereof. Such a functional portion, derivative, or analog comprises at least a binding domain of the antibody or antibody fragment described herein, comprising a heavy chain variable region and / or a light chain variable region comprising a CDR disclosed herein. A variant may comprise one to five amino acid substitutions within one or more of the CDRs. For example, an amino acid residue may be substituted with a conserved amino acid residue. A variant may also comprise one or more amino acid substitutions within one or more framework regions. Preferably, a variant comprises a VH region having at least 80%, 85%, 90%, 92%, 94%, 96%, 97%, 98%, or 99% sequence identity with the VH amino acid sequence of the antibody or antibody fragment of the present invention. Preferably, the variant includes a VL region having at least 80%, 85%, 90%, 92%, 94%, 96%, 97%, 98%, or 99% sequence identity with the VL amino acid sequence of the antibody or antibody fragment of the present invention. 【0036】 In this specification, “identity percentage (%)” for nucleic acid sequences or amino acid sequences is defined as the percentage of residues in a candidate sequence that are identical to residues in a selected sequence after the sequences have been aligned for optimal comparison purposes. To optimize the alignment between these two sequences, gaps may be introduced in either of the two sequences being compared. Such alignment may be performed over the entire length of the sequences being compared. Alternatively, the alignment may be performed over shorter lengths, e.g., about 20, about 50, about 100, or more nucleic acids / bases or amino acids. Sequence identity is the percentage of perfect match between these two sequences across the reported aligned region. 【0037】 The comparison of sequences and the determination of the percentage of sequence identity between two sequences can be achieved using mathematical algorithms. Those skilled in the art will recognize that several different computer programs are available for aligning two sequences and determining their identity (Kruskal, JB (1983) An overview of sequence comparison In D. Sankoff and JB Kruskal, (ed.), Time warps, string edits and macromolecules: the theory and practice of sequence comparison, pp. 1-44 Addison Wesley). 【0038】 Specifically, the sequence identity percentage according to the present invention described herein between two nucleic acid sequences can be determined using the AlignX application of Vector NTI Program Advance 11.5.2 software with default settings, employing the modified ClustalW algorithm (Thompson, JD, Higgins, DG, and Gibson TJ (1994) Nuc. Acid Res. 22: 4673-4680), the swgapdnamt score matrix, a gap opening penalty of 15, and a gap elongation penalty of 6.66. The amino acid sequences can be aligned using the AlignX application of Vector NTI Program Advance 11.5.2 software with default settings, employing the modified ClustalW algorithm (Thompson, JD, Higgins, DG, and Gibson TJ, 1994), the bloomum62mt2 score matrix, a gap opening penalty of 10, and a gap elongation penalty of 0.1. 【0039】 The variant maintains the binding specificity, e.g., antigen specificity, of the antibody or antibody fragment of the present invention. However, the binding affinity of the variant may differ from the binding affinity of the original antibody or antibody fragment of the present invention. The variant may have a lower or higher K than, for example, the antibody or antibody fragment described herein. on Speed ​​and / or K off It may have speed. 【0040】 The functional derivatives of the antibody or antibody fragment of the present invention may be antibody mimes, polypeptides, aptamers, or combinations thereof. These proteins or aptamers typically bind to a single target. It should be understood that any combination of these antibodies, antibody mimes, polypeptides, and aptamers can be linked together by methods known in the art. For example, in some embodiments, the antibody or antibody fragment of the present invention is part of a conjugate or fusion protein. 【0041】 Antibody mimetics are polypeptides that, like antibodies, can specifically bind to antigens but are not structurally related to antibodies. Antibody mimetics are typically artificial peptides or proteins with a molar mass of approximately 3–20 kDa. Non-limiting examples of antibody mimetics include afibody molecules (typically based on the Z domain of protein A), affines (typically based on gamma-B crystals or ubiquitin), affimers (typically based on cystatins), afitins (typically based on Sac7d from Sulfolobus acidocaldarius), alphabodies (typically based on triple-helix coiled coils), anticarin (typically based on lipocalin), avimers (typically based on the A domains of various membrane receptors), DARPin (typically based on the ankyrin repeat motif), finomers (typically based on the SH3 domain of Fyn 7), Knitz domain peptides (typically based on the Knitz domains of various protease inhibitors), and monobodies (typically based on the type III domain of fibronectin). 【0042】 Monobodies are synthetic binding proteins constructed using the fibronectin type III domain (FN3) as a molecular backbone. Monobodies are antibody substitutes for producing target-binding proteins. Monobodies and other antibody mimics are typically generated from combinatorial libraries in which parts of the backbone are diversified using molecular displays and directed evolution techniques, such as phage displays, mRNA displays, and yeast surface displays. 【0043】 Aptamers are oligonucleotide or peptide molecules that bind to specific target molecules. Aptamers are typically created by selecting them from a large pool of random sequences, although natural aptamers also exist in riboswitches. As macromolecules, aptamers can be used for both basic research and clinical purposes. 【0044】 The antibody of the present invention is preferably an IgG antibody, preferably an IgG1 or IgG4 antibody. Most preferably, the antibody is an IgG1 antibody. Such full-length IgG antibodies are preferred because of their favorable half-life and because, for reasons of immunogenicity, they are desired to remain completely close to their own (human) molecules. IgG1 is preferred based on its long circulating half-life in humans. 【0045】 The terms "full-length IgG" or "full-length antibody" according to the present invention are defined as containing essentially complete IgG, but not necessarily possessing all the functions of intact IgG. To avoid misunderstanding, full-length IgG contains two heavy chains and two light chains. Each of these chains contains a constant (C) region and a variable (V) region, which can be classified into domains designated as CH1, CH2, CH3, VH, and CL, VL. IgG antibodies bind to antigens via the variable region domain contained in the Fab portion, and after binding, they can interact with molecules and cells of the immune system via the constant domain, primarily via the Fc portion. Full-length antibodies according to the present invention contain IgG molecules in which mutations may exist that provide desired characteristics. 【0046】 Full-length IgG may contain mutations in its constant region that modulate effector functions, including antibody-dependent cytotoxicity (ADCC) or cell-dependent cytotoxicity (CDC) (both increasing and relaxing such functions), increase homodimerization or heterodimerization to produce monospecific or multispecific antibodies from host cells containing nucleic acids encoding different heavy chains, and facilitate the separation of antibodies or antibody fragments produced by such host cells. 【0047】 For example, the leucine at position 235 according to the EU numbering system may be replaced with glycine, and / or the glycine at position 236 according to the EU numbering system may be replaced with arginine. Such modifications ensure that binding to the Fc receptor and / or effector function is eliminated or reduced. Other mutations in the CH2 and Fc regions are also included in the present invention. 【0048】 Full-length IgG should not have any substantial deletions in any region. However, an IgG molecule with one or more amino acid residues deleted without essentially altering the binding properties of the resulting IgG molecule is included in the term "full-length IgG." For example, such an IgG molecule may have 1 to 10 amino acid residues deleted, preferably within a non-CDR region, and the deleted amino acids are not essential for the binding specificity of IgG. 【0049】 For example, the lysine at position 447 according to the EU numbering system may be deleted. Such a deletion reduces antibody heterogeneity. Furthermore, to suppress swapping within the IgG4 antibody molecule, the serine located in the hinge region at position 228 according to the EU numbering system may be replaced with proline. 【0050】 Suitable light chains for use in the antibodies or antibody fragments of the present invention include light chains produced in response to immunization with an antigen, or light chains produced synthetically based thereon, referred to as homogeneous light chains. Suitable light chains include common light chains (cLCs), which can be identified, for example, by screening for the most commonly used light chains in existing antibody libraries (wet libraries or in silicos), and these light chains do not substantially interfere with the affinity and / or selectivity of the epitope-binding domain of the heavy chain, but are also suitable for pairing with heavy chain arrays. Common light chains are preferably encoded by germline sequences of V and J gene segments that have been rearranged but have not undergone somatic hypermutation or have undergone minimal somatic hypermutation. Suitable light chains, for example, include those derived from transgenic non-human animals, such as MeMo®, which can be used to purify a large panel of common light chain antibodies that incorporate common light chains into their genome, have diversity in the heavy chain, and can specifically bind to the antigen upon exposure to that antigen. 【0051】 Therefore, the term “common light chain” refers to a light chain that can associate with two or more different heavy chains and exhibits antigen-binding ability (see, e.g., WO2009 / 157771, WO2019 / 190327, and WO2014 / 051433). The preferred light chain V gene for such a common light chain is IGKV1-39. The preferred light chain J genes are jk1 and jk5. The combined sequences are shown as IGKV1-39 / jk1 and IGKV1-39 / jk5, with alternative names being IgVκ1-39*01 / IGJκ1*01 or IgVκ1-39*01 / IGJκ5*01 (named by the IMGT database at www.imgt.org). Preferred examples of common light chains include the human κ light chain IgVκ1-39*01 / IGJκ1*01 (named in the IMGT database) germline gene (hereinafter abbreviated as "IGVK1-39 / JK1 common light chain") and IgVκ1-39*01 / IGJκ5. The various MeMo® transgenic animals mentioned above contain the IGVK1-39 / JK1 common light chain. 【0052】 The common light chain according to the present invention refers to a light chain that may be identical or have some amino acid sequence differences, but whose binding specificity to the antibody or antibody fragment of the present invention is not affected. Those skilled in the art will recognize that “common” also refers to functional equivalents of light chains that are not identical in amino acid sequence. There exist variants of such light chains that have changes compared to a parent common light chain that do not substantially affect the formation of the functional binding domain. Therefore, such variants can also bind to different heavy chains and form a functional antigen-binding domain. For example, within the definition of a common light chain as used herein, it is possible to prepare or find variable light chains that are not identical but are still functionally equivalent by testing for, for example, conservative amino acid changes, changes in amino acids in regions that do not contribute to binding specificity, or contribute only partially, when paired with a homogeneous chain. Therefore, such variants can also bind to different homogeneous chains and form a functional antigen-binding domain. Thus, the term “common light chain” as used herein refers to a light chain that may be identical or have some amino acid sequence differences, but which retains the binding specificity of the antibody resulting after pairing with a heavy chain. The term “common light chain” encompasses any combination of a particular common light chain and such functionally equivalent variants. For a detailed description of the use of common light chains, see WO2004 / 009618, WO2019 / 190327, and WO2009 / 157771. Preferably, the common light chain used in the present invention is a germline-like light chain, more preferably a germline light chain, preferably a rearranged germline human kappa light chain, most preferably a rearranged germline human kappa light chain, either IgVκ1-39 / Jκ or IGVκ3-20 / Jκ. 【0053】 Antibodies or antibody fragments can be produced from hybridomas, for example, using the hybridoma method. Alternatively, antibodies or antibody fragments can be produced by secretion from mammalian cells co-expressing heavy chains and / or light chains, or fragments thereof. Preferably, antibodies or antibody fragments are produced by immunizing non-human animals. These and other methods are known in the art and can be suitably used for the production of antibodies or antibody fragments of the present invention. 【0054】 Antibodies can be produced from various animal species. The aforementioned MeMo® transgenic animals containing the IGVK1-39 / JK1 common light chain can be suitably used. Generally, transgenic mice are immunized with human target DNA and / or proteins, followed by an immune boost, which triggers an immune response including the production of antigen-specific antibodies. Serum titers from immunized mice can be determined by ELISA and FACS analysis. Subsequently, spleen and lymphoid excretory material from the immunized mice can be collected to produce a single-cell suspension. RNA encoding the heavy chain and / or variable region of such antibodies can be isolated and cDNA synthesized. Subsequently, VH and / or VL family-specific PCR can be performed to generate a phage display library. Then, for example, a Kingfisher selection robot can be used to select human target protein-binding Fabs. The nucleic acids encoding the heavy chain and / or light chain variable region of Fabs that bind to the target protein can be used for antibody production in host cells. 【0055】 While antibodies are produced by immunization of transgenic organisms, there are cases where such antibodies are not cross-reactive to humans and transgenic animals, reducing the efficiency of assays and tests using such antibodies. Therefore, it may be beneficial to obtain binding domains or antibodies containing chimeric or humanization binding domains or antibodies that include variable regions and / or complementary determining regions (CDRs), as well as nucleic acids that encode such variable regions and / or CDRs, based on, derived from, or obtained from nucleic acids of evolutionarily distant species from humans. One potential source of such variable regions may be birds, such as domestic birds like chickens, ducks, or ostriches. The antibody repertoire produced by immunization of birds, such as chickens, ducks, or ostriches, may identify unique epitopes compared to antibodies produced by immunization of mice or other species evolutionarily close to humans (e.g., rodents and cynomolgus monkeys). 