Fc-cell complex and method for preparing the same

Abstract

An Fc-cell complex comprising a cell and an antibody Fc region bound to the surface of the cell, wherein the antibody Fc region is formed by disulfide bonding of two Fc constituent polypeptides, and the antibody Fc region is chemically bound to the cell surface through a linker introduced into a functional group in the side chain of a specific amino acid residue present at one or more positions of one of the two antibody Fc constituent polypeptides.

Description

Technology Field The present invention relates to an Fc-cell complex (also called an Fc-cell conjugate) and a method for preparing the same. Background Technology A technology is known to bind antibodies to the surface of cells to confer function upon them. For example, Patent Document 1 (Japanese Patent Publication No. JP 2016-523237) discloses a technique for producing a protein-cell conjugate by binding a protein, such as an antibody, to the cell surface by reacting the sulfhydryl group of the cell surface with the side chain amino group of the protein with a bifunctional crosslinking agent. However, in this technique, since the crosslinking agent reacts randomly with the side chain amino group of the protein, such as the antibody, it is difficult to control the ratio of protein introduction into the cell, and there is also a problem that the binding site of the linker in the protein becomes non-uniform. Prior art literature Patent Document 1: Japanese Patent Publication No. JP 2016-523237 Patent Document 2: International Publication WO2018 / 199337 Patent Document 3: International Publication WO2019 / 240287 Patent Document 4: International Publication WO2019 / 240288 Patent Document 5: International Publication WO2020 / 090979 The problem to be solved The objective of the present invention is to provide a technology for efficiently introducing an antibody-like molecule, such as an antibody variable region or a functional protein-Fc fusion protein, into a cell surface by controlling the binding site of the linker in the Fc region or the introduction rate of the Fc region into the cell, in the preparation of an Fc-cell complex in which the Fc region of an antibody is introduced into the cell surface via a linker, for the purpose of introducing an antibody-like molecule, such as an antibody variable region or a functional protein-Fc fusion protein, into the cell surface through the Fc region of an antibody. The objective of the present invention is also to provide an Fc-cell complex in which the binding site of the linker in the Fc region or the introduction rate of the Fc region into the cell is controlled. means of solving the problem The applicant has reported a technology capable of formulating an antibody having a functional substance, such as a drug, in a site-selective manner by a chemical synthetic method using a predetermined compound containing an affinity peptide (Patent Documents 2 to 5). In this technology, linkers are introduced on both sides of polypeptides derived from two heavy chain normal regions constituting the Fc region, but the inventors considered that introducing linkers on only one side of polypeptides derived from two heavy chain normal regions constituting the Fc region is more desirable for the above purpose. Therefore, with the goal of developing a technology that can easily chemically modify only one of the two heavy chain normal region-derived polypeptides constituting the Fc region, we conducted a detailed review to improve the technology. As a result, it was discovered that by using an affinity material having affinity for the Fc region, preferably an affinity material comprising first and second affinity portions and a compound comprising a reactive group for the Fc region, only one heavy chain normal region-derived polypeptide in the constituent unit of the Fc region can be easily chemically modified, and by using this technique, an Fc-cell complex is obtained in which the Fc region is bound to the cell surface through the polypeptide on one side, and if the Fc region contains an antibody variable region or a functional protein, an antibody or a functional protein can be introduced to the cell surface through the Fc region. According to the above description, an affinity substance having affinity for an Fc region, preferably an affinity substance (A) comprising first and second affinity portions, and a compound comprising a reactive group (R) for an Fc region, can associate with the Fc region through the affinity substance (A), and then specifically react with the side chain of a specific amino acid residue in a polypeptide derived from one heavy chain normal region in a constituent unit of the Fc region through the reactive group (R), thereby producing an affinity substance modified Fc region in which only one of the two heavy chain normal region derived polypeptides constituting the Fc is modified (Fig. 1) (International Publication WO2023 / 234416). Although the present invention is not intended to be limited by theory, the modification mechanism of only the polypeptide derived from one heavy chain normal region in the constituent unit of the Fc region is as follows. Since the affinity substance (A) included in the above compound can stably associate with two heavy chain normal region-derived polypeptides constituting the Fc region, the reactive group (R) included in the above compound can modify only one heavy chain normal region-derived polypeptide (Fig. 1). At this time, since the affinity portion of the other heavy chain normal region-derived polypeptide is associated and steric hindrance occurs, the reactive group (R) of the other molecule of the compound cannot react with the side chain amino acid of the other heavy chain normal region-derived polypeptide, and thus can modify only one heavy chain normal region-derived polypeptide (Fig. 1). By using the Fc region modified only by one heavy chain normal region-derived polypeptide obtained in this way, and binding it to the cell surface through a linker, an Fc-cell complex can be obtained in which the Fc region is chemically bound to the cell surface through a linker introduced to a functional group in the side chain of a specific amino acid residue located at one or more positions of one of the two heavy chain normal region-derived polypeptides included therein. If the Fc region includes an antibody variable region or a functional protein, an antibody-like molecule such as an antibody or a functional protein-Fc fusion protein can be obtained in which the antibody-like molecule is chemically bound to the cell surface through a linker introduced to a functional group in the side chain of a specific amino acid residue located at one or more positions of one of the two heavy chain normal region-derived polypeptides included in the Fc region. That is, the present invention has the following aspects. [1] An Fc-cell complex comprising a cell and an antibody Fc region bound to the surface of the cell, the Fc-cell complex comprising a cell, the antibody Fc region bound to the surface of the cell, The Fc region of the above antibody is formed by disulfide bonding of two Fc constituent polypeptides, and The above antibody Fc region is chemically bound to the cell surface through a linker introduced into a functional group in the side chain of a specific amino acid residue present at one or more positions of one of the two antibody Fc constituent polypeptides. The above Fc-cell complex. [2] The Fc-cell complex described in [1], wherein the specific amino acid residue is one or more of the 14 amino acid residues consisting of asparagine, glutamine, methionine, proline, serine, threonine, tryptophan, tyrosine, aspartic acid, glutamic acid, arginine, histidine, and lysine. [3] The specific amino acid residue mentioned above is a lysine residue, the Fc-cell complex described in [1]. [4] The Fc-cell complex described in [3], wherein the lysine residue is one or more of the lysine residues at positions 246, 248, 274, 288, 290, 317, 320, 322, 360, 414, and 439. [5] The Fc-cell complex described in any one of [1] to [4], wherein the antibody Fc region has a functional substance introduced through a linker introduced into a functional group in the side chain of a specific amino acid residue located at one or more positions of the other of the two Fc constituent polypeptides. [6] The functional substance is a drug, a labeling substance, an affinity substance, a transport substance, a stabilizer, the Fc-cell complex described in [5]. [7] The above antibody Fc region comprises an antibody variable region, an Fc-cell complex described in any one of [1] to [6]. [8] The above antibody Fc region comprises a fusion protein of an antibody Fc constituent polypeptide and a functional polypeptide, an Fc-cell complex described in any one of [1] to [6]. [9] The above antibody Fc region is an Fc-cell complex described in any one of [1] to [8], wherein the above antibody Fc region is introduced to the cell surface by a reaction between a bio-direct functional group introduced through a linker introduced to a functional group in the side chain of a specific amino acid residue present at one or more positions of one of the two Fc constituent polypeptides, and a group present on the cell surface or reacting with the introduced bio-direct functional group.

[10] As a method for preparing a cell-Fc region complex, (I) A process for preparing an antibody Fc region in which two antibody Fc constituent polypeptides are disulfide-bound, (II) In the Fc region of the above antibody, A process of reacting a compound represented by the following formula (Ia) or formula (Ib) to form an Fc-compound (Ia) complex or an Fc-compound (Ib) complex, [Painting 1] [In the formula, R represents a reactive group for the Fc region, L1 represents a first linker, L2 represents a second linker, CLE(B) represents a cleavable portion capable of generating a bio-orthogonal functional group on the reactive group side by cleavage, and A represents an affinity substance comprising an affinity peptide.] [Painting 2] [In the formula, R represents the reactive group, L5 represents the fifth linker, L6 represents the sixth linker, B represents a group including a bio-orthogonal functional group, CLE represents a cleavable portion, and A represents the affinity substance.] (III) A process of cutting the Fc-compound (Ia) complex or the Fc-compound (Ib) complex at the cutting portion to form an Fc region that does not contain the affinity substance and has a bio-orthogonal functional group introduced, (IV) A process for preparing cells having functional groups on their surface that react with bio-orthogonal functional groups, (V) A process of introducing the Fc region into the cell surface by reacting the Fc region into which the bio-orthogonal functional group is introduced and the cell with the bio-orthogonal functional group of the Fc region and the functional group that reacts with the bio-orthogonal functional group of the cell, A method including

[11] Compound (Ia) is, formula (Ia-1): [Tuesday 3] A method for preparing a cell-Fc region complex described in

[10] , represented by [wherein X represents a degreasing agent, W1, W2 and W3 each independently represent an oxygen atom or a sulfur atom, L3 represents a third linker, L4 represents a fourth linker, S represents a sulfur atom, and A represents the affinity substance.]

[12] Compound (Ib) is, formula (Ib-1): [Painting 4] A method for preparing a cell-Fc region complex described in

[10] , represented by [wherein X represents a degreasing group, W1, W2 and W3 each independently represent an oxygen atom or a sulfur atom, L7 represents a seventh linker, L8 represents an eighth linker, B represents a group containing a bio-orthogonal functional group, V represents an oxygen atom or a sulfur atom, and A represents the affinity substance.]

[13] A is AP1-L A -AP2(wherein, AP1 represents a first affinity peptide having affinity for the normal region of the heavy chain of the antibody, AP2 represents a second affinity peptide having affinity for the normal region of the heavy chain of the antibody, and L A A method described in any one of

[10] to

[12] , indicated as a linker.

[14] A method for preparing a cell-Fc region complex described in any one of

[10] to

[13] , wherein the bio-orthogonal functional group is an azide group, an alkyne residue, a tetrazine residue, an alkene residue, a thiol group, a maleimide residue, a furan residue, or a halocarbonyl residue.

[15] A method for preparing a cell-Fc region complex described in any one of

[10] to

[14] , wherein the cell-Fc region complex is an Fc-cell complex described in any one of [1] to [9].

[16] A method for preparing a cell-Fc region complex as described in any one of

[10] to

[14] , wherein the cell-Fc region complex is the Fc-cell complex described in [5], and the method comprises a process of introducing a functional substance to a functional group in the side chain of a specific amino acid residue present at one or more positions of the other of the two Fc constituent polypeptides in the antibody Fc region. Effects of the invention According to the present invention, only one side of the constituent unit (a polypeptide derived from two heavy chain normal regions) of the Fc region of an antibody can be easily modified. Furthermore, according to the present invention, a positionally modified Fc region can be provided while easily modifying only one side of the polypeptide derived from the heavy chain normal region of the constituent unit of the antibody Fc region. By using a modified Fc in which a bio-orthogonal functional group is introduced only on one side of the constituent unit of the Fc region obtained by this positionally selective modification technique, an Fc-cell complex can be obtained in which the Fc region is positionally introduced to the cell surface through only one side of the constituent unit. This allows for the control of the orientation of the antibody or fusion protein containing the Fc region presented on the cell surface, thereby enabling the antibody or fusion protein to exert an effect with a small amount without impairing its activity. Brief explanation of the drawing [Fig. 1] Fig. 1 is a diagram illustrating the presumed principle of a method for modifying only one of the two heavy chain normal region-derived polypeptides constituting Fc with an affinity substance. [Fig. 2] Fig. 2 is a diagram showing the reaction (process (II) and process (III)) using compound (Ia). r represents the modification rate into immunoglobulin units (hereinafter the same). [Fig. 3] Fig. 3 is a diagram showing the reactions (process (II) and process (III)) using compound (Ia-1). [Fig. 4] Fig. 4 is a diagram showing reactions (process (II) and process (III)) using compound (Ib). T1 represents a monovalent group generated by cleavage (hereinafter, T2, etc. are the same). [Fig. 5] Fig. 5 is a diagram showing the reactions (process (II) and process (III)) using compound (Ib-1). [Fig. 6] Fig. 6 is a diagram showing the reactions using compound (Ia) (Process (II) (Reactions 1, 2) and Process (III) (Reaction 3)) (introduction of bio-orthogonal functional groups into each of the polypeptides derived from the two heavy chain normal regions constituting Fc). [Fig. 7] Fig. 7 is a diagram showing the reaction using compound (Ib) (Process (II) (Reactions 1, 2) and Process (III) (Reaction 3)) (introduction of bio-orthogonal functional groups into each of the polypeptides derived from the two heavy chain normal regions constituting Fc). [Fig. 8] Fig. 8 shows the percentage of T-4 antibody-positive cells after adding T-4 antibodies to cells at each concentration and reacting for 1 hour or 24 hours in the presence or absence of DBCO. The results of flow cytometry are shown in a graph. [Fig. 9] Fig. 9 is a diagram showing the amount of T-5-derived fluorescence (left) or HER2-biotin / StAv-AF488-derived fluorescence (right) bound to cells immediately after addition or 48 hours after addition, after adding T-5 antibody (left) and additionally adding HER2-biotin / StAv-AF488 (right). [Fig. 10] Fig. 10 is a micrograph showing AF488-derived fluorescence in HEL cells / HER2-Fc / StAv-AF488 or HEL cells / DBCO modified T-5 / HER2-Fc / StAv-AF488. [Fig. 11] Fig. 11 is a graph showing Cy5-derived fluorescence (top) and AF488-derived fluorescence (middle) after 0, 24, 48, 72, or 96 hours following the addition of T-5 antibody (with or without DBCO modification) to cells and the additional addition of HER2-biotin / StAv-AF488, and a graph showing the HER2 binding ability per antibody after 0, 24, and 48 hours (bottom). The results of flow cytometry are shown in the graph. [Fig. 12A] Fig. 12A is a diagram showing the amount of T-5, T-8, or T-9 derived fluorescence (left) or HER2-biotin / StAv-AF488 derived fluorescence (right) bound to cells immediately after addition or 48 hours after addition, after adding 0.3 μM or 1 μM of T-5 antibody, T-8 antibody, or T-9 antibody to cells (left) and additionally adding HER2-biotin / StAv-AF488 (right). [Fig. 12B] Fig. 12B is a graph showing the results of calculating the HER2 binding ability per antibody based on the amount of T-5, T-8, or T-9 derived fluorescence and HER2-biotin / StAv-AF488 derived fluorescence bound to cells immediately after addition or 24 hours after addition, after adding 0.3 μM or 1 μM of T-5 antibody, T-8 antibody, or T-9 antibody to cells and additionally adding HER2-biotin / StAv-AF488. [Fig. 13] Fig. 13 shows the percentage of T-4 antibody-positive cells after adding T-4 antibodies to cells at each concentration and reacting for 1 hour or 24 hours in the presence or absence of DBCO. The left side is Gated (%), and the right side is MFI (average fluorescence intensity: background excluded). The results of flow cytometry are graphed. [Fig. 14] Fig. 14 is a diagram showing the expression of each polypeptide in each transformant (electrophoretic photograph). [Fig. 15] Fig. 15 is a diagram showing the luminescence intensity from the surface antibody of the antibody-NK cell conjugate (ACC-1). The NK cell is shown as a control. [Fig. 16] Fig. 16 is a graph showing the luminescence intensity from the antibody-NK cell conjugates (ACC-3, ACC-4, and ACC-5) and surface antibodies. NK cells were shown as a control. [Fig. 17] Fig. 17 shows the cell damage assessment of ACC-1, ACC-2, ACC-3, ACC-4, and ACC-5 (NK cell (control) or ratio of antibody-NK cell conjugate to SK-BR-3 = 6:1). [Fig. 18] Fig. 18 is a graph showing the cellular damage assessment (effector:target ratio = 6:1) of ACC-3, ACC-4, ACC-5, and ACC-6. NK cells were shown as a control. [Fig. 19] Fig. 19 is a diagram showing the HER2 binding ability of ACC-5 and ACC-6. NK cells were shown as a control. Specific details for implementing the invention <Fc-세포 복합체> The Fc-cell complex of the present invention comprises a cell and an Fc region bound to the surface of the cell, and The above Fc region is formed by disulfide bonding between two Fc region constituent units (i.e., polypeptides derived from the heavy chain normal region), and The above Fc region is characterized by being chemically bound to the cell surface through a linker introduced into a functional group in the side chain of a specific amino acid residue present at one or more positions, preferably one position, of one of the two Fc region constituent units. Cell The type or origin of the cell is not particularly restricted, and it may be either a eukaryotic or a prokaryotic cell. Examples of eukaryotic cells include animal cells, plant cells, yeast cells, and fungal cells, while examples of prokaryotic cells include bacterial cells, but are not limited to these. The cell is preferably a eukaryotic cell, for example, a mammalian cell, and typically includes human cells, mouse cells, rat cells, etc., and is preferably a human cell. The cells may be either somatic cells or germ cells. Examples of somatic cells are not limited to blood cells, but include blood cells, immune cells, vascular cells, skeletal muscle cells, cardiac muscle cells, nerve cells, retinal cells, liver cells, digestive system cells, fibroblasts, ovarian cells, and testicular cells. Examples of germ cells include sperm cells and egg cells. The cells may be stem cells. Stem cells include, for example, pluripotent and multipotent stem cells, and include artificially pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), etc. The cells may be cells of the immune system. Examples of immune system cells include B cells, T cells, and natural killer (NK) cells. T cells are exemplified by naive T (TN) cells, effector T cells (TEFF), memory T cells and their subtypes, e.g., stem cell memory T (TSCM), central memory T (TCM), effector memory T (TEM) or terminally differentiated effector memory T cells, tumor-infiltrating lymphocytes (TIL), immature T cells, mature T cells, helper T cells, cytotoxic T cells, mucosa-associated invariant T (MAIT) cells, natural and adaptive regulatory T (Treg) cells, helper T cells, e.g., TH1 cells, TH2 cells, TH3 cells, TH17 cells, TH9 cells, TH22 cells, follicular helper T cells, alpha / beta T cells, and delta / gamma T cells. Cells may be monocytes, granulocytes, bone marrow cells, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, and / or basophils. The cell may be a cell containing one or more types of nucleic acids introduced by genetic engineering and expressing the recombinant product of the nucleic acid introduced by this. The cell may be a phylogenetic cell or a primary cell. Coined cells can be obtained, for example, from cell banks, etc. Where the cell is a primary cell isolated from the subject, the sample from which the cell is isolated includes, for example, whole blood, peripheral blood mononuclear cells (PBMC), leukocytes, bone marrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph node, intestinal lymphoid tissue, mucosal lymphoid tissue, spleen, other lymphoid tissue, liver, lung, stomach, intestine, colon, kidney, pancreas, breast, bone, prostate, neck, testis, ovary, tonsil, or other organs, and / or cells derived therefrom. <Fc 영역> The antibody Fc region is formed by disulfide bonding between two Fc region constituent units (i.e., polypeptides derived from the heavy chain normal region), wherein the Fc region constituent units may include polypeptides comprising the hinge region, CH2 region, and CH3 region of the heavy chain normal region, and the two antibody Fc region constituent units form disulfide bonds by reacting the thiol groups of the cysteine ​​residues in each hinge region. The antibody Fc region can be obtained, for example, by digesting immunoglobulin with papain by a known method. The Fc region may additionally include an antibody variable region, for example, an F(ab')2 region. That is, the Fc-cell complex of the present invention may be an antibody-cell conjugate in which an antibody, i.e., an immunoglobulin, comprising an F(ab')2 region and an Fc region is bound to a cell surface through a linker introduced to a side chain functional group of a specific amino acid residue present in one of the heavy chain normal regions, preferably the CH2 region and the CH3 region. The origin of Fc and the antibody containing Fc is not particularly limited and may be derived from animals such as mammals or birds (e.g., chickens). Preferably, the immunoglobulin unit is derived from mammals. Examples of such mammals include primates (e.g., humans, monkeys, chimpanzees), rodents (e.g., mice, rats, guinea pigs, hamsters, rabbits), pets (e.g., dogs, cats), livestock (e.g., cattle, pigs, goats), and working animals (e.g., horses, sheep), and are preferably primates or rodents, and more preferably humans. The type of antibody may be a polyclonal antibody or a monoclonal antibody. The antibody may also be a divalent antibody (e.g., IgG, IgD, IgE) or a tetravalent or higher antibody (e.g., IgA antibody, IgM antibody). Preferably, the antibody is a monoclonal antibody. Examples of monoclonal antibodies include chimeric antibodies, humanized antibodies, human antibodies, antibodies with a specific glycosylated chain (e.g., antibodies modified to have a glycosylated chain-binding consensus sequence such as an N-type glycosylated chain-binding consensus sequence), bispecific antibodies, Fc region proteins, Fc fusion proteins, and disulfide-binding-reducing antibodies. Examples of isotypes of monoclonal antibodies include IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgM, IgA, IgD, IgE, and IgY. When the Fc-cell conjugate is an antibody-cell conjugate, any antigen may be used as the antigen of the antibody. For example, such antigens may include proteins [including oligopeptides and polypeptides; proteins modified by biomolecules such as sugars (e.g., glycoproteins)], sugar chains, nucleic acids, and small molecule compounds. Preferably, the antibody may be an antibody that uses a protein as an antigen. Examples of proteins may include cell membrane receptors, cell membrane proteins other than cell membrane receptors (e.g., extracellular matrix proteins), ligands, and soluble receptors. Specific examples of monoclonal antibodies include specific chimeric antibodies (e.g., rituximab, basiliximab, infliximab, cetuximab, ciltuximab, dinutuximab, ortatoxasimab), specific humanized antibodies (e.g., daclizumab, palivizumab, trastuzumab, alemtuzumab, omalizumab, epalizumab, bevacizumab, natalizumab (IgG4), tocilizumab, eculizumab (IgG2), mogamulizumab, pertuzumab, obinutuzumab, vedolizumab, pembrolizumab (IgG4), mepolizumab, elotuzumab, daratumumab, ixekizumab (IgG4), reslizumab (IgG4), atezolizumab), and specific human antibodies (e.g., adalimumab (IgG1), panitumumab, Examples include golimumab, ustekinumab, canakinumab, ofatumumab, denosumab (IgG2), ipilimumab, belimumab, lacibakumab, ramucirumab, nivolumab, dupilumab (IgG4), secukinumab, evolocumab (IgG2), alirocumab, necitumumab, brodalumab (IgG2), and olaratumab (whereas if not mentioned in the IgG subtype, it indicates IgG1). In another embodiment, the Fc region may additionally include a functional polypeptide. That is, the fusion protein of the Fc region and the functional polypeptide may be an Fc fusion protein-cell conjugate in which the protein is bound to the cell surface through a linker introduced to a side chain functional group of a specific amino acid residue present in one heavy chain normal region, preferably the CH2 and CH3 regions, constituting the Fc region. In this case, the Fc fusion protein may be a dimer of functional polypeptide-Fc constituent polypeptide (heavy chain normal region polypeptide) fusion proteins, or a dimer of functional polypeptide-Fc constituent polypeptide fusion protein and Fc constituent polypeptide. In the latter case, either of the two Fc constituent polypeptides may be bound to the cell. Functional polypeptides are not particularly limited, but examples include enzymes, fluorescent proteins, growth factors, hormones, cytokines, blood proteins, enzymes, antigens, antibodies, transcription factors, receptors, or partial peptides thereof. Here, examples of enzymes include lipase, protease, steroid synthase, kinase, phosphatase, xylanase, esterase, methylase, demethylase, oxidase, reductase, cellulase, aromatase, collagenase, transglutaminase, glycosidase, and chitinase. Examples of growth factors include epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor (TGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), erythropoietin (EPO), thrombopoietin (TPO), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). Examples of cytokines include interleukin, interferon (IFNα, IFNβ, IFNγ), and tumor necrosis factor (TNF). Examples of blood proteins include thrombin, serum albumin, factor VII, factor VIII, factor IX, factor X, and tissue plasminogen activating factor. Such fusion proteins can be obtained by linking a polynucleotide encoding Fc and a polynucleotide encoding a functional polypeptide using a translation framework, expressing them in a host cell, and purifying them. The above antibody Fc region is chemically bound to the cell surface through a linker introduced into a functional group in the side chain of a specific amino acid residue present at one or more positions, preferably one position, of one of the polypeptides constituting the two antibody Fc regions. Here, the specific amino acid residue can be selected from one or more (e.g., two, three, or four) of 14 amino acid residues consisting of asparagine, glutamine, methionine, proline, serine, threonine, tryptophan, tyrosine, aspartic acid, glutamic acid, arginine, histidine, and lysine present in the Fc region, preferably the CH2 domain. Examples of such specific amino acid residues include, more preferably, lysine residues, tyrosine residues, serine residues, and threonine residues. For example, in human IgG such as human IgG1, the following amino acid residues present in the normal region of the heavy chain can be exposed on the antibody surface, so these amino acid residues can be used for the introduction of specific cleavage sites. Exposed ricin residue CH2 domain(e.g., position 246, position 248, position 274, position 288, position 290, position 317, position 320, position 322) CH3 domain (e.g., position 360, position 414, position 439) exposed tyrosine residue CH2 domain (e.g., position 278, position 296, position 300) CH3 domain (e.g., location 436) Exposure Serine residue CH2 domain (e.g., position 254, position 267, position 298) CH3 domain (e.g., position 400, position 415, position 440) Exposure to threonine residue CH2 domain (e.g., position 256, position 289) CH3 domain (e.g., location 335, location 359) The positions of amino acid residues in the antibody and the positions of the normal region of the heavy chain (e.g., CH2 domain) follow EU numbering (see http: / / www.imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html). For example, when targeting human IgG, the lysine residue at position 246 corresponds to the 16th amino acid residue of the human IgG CH2 region, the lysine residue at position 248 corresponds to the 18th amino acid residue of the human IgG CH2 region, the lysine residue at position 288 corresponds to the 58th amino acid residue of the human IgG CH2 region, the lysine residue at position 290 corresponds to the 60th amino acid residue of the human IgG CH2 region, and the lysine residue at position 317 corresponds to the 87th amino acid residue of the human IgG CH2 region. The notation at position 246 / 248 indicates that the lysine residue at position 246 or 248 is the target. The notation at position 288 / 290 indicates that the target is a lysine residue at position 288 or 290 (see, for example, International Publication No. 2016 / 186206, International Publication No. 2018 / 199337, International Publication No. 2019 / 240287, International Publication No. 2019 / 240288, International Publication No. 2020 / 009165, International Publication No. 2020 / 090979). Preferably, a specific amino acid residue in the normal region of the heavy chain that is positionally modified can positionally modify a lysine residue (e.g., a lysine residue at the 246 / 248 position or the 288 / 290 position). The linker introduced into the side chain of a specific amino acid residue of one of the polypeptides constituting the above Fc region is, on the other hand, chemically bonded to the position of a functional group, such as an amino group or a carboxyl group, of a protein or sugar chain present on the surface of the cell. The length or structure of the above linker is not particularly limited as long as it does not impede the function of the cell, antibody, or fusion protein, and any length and structure can be selected by a person skilled in the art, and depending on the type of linker compound used in the production of the Fc-cell complex, for example, a divalent group such as the following may be used. The divalent group is a divalent straight-chain hydrocarbon group, a divalent cyclic hydrocarbon group, a divalent complex cyclic group, -C(=O)-, -C(=S)-, -NR1-, -C(=O)-NR1-, -NR1-C(=O)-, -C(=S)-NR1-, -NR1-C(=S)-, -O-, -S-, -(O-R2) n -, and -( S-R2) m It is a group having a main chain structure comprising one group selected from the group consisting of - or two or more of these groups. R1 represents a hydrogen atom or a substituent described below. R2 represents a divalent straight-chain hydrocarbon group, a divalent cyclic hydrocarbon group, or a divalent complex hydrocarbon group. n and m are each integers from 1 to 10, preferably integers from 1 to 8, more preferably integers from 1 to 6, even more preferably integers from 1 to 5, and particularly preferably integers from 1 to 3. The divalent straight-chain hydrocarbon group is a straight-chain alkylene, a straight-chain alkenylene, or a straight-chain alkynylene. The straight-chain alkylene is a straight-chain alkylene having 1 to 6 carbon atoms, and a straight-chain alkylene having 1 to 4 carbon atoms is preferred. Examples of straight-chain alkylenes include methylene, ethylene, n-propylene, n-butylene, n-pentylene, and n-hexylene. Straight-chain alkenylene is a straight-chain alkenylene having 2 to 6 carbon atoms, and a straight-chain alkenylene having 2 to 4 carbon atoms is preferred. Examples of straight-chain alkenylene include ethylenylene, n-propynylene, n-butenylene, n-pentenylene, and n-hexenylene. Straight-chain alkynylene is straight-chain alkynylene having 2 to 6 carbon atoms, and straight-chain alkynylene having 2 to 4 carbon atoms is preferred. Examples of straight-chain alkynylene include ethynylene, n-propynylene, n-butynylene, n-pentynylene, and n-hexynylene. As a divalent straight-chain hydrocarbon group, straight-chain alkylene is preferred. The divalent cyclic hydrocarbon group is arylene, or a divalent non-aromatic cyclic hydrocarbon group. As for arylene, arylene having 6 to 14 carbon atoms is preferred, arylene having 6 to 10 carbon atoms is more preferred, and arylene having 6 carbon atoms is particularly preferred. Examples of arylene include phenylene, naphthylene, and anthracenylene. As for the divalent non-aromatic cyclic hydrocarbon group, a monocyclic or polycyclic divalent non-aromatic cyclic hydrocarbon group having 3 to 12 carbon atoms is preferred, a monocyclic or polycyclic divalent non-aromatic cyclic hydrocarbon group having 4 to 10 carbon atoms is more preferred, and a monocyclic divalent non-aromatic cyclic hydrocarbon group having 5 to 8 carbon atoms is particularly preferred. Examples of divalent non-aromatic cyclic hydrocarbon groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and cyclooctylene. As a divalent cyclic hydrocarbon group, arylene is preferred. The divalent complex ring is a divalent aromatic complex ring or a divalent non-aromatic complex ring. As heteroatoms constituting the complex ring, it is preferable to include one or more selected from the group consisting of oxygen atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, boron atoms, and silicon atoms, and it is more preferable to include one or more selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. As for the divalent aromatic complex ring, a divalent aromatic complex ring having 3 to 15 carbon atoms is preferable, a divalent aromatic complex ring having 3 to 9 carbon atoms is more preferable, and a divalent aromatic complex ring having 3 to 6 carbon atoms is particularly preferable. Examples of divalent aromatic complex groups include pyrroldyl, furandyl, thiophenediyl, pyridindiyl, pyridazinediyl, pyrimidindiyl, pyrazinediyl, triazinediyl, pyrazoldiyl, imidazolediyl, thiazoldiyl, isothiazoldiyl, oxazoldiyl, isooxazoldiyl, triazoldiyl, tetrazoldiyl, indolediyl, prindiyl, anthraquinonediyl, carbazolediyl, fluorendyl, quinolindiyl, isoquinolindiyl, quinazolindiyl, and phthalazinediyl. As for the divalent non-aromatic complex group, a non-aromatic complex group having 3 to 15 carbon atoms is preferred, a non-aromatic complex group having 3 to 9 carbon atoms is more preferred, and a non-aromatic complex group having 3 to 6 carbon atoms is particularly preferred. Examples of divalent non-aromatic complex groups include pyrroledione, pyrrolinedione, oxilandil, aziridindione, azetidindione, oxetanedione, tietanedione, pyrrolidindione, dihydrofurandil, tetrahydrofurandil, dioxolandione, tetrahydrothiophenedione, pyrrolinedione, imidazolidindione, oxazolidindione, piperidindione, dihydropyrandione, tetrahydropyrandione, tetrahydrothiopyrandione, morpholinedione, thiomorpholinedione, piperazinedione, dihydrooxazandil, tetrahydrooxazandil, dihydropyrimidinedione, and tetrahydropyrimidinedione. As a divalent complex circulator, a divalent aromatic complex circulator is preferred. The following can be cited as substituents: (i) Halogen atom; (ii) a monovalent hydrocarbon group; (iii) a univalent complex circulator; (iv) Aralkill; (v) R a -O-, R a -C(=O)-, R a -OC(=O)-, or Ra-C(=O)-O-(Ra represents a hydrogen atom or a monovalent hydrocarbon group); or (vi) NR b R c -, NR b R c -C(=O)-, NR b R c -C(=O)-O-, or R b -C(=O)-NR c -(R b and R c is identical or different and represents a hydrogen atom or a monovalent hydrocarbon group.); (vii) nitro group, sulfate group, sulfonic acid group, cyano group, and carboxyl group. The definitions, examples, and preferred examples of the halogen atom, monovalent hydrocarbon group, and monovalent complex group in the above substituents are each the same as those described above. An aralkyl refers to an arylalkyl. The definitions, examples, and preferred examples of aryl and alkyl in arylalkyls are as described above. As for aralkyls, aralkyls having 3 to 15 carbon atoms are preferred. Examples of such aralkyls include benzoyl, phenethyl, naphthylmethyl, and naphthylethyl. In addition, as a linker, one or more types of divalent groups derived from a substance selected from, for example, amino acids, peptides, nucleic acids, sugars, other polymeric substances (e.g., polyethylene glycol)) may be used in combination, or they may be used in combination with the divalent groups described above. The total number of atoms constituting the main chain in the linker is not particularly limited, but, for example, it may be 1 or more, 2 or more, 5 or more, 10 or more, or 20 or more. The total number of such atoms may be 1,000 or less, 500 or less, 300 or less, 200 or less, or 100 or less. The linker may be a chemical structure of a portion connecting Fc and the cell surface, which is formed by the reaction of a bio-orthogonal functional group introduced to a specific amino acid residue of a polypeptide on one side of the Fc region and a group present on the cell surface or reacting with the introduced bio-orthogonal functional group; more specifically, it may be a chemical structure of a portion connecting a functional group in the side