【0056】 Primary DNA or protein immunization is performed, followed by additional booster immunization. IgY antibodies can be isolated from the yolk of collected eggs or from serum derived from immunized birds. Spleen and / or bone marrow are removed from birds showing a significant humoral response to the target protein. RNA can then be isolated, and cDNA is synthesized. The generated cDNA sample is then used as a template for amplifying and digesting the VH and / or VL genes using two primers. The PCR product is then cloned in a phagemide vector for display of Fab fragments on phages, essentially as described in de Haard et al. (J Biol Chem. (1999), Vol.274(26), pp.18218-18230). Nucleic acids encoding the VH and / or VL regions are ligated into the vector, and the resulting ligated vector is transformed into cells to obtain a library. Panning selection using KingFisher Flex can then be performed to select phages that bind to the target protein. Screening can be performed by FACS in cells expressing human or mouse target proteins. The VH and / or VL genes of all clones that specifically bind to human and / or mouse target proteins are sequenced. Nucleic acids encoding the heavy chain and / or light chain variable regions of the binding domain that binds to the target protein can be used for antibody production in host cells. 【0057】 Antibody fragments can be produced by methods known in the art. 【0058】 scFv antibodies can be produced by isolating mRNA from hybridomas or mammalian cells and then reverse transcribing it into cDNA for PCR amplification. This produces a large library containing a wide range of VH and VL antibody genes (Marks and Hoogenboom, Journal of Molecular Biology (1991), Vol. 222, pp. 581-597). While constructing ScFv, the domains can be ordered as VH-linker-VL or VL-linker-VH (Hu, O'Dwyer and Wall, Journal of Biotechnology (2005), Vol. 120, pp. 38-45). An example of a linker is the classical (G4S)3 linker (Huston et al., Proc Natl Acad Sci USA (1988), Vol. 85, pp. 5879-5883). For minibodies, the DNA fragment encoding the hinge-CH3 domain can be based, for example, on the sequence of human IgG1 (Kim et al., PLOS One (2014), Vol.9(12), e113442). The scFv and hinge-CH3 regions can be assembled either by ligating the aggregated ends generated by XhoI and SALI, or by using PCR to bring the XhoI restriction site of the scFv product together with the hinge at the NH2 terminus of CH3 (Hu et al., Cancer Research (1996), Vol.56, pp.3055-3061). After PCR, the V domain of the antibody can be recombined by in vitro recombination of plasmids or phagemids (Lilley et al., Journal of Immunological Methods (1994), Vol.171, pp.211-226; Hogrefe et al., Gene (1993), Vol.128, pp.119-126).This phage display technique relies on the fusion of antibody fragments to the phage minor coat protein pIII or its C-terminal domain (Smith, Science (1985), Vol.228, pp.1315-1317; Hoogenboom, Nature Biotechnology (2005), Vol.23, pp.1105-1116). In addition to displaying scFv fragments, phage display is now also widely used to display Fab fragments (Wieland et al., Veterinary Immunology and Immunopathology (2006), Vol.110, pp.129-140). 【0059】 Fab fragments can be generated from monoclonal antibodies by enzymatic digestion using papain or pepsin. Papain digestion of the antibody produces three distinct fragments: two antigen-binding fragments called Fab fragments or regions, each having a single antigen-binding site, and one Fc region resulting from cleavage under the CH1 domain (Porter, Biochem (1959), Vol. 73, pp. 119-126). Pepsin digestion of the antibody produces two fragments: an F(ab')2 fragment containing two antigen-binding regions linked via disulfide crosslinks in a hinge region, and an Fc fragment (Valedkarimi et al., Human Antibodies (2018), Vol. 26, pp. 171-176). These Fab and F(ab')2 fragments can be purified by a combination of the following techniques: ion exchange, protein A or G affinity, antigen affinity, or gel filtration chromatography (Mage and Lamoyi. Monoclonal Antibody Production Techniques and Applications, Marcel Dekker Inc, New York, 1987, pp. 79-97). F(ab')n or (modified F(ab')n) can be produced in connection with the present invention as described herein and can be obtained using any suitable enzymatic cleavage and / or digestion technique. In certain embodiments, the antibody fragment can be obtained by cleavage with IdeS protease, an IgG-degrading enzyme of Streptococcus pyogenes, which cleaves human IgG1 at a specific site below the hinge, leaving an intact F(ab')n antibody fragment, where n is the number of antibody domains present on the IgG, and the heavy chain on one side of F(ab')n is paired with the heavy chain on the other side at their respective C-terminuses, and this pairing includes two or more disulfide crosslinks. Methods for generating bispecific and multispecific antibodies where n is 2 or greater have been previously described. See PCT / NL2019 / 050199, PCT / NL2013 / 050294, and PCT / NL2013 / 050293, which are incorporated herein by reference. 【0060】 Alternatively, antibody fragments lacking the Fc region can be obtained by using a cysteine ​​protease derived from Porphyoromonas gingivalis, which digests human IgG1 at a specific site on the hinge (KSCDK / THTCPPC) to produce intact Fab and Fc fragments. The antibody fragments can be formed by this technique by the expression of a heavy chain (e.g., CH1, CH2, and / or CH3) containing variable and constant domains paired with a light chain linked to additional variable domains via the linker described herein, and a protease, e.g., derived from Porphyoromonas gingivalis, cleaves the constant domain of the heavy chain, leaving intact cleaved antibody-bound fragments. 【0061】 The generation of sdAbs has been achieved by phage display and by using a repertoire of naive or synthetic VH or VL dAbs based on the incorporation of solubilized residues derived from camelid sdAbs into human VH (Tanha et al., J. Biol. Chem (2001), Vol. 276, pp. 24774-24780; Davies and Riechmann, Biotechnology (1995), Vol. 13, pp. 475-479). Human sdAbs have also been achieved without manipulation by a reversible unfolding and affinity-based selection method that yielded several VHs from a synthetic human VH phage display library (Jespers et al, Nat. Biotechnol (2004), Vol. 337, pp. 893-903). Using an alternative phage selection method, exclusively non-aggregated human VH domains can be obtained from naive human VH display libraries (To et al., J Biol Chem (2005), Vol.280, pp.41395-41403). This same technique can be applied to the obtained VL (Kim et al., Landes Bioscience (2014), Vol.6:1, pp.219-235). 【0062】 The antibody or antibody fragment of the present invention can be used to treat cancer by administering an effective amount of the antibody or antibody fragment to a subject requiring cancer treatment. 【0063】 As used herein, the terms “subject” and “patient” are used interchangeably and refer to mammals such as humans, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, monkeys, cattle, horses, and pigs (for example, patients such as human patients with cancer). 【0064】 As used herein, the terms “to treat,” “to treat,” and “treatment” refer to any type of intervention or process performed on a subject or administered to a subject with an active agent or combination of active agents for the purpose of curing or improving a disease or its symptoms. This includes reversing, alleviating, improving, suppressing or delaying symptoms, complications, conditions, or biochemical signs associated with the disease, as well as preventing the onset, progression, occurrence, worsening, or recurrence of symptoms, complications, conditions, or biochemical signs associated with the disease. 【0065】 As used herein, “effective treatment” or “positive treatment response” means a treatment that results in a beneficial effect, e.g., improvement of at least one symptom of a disease or disorder, e.g., cancer. A beneficial effect can take the form of improvement above baseline, including improvement beyond measurements or observations made before initiating treatment according to the method. For example, a beneficial effect can take the form of delaying, stabilizing, stopping, or reversing the progression of cancer in a subject at any clinical stage, demonstrated by a reduction or elimination of clinical or diagnostic symptoms of the disease, or markers of cancer. An effective treatment may, for example, reduce tumor size, reduce the presence of circulating tumor cells, reduce or prevent tumor metastasis, delay or stop tumor growth, and / or prevent or delay tumor recurrence or relapse. 【0066】 The terms “therapeutic dose” or “effective dose” refer to the amount of an agent or combination of agents that provides a desired biological, therapeutic, and / or preventive outcome. The outcome may be reduction, improvement, remission, lessening, delay, and / or mitigation of one or more signs, symptoms, or causes of a disease, or any other desired change in the biological system. In some embodiments, the therapeutic dose is sufficient to delay tumor development. In some embodiments, the therapeutic dose is sufficient to prevent or delay tumor recurrence. 【0067】 A therapeutic dose of a drug or composition may (i) reduce the number of cancer cells, (ii) reduce tumor size, (iii) inhibit, delay, to some extent delay, and halt the invasion of cancer cells into peripheral organs, (iv) inhibit tumor metastasis, (v) inhibit tumor growth, (vi) prevent or delay tumor development and / or recurrence, and / or (vii) alleviate to some extent one or more of the symptoms associated with cancer. 【0068】 The therapeutic dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the drug or drug combination to induce the desired response in the individual. 【0069】 The therapeutic dose can be administered in one or more doses. 【0070】 The therapeutic dose also includes the amount that balances any toxic or adverse effects of the drug or combination of drugs with the therapeutically beneficial effects. 【0071】 More specifically, the present invention provides an antibody or antibody fragment that specifically binds to the extracellular domain of human TGF-βRII, wherein the antibody or antibody fragment binds to an epitope of the extracellular domain of human TGF-βRII, and phenylalanine (F) at position 25 is an essential residue for binding. 【0072】 The research leading to this invention identified an antibody that binds to a specific epitope in the extracellular domain of human TGF-βRII. This epitope contains at least one amino acid residue at position 25 of the extracellular domain of isoform A of human TGF-βRII. The amino acid sequence of the extracellular domain of isoform A of human TGF-βRII is as described in SEQ ID NO: 102. The amino acid at position 25 of this sequence is phenylalanine (F) (bold and underlined). The database acceptance number for the human TGF-βRII protein and the gene encoding isoform A is GenBank NM_001024847.2 (protein sequence reference number is NP_001020018.1 (SEQ ID NO: 102)). The splice variant encoding a longer isoform resulting from an insertion into the extracellular domain is isoform B. The gene encoding isoform B is GenBank NM_003242.6 (protein sequence reference is NP_003233.4 (sequence number 103), with the insertion underlined). The amino acid at position 25 of the extracellular domain of isoform A corresponds to the amino acid at position 50 of the extracellular domain of isoform B. The amino acid sequence of the extracellular domain of human TGF-βRII isoform B is as described in sequence number 104. The amino acid at position 50 of this sequence, phenylalanine (F), is shown in bold and underlined. These acceptance numbers are provided primarily to provide further methods for targeting and identifying the TGF-βRII protein, and the actual sequence of the antibody-bound TGF-βRII protein may change due to mutations in the encoding gene, such as mutations that occur in some cancers. 【0073】 Wherever this description refers to the amino acid at position 25 of human TGF-βRII, it refers to the amino acid at position 25 of the extracellular domain of isoform A of human TGF-βRII, as well as the corresponding position of another isoform of human TGF-βRII, specifically position 50 of isoform B. The same applies to other amino acid positions identified herein. 【0074】 The amino acid residue at position 25 of the extracellular domain of human TGF-βRII was found to be an essential residue for antibody binding, as determined by alanine scanning. In alanine scanning, one amino acid at each position of the antigen, in this case TGF-βRII, is substituted with alanine. If this weakens or significantly reduces the binding of the antibody to the unmodified antigen, the substituted amino acid is considered to contribute to binding and is an essential residue. Thus, the antibody or antibody fragment specifically binds to the epitope containing such residue. In this context, an amino acid residue is considered essential if its binding activity or reactivity is reduced by more than 50% compared to the unmodified amino acid sequence. Therefore, "significantly reduced" means a binding activity or reactivity of at least more than 50% compared to the unmodified amino acid sequence of the extracellular domain of human TGF-βRII. 【0075】 Therefore, when the phenylalanine (F) at position 25 of the amino acid sequence of the extracellular domain of human TGFβRII (its wild-type sequence is as described in SEQ ID NO: 102) is replaced with alanine (A), the antibody or antibody fragment of the present invention has a binding activity or reactivity of less than 50%, preferably 40%, 30%, 20%, 10%, 5%, or less than 2%, compared to the wild-type amino acid sequence of the extracellular domain of human TGFβRII. 【0076】 Therefore, the antibody or antibody fragment of the present invention specifically binds to an epitope of human TGF-βRII containing phenylalanine (F) at position 25 of the amino acid sequence of the extracellular domain of human TGF-βRII. Preferably, the binding of the antibody or antibody fragment to this epitope is determined by alanine scanning, where the antibody or antibody fragment that binds to this epitope has less than 50%, preferably 40%, 30%, 20%, 10%, 5%, or less than 2%, when alanine (A) is present at position 25 of the amino acid sequence of the extracellular domain of human TGF-βRII, compared to when phenylalanine (F) is present at position 25. 【0077】 Another way to define the antibody or antibody fragment of the present invention is that it binds to an epitope in the extracellular domain of human TGFβRII, such that the binding of the antibody or antibody fragment is reduced by at least 50%, preferably at least 60%, 70%, 80%, 90%, 95%, or 98%, by the substitution of the phenylalanine (F) residue at position 25 of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) with alanine (A). 【0078】 The antibody or antibody fragment of the present invention may also be defined as an antibody or antibody fragment that binds to an epitope in the extracellular domain of human TGF-βRII, which contains the phenylalanine (F) residue at position 25 of isoform A of human TGF-βRII (whose wild-type sequence is as described in SEQ ID NO: 102). In addition to the essential amino acid residue at position 25, aspartic acid (D) at position 119 of the epitope in the extracellular domain of isoform A of human TGF-βRII was identified as a further essential residue for binding. The amino acid at position 119 of isoform A of human TGF-βRII corresponds to the amino acid at position 144 of the extracellular domain of isoform B (SEQ ID NO: 104). The antibody or antibody fragment of the present invention preferably has a binding reactivity of less than 10%, more preferably 5%, 4%, 3%, or less than 2%, compared to the wild-type amino acid sequence of the extracellular domain of human TGF-βRII, when the aspartic acid (D) at position 119 of the wild-type amino acid sequence of the extracellular domain of human TGF-βRII is substituted with alanine (A). 【0079】 In certain embodiments, the antibody or antibody fragment is preferably compared to the wild-type amino acid sequence of the extracellular domain of human TGFβRII. -When phenylalanine (F) at position 25 of the wild-type amino acid sequence of the extracellular domain of human TGF-βRII is substituted with alanine (A), the binding reactivity is less than 5%, preferably less than 3%. -When the aspartic acid (D) at position 119 of the wild-type amino acid sequence in the extracellular domain of human TGF-βRII is substituted with alanine (A), it has a binding reactivity of less than 5%, preferably less than 3%. 