chain of a specific amino acid residue present in the polypeptide constituting the Fc region and a functional group on the cell surface. <Mathematical formula of the polypeptide on the other side> The above antibody Fc region may have a functional substance introduced through a linker introduced to a functional group in the side chain of a specific amino acid residue located at one or more positions of the other of the two Fc region constituent polypeptides, that is, the polypeptide that is not involved in cell binding. (Functional substance) The functional substance is not particularly limited as long as it is a substance that imparts any function to the antibody, and examples include drugs, labeling substances, affinity substances, transport substances, and stabilizers, but preferably, it may be a drug, labeling substance, affinity substance, or transport substance. The functional substance may also be a single functional substance or a substance in which two or more functional substances are linked. As for the drug, any drug for any disease is acceptable. These diseases include, for example, cancer (e.g., lung cancer, stomach cancer, colorectal cancer, pancreatic cancer, kidney cancer, liver cancer, thyroid cancer, prostate cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, skin cancer, brain tumor, melanoma), autoimmune and inflammatory diseases (e.g., allergic diseases, rheumatoid arthritis, systemic lupus erythematosus), neurological diseases (e.g., cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), infections (e.g., bacterial infections, viral infections), hereditary and rare diseases (e.g., hereditary spherocytosis, non-dystrophic myotonia), eye diseases (e.g., macular degeneration, diabetic retinopathy, retinitis pigmentosa), diseases in the field of bone and orthopedics (e.g., osteoarthritis), blood diseases (e.g., leukemia, purpura), and other diseases (e.g., metabolic disorders such as diabetes and hyperlipidemia, liver disease, kidney disease, lung disease, circulatory system disease, Diseases of the digestive system can be cited. The medication may be a preventive or therapeutic agent for the disease, or a remedy to alleviate side effects. More specifically, the drug may be an anticancer agent. Examples of anticancer agents include chemotherapy agents, toxins, radioisotopes, or substances containing the same. Examples of chemotherapy agents include DNA damaging agents, metabolic antagonists, enzyme inhibitors, DNA intercalating agents, DNA cleavage agents, topoisomerase inhibitors, DNA binding inhibitors, tubulin binding inhibitors, cytotoxic nucleosides, and platinum compounds. Examples of toxins include bacterial toxins (e.g., diphtheria toxin) and plant toxins (e.g., ricin). Examples of radioisotopes include radioisotopes of hydrogen atoms (e.g., 3 H), radioactive isotopes of carbon atoms (e.g., 14 C), radioactive isotopes of phosphorus atoms (e.g., 32 P), radioactive isotopes of sulfur atoms (e.g., 35 S ), radioactive isotopes of yttrium (e.g., 90 Y), radioactive isotopes of technetium (e.g., 99m Tc), radioactive isotopes of indium (e.g., 111 In), radioactive isotopes of iodine atoms (e.g., 123 I, 125 I, 129 I, 131 I), radioactive isotopes of samarium (e.g., 153 Sm), radioactive isotopes of rhenium (e.g., 186 Re), radioisotopes of astatine (e.g., 211 At), radioactive isotopes of bismuth (e.g., 212 Examples include Bi). More specifically, as drugs, examples include oristatin (MMAE, MMAF), metansine (DM1, DM4), PBD (pyrrolobenzodiazepine), IGN, camtothecin derivative, chalichemycin, duocarmycin, eribulin, anthracycline, dmDNA31, and tubulosin. A labeling substance is a substance that enables the detection of a target (e.g., tissue, cell, substance). Examples of labeling substances include enzymes (e.g., peroxidase, alkaline phosphatase, luciferase, β-galactosidase), affinity substances (e.g., streptavidin, biotin, digoxigenin, aptamers), fluorescent substances (e.g., fluorescein, fluorescein isothiocyanate, rhodamine, green fluorescent protein, red fluorescent protein), luminescent substances (e.g., luciferin, equorin, acridinium ester, tris(2,2'-bipyridyl)ruthenium, luminol), radioactive isotopes (e.g., those described above), or substances containing these. An affinity substance is a substance that has affinity for a target. Examples of affinity substances include affinity proteins or peptides such as antibodies, aptamers, lectins, and complementary chains to target nucleic acids. Preferably, the affinity substance is an affinity protein or an affinity peptide, and may also be an antibody. The type of animal from which the antibody used as a functional substance originates is the same as described above. Examples of antibodies used as functional substances include full-length antibodies and their fragments (fragment antibodies). The fragment antibody may maintain binding affinity to the desired antigen, and examples include Fab, Fab', F(ab')2, scFv, and VHH antibodies. A transport material is a substance that possesses the ability to transport a compound. As a transport material, a substance capable of containing a compound within a protein outer shell (e.g., multimer) (e.g., ferritin, virus particles, virus-like particles) is preferred. A stabilizer is a substance that enables the stabilization of antibodies. Examples of stabilizers include diols, glycerin, nonionic surfactants, anionic surfactants, natural surfactants, saccharides, and polyols. Functional substances may also be peptides, proteins, nucleic acids, organic compounds, inorganic compounds, glycosylation chains, lipids, high-molecular-weight polymers, metals (e.g., gold), or chelators. Examples of peptides include cell membrane-permeable peptides, blood-brain barrier-permeable peptides, and peptide pharmaceuticals. Examples of proteins include enzymes, cytokines, fragment antibodies, lectins, interferons, serum albumin, antibodies, and ferritin. Examples of nucleic acids include DNA, RNA, and artificial nucleic acids. Examples of nucleic acids include RNA interference-inducing nucleic acids (e.g., siRNA), aptamers, and antisense. Examples of organic compounds include low-molecular-weight organic compounds such as protein degradation-inducing chimeric molecules, pigments, and photodegradable compounds. Examples of inorganic compounds include silica, talc, and alumina. Among the constituent polypeptides of Fc, the specific amino acid residue to which the functional substance binds in the polypeptide that is not involved in cell binding may be an amino acid residue such as lysine described above. The functional substance is introduced into the corresponding specific amino acid residue through a linker. The linker connecting the functional substance to Fc may be a divalent group, and the divalent group described above may be used. As for the substituents in the case where the divalent group is substituted, the above-described ones may be used. Here, the total number of atoms constituting the main chain in the linker is not particularly limited, but, for example, it may be 1 or more, 2 or more, 5 or more, 10 or more, or 20 or more. The total number of such atoms may be 1,000 or less, 500 or less, 300 or less, 200 or less, 100 or less, or 50 or less. The linker may be a chemical structure of a portion connecting Fc and a functional substance, which is formed by the reaction of a bio-orthogonal functional group introduced into a specific amino acid residue of the polypeptide that is not involved in cell binding in the Fc region and a group that reacts with a bio-orthogonal functional group connected to the functional substance, more specifically, a chemical structure of a portion connecting a functional group in the side chain of a specific amino acid residue present in the polypeptide constituting the Fc region and a functional substance. <Fc-세포 복합체의 용도> Fc-cell complexes can be used for various purposes. When the Fc-cell complex is an antibody-cell complex, for example, when the antibody is an antibody against a surface antigen of a target tissue, it can be used as a cell medicine capable of delivering cells to the target tissue. In addition, if the Fc-cell complex is an antibody-cell complex where the antibody is an antibody against a cancer cell-specific surface antigen and the cell is an NK cell or T cell, it can be used as a cell medicine that has a cancer cell damage effect. In addition, if the Fc-cell complex is a cell-Fc enzyme fusion protein complex, it can be used for material production by performing enzymatic reactions on the cell surface. <Fc-세포 복합체의 제조 방법> The method for preparing an Fc-cell complex of the present invention comprises the following processes (I) to (V). (I) A process for preparing antibody Fc regions in which constituent polypeptides of two antibody Fc regions are disulfide-bound, (II) In the Fc region of the above antibody, A process of reacting a compound represented by the following formula (Ia) or formula (Ib) to form an Fc-compound (Ia) complex or an Fc-compound (Ib) complex, (III) A process of cutting the Fc-compound (Ia) complex or the Fc-compound (Ib) complex at the cutting portion to form an Fc region that does not contain the affinity substance and has a bio-orthogonal functional group introduced, (IV) A process for preparing cells having functional groups on their surface that react with bio-orthogonal functional groups, (V) A process of introducing the Fc region into the cell surface by reacting the Fc region into which the bio-orthogonal functional group is introduced and the cell with the bio-orthogonal functional group of the Fc region and the functional group that reacts with the bio-orthogonal functional group of the cell. The following describes each process. <Process (I): Process for preparing the antibody Fc region> The antibody Fc region is as described above, and the Fc region may additionally be an antibody containing F(ab')2, i.e., an immunoglobulin, or the Fc region may additionally be an Fc fusion protein containing a functional polypeptide. These antibodies or Fc fusion proteins may be commercially available or prepared by known methods. For example, antibodies or Fc fusion proteins can be produced through genetic recombination. <Process (II): A process of reacting a compound represented by formula (Ia) or formula (Ib) (also referred to as compound (Ia) or compound (Ib)) with the antibody Fc region to form an Fc-compound (Ia) complex or an Fc-compound (Ib) complex> First, the components of Equation (Ia) or Equation (Ib) will be explained. <Affinity Substance A> Affinity substance A is an affinity substance comprising a peptide having affinity for the normal region of the heavy chain of the antibody. Here, the peptide having affinity for the normal region of the heavy chain of the antibody may be selected from the affinity peptide having a lysine residue and the affinity peptide not having a lysine residue described below. Affinity substance A is AP1-L A -AP2(wherein, AP1 represents a first affinity peptide having affinity for the normal region of the heavy chain of the antibody, AP2 represents a second affinity peptide having affinity for the normal region of the heavy chain of the antibody, and L A It may also be an affinity substance indicated as (representing a linker). In addition, in formula (A) and other formulas presented in connection with the present invention, - (hyphen) indicates that two units existing on both sides are covalently bonded. Thus, in formula (A), AP1 is covalently bonded with L, L is covalently bonded with both AP1 and AP2, and AP2 is covalently bonded with L. The first and second affinity peptides are not particularly limited as long as they are peptides having affinity for the normal region of the heavy chain of the antibody, but can be selected from affinity peptides having lysine residues and affinity peptides not having lysine residues. Preferably, one of the first and second affinity peptides is an affinity peptide having one lysine residue, and the other may be an affinity peptide not having lysine residues. Many peptides have been reported as affinity peptides having affinity for the normal region of the heavy chain of an antibody and also having one lysine residue (e.g., see International Publication No. 2016 / 186206, International Publication No. 2018 / 199337, International Publication No. 2019 / 240287, International Publication No. 2019 / 240288, International Publication No. 2020 / 090979). Accordingly, in the present invention, such peptides can be used as one of the first and second affinity peptides. More specifically, as an affinity peptide having affinity for the normal region of the heavy chain of an antibody and also having one lysine residue, the following may be used: Affinity peptide comprising the amino acid sequences of SEQ ID NOs 39 to 72 of International Publication No. 2018 / 199337; Affinity peptide comprising the amino acid sequences of SEQ ID NOs. 5, 6, 37 to 100 of International Publication No. 2019 / 240288; Affinity peptide comprising the amino acid sequences of SEQ ID NOs 5, 8 to 57, 68 to 