【0080】 Accordingly, the present invention encompasses an antibody or antibody fragment that specifically binds to an epitope of human TGF-βRII comprising phenylalanine (F) at position 25 of the amino acid sequence of the extracellular domain of human TGF-βRII and aspartic acid (D) at position 119. Preferably, the binding of the antibody or antibody fragment to this epitope is determined by alanine scanning, where the antibody or antibody fragment that binds to this epitope has a binding activity or reactivity of less than 50%, preferably less than 5% or less than 3%, when alanine is present at position 25 of the amino acid sequence of the extracellular domain of human TGF-βRII, and a binding activity or reactivity of less than 10%, preferably less than 5% or less than 3%, when alanine (A) is present at position 119 of the amino acid sequence of the extracellular domain of human TGF-βRII, compared to when phenylalanine (F) and aspartic acid (D) are present at their respective positions, and each change is tested individually rather than as a combination of the two changes compared to the wild-type extracellular domain. 【0081】 Another way to define the antibody or antibody fragment of the present invention is that it is - Substitution of the phenylalanine (F) residue at position 25 of human TGFβRII isoform A (its wild-type sequence is as described in SEQ ID NO: 102) with alanine (A) reduces the binding of the antibody or antibody fragment by at least 50%, preferably at least 95% or 97%, and - The binding of the antibody or antibody fragment to the epitope of the extracellular domain of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) is reduced by at least 90%, preferably at least 95% or 97%, by alanine (A) substitution of the aspartic acid (D) residue at position 119 of human TGFβRII isoform A. 【0082】 The antibody or antibody fragment of the present invention may also be defined as an antibody or antibody fragment that binds to an epitope in the extracellular domain of human TGF-βRII, which comprises a phenylalanine (F) residue and an aspartic acid (D) residue at positions 25 and 119 of isoform A of human TGF-βRII (whose wild-type sequence is as described in SEQ ID NO: 102), respectively. 【0083】 In another embodiment, the antibody or antibody fragment binds to an epitope in the extracellular domain of human TGF-βRII, where the threonine (T) at position 52 of the extracellular domain epitope of isoform A of human TGF-βRII is a further essential residue for binding. The amino acid at position 52 of isoform A of human TGF-βRII corresponds to the amino acid at position 77 of isoform B. In this embodiment, the antibody or antibody fragment is preferably compared to the wild-type amino acid sequence of the extracellular domain of human TGF-βRII. -When phenylalanine (F) at position 25 of the wild-type amino acid sequence of the extracellular domain of human TGF-βRII is substituted with alanine (A), the binding reactivity is less than 5%, preferably less than 2%. -When the threonine (T) at position 52 of the wild-type amino acid sequence of the extracellular domain of human TGF-βRII is substituted with alanine (A), the binding reactivity is less than 60%, preferably less than 40% or 30%, more preferably less than 20%, and - When the aspartic acid (D) at position 119 of the wild-type amino acid sequence in the extracellular domain of human TGF-βRII is substituted with alanine (A), it exhibits a binding reactivity of less than 3%. 【0084】 Accordingly, the present invention encompasses antibodies or antibody fragments that specifically bind to an epitope of human TGF-βRII, which contains phenylalanine (F) at position 25, threonine (T) at position 52, and aspartic acid (D) at position 119 of the amino acid sequence of the extracellular domain of human TGF-βRII. Preferably, the binding of an antibody or antibody fragment to this epitope is determined by alanine scanning, where the antibody or antibody fragment that binds to this epitope has a binding activity or reactivity of less than 50%, preferably less than 5%, or less than 2%, when alanine (A) is located at position 25 of the amino acid sequence of the extracellular domain of human TGF-βRII, compared to when phenylalanine (F), threonine (T), and aspartic acid (D) are located at their respective positions; a binding activity or reactivity of less than 60%, preferably less than 40%, 30%, or less than 20%, when alanine (A) is located at position 52 of the amino acid sequence of the extracellular domain of human TGF-βRII; and a binding activity or reactivity of less than 10%, preferably less than 3%, when alanine (A) is located at position 119 of the amino acid sequence of the extracellular domain of human TGF-βRII, and each change is tested individually rather than as a combination of two changes compared to the wild-type extracellular domain. 【0085】 Another way to define the antibody or antibody fragment of the present invention is that it is - Substitution of the phenylalanine (F) residue at position 25 of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) with alanine (A) reduces antibody or antibody fragment binding by at least 50%, preferably at least 95% or 98%. - Substitution of the threonine (T) residue at position 52 of human TGFβRII isoform A (its wild-type sequence is as described in SEQ ID NO: 102) with alanine (A) reduces antibody or antibody fragment binding by at least 60%, preferably at least 70% or 80%, and - The binding to the epitope of the extracellular domain of human TGFβRII is characterized by a substitution of the aspartic acid (D) residue at position 119 of isoform A of human TGFβRII (whose wild-type sequence is as described in SEQ ID NO: 102) with alanine (A), which reduces the binding of the antibody or antibody fragment by at least 90%, preferably at least 97%. 【0086】 The antibodies or antibody fragments of the present invention may also be defined as antibodies or antibody fragments that bind to epitopes in the extracellular domain of human TGF-βRII, the epitopes comprising phenylalanine (F) residues at positions 25, 52, and 119 of isoform A of human TGF-βRII (whose wild-type sequence is as described in SEQ ID NO: 102), a threonine (T) residue, and an aspartic acid (D) residue, respectively. 【0087】 In another embodiment, the antibody or antibody fragment binds to the epitope of the extracellular domain of human TGF-βRII, with isoleucine (I) at position 54 and glutamic acid (E) at position 120 of the extracellular domain epitope of isoform A of human TGF-βRII being further essential residues for binding. The amino acids at positions 54 and 120 of isoform A of human TGF-βRII correspond to the amino acids at positions 79 and 145 of isoform B, respectively. In this embodiment, the antibody or antibody fragment is preferably compared to the wild-type amino acid sequence of the extracellular domain of human TGF-βRII. -When phenylalanine (F) at position 25 of the wild-type amino acid sequence in the extracellular domain of human TGF-βRII is substituted with alanine (A), the binding reactivity is less than 10%. - When isoleucine (I) at position 54 of the wild-type amino acid sequence in the extracellular domain of human TGF-βRII is substituted with alanine (A), the binding reactivity is less than 20%. -When the aspartic acid (D) at position 119 of the wild-type amino acid sequence of the extracellular domain of human TGF-βRII is substituted with alanine (A), the binding reactivity is less than 3%, preferably less than 2%, more preferably less than 1%, and -When the glutamic acid (E) at position 120 of the wild-type amino acid sequence of the extracellular domain of human TGF-βRII is substituted with alanine (A), it has a binding reactivity of less than 80%, preferably 70%, 60%, 50%, 40%, more preferably less than 30%, and most preferably less than 10% or 5%. 【0088】 Accordingly, the present invention includes an antibody or antibody fragment that specifically binds to an epitope of human TGF-βRII containing phenylalanine (F) at position 25, isoleucine (I) at position 54, aspartic acid (D) at position 119, and glutamic acid (E) at position 120 of the amino acid sequence of the extracellular domain of human TGF-βRII. Preferably, the binding of the antibody or antibody fragment to this epitope is determined by alanine scanning, where the antibody or antibody fragment that binds to this epitope has a binding activity or reactivity of less than 50%, preferably less than 10%, when alanine (A) is present at position 25 of the amino acid sequence of the extracellular domain of human TGF-βRII, compared to when phenylalanine (F), threonine (T), aspartic acid (D), and glutamic acid (E) are present at their respective positions, and when alanine (A) is present at position 54 of the amino acid sequence of the extracellular domain of human TGF-βRII If alanine(A) is present at position 119 of the amino acid sequence of the extracellular domain of human TGF-βRII, it has less than 20% binding activity or reactivity. If alanine(A) is present at position 120 of the amino acid sequence of the extracellular domain of human TGF-βRII, it has less than 10% binding activity or reactivity. If alanine(A) is present at position 120 of the amino acid sequence of the extracellular domain of human TGF-βRII, it has less than 80% binding activity or reactivity. If alanine(A) is present at position 120 of the amino acid sequence of the extracellular domain of human TGF-βRII, it has less than 70%, 60%, 50%, 40%, 30%, 10%, or 5% binding activity or reactivity. Each change is tested individually rather than as a combination of two changes compared to the wild-type extracellular domain. 【0089】 Another way to define the antibody or antibody fragment of the present invention is that it is - Substitution of the phenylalanine (F) residue at position 25 of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) with alanine (A) reduces antibody or antibody fragment binding by at least 50%, preferably at least 90%. - Substitution of the isoleucine (I) residue at position 54 of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) with alanine (A) reduces antibody or antibody fragment binding by at least 80%. - Substitution of the aspartic acid (D) residue at position 119 of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) with alanine (A) reduces the binding of antibody or antibody fragment by at least 90%, preferably at least 97%, 98%, or 99%, and - The binding of an antibody or antibody fragment to an epitope in the extracellular domain of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102) is reduced by at least 30%, preferably at least 40%, 50%, 60%, 70%, 90%, or 95%, by alanine (A) substitution of the glutamic acid (E) residue at position 120 of human TGFβRII isoform A (whose wild-type sequence is as described in SEQ ID NO: 102). 【0090】 The antibodies or antibody fragments of the present invention may also be defined as antibodies or antibody fragments that bind to epitopes in the extracellular domain of human TGF-βRII, the epitopes comprising phenylalanine (F) residues, isoleucine (I) residues, aspartic acid (D) residues, and glutamic acid (E) residues located at positions 25, 54, 119, and 120 of isoform A of human TGF-βRII (whose wild-type sequence is as described in SEQ ID NO: 102). 【0091】 The inventors have identified several antibodies containing a heavy chain variable region that specifically binds to an extracellular TGF-βRII epitope in which phenylalanine (F) at position 25 is essential for binding. An example of such an antibody has a heavy chain variable region (VH) having the following: (a) VH-CDR1 containing the amino acid sequence described in SEQ ID NO: 1, (b) VH-CDR2 containing the amino acid sequence described in Sequence ID No. 2, and (c) Contains VH-CDR3 containing the amino acid sequence described in SEQ ID NO: 3, Here, 1 to 5 amino acid residues may be replaced with their conserved amino acids within one or more CDRs selected from VH-CDR1, VH-CDR2, and VH-CDR3. This antibody is included in the present invention. 【0092】 Another example of such an antibody is a heavy chain variable region (VH) having the following: (a) VH-CDR1 containing the amino acid sequence described in SEQ ID NO: 4, (b) VH-CDR2 containing the amino acid sequence described in Sequence ID No. 5, and (c) Contains VH-CDR3 having the amino acid sequence described in SEQ ID NO. 6, Here, 1 to 5 amino acid residues may be replaced with their conserved amino acids within one or more CDRs selected from VH-CDR1, VH-CDR2, and VH-CDR3. This antibody is also included in the present invention. 【0093】 Another example of such an antibody is a heavy chain variable region (VH) having the following: (a) VH-CDR1 containing the amino acid sequence described in Sequence ID No. 7, (b) VH-CDR2 containing the amino acid sequence described in Sequence ID No. 8, and (c) Contains VH-CDR3 containing the amino acid sequence described in SEQ ID NO. 9, Here, 1 to 5 amino acid residues may be replaced with their conserved amino acids within one or more CDRs selected from VH-CDR1, VH-CDR2, and VH-CDR3. This antibody is also included in the present invention. 【0094】 Accordingly, the heavy chain variable region of the antibody or antibody fragment of the present invention may include a CDR1 selected from the group consisting of sequences described in SEQ ID NOs: 1, 4, and 7, a CDR2 selected from the group consisting of sequences described in SEQ ID NOs: 2, 5, and 8, and / or a CDR3 selected from the group consisting of sequences described in SEQ ID NOs: 3, 6, and 9, wherein 1 to 5 amino acid residues may be replaced with their conserved amino acids in any one or more of the CDRs selected from CDR1, CDR2, and CDR3. 【0095】 The framework region of the heavy chain variable region can be selected from any suitable framework region. Examples of suitable framework regions are those encoded by the human V genes IGHV3-15 and IGHV3-23. These germline V genes may contain one or more somatic mutations. 【0096】 In one embodiment of the present invention, the antibody or antibody fragment comprises a VH having the amino acid sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS (SEQ ID NO: 10), or a VH amino acid sequence having at least 80%, preferably at least 90%, and more preferably at least 95% identity thereto. 【0097】 In another embodiment, the antibody or antibody fragment comprises a VH having the amino acid sequence:QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKTTISGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS (SEQ ID NO: 11), or a VH amino acid sequence having at least 80%, preferably at least 90%, and more preferably at least 95% identity thereto. 【0098】 In another embodiment, the antibody or antibody fragment comprises a VH having the amino acid sequence:QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAASGKNYFDPWGQGTLVTVSS (SEQ ID NO: 12), or a VH amino acid sequence having at least 80%, preferably at least 90%, and more preferably at least 95% identity thereto. 【0099】 The heavy chain variable region may have 0 to 10, preferably 0 to 5, amino acid mutations relative to the indicated amino acid sequence. In a preferred embodiment, the heavy chain variable region may contain 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, preferably 0 to 3, preferably 0 to 2, preferably 0 to 1, more preferably 0 amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof at positions other than the CDR relative to the indicated amino acid sequence. The combination of insertions, additions, deletions, or substitutions is such that no more than 10, preferably 5, positions of the aligned sequences are identical. Gaps in one of the aligned sequences correspond to the same number of amino acids skipped in the other sequence. Amino acid substitutions, if present, are preferably conservative amino acid substitutions. Substitutions in the heavy chain variable region may be added to the substitutions in one or more CDRs described above. Conservative amino acids are known in the art based on the similarity of their respective functional groups based on characteristics such as charge, hydrophobicity, hydrophilicity, acidity, basicity, and size. 【0100】 Amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof are preferably not performed at the heavy-chain-light-chain binding interface. 【0101】 When an amino acid changes at the heavy-chain / light-chain interaction interface, it is preferable that the corresponding amino acid in the other chain changes to adapt to that change. Amino acid insertion or addition is preferably not accompanied by proline insertion or addition. 【0102】 The present invention encompasses antibodies or antibody fragments comprising variants of antibodies or antibody fragments described herein. Specifically, it encompasses antibodies or antibody fragments comprising a VH having any one of SEQ ID NOs: 22-91 and 93, i.e., any one of the VH sequences shown in Figure 4. It also encompasses antibodies or antibody fragments comprising at least one HCDR3 or all CDRs from any one of SEQ ID NOs: 22-91 and 93. Preferred antibodies or antibody fragments comprise a heavy chain variable region having or derived from the amino acid sequence described in SEQ ID NOs: 40, 43, 46, 47, 48, or 54, which is a variant of an antibody comprising a heavy chain variable region comprising the amino acid sequence described in SEQ ID NOs: 11. Other preferred antibodies or antibody fragments comprise a heavy chain variable region having or derived from the amino acid sequence described in SEQ ID NOs: 67, 70, 75, 76, 77, 78, 83, 84, or 88, which is a variant of an antibody comprising a heavy chain variable region comprising the amino acid sequence described in SEQ ID NOs: 12. Other preferred antibodies or antibody fragments include a heavy chain variable region having or derived from the amino acid sequence described in SEQ ID NO: 24 or 26, which is a variant of the antibody containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 10. The most preferred variants are those containing a heavy chain variable region having the amino acid sequence described in SEQ ID NOs: 40, 43, 46, 47, 48, 54, 67, 70, 75, 76, 77, 78, 83, 84, or 88. 【0103】 The heavy chain variable region of such variants may have 0 to 10, preferably 0 to 5, amino acid mutations relative to the indicated amino acid sequence. In preferred embodiments, the heavy chain variable region may contain 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, preferably 0 to 3, preferably 0 to 2, preferably 0 to 1, more preferably 0, amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof at positions other than the CDR relative to the indicated amino acid sequence. 【0104】 The antibody or antibody fragment, or binding domain of the present invention, may include any suitable light chain, such as a homogeneous light chain or common light chain as defined herein. 【0105】 In one embodiment, the light chain variable region contains the amino acid sequence of the IgVκ1-39*01 gene segment shown in Figure 1B, which has 0 to 10, preferably 0 to 5, amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof. IgVκ1-39 is an abbreviation for the immunoglobulin variable kappa 1-39 gene. This gene is also known as immunoglobulin variable kappa 1-39, IGKV139, or IGKV1-39. The external ID of this gene is HGNC:5740, Entrez Gene:28930, Ensembl:ENSG00000242371. A preferred amino acid sequence of IgVκ1-39 is shown in Figure 1A. This figure lists the sequence of the V region. The V region can be combined with one of five J regions. Figures 1B and 1C describe two preferred sequences of IgVκ1-39 combined with a J region. The combined sequences are indicated as IGKV1-39 / jk1 and IGKV1-39 / jk5, with alternative names IgVκ1-39*01 / IGJκ1*01 or IgVκ1-39*01 / IGJκ5*01 (named by the IMGT database at www.imgt.org). 【0106】 It is preferable that IgVκ1-39*01, which includes the light chain variable region, is a germline sequence. It is even more preferable that IGJκ1*01 or IGJκ5*01, which includes the light chain variable region, is a germline sequence. It is even more preferable that IGKV1-39 / jk1 or IGKV1-39 / jk5, which includes the light chain variable region, is a germline sequence. 【0107】 Mature B cells that produce antibodies containing light chains often produce light chains that have undergone one or more mutations in the germline sequence, which is the normal sequence in the organism's non-lymphoid cells. The process involved in these mutations is called somatic hypermutation. The resulting light chain is called affinity mature light chain. Such a light chain is an IgVκ1-39*01-derived light chain if it originates from the germline IgVκ1-39*01 sequence. In this specification, the term "IgVκ1-39*01" includes IgVκ1-39*01-derived light chains. Mutations introduced into the nucleic acid encoding the light chain by somatic hypermutation can also be artificially introduced in the laboratory. In the laboratory, other mutations in the light chain can also be introduced without necessarily affecting the properties of the light chain in terms of type rather than quantity. The light chain is at least an IgVκ1-39*01 light chain if it contains the sequence shown in Figure 1A, Figure 1B, or Figure 1C having 0 to 10, preferably 0 to 5, amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof. Preferably, the IgVκ1-39*01 light chain is the sequence shown in Figure 1A, Figure 1B, or Figure 1C having 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, or 0 to 4 amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof; more preferably, the sequence shown in Figure 1A, Figure 1B, or Figure 1C having 0 to 5, preferably 0 to 4, 0 to 3, 0 to 2, or 0 to 1 amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof; even more preferably, 0 to 3 amino acid mutations, insertions, deletions, substitutions, additions, and Or a light chain containing the sequence shown in Figure 1A, Figure 1B, or Figure 1C having a combination of these, more preferably the sequence shown in Figure 1A, Figure 1B, or Figure 1C having 0 to 2 amino acid mutations, insertions, deletions, substitutions, additions, or a combination thereof, more preferably the sequence shown in Figure 1A, Figure 1B, or Figure 1C having 0 amino acid mutations, insertions, deletions, substitutions, additions, or a combination thereof, most preferably the sequence shown in Figure 1A, Figure 1B, or Figure 1C having 0 amino acid mutations, insertions, deletions, substitutions, additions, or a combination thereof. 【0108】 In one embodiment, the antibody or its antibody fragment, or the binding domain, has a light chain variable region (VL) having the following: (a) VL-CDR1 containing the amino acid sequence described in SEQ ID NO: 19, (b) VL-CDR2 containing the amino acid sequence described in SEQ ID NO. 20, and (c) Contains VL-CDR3 having the amino acid sequence described in SEQ ID NO. 21, Here, 1 to 5 amino acid residues may be substituted with their conserved amino acids from one or more CDRs selected from VL-CDR1, VL-CDR2, and VL-CDR3. 【0109】 The antibody or antibody fragment of the present invention, or the light chain variable region of the binding domain, preferably comprises the CDR1, CDR2, and CDR3 regions, i.e., the CDRs of IGKV1-39 (according to IMGT), including the amino acid sequences CDR1-QSISSY (SEQ ID NO: 13), CDR2-AAS (SEQ ID NO: 14), and CDR3-QQSYSTPPT (SEQ ID NO: 15), allowing for 0 to 5 amino acid substitutions relative to the indicated amino acid sequence. According to Kabat numbering, the amino acid sequences are CDR1-RASQSISSYLN (SEQ ID NO: 19), CDR2-AASSLQS (SEQ ID NO: 20), and CDR3-QQSYSTPPT (SEQ ID NO: 21). Any amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof are preferably not present in the CDR3 region of the light chain variable region, and preferably not in the CDR1 or CDR2 region of the light chain variable region. Amino acid substitutions are preferably conservative amino acid substitutions. 【0110】 Specifically, the antibody or antibody fragment of the present invention, or the light chain variable region of the binding domain, preferably contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 16), or a VL amino acid sequence having at least 80% identity thereto. This allows for 0 to 5 amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof. Amino acid substitutions are preferably conservative amino acid substitutions. 【0111】 The antibody of the present invention may be of any isotype: IgA, IgM, IgG, IgD, or IgE. Preferably, the antibody is IgG, specifically IgG1 or IgG4. Most preferably, the antibody is IgG1. 【0112】 The constant region of the antibody of the present invention is preferably a human constant region, but may be that of any animal. This can be a mouse or rat constant region. Depending on the host organism being immunized, or depending on the screening method used to select recombinant antibodies produced in response to the antigen, the mouse or rat constant region may be advantageously used. 【0113】 The antibody or antibody fragment may include a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17. The antibody or antibody fragment may include a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. The constant region may contain a difference of one or more, preferably 10 or fewer, and preferably 5 or fewer amino acids from the constant region of a conventional human antibody. 【0114】 Some antibodies have modifications to their CH2 / lower hinge region to, for example, reduce Fc receptor interaction or ADCC, C1q binding, or other effector activity. The antibody of the present invention may be an IgG antibody having a variant CH2 and / or lower hinge domain such that the interaction between the antibody and the Fc-gamma receptor is reduced. Such a variant CH2 and / or lower hinge domain preferably contains an amino mutation at positions 235 and / or 236 (EU numbering), and preferably contains a residue at positions 235G and / or 236R. 【0115】 The isolated monoclonal antibody may contain two heavy chain constant regions of the IgG1 antibody, where lysine at position 447 according to the EU numbering system is deleted. 【0116】 Preferred antibodies or antibody fragments of the present invention include combinations of heavy chain variable region CDRs and light chain variable region CDRs listed in Table 1. [Table 1] 【0117】 A preferred antibody or antibody fragment of the present invention comprises a heavy chain having a VH containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 11, 12, 22-91, and 93, specifically a preferred VH as described herein, and a light chain having a VL containing the amino acid sequence described in SEQ ID NO: 16. This antibody or antibody fragment may contain any constant domain as described herein. 【0118】 In one embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 10 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0119】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 11 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0120】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 12 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0121】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 43 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0122】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 75 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0123】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 70 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0124】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 84 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0125】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 88 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0126】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 40 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0127】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 83 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0128】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 78 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0129】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 47 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0130】 In another embodiment, the antibody or antibody fragment described herein comprises a heavy chain having VH containing the amino acid sequence described in SEQ ID NO: 76 and a light chain having VL containing the amino acid sequence described in SEQ ID NO: 16. 【0131】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 10 and two light chain variable regions of SEQ ID NO: 16. 【0132】 In another embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 11 and two light chain variable regions of SEQ ID NO: 16. 【0133】 In another embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 12 and two light chain variable regions of SEQ ID NO: 16. 【0134】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 43 and two light chain variable regions of SEQ ID NO: 16. 【0135】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 75 and two light chain variable regions of SEQ ID NO: 16. 【0136】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 70 and two light chain variable regions of SEQ ID NO: 16. 【0137】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 84 and two light chain variable regions of SEQ ID NO: 16. 【0138】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 88 and two light chain variable regions of SEQ ID NO: 16. 【0139】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 40 and two light chain variable regions of SEQ ID NO: 16. 【0140】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 83 and two light chain variable regions of SEQ ID NO: 16. 【0141】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 78 and two light chain variable regions of SEQ ID NO: 16. 【0142】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 47 and two light chain variable regions of SEQ ID NO: 16. 【0143】 In one embodiment, the antibody or antibody fragment described herein comprises two heavy chain variable regions of SEQ ID NO: 76 and two light chain variable regions of SEQ ID NO: 16. 【0144】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 10 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0145】 In another embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 11 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0146】 In another embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 12 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0147】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 43 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0148】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 75 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0149】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 70 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0150】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 84 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0151】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 88 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0152】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 40 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0153】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 83 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0154】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 78 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0155】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 47 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0156】 In one embodiment, the antibody of the present invention is (A) A heavy chain having a VH containing the amino acid sequence described in SEQ ID NO: 76 and a heavy chain constant region containing the amino acid sequence described in SEQ ID NO: 17, and (B) A light chain comprising a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO: 18. 