92 of International Publication No. 2019 / 240287; Affinity peptides having a QET at the N-terminus (SEQ Nos. 7 to 10, 22 to 25, 52, 53 of International Publication No. 2020 / 090979); and Affinity peptide having one lysine residue among the affinity peptides of (1) to (12) below. (1) Various IgG binding peptides having affinity for a specific region (CH2 domain) of human IgG in general (i.e., human IgG1, IgG2, IgG3 and IgG4; hereinafter the same) (e.g., see International Publication No. 2008 / 054030, International Publication No. 2013 / 027796, International Publication No. 2016 / 186206); (2) ProteinAMimetic (PAM) peptide having affinity for a specific region (CH2 domain) of human IgG (e.g., see Fassina G et al., JOURNAL OF MOLECULAR RECOGNITION, 1996, VOL. 6, 564-569); (3) EPIHRSTLTALL (SEQ No. 1) having affinity for a specific region (CH2 domain) of human IgG (e.g., Ehrlich G. K et al., J. Biochem. Biophys. Methods, 2001, VOL. 49, 443-454); (4) (NH2-Cys1-X1-X2-X3-X4)2-Lys-Gly-OH having affinity for a specific region (Fc region) of human IgG (e.g., see RuvoM et al., ChemBioChem, 2005, VOL.6, 1242-1253); (5) FARLVSSIRY (SEQ No. 2), FGRLVSSIRY (SEQ No. 3), and TWKTSRISIF (SEQ No. 4) having affinity for a specific region (Fc region) of human IgG (e.g., Krook M et al., Journal of Immunological Methods, 1998, VOL.221, 151-157); (6) QSYP (sequence number 5) having affinity for specific regions of human IgG (e.g., Jacobs JM et al., Bio. Techniques, 2003, VOL. 34, 132-141); (7) HWRGWV (SEQ No. 6), HYFKFD (SEQ No. 7), and HFRRHL (SEQ No. 8) which have affinity for a specific region (Fc region) of human IgG (e.g., Carbonell RG et al., Journal of Chromatography A, 2009, VOL.1216, 910-918); (8) DAAG (sequence number 9) having affinity for a specific region (Fc region) of human IgG (e.g., Lund LN et al., Journal of Chromatography A, 2012, VOL.1225, 158-167); (9) Fc-I, Fc-II, and Fc-III having affinity for a specific region (Fc region) of human IgG (e.g., Warren L. Delano et al., Science, 2000, VOL.287, 1279-1283; see International Publication No. 2001 / 045746); and (10) NARKFYKG (Sequence No. 10) and NKFRGKYK (Sequence No. 11) having affinity for a specific region (Fc region) of human IgG (e.g., Biochemical Engineering Journal, 2013, VOL.79, 33-40); (11) Protein A, Protein G, Protein L, or Protein Z, or fragments thereof, having an affinity for a specific region (Fc region) of human IgG (e.g., Moks et al., Eur J Biochem. 1986 May 2; 156(3):637-43; Sjobring UJ et al., Biol Chem. 1991 Jan 5; 266(1): 399-405; Graille M et al., Structure. 2001 Aug; 9(8): 679-87; Nilsson B et al., Protein Eng. 1987 Feb-Mar; 1(2): 107-13); (12) Various IgG binding peptides having affinity for specific regions of human IgG (Fc region or CH2 domain) (e.g., see International Publication No. 2018 / 199337, International Publication No. 2019 / 240287, International Publication No. 2019 / 240288, International Publication No. 2020 / 090979). In certain embodiments, the affinity peptide having affinity for the normal region of the heavy chain of the antibody and also having one lysine residue may be, for example, the following (1) to (4): (1) Affinity peptide comprising the amino acid sequence (Fc3K) of RGNCAYHKGQIIWCTYH (Sequence No. 12); (2) An affinity peptide comprising an amino acid sequence in which one or two amino acid residues other than the lysine residue and the cysteine ​​residue are substituted with amino acid residues other than the lysine residue and the cysteine ​​residue, and also having affinity for the normal region of the heavy chain of the antibody; (3) an affinity peptide comprising the amino acid sequence (Z34CK) of FNKQCQRRFYEALHDPNLNEEQRNARIRSIREEC (SEQ 13); and (4) An affinity peptide comprising an amino acid sequence of FNKQCQRRFYEALHDPNLNEEQRNARIRSIREEC (SEQ No. 13), wherein one or two amino acid residues other than the lysine residue and the cysteine ​​residue are substituted with other amino acid residues other than the lysine residue and the cysteine ​​residue, and having affinity for the normal region of the heavy chain of an antibody. Here, the two cysteine ​​residues included in the above amino acid sequence may be cross-linked by disulfide bonds. A number of peptides have been reported as affinity peptides that have affinity for the normal region of the antibody heavy chain and do not have a lysine residue. In addition, the lysine residue in the above affinity peptides that have affinity for the normal region of the antibody heavy chain and also have one lysine residue is, in many cases, introduced to derivatize an affinity substance by covalently bonding with another part (e.g., a partial compound containing a reactive group) rather than to maintain affinity for the normal region of the antibody heavy chain (e.g., see International Publication No. 2016 / 186206, International Publication No. 2018 / 199337, International Publication No. 2019 / 240287, International Publication No. 2019 / 240288, International Publication No. 2020 / 090979), so even if this lysine residue is substituted with another amino acid residue, affinity for the normal region of the antibody heavy chain can be maintained. Accordingly, as an affinity peptide having affinity for the normal region of the antibody heavy chain and not having a lysine residue, an affinity peptide having affinity for the normal region of the antibody heavy chain and having one lysine residue, wherein the lysine residue is substituted with another amino acid residue (preferably, a normal natural amino acid residue constituting the protein other than a lysine residue and a cysteine ​​residue), and having affinity for the normal region of the antibody heavy chain can be used. More specifically, as an affinity peptide having affinity for the normal region of the heavy chain of an antibody and also not having a lysine residue, the following may be used: Sequence numbers 20 to 38, 73 to 75 of International Publication No. 2018 / 199337 (where Xaa1 is not a ricin residue), Sequence number 92; Sequence numbers 7, 11 to 14, 108 of International Publication No. 2019 / 240288; an affinity peptide among (1) to (4) listed as examples of affinity peptides having affinity for a normal region of an antibody heavy chain and having one lysine residue, wherein the lysine residue is substituted with another amino acid residue (preferably, an amino acid residue other than a cysteine ​​residue); and Among the affinity peptides of (1) to (12) listed as examples of affinity peptides, an affinity peptide that does not have a lysine residue. In certain embodiments, affinity peptides that do not have lysine residues may be, for example, the following (5) to (10): (5) Affinity peptide comprising the amino acid sequence (Z34CM) of FNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC (Sequence No. 14); (6) An affinity peptide comprising an amino acid sequence of FNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC (SEQ No. 14), wherein one or two amino acid residues other than a cysteine ​​residue are substituted with an amino acid residue other than a lysine residue and a cysteine ​​residue, and also having an affinity for a normal region of the heavy chain of an antibody; (7) Affinity peptide comprising the amino acid sequence (ProAR) of FNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA (Sequence No. 15); (8) An affinity peptide comprising an amino acid sequence in which one or two amino acid residues other than a cysteine ​​residue are substituted with an amino acid residue other than a lysine residue and a cysteine ​​residue, wherein the amino acid sequence of FNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA (SEQ No. 15) is substituted with an amino acid residue other than a lysine residue and a cysteine ​​residue, and also having an affinity for a normal region of the heavy chain of an antibody; (9) an affinity peptide comprising the amino acid sequence of RGNCAYHRGQIIWCTYH (SEQ No. 16); and (10) An affinity peptide having an affinity for a normal region of the heavy chain of an antibody, comprising an amino acid sequence of RGNCAYHRGQIIWCTYH (sequence number 16) in which one or two amino acid residues other than the cysteine ​​residue are substituted with a lysine residue and an amino acid residue other than the cysteine ​​residue. Here, the two cysteine ​​residues included in the above amino acid sequence may be cross-linked by disulfide bonds. Substitution of amino residues may be conservative substitution. The term "conservative substitution" refers to substituting a specific amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are well known in the relevant industry. For example, such families include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), amino acids having uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids having nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids having β-position branched side chains (e.g., threonine, valine, isoleucine), amino acids having aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine), amino acids having side chains containing hydroxyl groups (e.g., alcoholic, phenolic) (e.g., serine, threonine, tyrosine), and amino acids having sulfur-containing side chains (e.g., cysteine, Examples include methionine. Amino acids having non-charged polar side chains and amino acids having non-polar side chains are collectively referred to as neutral amino acids. Preferably, conservative substitution of amino acids may be substitution between aspartic acid and glutamic acid, substitution between arginine, lysine, and histidine, substitution between tryptophan and phenylalanine, substitution between phenylalanine and valine, substitution between leucine, isoleucine, and alanine, and substitution between glycine and alanine. L AThe linker represented by is a divalent group. The divalent group may or may not be substituted. Examples of divalent groups include those described above. Examples of substituents when the divalent group is substituted include those described above. Here, the total number of atoms constituting the main chain in the linker may be 2 to 10. The total number of such atoms may be 3 or more, or 4 or more. The total number of such atoms may be 9 or fewer, 8 or fewer, or 7 or fewer. More specifically, the total number of such atoms may be 3 to 9, 4 to 8, or 4 to 7. As a linker, for example, materials such as peptides, nucleic acids, sugars, other polymeric materials (e.g., polyethylene glycol), and divalent hydrocarbon groups (e.g., alkyl chains) may be used, but peptide linkers are more preferred. The number of amino acid residues constituting the peptide linker can be appropriately set according to conditions such as the type of amino acid residue (e.g., α-amino acid, β-amino acid, γ-amino acid; preferably α-amino acid). For example, the peptide linker may consist of 20 or more amino acid residues. The peptide linker may consist of 22 or more, 24 or more, 26 or more, 28 or more, 30 or more, 32 or more, 34 or more, 36 or more, 38 or more, or 40 or more amino acid residues. The peptide linker may also consist of fewer than 50, fewer than 49, fewer than 48, fewer than 47, fewer than 46, or fewer than 45 amino acid residues. As amino acid residues constituting the peptide linker, residues of the natural amino acids or non-natural amino acids described above may be used. Preferably, amino acid residues constituting the peptide linker may include only residues of the natural amino acids described above. Examples of amino acid residues suitable for the peptide linker include alanine, proline, serine, and glycine, but are not limited thereto. As peptide linkers, those disclosed in International Publication No. 2021 / 112249 and International Publication No. 2011 / 144756 may also be used. <Reactivity to antibody R> As a reactive group for the antibody, a reactive group for an amino acid residue having a side chain that is reactive among the amino acid residues constituting the antibody (protein) may be used. Among the 20 types of natural amino acids constituting the protein as described above, glycine, which has no side chain, and alanine, isoleucine, leucine, phenylalanine, and valine, whose side chains are hydrocarbon groups, are inactive to normal reactions. Therefore, the reactive group for the antibody is a group capable of reacting with one or more (e.g., 2, 3, or 4) side chains of any one of the 14 types of amino acids consisting of asparagine, glutamine, methionine, proline, serine, threonine, tryptophan, tyrosine, aspartic acid, glutamic acid, arginine, histidine, and lysine. The reactive group for the antibody is, more preferably, a reactive group specific to the side chain of any one of the amino acids lysine, tyrosine, tryptophan, or cysteine; even more preferably, a reactive group specific to the side chain of any one of the amino acids lysine, tyrosine, or tryptophan; and particularly preferably, a reactive group specific to the side chain of lysine or tyrosine, among others, a reactive group specific to the side chain of lysine. For details of such reactive groups, refer, for