【0157】 The present invention relates to a binding domain that specifically binds to human TGF-βRII, The following heavy chain variable region (VH) can be selected: (A) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 12, (B) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 26, (C) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 30, (D) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 40, (E) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 61, (F) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 65, (G) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 70, (H)VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 76, (I) VH having VH-CDR1, VH-CDR2, and VH-CDR3, and having the amino acid sequence described in SEQ ID NO: 85, and (J) A VH having VH-CDR1, VH-CDR2, and VH-CDR3, comprising any one of the VH having the amino acid sequence described in SEQ ID NO: 86, Herein, we further provide a binding domain in which 1 to 5 amino acid residues may be substituted with the conserved amino acids in any one or more CDRs selected from VH-CDR1, VH-CDR2, and VH-CDR3. 【0158】 These VH-CDR1, VH-CDR2, and VH-CDR3 sequences are shown in bold and underlined in the sequence listings provided herein. 【0159】 In one embodiment, the binding domain of the present invention includes a VH amino acid sequence selected from SEQ ID NOs: 12, 26, 30, 40, 61, 65, 70, 76, 85, and 86, or a VH amino acid sequence having at least 80% identity thereto. 【0160】 The binding domain of the present invention has been shown to be useful in monovalent and polyvalent forms, and offers various applications as one or more binding domains incorporated into monovalent or divalent molecules, or into multispecific molecules. In monovalent form, the binding domain has superior TGF-βRII blocking ability compared to monovalent control antibodies, making them suitable for the above applications. 【0161】 In certain embodiments, the present invention provides an antibody, preferably a multispecific antibody, comprising the binding domain of the present invention in a monovalent form, which has equivalent receptor blocking activity at equimolar concentrations compared to a bivalent monospecific control antibody, preferably measured in the same assay. In certain embodiments, the control antibody comprises two heavy chain variable regions having the amino acid sequence described in SEQ ID NO: 97 and two light chain variable regions having the amino acid sequence described in SEQ ID NO: 135. In certain embodiments, the assay is a TGFβ-reporter assay, preferably the TGFβ-reporter assay described in Example 5. In certain embodiments, equivalent receptor blocking activity includes a 5-2, preferably 3-fold deviation from the receptor blocking activity of the control antibody. 【0162】 The antibodies and binding domains described herein and claimed, such as the antibodies and binding domains described in the embodiments above, are preferably isolated antibodies or binding domains. Preferably, they are monoclonal antibodies. More preferably, they are isolated monoclonal antibodies. 【0163】 The antibody or antibody fragment, or binding domain of the present invention, interferes with the binding of ligands TGF-β1, TGF-β2, and / or TGF-β3 to TGF-βRII. The term "interferes with binding" means that the antibody or antibody fragment is directed to an epitope on TGF-βRII and competes with TGB-β1, TGB-β2, and / or TGB-β3 for binding to TGF-βRII. The antibody or antibody fragment, or binding domain, may weaken ligand binding, or, if it is already bound to TGF-βRII, may substitute ligand binding, or, for example, sterically hindrance, at least partially prevent the ligand from binding to TGF-βRII and / or interfere with or prevent TGF-βRI-TGF-βRII complex formation. The antibody or antibody fragment, or the binding domain, weakens the formation of a complex between TGF-βRI and TGF-βRII, and if a complex has already formed, it may replace such complex, or, for example, sterically hindrance may at least partially prevent TGF-βRI from forming a complex with TGF-βRII. The term "interferes with binding" means that the antibody or antibody fragment, or the binding domain of the present invention, blocks the binding of ligands TGF-β1, TGF-β2, and / or TGF-β3 to TGF-βRII. 【0164】 The present invention further provides expression vectors comprising an antibody or antibody fragment described herein, or a polynucleotide encoding either or both of the heavy and light chains of a binding domain. Examples of vectors include plasmids, phagemids, cosmids, viruses, and phage nucleic acids, or other nucleic acid molecules that can replicate in prokaryotic or eukaryotic host cells, such as mammalian cells. The vector may be an expression vector in which a polynucleotide encoding either or both of the heavy and light chains of the antibody or antibody fragment of the present invention is operably linked to an expression regulatory element. A typical expression vector includes transcription and translation terminators, start sequences, and promoters useful for regulating the expression of the polynucleotide. 【0165】 In the art, various methods exist for producing antibodies. Antibodies are typically produced by cells that express the nucleic acid encoding the antibody. Accordingly, the present invention also provides isolated cells or cells in tissue cultures that produce and / or contain the antibody or antibody fragment of the present invention. Typically, these are in vitro cells, isolated cells, or recombinant cells. Such cells contain the nucleic acid encoding the antibody or antibody fragment of the present invention. These cells are preferably animal cells, more preferably mammalian cells, more preferably primate cells, and most preferably human cells. Suitable cells for the purposes of the present invention are any cells that can contain, preferably produce, and / or contain the antibody according to the present invention. Preferably, these cells are hybridoma cells, Chinese hamster ovary (CHO) cells, NS0 cells, or PER.C6 cells. It is particularly preferred that the cells are CHO cells. 【0166】 Cell cultures or cell lines containing cells according to the present invention are further provided. Cell lines developed for the industrial-scale production of proteins and antibodies are further referred to herein as industrial cell lines. 【0167】 The present invention provides a method for producing the antibody or antibody fragment or binding domain of the present invention, further comprising culturing cells of the present invention and collecting the antibody or antibody fragment or binding domain from the culture. The cells may be cultured in serum-free medium. Preferably, the cells are suitable for suspension growth. The antibody or antibody fragment or binding domain may be purified from the culture medium. Preferably, the antibody or antibody fragment or binding domain is purified by affinity. 【0168】 The present invention further provides pharmaceutical compositions comprising an antibody or antibody fragment or binding domain described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. 【0169】 When the antibody or antibody fragment of the present invention is formulated for use as an intravenous injection or infusion solution, the injection or infusion solution may be any form of aqueous solution, suspension, or emulsion, or it may be formulated as a solid drug with a pharmaceutically acceptable carrier so that the drug dissolves, suspends, or emulsifies in the solvent at the time of use. Examples of solvents used in intravenous injection or infusion solutions include distilled water for injection, saline solution, glucose solution, and isotonic solutions (in which sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, propylene glycol, etc. are soluble). 【0170】 Examples of pharmaceutically acceptable carriers include stabilizers, solubilizers, suspending agents, emulsifiers, sedatives, buffers, preservatives, disinfectants, pH adjusters, and antioxidants. Stabilizers that can be used include various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, and dibutylhydroxytoluene. Solubilizers that can be used include alcohols (e.g., ethanol), polyols (e.g., propylene glycol and polyethylene glycol), and nonionic surfactants (e.g., Polysorbate 20®, Polysorbate 80®, and HCO-50). Suspending agents that can be used include glyceryl monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, and sodium lauryl sulfate. Emulsifiers that can be used include gum arabic, sodium alginate, and tragacanth. As sedatives, benzyl alcohol, chlorobutanol, sorbitol, etc., can be used. As buffers, phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, epsilon-aminocaproate buffer, etc., can be used. As preservatives, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, borax, etc., can be used. As disinfectants, benzalkonium chloride, parahydroxybenzoic acid, chlorobutanol, etc., can be used. As pH adjusters, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc., can be used.As antioxidants, (1) aqueous antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium bisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, and α-tocopherol; or (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, and phosphoric acid can be used. 【0171】 Infusion solutions or infusion solutions for intravenous infusion can be produced by sterilizing or performing aseptic procedures in the final process, such as sterilization by filtration, and then filling them into sterile containers. Infusion solutions or infusion solutions for intravenous infusion can be used by dissolving a vacuum-dried or lyophilized sterile powder (which may contain pharmaceutically acceptable carrier powder) in a suitable solvent at the time of use. 【0172】 The present invention further provides a method for treating cancer in a subject, comprising administering an effective amount of an antibody or antibody fragment, binding domain, or pharmaceutical composition described herein to a subject in need thereof. Accordingly, the present invention provides an antibody or antibody fragment or binding domain described herein for use in treating cancer in a subject. The present invention further provides a pharmaceutical for preventing cancer, suppressing the progression or recurrence of cancer symptoms, and / or treating cancer, comprising an antibody or antibody fragment or binding domain described herein as an active ingredient. 【0173】 Cancer patients typically have abnormal cells that are removed from their bodies. As used herein, “abnormal cells” include tumor cells, more specifically, tumor cells present on any type of cancerous tissue associated with cancer type that correlate with higher TGF-βRII expression than normal. Abnormal cells, as used herein, also mean cells with increased signaling as a result of increased TGF-β expression and / or TGF-β release, as well as cells that form a suppressive environment that reduces the effectiveness of tumor immunity due to abnormal TGF-β signaling and / or expression, or higher than normal TGF-β, TGF-βRI, and / or TGF-βRII expression, and / or higher than normal latent TGF-β release. 【0174】 The antibodies, antibody fragments, or binding domains of the present invention may be effective in treating several types of cancer, including those that correlate with higher-than-normal TGF-β signaling, specifically, higher-than-normal TGF-βRII expression. Examples include, but are not limited to, breast cancer, colon cancer, colorectal cancer, gastric cancer, glioblastoma, cervical cancer, hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, melanoma, myelodysplastic syndrome, pancreatic cancer, prostate cancer, and kidney cancer. 【0175】 The antibody, antibody fragment, or binding domain of the present invention blocks the binding of human TGF-β to human TGF-βRII on cells, thereby inhibiting TGF-βRII signaling. This results in a reduction of the proliferation of harmful or abnormal cells, as well as / or enhancement of tumor immunity and other beneficial effects. 【0176】 Accordingly, the present invention also provides a method for blocking the binding of human TGF-β from cells to human TGF-βRII, comprising: providing cells with an antibody or antibody fragment or binding domain as described herein; and enabling the antibody or antibody fragment to bind to human TGF-βRII in cells, thereby blocking the binding of human TGF-β from cells to human TGF-βRII. This may be an in vitro method. 【0177】 Depending on the desired activity, the antibodies of the present invention may possess regulated effector function. Antibody-dependent cytotoxicity (ADCC), also known as antibody-dependent cell-mediated cytotoxicity, is a cell-mediated immune defense mechanism in which effector cells of the immune system actively lyse target cells to which membrane surface antigens are bound by specific antibodies. ADCC effector function is typically mediated by Fc receptors (FcRs). These receptors are the major immunomodulatory receptors that link antibody-mediated (humoral) immune responses to cellular effector function. Receptors for all classes of immunoglobulins have been identified, including FcγR (IgG), FcεRI (IgE), FcαRI (IgA), FcμR (IgM), and FcδR (IgD). Three classes of human IgG receptors are found on leukocytes: CD64 (FcγRI), CD32 (FcγRIIa, FcγRIIb, and FcγRIIc), and CD16 (FcγRIIIa and FcγRIIIb). FcγRI is classified as a high-affinity receptor (KD in the nanomolar range), while FcγRII and FcγRIII are low to intermediate affinity receptors (KD in the micromolar range). In antibody-dependent cytotoxicity (ADCC), FcvR on the surface of effector cells (natural killer cells, macrophages, monocytes, and eosinophils) binds to the Fc region of IgG that itself binds to target cells. Upon binding, a signaling pathway is triggered that leads to the secretion of various substances such as lytic enzymes, perforin, granzymes, and tumor necrosis factor, which mediate the destruction of target cells. The level of ADCC effector function varies depending on the human IgG subtype. Simply put, ADCC effector function is high in human IgG1 and IgG3, and low in IgG2 and IgG4, depending on the allotype and specific FcvR. The knowledge that FcvR binding sites are present on antibodies has led to the development of manipulated antibodies lacking ADCC effector function. 【0178】 Another type of effector function, independent of effector cells, is called complement-dependent cytotoxicity (CDC). This is the effector function of IgG and IgM antibodies. It is another mechanism by which therapeutic antibodies or antibody fragments can achieve antitumor effects. CDC is initiated when C1q, the initiating component of the classical complement pathway, is immobilized on the Fc portion of a target-binding antibody. This is the first step in the complex complement activation cascade, which can ultimately lead to the lysis of antibody-labeled cells. 【0179】 In the antibodies of the present invention, ADCC activity can be enhanced by different techniques, one of which is fucose removal. Fucose removal has resulted in increased antitumor activity in several in vivo models (Junttila et al., Cancer Research (2010), Vol.70(22), pp.4481-4489). Afucosylation techniques may also be applied to prevent fucosylation of the N-linked carbohydrate structure within the Fc region. 【0180】 The antibodies of the present invention can have their effector function reduced or eliminated. For example, leucine at position 235 according to the EU numbering system may be replaced with glycine, and / or glycine at position 236 according to the EU numbering system may be replaced with arginine. Such modifications ensure that binding to the Fc receptor and / or effector function is eliminated or reduced. In the same spirit, other substitutions, deletions, or insertions known in the art are also incorporated into the present invention. 【0181】 The present invention further provides a method for inhibiting signal transduction to cells induced by the binding of human TGF-β to human TGF-βRII, comprising: providing cells with an antibody or antibody fragment or binding domain as described herein; and enabling the antibody or antibody fragment to bind to human TGF-βRII in cells, thereby inhibiting signal transduction to cells. This may be an in vitro method. 【0182】 The present invention also provides a method for preventing or suppressing metastasis, comprising administering to a subject an effective amount of an antibody or antibody fragment, binding domain, or pharmaceutical composition described herein. 【0183】 The antibodies, antibody fragments, or binding domains of the present invention may be used as monotherapy to treat cancer, but may also be used in combination with other anticancer agents. Other anticancer agents include, but are not limited to, therapeutic antibodies that target the same or different tumor antigens or modulate elements of the immune system, agents used in chemotherapy (e.g., cyclophosphamide), and agents used in applications related to topical administration, including hormone therapy or oncolytic viruses. Therapy with the antibodies, antibody fragments, or binding domains of the present invention may also be used in combination with other anticancer treatments, such as surgery or radiotherapy. Therapy combinations may be simultaneous, separate, or sequential. 【0184】 Throughout this specification and the appended claims, the words “comprise,” “include,” and “having,” as well as variations such as “comprises,” “comprising,” “includes,” and “including,” shall be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically enumerated, where the content permits. 【0185】 The articles "a" and "an" are used herein to refer to one or more (i.e., one or at least one) grammatical objects of the article. For example, "an element" can mean one or more elements. 【0186】 "Multiple" means two or more. 【0187】 In this specification, unless otherwise noted, amino acid positions assigned to the CDR and framework within the variable region of an antibody or antibody fragment are specified by Kabat numbering (see Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md., 1987 and 1991)). Amino acids within the constant region are indicated by the EU numbering system based on Kabat amino acid positions (see Sequences of proteins of immunological interest, NIH Publication No. 91-3242). 【0188】 The acceptance number is primarily provided to offer a further method for target identification, and the actual sequence of the bound protein may change due to mutations in coding genes, such as mutations that occur in some cancers. The antigen-binding site binds to the antigen and its various variants, such as those expressed by some antigen-positive immune cells or tumor cells. 【0189】 Where a gene or protein is referred to herein, preferably the human form of that gene or protein is referred to. Where a gene or protein is referred to herein, preferably a native gene or protein, as well as a variant of that gene or protein that can be detected in tumors, cancers, etc., preferably a variant of that gene or protein that can be detected in human tumors, cancers, etc. 【0190】 HGNC is an abbreviation for the HUGO Gene Nomenclature Committee. The number following the abbreviation is an access number that allows information about the gene and the protein encoded by that gene to be retrieved from the HGNC database. Entrez Gene provides an access number or gene ID that allows information about the gene or the protein encoded by that gene to be retrieved from the NCBI (National Center for Biotechnology Information) database. Ensemble provides an access number that allows information about the gene or the protein encoded by that gene to be obtained from the Ensemble database. Ensemble is a joint project between EMBL-EBI and the Wellcome Trust Sanger Institute to develop a software system that generates and maintains automated annotations for selected eukaryotic genomes. [Brief explanation of the drawing] 【0191】 [Figure 1] The amino acid sequences of the IGKV1-39 light chain variable V region (Figure 1A), the IGKV1-39 / jk1 light chain variable region (Figure 1B), and the IGKV1-39 / jk5 light chain variable region (Figure 1C) are shown. [Figure 2] Figure 2A shows FACS data of antibody binding to endogenously expressed TGF-βRII on CCD18Co cells. Figure 2A shows MFI PE of antibodies containing heavy chain variable regions with SEQ ID NO: 92 (negative control), SEQ ID NO: 93, and SEQ ID NO: 94. Figure 2B shows MFI PE of antibodies containing heavy chain variable regions with SEQ ID NO: 92 (negative control), SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 95, and SEQ ID NO: 96. [Figure 3] ELISA data of ligand-blocking activity for antibodies containing heavy chain variable regions with SEQ ID NO: 92 (negative control), SEQ ID NO: 93, and SEQ ID NO: 94 (Figure 3A), and antibodies containing heavy chain variable regions with SEQ ID NO: 92 (negative control), SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 95, and SEQ ID NO: 96 (Figure 3B) are presented. [Figure 4]The amino acid sequence alignments of the heavy chain, including the heavy chain variable region with SEQ ID NO: 10 (central alignment), SEQ ID NO: 11 (lower alignment), and SEQ ID NO: 12 (upper alignment), generated using the AlignX application of the Vector NTI Program Advance 11.5.2 software, are presented along with their respective affinity maturation variants. Identical amino acids are shown in black text against a white background, slightly similar amino acids in white text against a gray background, conservative changes in black text against a gray background, and dissimilar amino acids in white text against a dark gray background. [Figure 5] This shows the binding affinity of the parent antibodies (SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12) and affinity-matured variants (SEQ ID NO: 10 variant, SEQ ID NO: 11 variant, SEQ ID NO: 12 variant). ka is the on-rate in 1 / millisecond, and kd is the off-rate in 1 / second. [Figure 6] The graphs show data from a luciferase reporter assay of affinity-matured variants. The X-axis represents antibody concentration (μg / mL). The Y-axis represents the induction ratio of the Smad complex as a measure of TGF-β signaling inhibition. Graphs A-K each compare the activity of the affinity-matured variant with that of the control antibody (SEQ ID NO: 97). Basal TGF-β is included as a control for TGF-β stimulation of cells. [Figure 7] The data from alanine scanning is shown. Figure 7A provides an overview of how essential residues are identified and mapped. Figure 7B shows the average fluorescence percentages for SEQ ID NO: 10, SEQ ID NO: 12, and SEQ ID NO: 93 compared to the wild type. Figure 7C is a table showing the binding reactivity percentages for SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 93, and SEQ ID NO: 98 (control) compared to the wild type. Essential residues for binding are enclosed in rectangles. Figure 7D shows the mapping of essential residues on TGFβRII. [Figure 8]The results from screening various bispecific antibodies containing the TGF-βRII binding domain of the present invention in a TGF-β reporter assay are shown. The X axis represents the antibody concentration (μg / mL). The Y axis represents the induction factor of Smad signaling. Graphs A-E each compare the activity of a bispecific antibody containing a single TGF-βRII binding domain with a positive control antibody known to block ligand binding to TGF-βRII(+), as described in Example 1. Basal TGF-β is included as a control for TGF-β stimulation of cells. A) Δ ​​is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 76, □ is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 61, and ● is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 26. B) ○ represents a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 70, * represents a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 70, □ represents a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 61, ● represents a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 86, and Δ represents a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 65. C) * is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 65, ○ is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 40, ● is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 12, □ is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 76, and Δ is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 26. D) ● is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 12, and □ is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in SEQ ID NO. 85.E)● is a TGF-βRII binding domain containing a heavy chain variable region having the amino acid sequence described in Sequence ID No. 86. 【0192】 The following examples illustrate the present invention and are not intended to limit it in any way. [Examples] 【0193】 Example 1 - Antibody Production Transgenic mice containing a common IGKV1-39 light chain (MeMo® mice) were immunized with human TGF-βRII (isoform A), thereby generating an immune response including the production of human anti-TGF-βRII-specific antibodies. Lymphatic material from the immunized mice was collected, and nucleic acids were extracted therefrom and used to synthesize cDNA encoding the heavy chain variable region of such antibodies. A phage display library was generated using the cDNA, and human TGF-βRII-binding Fab was selected therefrom using a Kingfisher selection robot. 【0194】 Two rounds of affinity-driven selection using biotinylated recombinant protein at different concentrations were performed using a Kingfisher robot. Human TGF-βRII-Fc was biotinylated using the EZ-Link® Sulfo-NHS-Biotin kit (ThermoFisher, catalog no. 21217) according to the manufacturer's protocol, divided into equal volumes, and stored at -20°C until use. Two subsequent rounds of in-solution selection were performed using biotinylated human TGF-βRII-Fc with a Kingfisher robot. Three different concentrations of protein were used in the first selection round. An antigen-free selection was included as a negative control. 50 μg / mL of total human IgG (Sigma, catalog no. 1456) was added to the solution during all phage library incubation to minimize selection of Fc conjugates. After washing, conjugated phages were eluted with trypsin. Phage output was determined according to the spot method, where TG1 cells were infected, plated onto LB-Amp / Glu agar plates, and single colonies were harvested for screening. A second selection round was performed using the output from the first round. In the second selection round, TGF-βRII-Fc-biotin was used, starting from the concentration used in each first selection round output and decreasing in protein levels. 【0195】 Colonies were collected in 96-well plates, and periplasmic extracts containing soluble Fab were prepared. The resulting Fab-containing fraction was used to identify TGF-βRII-specific clones using FACS. 【0196】 HEK293T cells transiently transfected with human TGF-βRII were used for FACS screening. The final Fab concentration was 0.5–5 μg / mL. Fab binding to TGF-βRII was detected using goat anti-kappa light chain antibody (Ab0646, 5 μg / mL), followed by rabbit anti-goat PE (Ab0330, 1 / 100 dilution). 【0197】 Two rounds of immunization were performed to obtain a large panel of Fab for further characterization. In the second round of immunization, different vectors were used to increase expression levels, and mice were co-immunized with human TGF-βRI. This may have contributed to the higher immune response generated in the mice observed during the second round of immunization. 【0198】 Based on information obtained from US2010 / 0119516, a positive control antibody was produced. This positive control antibody contains two heavy chain variable regions and two light chain variable regions having the amino acid sequences of mAb TGF1 described therein (SEQ ID NO: 97 and SEQ ID NO: 135, respectively). Antibodies containing these heavy chain and light chain variable regions have been reported to block ligand binding to TGF-βRII. 【0199】 A negative control antibody against RSV was produced. This negative control antibody contains two heavy chain variable regions having the amino acid sequence described in SEQ ID NO: 136 and two light chain variable regions described in SEQ ID NO: 16. 【0200】 Example 2 - Characterization of Antibodies The VH fragment of TGF-βRII-binding Fab identified in Example 1 was re-cloned into an IgG expression format, expressed as IgG, and purified from 293T freestyle cells. 【0201】 antigen binding Antibodies were screened for binding to endogenously expressed human TGF-βRII on CCD18Co cells using FACS. The results are shown in Figure 2. All tested antibodies showed similar binding to CCD18Co cells. 【0202】 Fabs containing a heavy chain variable region having the amino acids described in SEQ ID NO: 11, obtained from the first immunization round, also contain Fabs containing a heavy chain variable region having the same HCDR3 sequence as Fabs obtained from the second immunization round, e.g., the amino acid sequence described in SEQ ID NO: 93. This indicates that the recombination of the VDJ gene segment in mice is nearly identical in response to this antigen. 【0203】 binding affinity The binding affinity of antibodies containing heavy chain variable regions having the amino acid sequences described in SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 93, and SEQ ID NO: 12 was determined by SPR. For this purpose, the antibodies were reformatted as single-specific divalent IgG for TGFβRII. 【0204】 Anti-TGF-βRII IgG antibody was captured on the surface of a CM5 sensor chip using immobilized anti-CH1 antibody (Ab0669, BD catalog number BD555784), and then human recombinant TGF-βRII (R&D systems catalog number 241-R2 / CF, region Ile24-Aps195) was added. Measurements were performed at 25°C. Coupling was performed at pH 4.5. The results are shown in Table 2. [Table 2] 【0205】 Ligand blockade The ligand-blocking activity of IgG samples was determined using an ELISA assay. 【0206】 An ELISA plate was coated with 0.4 μg / mL of TGF-β1. Human TGF-βRII-Fc (R&D, catalog number 341-BR) was added at a final concentration of 0.01 μg / mL. The antibody was incubated in a 3-fold concentration range, starting from a final concentration of 10 μg / mL. An antibody that specifically binds to tetanus toxoid containing a heavy chain variable region with the amino acid sequence described in SEQ ID NO: 92 was included as a control. Antibodies that bind to human TGF-βRII-Fc were detected with biotin-conjugated anti-human Fc antibody (1:10.000) and streptavidin-HRP (1:2000). 【0207】 As shown in Figure 3, all tested antibodies exhibited good ligand-blocking activity compared to the control antibody. The IC50 values ​​of the selected antibodies are shown in Table 3. [Table 3] 【0208】 Example 3 - Affinity Maturation We evaluated whether antibodies with higher affinity could be produced by generating Fab phage display libraries of variant heavy chains containing variable heavy chain regions having the amino acid sequences described in SEQ ID NOs: 10, 11, and 12, which specifically bind to TGF-βRII and block ligand interactions with TGF-βRII and heterodimerization between TGF-βRII and TGF-βRII. These libraries were designed to generate heavy chain variable regions with increased affinity and typically have 3-4 mutations, i.e., one in CDR1, one in CDR2, and one or two in CDR3, with a certain number of mutations having more than 4 overall. A summary of these variants is provided in Figure 4 as sequence alignments. 