example, to International Publication No. 2016 / 186206, International Publication No. 2018 / 199337, International Publication No. 2019 / 240287, International Publication No. 2019 / 240288, and International Publication No. 2020 / 090979. The reactive group specific to the side chain of the lysine residue is a group that can specifically react with the amino group (NH2) present in the side chain of the lysine residue, and examples include an activated ester residue (e.g., N-hydroxysuccinimide residue), a vinylsulfone residue, a sulfonyl chloride residue, an isocyanate residue, an isothiocyanate residue, an aldehyde residue, a 1,4,7,10-tetraazaccyclododecane-1,4,7,10-tetraacetic acid residue, a 2-imino-2-methoxyethyl residue, a diazonium terephthalic acid residue, an α-halogen-substituted acetamide, and an α-halogen-substituted methyl ketone. According to the reaction between the reactive group described above, which is specific to the side chain of the lysine residue, and the amino group (NH2) present in the side chain of the lysine residue, as a linkage part, for example, an amide residue, a urea residue, a pyridine residue, a carbamate residue, or a sulfonamide residue can be produced. (Group B containing bio-orthogonal functional groups) Bioorthogonal functional groups refer to groups that do not react with biological components (e.g., amino acids, proteins, nucleic acids, lipids, sugars, phosphates) or react slowly with biological components, but react selectively with components other than biological components. Bioorthogonal functional groups are well known in the relevant technical field (e.g., see Sharpless KB et al., Angew. Chem. Int. Ed. 40, 2004(2015); Bertozzi CR et al., Science 291, 2357(2001); Bertozzi CR et al., Nature Chemical Biology 1,13(2005)). A bio-orthogonal functional group for a protein is a group that does not react with the side chains of the 20 natural amino acid residues that make up the protein, or has a slow reaction rate with the said side chains but reacts with the target functional group. The 20 natural amino acids that make up the protein are alanine (A), asparagine (N), cysteine ​​(C), glutamine (Q), glycine (G), isoleucine (I), leucine (L), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), valine (V), aspartic acid (D), glutamic acid (E), arginine (R), histidine (H), and lysine (L). Among these 20 natural amino acids, glycine, which has no side chain (i.e., hydrogen atoms), and alanine, isoleucine, leucine, phenylalanine, and valine, which have side chains that are hydrocarbon groups (i.e., do not contain heteroatoms selected from the group consisting of sulfur atoms, nitrogen atoms, and oxygen atoms in the side chain), are inactive to normal reactions. Therefore, the bio-orthogonal functional groups for proteins are groups that do not react with the side chains of asparagine, glutamine, methionine, proline, serine, threonine, tryptophan, tyrosine, aspartic acid, glutamic acid, arginine, histidine, and lysine, in addition to the side chains of these amino acids that have side chains inactive to normal reactions, or that react with the target functional group at a slow rate. As such bioorthogonal functional groups, for example, azide groups, aldehyde residues, thiol groups, alkene residues (in other words, preferably having a vinylene (ethenylene) portion which is the smallest unit having a double bond between carbon atoms; the same applies hereinafter), alkyne residues (in other words, preferably having an ethinylene portion which is the smallest unit having a triple bond between carbon atoms; the same applies hereinafter), halogen residues, tetrazine residues, nitron residues, hydroxylamine residues, nitrile residues, hydrazine residues, ketone residues, boronic acid residues, cyanobenzothiazole residues, allyl residues, phosphine residues, maleimide residues, disulfide residues, thioester residues, α-halocarbonyl residues (e.g., carbonyl residues having a fluorine, chlorine, bromine, or iodine atom at the α-position; the same applies hereinafter), isonitrile residues, sidnon residues, and selenium. Examples of residues include alkyne residues (i.e., the ethinylene moiety). Examples of groups having alkyne residues include dibenzocyclooctine (DBCO) and diazacyclononine (DACN). Bio-orthogonal functional groups may be protected or unprotected. Bio-orthogonal functional groups refer to unprotected bio-orthogonal functional groups or protected bio-orthogonal functional groups. Unprotected bio-orthogonal functional groups correspond to the bio-orthogonal functional groups described above. Protected bio-orthogonal functional groups are groups that generate bio-orthogonal functional groups by cleavage of the protecting group. Cleaving of the protecting group can be performed by specific treatment under conditions (mild conditions) that cannot cause denaturation or degradation of the protein (e.g., cleavage of amide bonds). Examples of such specific treatments include (a) treatment with one or more substances selected from the group consisting of acidic substances, basic substances, reducing agents, oxidizing agents, and enzymes; (b) treatment with physicochemical stimulation selected from the group consisting of light; or (c) exposure when using a cleavable linker containing a self-degradable cleavable portion. These protecting groups and their cutting conditions are common technical knowledge in the field (e.g., G. Leriche, L. Chisholm, A. Wagner, Bioorganic & Medicinal Chemistry. 20, 571(2012); Feng P. et al., Journal of American Chemical Society. 132, 1500(2010).; Bessodes M. et al., Journal of Controlled Release, 99, 423(2004).; DeSimone, JM, Journal of American Chemical Society. 132, 17928(2010); Thompson, DH, Journal of Controlled Release, 91, 187(2003); Schoenmarks, RG, Journal of Controlled Release, 95, 291(2004)). Reaction conditions for mild conditions (e.g., reaction temperature, reaction time, reaction solution) are as described below. Examples of protected bioorthogonal functional groups include disulfide residues, ester residues, acetal residues, ketal residues, imine residues, and vicinaldiol residues. Preferably, the bio-orthogonal functional group is an unprotected bio-orthogonal functional group. More preferably, the bio-orthogonal functional group may be a specific bio-orthogonal functional group that has excellent reactivity (e.g., reaction level and / or reaction specificity) with other bio-orthogonal functional groups. Examples of such bio-orthogonal functional groups include azide groups, alkyne residues (preferably having a triple bond between carbon atoms, which may be substituted by a substituent as described above), tetrazine residues, alkene residues, thiol groups, maleimide residues, furan residues, and halocarbonyl residues. The group comprising the bio-orthogonal functional group represented by B may be a group consisting of the bio-orthogonal functional group, or a group comprising the bio-orthogonal functional group and other parts. Examples of other parts include the connecting part between the bio-orthogonal functional group and the linker. The connecting part is, for example, a divalent group. The divalent group may or may not be substituted. The definitions, examples, and preferred examples of the bio-orthogonal functional group, the divalent group, and the substituent when the divalent group is substituted are as described above. <Amputable Part CLE> A cleavable portion is a region that can be cleaved by a specific treatment under conditions (mild conditions) where protein denaturation or degradation (e.g., cleavage of amide bonds) cannot be caused. Therefore, a cleavable portion can be described as a region (a bond other than an amide bond) that can be cleaved by a specific cleavage treatment under mild conditions. Examples of such specific treatments include (a) treatment with one or more substances selected from the group consisting of acidic substances, basic substances, reducing agents, oxidizing agents, and enzymes; (b) treatment with physicochemical stimuli such as light; or (c) incubation when using a cleavable linker containing a self-degradable cleavable portion. Such cleavable linkers and their cleavage conditions are common technical knowledge in the field (e.g., G. Leriche, L. Chisholm, A. Wagner, Bioorganic & Medicinal Chemistry. 20, 571(2012); Feng P. et al., Journal of American Chemical Society. 132, 1500(2010).; Bessodes M. et al., Journal of Controlled Release, 99, 423(2004).; DeSimone, JM, Journal of American Chemical Society. 132, 17928(2010); Thompson, DH, Journal of Controlled Release, 91, 187(2003); Schoenmarks, RG, Journal of Controlled Release, 95, 291(2004)). Reaction conditions for mild conditions (e.g., reaction temperature, reaction time, reaction solution) are as described below.Examples of such cutting portions include, for instance, disulfide residues, acetal residues, ketal residues, ester residues, carbamoyl residues, alkoxyalkyl residues, imine residues, tertiary alkyloxycarbamate residues (e.g., tert-butyloxycarbamate residues), silane residues, hydrazone-containing residues (e.g., hydrazone residues, acylhydrazone residues, bisarylhydrazone residues), phosphoramidate residues, aconityl residues, trityl residues, azo residues, vicinaldiol residues, selenium residues, aromatic ring-containing residues having electron-withdrawing groups, coumarin-containing residues, sulfone-containing residues, unsaturated bond-containing chain residues, and glycosyl residues. The aromatic ring having an electron-withdrawing group is preferably selected from the group consisting of aryl, aralkyl, aromatic heterocyclic, and alkyl having an aromatic heterocyclic group, and aralkyl and alkyl having an aromatic heterocyclic group are more preferred. The electron-withdrawing group is preferably bonded to the 2nd position of the ring. Even more preferably, the aromatic ring-containing residue having an electron-withdrawing group is, for example, an aralkyl having an electron-withdrawing group at the 2nd position (e.g., benzyl). Examples of electron-withdrawing groups include a halogen atom, an alkyl substituted with a halogen atom (e.g., trifluoromethyl), a boronic acid residue, a mesyl, a tosyl, a trilate, a nitro, a cyano, a phenyl group, and a keto group (e.g., acyl). Examples of ester residues include, for instance, conventional ester residues composed of carbon atoms and oxygen atoms [e.g., alkyl esters (e.g., tert-butyloxycarbonyl, etc., tertiary alkyloxycarbonyl), aryl esters (e.g., phenacyl esters, 2-(diphenylphosphino)benzoate), glycosyl ester residues, orthoester residues], ester residues containing sulfur atoms and oxygen atoms (e.g., thioester residues such as α-thiophenyl ester residues, alkylthioester residues), ester residues containing phosphorus atoms and oxygen atoms (e.g., phosphodiester residues, phosphotriester residues), and activated ester residues (e.g., N-hydroxysuccinimide residues). Examples of sulfone-containing residues include sulfone residues and quinolinylbenzenesulfonate residues. The silane residue is preferably a silane residue having a group selected from the group consisting of alkyl, aryl, aralkyl, and alkoxy. Examples of such silane residues include dialkyldialkoxysilane residues (e.g., dimethyldialkoxysilane, diethyldialkoxysilane) or dialyldialkoxysilane residues (e.g., diphenyldialkoxysilane). As for the alkoxyalkyl (i.e., alkyloxyalkyl) residue, it is a group combining alkyloxy and alkyl as described above, and examples include methoxymethyl residue, ethoxymethyl residue, methoxyethyl residue, and ethoxyethyl residue, but are not limited to these. The unsaturated bond-containing chain residue is a residue containing an unsaturated bond portion consisting only of carbon atoms [e.g., vinyl (ethenyl), the smallest unit having a double bond between carbon atoms, or acetylenyl (ethynyl), the smallest unit having a triple bond between carbon atoms], or a residue containing an unsaturated bond portion consisting of carbon atoms and heteroatoms (e.g., nitrogen atoms, sulfur atoms, oxygen atoms) (e.g., aldehyde, cyano). Examples of unsaturated bond-containing chain residues include vinyl ether residues, cyanoethyl residues, ethylene residues, and malondialdehyde residues. Examples of acidic substances (also referred to as electrochemical reagents) include inorganic acidic substances such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acidic substances such as formic acid, acetic acid, 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, 3-morpholinopropanesulfonic acid, sodium dihydrogen phosphate, citric acid, dodecyl sulfuric acid, N-dodecanoylsarcosic acid, and trifluoroacetic acid. Examples of sites that can be cleaved by acidic substances include alkyloxyarylalkyl residues, tertiary alkyloxycarbamate residues, acetal residues, silane residues, imine residues, vinyl ether residues, β-thiopropionate residues, trityl residues, hydrazone residues, aconityl residues, orthoester residues, carbamoyl residues, and 2-(diphenylphosphino)benzoate residues. Examples of basic substances (also referred to as nucleation reagents) include inorganic basic substances such as sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, and ammonium acetate, and organic basic substances such as hydroxylamine, triethylamine, and N,N'-diisopropylamine. Examples of sites that can be cleaved by basic substances include silane residues, cyanoethyl residues, sulfone residues, ethylene residues, glycosyl disuccinate residues, α-thiophenyl ester residues, unsaturated vinyl sulfide residues, malondialdehyde residues, acylhydrazone residues, and alkyl thioester residues. Examples of reducing agents include cysteine, dithiothreitol, reduced glutathione, and β-mercaptoethanol. Examples of sites that can be cleaved by the reducing agent include disulfide residues, alkoxyalkyl residues, and azo residues. Examples of oxidizing agents include sodium periodate and oxidized glutathione. Examples of sites that can be cleaved by an oxidizing agent include vicinaldiol residues and selenium residues. Examples of enzymes include trypsin, papain, TEV, thrombin, cathepsin B, cathepsin D, cathepsin K, caspase, protease, matrix metalloprotease, lipase, endoglycosytase, and PNGase F. Examples of sites that can be cleaved by enzymes include ester residues, phosphodiester residues, and glycosyl residues. Examples of sites that can be cut by light include 2-nitrobenzyl residues, phenacyl ester residues, 8-quinolinebenzenesulfonate residues, coumarin residues, phosphotriester residues, bisarylhydrazone residues, and bimandithiopropionic acid residues. Examples of self-degrading cleavable parts include, for instance, active ester residues (e.g., N-hydroxysuccinimide residues). <Mutilable part CLE (B) capable of generating bio-orthogonal functional groups by cleavage> The cleavable portion may be capable of generating a bio-orthogonal functional group on the reactive group side by cleavage. Examples of such cleavable portions include disulfide residues, ester residues (including other ester residues described above, such as conventional ester residues and thioester residues), acetal residues (including other acetal residues such as conventional ester residues and thioacetal residues), ketal residues, imine residues, and vicinaldiol residues. <Linker> The first linker represented by L1 and the second linker represented by L2 may be the same or different divalent groups. The divalent group may or may not be substituted. Examples of divalent groups include those described above. Examples of substituents when the divalent group is substituted include those described above. In addition, as a linker, materials such as peptides, nucleic acids, sugars, other polymeric materials (e.g., polyethylene glycol), and divalent hydrocarbon groups (e.g., alkyl chains) may be used. A person skilled in the art can appropriately determine the presence or absence of a linker and the type of linker depending on the type of the first and second affinity portions used. In certain embodiments, the sum of the atoms constituting the main chain in the first linker and the second linker may be 2 to 10. The sum of such atoms may be 3 or more, or 4 or more. The sum of such atoms may be 9 or fewer, 8 or fewer, or 7 or fewer. More specifically, the sum of such atoms may be 3 to 9, 4 to 8, or 4 to 7. The number of atoms constituting the main chain in the first linker and the second linker may be 1 to 9, each. Such number of atoms may be 2 or more, or 3 or more. Such number of atoms may be 8 or fewer, 7 or fewer, or 6 or fewer. More specifically, such number of atoms may be 2 to 8, 3 to 7, or 3 to 6. The main chain in the first linker and the second linker is composed of a structure including a chain structure, a ring structure, or a combination thereof. If the main chain is a chain structure that does not include a ring structure, the number of atoms in the main chain can be determined by counting the number of atoms in the chain structure. On the other hand, if the main chain is a structure that includes a ring structure, a predetermined number of atoms constituting the ring structure can be determined by counting the number of atoms in the main chain. Specifically, the number of atoms in the main chain in the ring structure can be determined by counting the number of atoms in the shortest path connecting two bonding hands in the ring structure (for example, refer to the bold paths in (a) to (d) below). If the main chain is a structure including a combination of a chain structure and a ring structure, the number of atoms in the main chain can be determined by adding the number of atoms in the chain structure that does not include a ring structure to the number of atoms in the shortest path connecting two bonding hands in the ring structure. The method of counting the number of atoms in the main chain is the same for other linkers. [Tuesday 5] * is a connecting hand. In case (a), since the shortest path is the thick path, the number of atoms in the divalent ring structure counted as the number of atoms in the main chain is 2. In case (b), since the shortest path is the thick path, the number of atoms in the divalent ring structure counted as the number of atoms in the main chain is 3. In case (c), since both paths are shortest paths (equidistant), the number of atoms in the divalent ring structure counted as the number of atoms in the main chain is 4. In the case of (d), since the path of the condensation site is the shortest path, the number of atoms in the divalent ring structure counted as the number of atoms in the main chain is 4. <Compound (Ia)> Compound (Ia) is a compound in which a reactive group and an affinity substance for the Fc region are connected by a linker, and the compound has a cleavable portion that can generate a bio-orthogonal functional group on the reactive group side by cleavage in the linker. [Tuesday 6] [In the formula, R represents a reactive group for the Fc region, L1 represents a first linker, L2 represents a second linker, CLE(B) represents a cleavable portion capable of generating a bio-orthogonal functional group on the reactive group side by cleavage, and A is AP1-L A -AP2(wherein, AP1 represents a first affinity peptide having affinity for the normal region of the heavy chain of the antibody, AP2 represents a second affinity peptide having affinity for the normal region of the heavy chain of the antibody, and L A ...represents an affinity substance indicated by (representing a linker). Reactions using compound (Ia) (process (II) and process (III)) are shown in Fig. 2. An example of compound (Ia) is the compound of the following formula (Ia-1). [Tuesday 7] [In the formula, X represents degreasing, W1, W2, and W3 each independently represent an oxygen atom or a sulfur atom, L3 represents the third linker, and L4 represents the fourth linker, S represents a sulfur atom, A represents an affinity substance comprising first and second affinity portions having affinity for the normal region of the heavy chain of an antibody. It may also be a compound or salt thereof represented by [A]. The definition, examples, and preferred examples of the affinity substance represented by A are as described above. The detachable group represented by X is a group that can be detached by a reaction between the carbon atom in C=W1 adjacent to X and the amino group. A person skilled in the art can appropriately set such a detachable group. Examples of such a detachable group include the following: (a) R A -S(here, R A represents a hydrogen atom, a monovalent hydrocarbon group that may have substituents, or a monovalent complex cellular group that may have substituents, and S represents a sulfur atom.); (b) R A -O(here, R A represents a hydrogen atom, a monovalent hydrocarbon group that may have substituents, or a monovalent complex valence group that may have substituents, and O represents an oxygen atom. (c) R A -(R B -)N(here, R A and R B Each represents, independently, a hydrogen atom, a monovalent hydrocarbon group that may have substituents, or a monovalent complex valence group that may have substituents, and N represents a nitrogen atom.); or (d) Halogen atom. W1, W2, and W3 each independently represent an oxygen atom or a sulfur atom. Preferably, W1, W2, and W3 may be oxygen atoms. The third linker represented by L3 and the fourth linker represented by L4 may be the same or different divalent groups. The divalent group may or may not be substituted. Examples of divalent groups include those described above. Examples of substituents in the case where the divalent group is substituted include those described above. In certain embodiments, the sum of the atoms constituting the main chain in the third linker and the fourth linker may be 2 to 10. The sum of such atoms may be 3 or more, or 4 or more. The sum of such atoms may be 9 or fewer, 8 or fewer, or 7 or fewer. More specifically, the sum of such atoms may be 3 to 9, 4 to 8, or 4 to 7. The number of atoms constituting the main chain in the third linker and the fourth linker may be 1 to 9, each. Such number of atoms may be 2 or more, or 3 or more. Such number of atoms may be 8 or fewer, 7 or fewer, or 6 or fewer. More specifically, such number of atoms may be 2 to 8, 3 to 7, or 3 to 6. Reactions using compound (Ia-1) (process (II) and process (III)) are shown in Fig. 3. <Compound (Ib)> Compound (Ib) is a compound in which a reactive group for the Fc region and an affinity substance are linked by a linker, and the linker has a cleavage portion, and additionally contains a bio-orthogonal functional group between the reactive group for the antibody and the cleavage portion. Bio-orthogonal functional groups are as described above. Preferably, bio-orthogonal functional groups may include an azide group, an alkyne residue (preferably a group having a triple bond between carbon atoms that may be substituted by a substituent as described above), a tetrazine residue, an alkene residue, a thiol group, a maleimide residue, a furan residue, and a halocarbonyl residue. [Tue 8] [In the formula, R represents the reactive group, L5 represents the fifth linker, L6 represents the sixth linker, B represents a group including a bio-orthogonal functional group, CLE represents a cleavable portion, and A represents the affinity substance.] Reactions using compound (Ib) (process (II) and process (III)) are shown in Fig. 4. An example of a compound (Ib) is a compound of the following formula (Ib-1). [Tue 9] [In the formula, X represents degreasing, W1, W2, and W3 each independently represent an oxygen atom or a sulfur atom, L7 represents the 7th linker, and L8 represents the 8th linker, B represents a group containing a bioorthogonal functional group, and V represents an oxygen atom or a sulfur atom, A represents an affinity substance comprising first and second affinity portions having affinity for the normal region of the heavy chain of an antibody.] It may also be a compound or its salt. The definition, examples, and preferred examples of the affinity substance represented by X, the group comprising a bio-orthogonal functional group represented by B, and the affinity substance represented by A are as described above. W1, W2, and W3 each independently represent an oxygen atom or a sulfur atom. Preferably, W1, W2, and W3 may be oxygen atoms. The seventh linker represented by L7 and the eighth linker represented by L8 may be the same or different divalent groups. The divalent group may or may not be substituted. Examples of divalent groups include those described above. Examples of substituents in the case where the divalent group is substituted include those described above. In certain embodiments, the sum of the atoms constituting the main chain in the seventh linker and the eighth linker may be 2 to 10. The sum of such atoms may be 3 or more, or 4 or more. The sum of such atoms may be 9 or fewer, 8 or fewer, or 7 or fewer. More specifically, the sum of such atoms may be 3 to 9, 4 to 8, or 4 to 7. The number of atoms constituting the main chain in the seventh linker and the eighth linker may be 1 to 9, each. Such a number of atoms may be 2 or more, or 3 or more. Such a number of atoms may be 8 or fewer, 7 or fewer, or 6 or fewer. More specifically, such a number of atoms may be 2 to 8, 3 to 7, or 3 to 6. V represents an oxygen atom or a sulfur atom. Preferably, V may be a sulfur atom. Reactions using compound (Ib-1) (Process (II) and Process (III)) are shown in Fig. 5. The preparation of a series of compounds or their salts as described above can be carried out by reacting an affinity substance with a partial compound containing a reactive group for antibodies. For example, such a reaction can be carried out in a suitable organic solvent system (e.g., an organic solvent containing an alkyl halide such as CH2Cl2 (e.g., a methyl halide) and an amine such as triethylamine) at an appropriate temperature (e.g., about -10 to 30°C). The reaction time is, for example, 1 minute to 20 hours, preferably 10 minutes to 15 hours, more preferably 20 minutes to 10 hours, and even more preferably 30 minutes to 8 hours.