【0209】 Variants with higher affinity were selected using two different selection methods, both using biotinylated human TGF-βRII-Fc as the antigen, and both using a Kingfisher selection robot. Several selection rounds were performed. The first selection round included affinity-based selection as described in Example 1, using different concentrations of biotinylated TGF-βRII-Fc. Subsequently, only the output from the selection with the lowest antigen concentration showing clear enrichment was further used in two separate selection methods. The first selection method involved two additional affinity-based selection rounds, but this time using antigen concentrations lower than the optimal antigen concentration used in the previous selection round. The second selection method also involved two additional affinity-based selection rounds, both using lower antigen concentrations, and also included an off-rate-based method that included a washing step in the presence of an excess amount of non-biotinylated antigen. 【0210】 During all phage library incubations, 50 μg / mL of total human IgG (Sigma, catalog number I4506) was added to the solution to minimize the selection of Fc binding agents. After washing, bound phages were eluted with trypsin. Phage output was determined according to the spot method, and TG1 cells were then infected with serial dilutions of the phage output, plated onto LB-Amp / Glu agar plates, and colonies were counted the following day. 【0211】 Phage output was rescued by bacterial infection, generating enough phages for subsequent selection, and plates containing bacterial colonies were also produced. The colonies were collected in 96-well plates for antibody production. The generated antibodies were used to prepare periplasmic extracts containing soluble Fab. 【0212】 Affinity-mature variants were reformatted as single-specific divalent IgG for TGF-βRII. SPR analysis was performed to determine the affinity of the variants for TGF-βRII. The results are shown in Table 4 and Figure 5. [Table 4-1] [Table 4-2] [Table 4-3] 【0213】 Variant reporter assay Affinity-matured variants were reformatted to the bivalent IgG format described in Example 2. The resulting antibodies were used in a TGF-βRII luciferase-based reporter assay to test their ability to inhibit ligand-induced activation of the receptor. 【0214】 Reporter CAGA in 293F Freestyle Cell 12Luciferase was transiently transfected. The following day, the transfected cells were plated and stimulated with 1 ng / mL of hTGF-β1 in the presence / absence of six semi-logarithmic serial dilutions of anti-TGF-βRII antibody. Anti-TGF-βRII antibody was added concurrently. The initial and maximum antibody concentrations were 10 μg / mL, and the minimum concentration was 0.03 μg / mL. The mixture of 293F freestyle cells, hTGF-β1, and anti-TGF-βRII antibody was incubated for 3 hours in a 5% CO2 incubator at 37°C. Titration of one well without TGF-β and a negative competing control containing the heavy chain variable region with SEQ ID NO: 97. As a readout, the Steady-Glo luciferase assay system detection reagent was added, and luciferase was measured on EnVision after a 5-minute incubation. The folding response was calculated as follows. 【number】 【0215】 The results are shown in Figure 6. This data indicates that some of the variants exhibit improved ligand-blocking activity compared to their parent antibodies. The IC50 values ​​for the selected antibodies are shown in Table 5. [Table 5] 【0216】 Example 4 - Epitope Mapping To identify the TGF-βRII residues that constitute a portion of the epitopes bound by the antibodies generated herein, shotgun mutagenesis experiments were performed using standard techniques (Davidson and Doranz, 2014). As a control in the shotgun mutagenesis approach, an antibody containing a heavy chain variable region with SEQ ID NO: 98 was used. This antibody was unable to block ligand binding to the receptor and was able to bind to the receptor in the presence of all functional TGF-βRII antibodies. The results are shown in Figure 7. 【0217】 TGF-βRII Blocking Activity of Antibodies Containing the Example 5 - TGF-βRII Binding Domain RSVxTGF-βRII and antigen AxTGF-βRII antibodies were screened in the TGFβ reporter assay. 【0218】 A bispecific antibody was produced that includes a first binding domain that binds to TGF-βRII and includes the VH region of a series of antibodies described herein, and a second binding domain that binds to RSV and includes the VH region having the amino acid sequence set forth in SEQ ID NO: 136, or a second binding domain that binds to an antigen (antigen A) expressed on the same cells as TGF-βRII. Antigen A is an arbitrarily selected antigen that does not react with TGFβ or affects the signal transduction cascade tested in the TGFβ reporter assay. Also included were the positive control antibody and negative control antibody described in Example 1. 【0219】 The TGFβ reporter assay uses a CAGA luciferase vector that contains 12 copies of the CAGA box, which are SMAD3 binding sequences and SMAD4 binding sequences. [Dennler et al, 1998]. Binding of TGFβ to TGF-βRII results in phosphorylation of TGF-βRI. Phosphorylation of TGF-βRI initiates a signal transduction cascade that results in phosphorylation and activation of SMAD2 and SMAD3, which then form a complex with SMAD4. The SMAD complex then moves to the nucleus and binds to the SMAD binding element (SBE) in the nucleus, resulting in transcription and expression of TGFβ / SMAD-responsive genes. CAGA 12 A luciferase reporter is used to monitor activation by TGFβ, and after transfecting the reporter into mammalian cells, TGF-βRII blocking antibodies can be screened. 12 After transfecting mammalian cells with the reporter, TGF-βRII blocking antibodies can be screened using the luciferase reporter to monitor activation by TGFβ. 【0220】 Frozen 293FF cells, stably transfected to express antigen A, were transiently transfected with a TGFβ reporter. IgG was tested at final concentrations of 10 μg / mL to 100 pg / mL. IgG was added to a final volume of 25 μL (4-fold enrichment). Subsequently, 25 μL of hTGFβ1 (4-fold enrichment) was added at a final concentration of 1 ng / mL. 50 μL of transfected cell suspension (5 × 10⁶) was then used. 4 Cells were added. 100 μL of Steady-Glo® substrate was added to each well and incubated for 5 minutes. Luminescence was measured on EnVision and the results were analyzed using Graphpad Prism. 【0221】 The results are shown in Figure 8. Bispecific antibodies containing a monovalent binding domain for TGF-βRII and a control binding domain for RSV, as well as bispecific antibodies containing a monovalent binding domain for TGF-βRII and antigen A, block the interaction between TGF-β and TGF-βRII. Bispecific antibodies targeting TGF-βRII and RSV, containing a TGF-βRII binding domain with a VH region having the amino acid sequences described in SEQ ID NOs. 76 and 70, are nearly as potent as bivalent monospecific positive control antibodies. Bispecific antibodies targeting TGF-βRII and antigen A, containing a TGF-βRII binding domain with a VH region having the amino acid sequences described in SEQ ID NOs. 70, 61, 86, 65, 12, and 76, are more potent than bivalent monospecific positive control antibodies. Therefore, the anti-TGF-βRII binding domain of this disclosure exhibits comparable, equivalent, and superior TGF-βRII blocking ability in monovalent form, providing various applications as one or more valencenes incorporated into monovalent, divalent, or multispecific molecules. 【0222】 Sequencing of the heavy chain variable region The nucleic acids encoding the VH region of a series of antibodies identified as binding to human TGF-βRII and blocking its interaction with its ligand were sequenced. The sequence information is provided below. array Sequence ID 1: HCDR1 by Kabat IYAMT Sequence ID 2: HCDR2 by Kabat VISGSGGTTYYADSVKG Sequence ID 3: HCDR3 by Kabat RGQYRDIVGATDY Sequence ID 4: HCDR1 by Kabat NAWMS Sequence ID 5: HCDR2 by Kabat RIKTTISGGATDFAAPVKG Sequence ID 6: HCDR3 by Kabat DLRDY Sequence ID 7: HCDR1 by Kabat RYAMS Sequence ID 8: HCDR2 by Kabat AISASGDRTHNTDSVKG Sequence ID 9: HCDR3 by Kabat GIAASGKNYFDP Sequence ID 10: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFTFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS Sequence ID 11: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKTTISGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS Sequence ID 12: Heavy Chain Variable Region [ka] QSISSY Sequence ID 14: LCDR2 by IMGT AAS Sequence ID 15: LCDR3 by IMGT QQSYSTPPT Sequence ID 16: Light chain variable region DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK SEQ ID NO: 17: Heavy chain constant region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Sequence ID 18: Light chain steady region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 19: LCDR1 by Kabat RASQSISSYLN Sequence ID 20: LCDR2 by Kabat AASSLQS Sequence ID 21: LCDR3 by Kabat QQSYSTPPT Sequence ID 22: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFTFDINAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS Sequence ID 23: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFTFDIQAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS Sequence ID 24: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFTFDIYRMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQGQYREIVGATDYWGQGTLVTVSS Sequence ID 25: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFYFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRSQYRDKVGATDYWGQGTLVTVSS Sequence ID 26: Heavy Chain Variable Region [ka] EVQLVESGGGLVQPGGSLRLSCAASGFAFDIYAMTWVRQAPGKGLEWVSVISGSGGTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS Sequence ID 28: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFTFDIYAMTWVRQAPGKGLEWVSVISGSGGTVYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIAGGTDYWGQGTLVTVSS Sequence ID 29: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFDFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRSQYRDKVGATDYWGQGTLVTVSS Sequence number 30: Heavy chain variable region 【Chem.】 EVQLVESGGGLVQPGGSLRLSCAASGFTFDINAMTWVRQAPGKGLEWVSVISGSGGTTAYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRYIAGATDYWGQGTLVTVSS Sequence number 32: Heavy chain variable region EVQLVESGGGLVQPGGSLRLSCAASGFTFDITAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIAGATDYWGQGTLVTVSS Sequence number 33: Heavy chain variable region EVQLVESGGGLVQPGGSLRLSCAASGFSFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRAQYRDKVGATDYWGQGTLVTVSS Sequence number 34: Heavy chain variable region EVQLVESGGGLVQPGGSLRLSCAASGFTFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRYVVGATDYWGQGTLVTVSS Sequence number 35: Heavy chain variable region EVQLVESGGGLVQPGGSLRLSCAASGFYFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRHIAGATDYWGQGTLVTVSS Sequence number 36: Heavy chain variable region EVQLVESGGGLVQPGGSLRLSCAASGFRFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS Sequence number 37: Heavy chain variable region EVQLVESGGGLVQPGGSLRLSCAASGFTFDINAMTWVRQAPGKGLEWVSVISGSGATTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYREIQGANDYWGQGTLVTVSS Sequence number 38: Heavy chain variable region QVQLVESGGGLVEPGGSLRLSCAASGFTFSRAWMSWVRQAPGKGLEWVGRIKTTISGGATQFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRNYWGQGTLVTVSS Sequence number 39: Heavy chain variable region QVQLVESGGGLVEPGGSLRLSCAASGFTFSRAWMSWVRQAPGKGLEWVGRIKTTVSGGATAFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRAYWGQGTLVTVSS Sequence number 40: Heavy chain variable region 【Chemical formula】 QVQLVESGGGLVEPGGSLRLSCAASGFTFSRAWMSWVRQAPGKGLEWVGRIKTTYSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRKYWGQGTLVTVSS Sequence number 42: Heavy chain variable region QVQLVESGGGLVEPGGSLRLSCAASGFTFSRAWMSWVRQAPGKGLEWVGRIKTTISGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRAYWGQGTLVTVSS Sequence number 43: Heavy chain variable region QVQLVESGGGLVEPGGSLRLSCAASGFKFSNAWMSWVRQAPGKGLEWVGRIKTTISGGATQFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS Sequence ID 44: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKTTYSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS Sequence ID 45: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKTTYSGGATEFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRKYWGQGTLVTVSS Sequence ID 46: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSNYWMSWVRQAPGKGLEWVGRIKTTISGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRAYWGQGTLVTVSS Sequence ID 47: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSRAWMSWVRQAPGKGLEWVGRIKTTISGAATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS Sequence ID 48: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFANAWMSWVRQAPGKGLEWVGRIKTTYSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRKYWGQGTLVTVSS Sequence ID 49: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFQFSNAWMSWVRQAPGKGLEWVGRIKTTYSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS Sequence ID 50: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAHMSWVRQAPGKGLEWVGRIKTTYSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRQYWGQGTLVTVSS Sequence ID 51: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFANAWMSWVRQAPGKGLEWVGRIKTTYSGGATEFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRTYWGQGTLVTVSS Sequence ID 52: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKTTYSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRSYWGQGTLVTVSS Sequence ID 53: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFQFSNAWMSWVRQAPGKGLEWVGRIKTTISGGATEFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS Sequence ID 54: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFVFSNAWMSWVRQAPGKGLEWVGRIKTTFSGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRKYWGQGTLVTVSS Sequence ID 55: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFHFSNAWMSWVRQAPGKGLEWVGRIKTTISGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRAYWGQGTLVTVSS Sequence ID 56: Heavy Chain Variable Region QVQLVESGGGLVEPGGSLRLSCAASGFKFSNAWMSWVRQAPGKGLEWVGRIKTTISGGKTEFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRRYWGQGTLVTVSS Sequence ID 57: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFAFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAKRGKNYFDPWGQGTLVTVSS Sequence ID 58: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFQFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAKSGKNYFDPWGQGTLVTVSS Sequence ID 59: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAKSGKNYFDPWGQGTLVTVSS Sequence ID 60: Heavy chain variable region QVQLVESGGGLVQPGGSLRLSCAVSGFKFRRYAMSWVRQAPGKGLEWVSSISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGLAASGKNYFDPWGQGTLVTVSS Sequence ID 61: Heavy Chain Variable Region [ka] QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTKNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGRNYFDPWGQGTLVTVSS SEQ ID NO: 63: Heavy chain variable region QVQLVESGGGLVQPGGSLRLSCAVSGFAFRRYAMSWVRQAPGKGLEWVSSISASGDRTKNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAASGKNYFDPWGQGTLVTVSS SEQ ID NO: 64: Heavy chain variable region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIFASGKHYFDPWGQGTLVTVSS SEQ ID NO: 65: Heavy chain variable region 【Chemical formula】 QVQLVESGGGLVQPGGSLRLSCAVSGFQFRRYAMSWVRQAPGKGLEWVSDISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIARSGKNYFDPWGQGTLVTVSS SEQ ID NO: 67: Heavy chain variable region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTLNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAARGKNYFDPWGQGTLVTVSS SEQ ID NO: 68: Heavy chain variable region QVQLVESGGGLVQPGGSLRLSCAVSGFAFRRYAMSWVRQAPGKGLEWVSAISAFGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGKNFFDPWGQGTLVTVSS Sequence ID 69: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTKNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGKNFFDPWGQGTLVTVSS Sequence ID 70: Heavy Chain Variable Region [ka] QVQLVESGGGLVQPGGSLRLSCAVSGFQFRRYAMSWVRQAPGKGLEWVSAISAHGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGKNYFDPWGQGTLVTVSS Sequence ID 72: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTIRRYAMSWVRQAPGKGLEWVSYISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTANSGKNYFDPWGQGTLVTVSS Sequence ID 73: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAARGKNYFDPWGQGTLVTVSS Sequence ID 74: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFERYAMSWVRQAPGKGLEWVSAISASGDRTQNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGRNYFDPWGQGTLVTVSS Sequence ID 75: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFEFRRYAMSWVRQAPGKGLEWVSAISAGGDRTANTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAARGKNYFDPWGQGTLVTVSS Sequence ID 76: Heavy Chain Variable Region [ka] QVQLVESGGGLVQPGGSLRLSCAVSGFSFRRYAMSWVRQAPGKGLEWVSAISASGDRTLNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAARGKNYFDPWGQGTLVTVSS Sequence ID 78: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFEFRRYAMSWVRQAPGKGLEWVSAISASGDRTDNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIARSGKNFFDPWGQGTLVTVSS Sequence ID 79: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFNFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVTGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGLAASGKNYFDPWGQGTLVTVSS Sequence ID 80: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFAFRRYAMSWVRQAPGKGLEWVSAISAHGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGKNYFDPWGQGTLVTVSS Sequence ID 81: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGLAASGKNFFDPWGQGTLVTVSS Sequence ID 82: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFAFRRYAMSWVRQAPGKGLEWVSSISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGLASSGKNYFDPWGQGTLVTVSS Sequence ID 83: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFQFRRYAMSWVRQAPGKGLEWVSSISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGLAASGKNYFDPWGQGTLVTVSS Sequence ID 84: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFQFRRYAMSWVRQAPGKGLEWVSAISASGDRYHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAASGKNYFDPWGQGTLVTVSS Sequence ID 85: Heavy Chain Variable Region [ka] [ka] QVQLVESGGGLVQPGGSLRLSCAVSGFTFKRYAMSWVRQAPGKGLEWVSAISASGDRSHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGLAARGKNYFDPWGQGTLVTVSS Sequence ID 88: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFNFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTAARGKNYFDPWGQGTLVTVSS Sequence ID 89: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAASGKNFFDPWGQGTLVTVSS Sequence ID 90: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAARGKNYFDPWGQGTLVTVSS Sequence ID 91: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAVSGFRFRRYAMSWVRQAPGKGLEWVSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAARGKNFFDPWGQGTLVTVSS Sequence ID 92: Heavy Chain Variable Region EVQLVETGAEVKKPGASVKVSCKASDYIFTKYDINWVRQAPGQGLEWMGWMSANTGNTGYAQKFQGRVTMTRDTSINTAYMELSSLTSGDTAVYFCARSSLFKTETAPYYHFALDVWGQGTTVTVSS Sequence ID 93: Heavy Chain Variable Region EVQLVESGGDLVKPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRVKTTVSGGTTDYAAAVKGRFTISRDDSKNTLYLQMNSLKTEDTAIYYCTIDLRDYWGQGTLVTVSS Sequence ID 94: Heavy Chain Variable Region EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYAMSWVRQAPGKGLEWVSSINTSGGNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCAKGIAATGKNYFDPWGQGTLVTVSS Sequence ID 95: Heavy Chain Variable Region QVQLVESGGGLVQPGGSLRLSCAASGFTFSRYAMSWVRQAPGKGLEWVSSINTSGGNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVKGIAAAGKNWFGPWGQGTLVTVSS Sequence ID 96: Heavy chain variable region QVQLVESGGGLVQPGGSLSLSCAASGFTFSRYAMSWVRQAPGKGLEWVSSINTSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGIAASGKNYFDPWGQGTLVTVSS Sequence ID 97: Heavy Chain Variable Region EVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVISYDGSTKYSADSLKGRFTISRDNSKNTLYLQMNSLRADDTAVYYCAKEGWSFDSSGYRSWFDSWGQGTLVTVSS Sequence ID 98: Heavy Chain Variable Region QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARSFRGGYTAFDVWGQGTLVTVSS Sequence ID 99: IGKV1-39 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTP Sequence ID 100: IGKV1-39 / jk5 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK Sequence ID 101: Isoform A of human TGF-βRII [ka] [ka] [ka] [ka] NAWMS Sequence ID 106: HCDR2 by Kabat RIKTTISGGATQFAAPVKG Sequence ID 107: HCDR3 by Kabat DLRDY Sequence ID 108: HCDR1 by Kabat RYAMS Sequence ID 109: HCDR2 by Kabat AISAGGDRTANTDSVKG Sequence ID 110: HCDR3 by Kabat GTAARGKNYFDP Sequence ID 111: HCDR1 by Kabat RYAMS Sequence ID 112: HCDR2 by Kabat AISASGDRTKNTDSVKG Sequence ID 113: HCDR3 by Kabat GTAAAGKNYFDP Sequence ID 114: HCDR1 by Kabat RYAMS Sequence ID 115: HCDR2 by Kabat AISASGDRYHNTDSVKG Sequence ID 116: HCDR3 by Kabat GTAASGKNYFDP Sequence ID 117: HCDR1 by Kabat RYAMS Sequence ID 118: HCDR2 by Kabat AISASGDRTHNTDSVKG Sequence ID 119: HCDR3 by Kabat GTAARGKNYFDP Sequence ID 120: HCDR1 by Kabat NYWMS Sequence ID 121: HCDR2 by Kabat RIKTTYSGGATDFAAPVKG Sequence ID 122: HCDR3 by Kabat DLRDY Sequence ID 123: HCDR1 by Kabat RYAMS Sequence ID 124: HCDR2 by Kabat SISASGDRTHNTDSVKG Sequence ID 125: HCDR3 by Kabat GLAASGKNYFDP Sequence ID 126: HCDR1 by Kabat RYAMS Sequence ID 127: HCDR2 by Kabat AISASGDRTDNTDSVKG Sequence ID 128: HCDR3 by Kabat GIARSGKNFFDP Sequence ID 129: HCDR1 by Kabat RAWMS Sequence ID 130: HCDR2 by Kabat RIKTTISGAATDFAAPVKG Sequence ID 131: HCDR3 by Kabat DLRDY Sequence ID 132: HCDR1 by Kabat RYAMS Sequence ID 133: HCDR2 by Kabat AISASGDRTLNTDSVKG Sequence ID 134: HCDR3 by Kabat GTAARGKNYFDP Sequence ID 135: Light chain variable region EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK Sequence ID 136: Heavy Chain Variable Region EVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVISYDGSTKYSADSLKGRFTISRDNSKNTLYLQMNSLRADDTAVYYCAKEGWSFDSSGYRSWFDSWGQGTLVTVSS

Claims

[Claim 1] An antibody or antibody fragment that specifically binds to the extracellular domain of human TGF-βRII, The antibody or antibody fragment is a heavy chain variable region (VH) selected from the following: (A) VH, (a) VH-CDR1 containing the amino acid sequence described in Sequence ID No. 1, (b) VH-CDR2 containing the amino acid sequence described in Sequence ID No. 2, and (c) VH, having VH-CDR3 containing the amino acid sequence described in Sequence ID No. 3 (B) VH, (a) VH-CDR1 containing the amino acid sequence described in Sequence ID No. 4, (b) VH-CDR2 containing the amino acid sequence described in Sequence ID No. 5, and (c) VH, having VH-CDR3 containing the amino acid sequence described in Sequence ID No. 6 (C) VH, (a) VH-CDR1 containing the amino acid sequence described in Sequence ID No. 7, (b) VH-CDR2 containing the amino acid sequence described in Sequence ID No. 8, and (c) VH having VH-CDR3 containing the amino acid sequence described in Sequence ID No. 9 It includes any one of the following: The antibody or antibody fragment is (a) VL-CDR1 containing the amino acid sequence described in SEQ ID NO: 19, (b) VL-CDR2 containing the amino acid sequence described in SEQ ID NO: 20, and (c) further comprising a light chain variable region (VL) having a VL-CDR3 containing the amino acid sequence described in SEQ ID NO: 21, An antibody or a fragment of that antibody. [Claim 2] The antibody or antibody fragment according to claim 1, wherein the FR1, FR2, FR3, and FR4 regions of the VH correspond to amino acid sequences encoded by germline V genes IGHV3-15 and IGHV3-23, which may include somatic mutations. [Claim 3] The aforementioned antibody EVQLVESGGGLLVQPGGSLRLSCAASGFTFDIYAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLVTVSS (Sequence No. 10), QVQLVESGGGLVEPGGGSLRLLSCAASGFTFFSNAWMSWVRQAPGKGLEWVGRIKTTISGGGATDFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTLDLRDYWGQGTLVTVSS (Sequence No. 11), QVQLVESGGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSSAISASGDRTHNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIAASGKNYFDPWGQGTLVTVSS (Sequence No. 12), The antibody or antibody fragment according to claim 1 or 2, comprising a VH amino acid sequence selected from, or a VH amino acid sequence having at least 90% identity thereto. [Claim 4] An antibody or antibody fragment that specifically binds to the extracellular domain of human TGF-βRII, wherein the antibody or antibody fragment comprises a VH amino acid sequence selected from any one of SEQ ID NOs: 22-24, 26-28, 32, 39, 40, 42, 43, 48, 51-53, 56, 61, 63, 65, 67, 70, 72, 74, 76, 79, 81, 83, 87, 93, or a VH amino acid sequence having at least 90% identity thereto, and any amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof are located at positions other than the CDR. The antibody or antibody fragment is (a) VL-CDR1 containing the amino acid sequence described in SEQ ID NO: 19, (b) VL-CDR2 containing the amino acid sequence described in SEQ ID NO: 20, and (c) further comprising a light chain variable region (VL) having a VL-CDR3 containing the amino acid sequence described in SEQ ID NO: 21, An antibody or a fragment of that antibody. [Claim 5] The antibody has the following VL amino acid sequence: An antibody or antibody fragment according to any one of claims 1 to 4, comprising DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 16), or a VL amino acid sequence having at least 90% identity thereto. [Claim 6] The antibody or antibody fragment according to any one of claims 1 to 3 and 5, wherein the antibody comprises the heavy chain variable region of SEQ ID NO: 10, 11, or 12 and the light chain variable region of SEQ ID NO:

16. [Claim 7] The antibody or antibody fragment according to claim 4 or 5, wherein the antibody comprises one heavy chain variable region from SEQ ID NOs: 22-24, 26-28, 32, 39, 40, 42, 43, 48, 51-53, 56, 61, 63, 65, 67, 70, 72, 74, 76, 79, 81, 83, 87, 93, and the light chain variable region of SEQ ID NO:

16. [Claim 8] The antibody or antibody fragment according to any one of claims 1 to 3 and 5, wherein the antibody comprises two heavy chain variable regions of SEQ ID NO: 10 and two light chain variable regions of SEQ ID NO: 16, two heavy chain variable regions of SEQ ID NO: 11 and two light chain variable regions of SEQ ID NO: 16, or two heavy chain variable regions of SEQ ID NO: 12 and two light chain variable regions of SEQ ID NO:

16. [Claim 9] The antibody or antibody fragment according to claim 4 or 5, wherein the antibody comprises two heavy chain variable regions from any one of SEQ ID NOs: 22-24, 26-28, 32, 39, 40, 42, 43, 48, 51-53, 56, 61, 63, 65, 67, 70, 72, 74, 76, 79, 81, 83, 87, 93, and two light chain variable regions of SEQ ID NO:

16. [Claim 10] The antibody or antibody fragment according to any one of claims 1 to 9, wherein the antibody is an IgG antibody. [Claim 11] The antibody or antibody fragment according to any one of claims 1 to 10, wherein the antibody is an IgG1 antibody or an IgG4 antibody. [Claim 12] The antibody or antibody fragment according to any one of claims 1 to 11, wherein the antibody is an IgG1 antibody. [Claim 13] The antibody or antibody fragment according to any one of claims 1 to 12, further comprising a heavy chain constant region containing the amino acid sequence described in SEQ ID NO:

17. [Claim 14] The antibody or antibody fragment according to any one of claims 1 to 13, further comprising a light chain constant region having the amino acid sequence described in SEQ ID NO:

18. [Claim 15] The antibody or antibody fragment according to any one of claims 1 to 14, wherein the binding of the antibody to the Fc receptor is eliminated or reduced. [Claim 16] An antibody that specifically binds to human TGF-βRII, (A) A heavy chain having a VH containing an amino acid sequence described in any one selected from SEQ ID NOs: 10-12 and SEQ ID NOs: 22-24, 26-28, 32, 39, 40, 42, 43, 48, 51-53, 56, 61, 63, 65, 67, 70, 72, 74, 76, 79, 81, 83, 87, 93, and a heavy chain constant region containing an amino acid sequence described in SEQ ID NO: 17, and (B) An antibody comprising a light chain having a VL containing the amino acid sequence described in SEQ ID NO: 16 and a light chain constant region containing the amino acid sequence described in SEQ ID NO:

18. [Claim 17] The antibody according to any one of claims 1 to 15 or an antibody fragment thereof, or the antibody according to claim 16, wherein the antibody is a monoclonal antibody. [Claim 18] A binding domain that specifically binds to human TGF-βRII, The binding domain is a heavy chain variable region (VH) selected from the following: (A) VH having VH-CDR1, VH-CDR2, and VH-CDR3 of VH having the amino acid sequence described in Sequence ID No. 12, (B) VH having VH-CDR1, VH-CDR2, and VH-CDR3 of VH having the amino acid sequence described in Sequence ID No. 26, (C) VH having VH-CDR1, VH-CDR2, and VH-CDR3 of VH having the amino acid sequence described in Sequence ID No. 40, (D) VH having VH-CDR1, VH-CDR2, and VH-CDR3 of VH having the amino acid sequence described in Sequence ID No. 61, (E) VH having VH-CDR1, VH-CDR2, and VH-CDR3 of VH having the amino acid sequence described in Sequence ID No. 65, (F) VH having VH-CDR1, VH-CDR2, and VH-CDR3, which have the amino acid sequence described in Sequence ID No.

70. (G) VH having VH-CDR1, VH-CDR2, and VH-CDR3 of VH having the amino acid sequence described in Sequence ID No. 76, It includes any one of the following: The aforementioned binding domain, (a) VL-CDR1 containing the amino acid sequence described in SEQ ID NO: 19, (b) VL-CDR2 containing the amino acid sequence described in SEQ ID NO: 20, and (c) further comprising a light chain variable region (VL) having a VL-CDR3 containing the amino acid sequence described in SEQ ID NO: 21, Joint domain. [Claim 19] The binding domain according to claim 18, wherein the binding domain comprises a VH amino acid sequence selected from SEQ ID NOs: 12, 26, 40, 61, 65, 70, and 76, or a VH amino acid sequence having at least 90% identity thereto. [Claim 20] The binding domain has the following VL amino acid sequence: The binding domain according to claim 18 or 19, comprising DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK (SEQ ID NO: 16), or a VL amino acid sequence having at least 90% identity thereto. [Claim 21] A cell that produces an antibody or antibody fragment according to any one of claims 1 to 15, or an antibody according to claim 16 or 17, or a binding domain according to any one of claims 18 to 20. [Claim 22] A pharmaceutical composition comprising an antibody or antibody fragment according to any one of claims 1 to 15, or an antibody according to claim 16 or 17, or a binding domain according to any one of claims 18 to 20, and a pharmaceutically acceptable carrier, diluent, or excipient. [Claim 23] A pharmaceutical product for use in the prevention of cancer, the suppression of the progression or recurrence of cancer symptoms, and / or the treatment of cancer, comprising as an active ingredient an antibody or antibody fragment according to any one of claims 1 to 15, or an antibody according to claim 16 or 17, or a binding domain according to any one of claims 18 to 20. [Claim 24] The pharmaceutical product according to claim 23, wherein the cancer is a type of cancer that correlates with higher-than-normal TGF-β signaling. [Claim 25] The pharmaceutical product according to claim 23, wherein the cancer is a type of cancer that correlates with higher-than-normal TGF-βRII expression. [Claim 26] The pharmaceutical product according to any one of claims 23 to 25, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, colorectal cancer, gastric cancer, glioblastoma, cervical cancer, hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, melanoma, myelodysplastic syndrome, pancreatic cancer, prostate cancer, and kidney cancer. [Claim 27] An in vitro method for blocking the binding of human TGF-β to human TGF-βRII on a cell, comprising: providing the cell with an antibody or antibody fragment according to any one of claims 1 to 15, or an antibody according to claim 16 or 17, or a binding domain according to any one of claims 18 to 20; and enabling the antibody or antibody fragment, or the binding domain, to bind to the human TGF-βRII on the cell, thereby blocking the binding of human TGF-β to the human TGF-βRII on the cell. [Claim 28] An in vitro method for inhibiting signal transduction to a cell induced by the binding of human TGF-β to human TGF-βRII, comprising: providing the cell with an antibody or antibody fragment according to any one of claims 1 to 15, or an antibody according to claim 16 or 17, or a binding domain according to any one of claims 18 to 20; and enabling the antibody or antibody fragment, or the binding domain, to bind to the human TGF-βRII of the cell, thereby inhibiting the signal transduction to the cell.

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