[0213] Confirmation of the formation of a series of compounds or their salts as described above can be carried out, for example, by electrophoresis, chromatography (e.g., gel filtration chromatography, ion exchange chromatography, reverse-phase column chromatography, HPLC), NMR, or mass spectrometry, depending on the specific raw materials and the molecular weights of the products. These compounds or their salts can be appropriately purified by any method such as chromatography (e.g., the chromatography described above, and affinity chromatography). The reaction between Fc and the compound represented by formula (Ia) or formula (Ib) is not particularly limited, but can be easily carried out by mixing Fc and the compound represented by formula (Ia) or formula (Ib) in solution. After the reaction, it is desirable to appropriately remove the unreacted compound. Thus, an Fc-compound (Ia) complex or an Fc-compound (Ib) complex is formed. <Process (III): A process of cleaving an Fc-compound (Ia) complex or an Fc-compound (Ib) complex at the cleavable portion to form an Fc region that does not contain the affinity substance and has a bio-orthogonal functional group introduced> Examples of cutting treatments include (a) treatment with one or more substances selected from the group consisting of acidic substances, basic substances, reducing agents, oxidizing agents, and enzymes as described above, (b) treatment with physicochemical stimuli such as light, or (c) incubation when using a cutting linker containing a self-degrading cutting portion. For such cutting treatments, reference may also be made to International Publication No. 2019 / 240287, International Publication No. 2019 / 240288, International Publication No. 2020 / 009165, and International Publication No. 2020 / 090979. Such cleavage reactions can be appropriately carried out under conditions (mild conditions) that do not cause denaturation or degradation of the protein (e.g., cleavage of amide bonds). For example, such mild conditions are as described above. In addition, when the cleavable site is an ester (e.g., a conventional ester or other esters such as a thioester), the cleavage reaction can be carried out by incubating for an appropriate time (e.g., 1 hour) in a hydroxylamine hydrochloride solution (e.g., pH 4.0 to 8.0, 10 mM to 10 M) (e.g., Vance, N. et al., Bioconjugate Chem. 2019, 30, 148-160). Confirmation of the production of an antibody or its salt that does not contain an affinity substance obtained by the cleavage reaction can be performed, for example, by electrophoresis, chromatography (e.g., gel filtration chromatography, ion exchange chromatography, reverse-phase column chromatography, HPLC), or mass spectrometry, although this is based on the specific molecular weight of the raw material and the product. Confirmation of regioselectivity can be performed by peptide mapping as described above. Confirmation of the number of affinity substances introduced can be performed by mass spectrometry (a DAR calculator (Agilent software) may be used in combination). The antibody or its salt modified with an affinity substance can be appropriately purified by any method such as chromatography (e.g., the chromatography described above, and affinity chromatography). Thus, a bio-orthogonal functional group can be attached to a side chain functional group possessed by a specific amino acid of one polypeptide constituting the Fc region. Additionally, by reacting a compound containing another bio-orthogonal functional group with this bio-orthogonal functional group, the latter bio-orthogonal functional group may be made into a bio-orthogonal functional group that reacts with a functional group on the cell surface. <Modification by functional substances> In the case where the Fc-cell region complex is formed such that a functional substance is introduced through a linker introduced to a functional group in the side chain of a specific amino acid residue located at one or more positions on the other side (a polypeptide not bound to a cell) of the two antibody Fc constituent polypeptides, the process further comprises introducing a functional substance to a functional group in the side chain of a specific amino acid residue located at one or more positions on the other side of the two antibody Fc constituent polypeptides in the antibody Fc region. In this case, in process (II), the reaction between the Fc region and compound (Ia) or compound (Ib) may be performed twice using compound (Ia) or compound (Ib) containing different types of bio-orthogonal functional groups, and one may be for cell binding and the other for functional material binding. Thus, a compound (Ia)-Fc-compound (Ia) complex or a compound (Ib)-Fc-compound (Ib) complex can be obtained. Additionally, a compound (Ia)-Fc-compound (Ib) complex is also acceptable. After obtaining a modified Fc in which two types of bio-orthogonal functional groups are bound to each Fc constituent polypeptide by cleaving the compound-Fc-compound complex at the cleavable portion, and before reacting with a cell in process (V), a functional substance bound to a functional group that reacts with the bio-orthogonal functional group can be reacted with one bio-orthogonal functional group to introduce a functional substance to one side of the polypeptide constituting the Fc region. Subsequently, by reacting cells with this, a cell-Fc-functional substance complex is obtained, that is, an Fc-cell complex in which Fc modified with a functional substance or an antibody or Fc fusion protein containing it is bound to a cell. Reactions using compound (Ia) (Process (II) (Reactions 1, 2) and Process (III) (Reaction 3)) are shown in Fig. 6. By cleaving at the cleavable portion, the affinity substance is removed, and at the same time, a modified Fc (VIa) is obtained in which two types of bio-orthogonal functional groups are bound to each Fc constituent polypeptide, so the two types of bio-orthogonal functional groups B L and B R A functional substance can be introduced into one side, and the other side can be used for cell introduction. Reactions using compound (Ib) (Process (II) (Reactions 1, 2) and Process (III) (Reaction 3)) are shown in Fig. 7. By cleaving at the cleavable portion, the affinity substance is removed, and since a modified Fc(VIb) is obtained in which two types of bio-orthogonal functional groups are bound to each Fc constituent polypeptide, the two types of bio-orthogonal functional groups B L and B R A functional substance can be introduced into one side, and the other side can be used for cell introduction. <Process (IV): Process of preparing cells having functional groups on their surface that react with bio-orthogonal functional groups> The cell can use the cell as described above. The functional group that reacts with the bio-orthogonal functional group can be appropriately selected depending on the type of bio-orthogonal functional group and is not particularly limited, but for example, for the azide group, alkyne residues, ortho-phosphane benzoic acid, etc., for the thiol group, maleimide residues, alkene residues, alkyne residues, haloamide residues, halocetone residues, etc., and for the tetrazine residue, norbornene, isonitrile, BCN (bicyclo[6.1.0]nonyne), etc., and similarly, for the alkyne residue, azide group, and for the maleimide residue, thiol group, the combination of the bio-orthogonal functional group and the functional group that reacts with the bio-orthogonal functional group may be reversed. If a cell possesses functional groups on its surface that react with bio-orthogonal functional groups, the cell may be used as is; however, it is generally preferable to modify the cell surface to introduce functional groups that react with bio-orthogonal functional groups onto the cell surface. For example, functional groups that react with bio-orthogonal functional groups can be introduced onto the cell surface by means such as cell surface modification using enzymes (e.g., GlcNAc-tagging (Glycocalyx Tagging) using O-GlcNAcase (OGA) and N-acetylglucosaminyltransferase (OGT), HaloTag Technology using haloalkanedehalogenase, Sortagging (Sortase-mediated Tagging) using Sortase A, Q-Tagging using transglutaminase), introduction of functional groups by modifying glycosylation chains on the cell surface, or introduction of functional groups into the lipid membrane via lipid chains. In addition, regarding functional groups such as thiol groups, amino groups, and carboxyl groups present on the cell surface, it is also desirable to introduce them by reacting a crosslinking compound containing a functional group that reacts with the bio-orthogonal functional group, or a reagent capable of generating a functional group that reacts with the bio-orthogonal functional group, such as Traut's Reagent. As the crosslinking compound, known crosslinking compounds may be used; for example, crosslinking compounds that react with thiol groups include maleimide compounds, haloacetic acid compounds, pyridyl disulfide compounds, thiosulfone compounds, vinylsulfone compounds, etc. Additionally, crosslinking compounds that react with amino groups include NHS ester compounds, imide ester compounds, pentafluorophenyl ester compounds, hydroxymethylphosphine compounds, etc. Additionally, crosslinking compounds that react with carboxyl groups include oxazoline compounds, etc.That is, by reacting a compound containing a functional group that reacts with a bio-orthogonal functional group with a crosslinking reactive group such as maleimide, haloacetic acid, pyridyl disulfide, thiosulfone, vinylsulfone, NHS ester, imide ester, pentafluorophenyl ester, hydroxymethylphosphine, oxazoline, etc., with a functional group such as a thiol group, amino group, carboxyl group on the cell surface, a cell having a functional group that reacts with a bio-orthogonal functional group on the surface can be prepared. In a compound comprising such a crosslinkable reactor and a functional group that reacts with a bio-orthogonal functional group, the linker portion connecting the crosslinkable reactor and the functional group that reacts with the bio-orthogonal functional group is a divalent straight-chain hydrocarbon group, a divalent cyclic hydrocarbon group, a divalent heterocyclic group, -C(=O)-, -C(=S)-, -NR1-, -C(=O)-NR1-, -NR1-C(=O)-, -C(=S)-NR1-, -NR1-C(=S)-, -O-, -S-, -(O-R2) n -, and -( S-R2) m Furthermore, examples may include a group having a main chain structure comprising one group selected from a group consisting of divalent groups derived from substances selected from amino acids, peptides, nucleic acids, sugars, and other polymeric materials (e.g., polyethylene glycol), or two or more of these groups. The total number of atoms constituting the main chain in the linker portion is not particularly limited, but, for example, it may be one or more, two or more, five or more, or ten or more. The total number of such atoms may be 1,000 or fewer, 500 or fewer, 300 or fewer, 200 or fewer, 100 or fewer, or 50 or fewer, or 20 or fewer. <Process (V): A process of introducing the Fc region into the surface of a cell by reacting the Fc region, into which a bio-orthogonal functional group has been introduced, and the cell, with the bio-orthogonal functional group of the Fc region and the functional group of the cell that reacts with the bio-orthogonal functional group of the cell.> The reaction between the Fc region into which bio-orthogonal functional groups have been introduced and the cell having functional groups on its surface that react with bio-orthogonal functional groups is not particularly limited, but can be carried out, for example, by adding and mixing the Fc region into which bio-orthogonal functional groups have been introduced into a solution such as a cell culture medium or physiological saline. After the reaction, it is desirable to appropriately remove the Fc region into which the cell and unreacted bioorthogonal functional groups have been introduced. Thus, an Fc-cell complex is formed. Examples The present invention will be described in detail below with reference to examples, but the present invention is not limited to the embodiments described below. Example 1 Synthesis of an antibody into which one molecule each of a fluorescent molecule and an azide group were introduced Example 1-1 Synthesis of AF488 and antibodies with one molecule of azide group introduced (T-4) Example 1-1-1 Synthesis of Trastuzumab (T-1) with one molecule of peptide reagent introduced [Tuesday 10] To a 10 mg / mL solution of the anti-human HER2 monoclonal antibody Trastuzumab (Chugai Seiyaku) in acetic acid buffer (50 mM Sodium acetate, pH 5.5), a dimethylformamide solution of the peptide reagent (P1) described in the prior art (International Publication No. 2019 / 240287A1) (1 equivalent to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and the mixture was shaken at room temperature for 1 hour. After purifying the reaction solution using a NAP-25 desalting column (manufactured by Cytiva), an antibody (T-1) into which 1 molecule of the peptide reagent was introduced was obtained using an AKTA pure25 (manufactured by Cytiva). HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that one peptide reagent was introduced. Purification using AKTA pure25 (manufactured by Cytiva) was performed under the following conditions. Column: RESOURCE S (Manufactured by Cytiva) Eluent A: 50mM Sodium acetate, 0.1% tween20 (pH5.0) Eluent B: 50mM Sodium acetate, 1M NaCl, 0.1% tween20 (pH5.0) Flow rate: 5.0 ml / min Detector: Detected at wavelengths of 215 and 280 nm. Example 1-1-2 Synthesis of Trastuzumab (T-2) with 2 molecules of peptide reagent introduced [Tuesday 11] Subsequently, following the method described in the prior art (International Publication No. 2022 / 191283A1), antibody (T-2) into which peptide reagents (P1) and (P2) were introduced was obtained using peptide reagent (P2). HIC-HPLC analysis was performed according to the prior art (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that two peptide reagents were introduced. Example 1-1-3 Synthesis of Trastuzumab (T-3) with 1 molecule each of thiol and azide groups introduced [Tuesday 12] For the antibody (T-2) into which the peptide reagents (P1) and (P2) obtained in Example 1-1-2 were introduced, a methoxyamine solution was added in accordance with the prior art (International Publication No. 2022 / 191283A1), and by shaking at room temperature for 3 hours, an antibody (T-3) into which one molecule each of a thiol group and an azide group was introduced was obtained. In accordance with the prior art (Anal. Chem., 2019, 91, 20, 12724-12732), HIC-HPLC analysis was performed to confirm that one molecule each of a thiol group and an azide group was introduced. Example 1-1-4 Synthesis of AF488 and Trastuzumab (T-4) with one molecule of azide group introduced [Tuesday 13] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-3) with one molecule of thiol and azide groups introduced in Example 1-1-3, a dimethylformamide solution of Alexa Fluor 488 C5 Maleimide (Invitrogen) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and the mixture was shaken at room temperature for 1 hour. The reaction solution was purified using a NAP-25 desalting column (manufactured by Cytiva) to obtain an antibody (T-4) with one molecule of fluorescent molecule introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that AF488 was introduced. Example 1-2 Synthesis of Trastuzumab (T-5) with 1 molecule each of Cy5 and azide group introduced [Tuesday 14] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-4) with 1 molecule of thiol and azide groups introduced in Example 1-1-3, a dimethylformamide solution of N-(m-PEG4)-N'-(PEG3-Mal)-Cy5 (BroadPharm) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and the mixture was shaken at room temperature for 1 hour. The reaction solution was purified using an NAP-25 desalting column (manufactured by Cytiva) to obtain an antibody (T-5) with 1 molecule of Cy5 introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that Cy5 was introduced. Comparative Example 1 Synthesis of one molecule of Cy5 and a plurality of azide groups introduced into an antibody Comparative Example 1-1 Synthesis of an antibody in which multiple azide groups are introduced through one molecule of Cy5 and lysine residues Comparative Example 1-1-1 Synthesis of Trastuzumab (T-6) with one molecule of thiol group introduced [Tuesday 15] With respect to the antibody (T-1) into which the peptide reagent (P1) obtained in Example 1-1-1 was introduced, a hydroxylamine solution was added according to the prior art (International Publication No. 2019 / 240287A1), and by shaking at room temperature for 1 hour, an antibody (T-6) into which one molecule of thiol group was introduced was obtained. HIC-HPLC analysis was performed according to the prior art (Anal. Chem., 2019, 91, 20, 12724-12732), and it was confirmed that a thiol group had been introduced. Comparative Example 1-1-2 Synthesis of Trastuzumab (T-7) with 1 molecule of Cy5 introduced [Tuesday 16] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-6) with one thiol molecule introduced in Comparative Example 1-1-1, a dimethylformamide solution of N-(m-PEG4)-N'-(PEG3-Mal)-Cy5 (BroadPharm) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added, and the mixture was shaken at room temperature for 1 hour. The reaction solution was purified using an NAP-25 desalting column (manufactured by Cytiva) to obtain an antibody (T-7) with one molecule of fluorescent molecule introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that Cy5 was introduced. Comparative Example 1-1-3 Synthesis of Trastuzumab (T-8) in which multiple azide groups are introduced through one molecule of Cy5 and lysine residues [Tuesday 17] To a 3 mg / mL PBS buffer solution (10 mM Phosphate Buffered Saline (PBS), pH 7.4) of 1 molecule of Cy5 introduced into Trastuzumab (T-7) obtained in Comparative Example 1-1-2, a dimethylformamide solution of 4-azidobenzoic acid N-hydroxysuccinimide ester (7 equivalents relative to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and shaken at room temperature for 1 hour. The reaction solution was purified using an NAP-25 desalting column (manufactured by Cytiva) to obtain an antibody (T-8) with 1 molecule of Cy5 and multiple azide groups introduced. QTOF-MS analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732), and it was confirmed that 4-5 molecules of azide groups were introduced. Comparative Example 1-2 Synthesis of Trastuzumab (T-9) in which multiple azide groups are introduced through one molecule of Cy5 and cysteine ​​residues [Tuesday 18] An equal amount of a dimethylformamide solution of 3-Azidopropylamine (20 mM) was added to a commercially available dimethylformamide solution of N-Succinimidyl 3-Maleimidopropionate (20 mM), and the mixture was shaken for 30 minutes to prepare a dimethylformamide solution of Azido-PEG3-Maleimide (10 mM). An aqueous solution of Tris(2-carboxyethyl)phosphine (12 equivalents relative to the antibody) was added to a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-7) into which 1 molecule of Cy5 was introduced, obtained in Comparative Example 1-1-2, and the mixture was shaken at 37°C for 1.5 hours. The reaction solution was purified using a NAP-25 desalting column (manufactured by Cytiva). An Azido-PEG3-Maleimide solution (12 equivalents relative to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added to the PBSE buffer of the obtained antibody, and the mixture was shaken at room temperature for 1 hour. The reaction solution was purified using a NAP-25 desalination column (manufactured by Cytiva) to obtain an antibody (T-9) with 1 molecule of Cy5 and multiple azide groups introduced. QOF-MS analysis was performed according to the record (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that 7-8 molecules of azide groups were introduced. Example 2 Synthesis of AF488 Antibody-Cell Conjugate Example 2-1 Cell Culture HEL cells (JCRB) were cultured in D-MEM / F12 medium (Thermo Fisher Scientific) supplemented with 10% FBS (Thermo Fisher Scientific) and 1% Penicillin-Streptomycin (Nakareitesk). Example 2-2 Synthesis of Antibody-Cell Conjugates After detaching HEL cells by pipetting, the cell count and viability were measured using a Countess Automated Cell Counter (Thermo Fisher Scientific). 2.0×10⁶ 6 HEL cells were aliquoted and centrifuged (at 6,000 rpm for 15 seconds), after which the supernatant was removed. 1 mL of PBS was added to the HEL cells to wash them, and then centrifuged to remove the supernatant. 1 mL of 0.1 mg / mL Traut's reagent (Sigma-Aldrich) / PBS was added to the HEL cells and incubated at room temperature for 20 minutes. By repeating the process of centrifuging to remove the supernatant, adding 1 mL of PBS to wash, and centrifuging to remove the supernatant twice, HEL cells modified with sulfhydryl groups on the cell surface were obtained. Next, 1 mL of 20 μM dibenzocyclooctine (DBCO)-PEG4-maleimide (BroadPharm) / PBS was added to the HEL cells and incubated at room temperature for 30 minutes. HEL cells with a cell surface modified with DBCO were obtained by centrifuging to remove the supernatant, washing with 1 mL of PBS, and repeating the process of centrifuging to remove the supernatant twice. HEL cells with a cell surface modified with DBCO or unmodified HEL cells 0.5×10 6Cells were aliquoted and suspended in 200 μL of D-MEM / F12 medium. 0.33 μM or 1 μM of T-4 was added to each, and the mixture was incubated at 37°C for 1 hour. After centrifuging to remove the supernatant, 1 mL of PBS was added for washing, and the process of centrifuging to remove the supernatant was repeated twice to obtain antibody-cell complexes. Example 2-3 Evaluation of antibody-cell conjugates 0.2×10 6 The amount of antibodies bound to the cells was evaluated by performing flow cytometry analysis using an Attune NxT Flow Cytometer (Thermo Fisher Scientific). The remaining cells were cultured in 200 μL of D-MEM / F12 + 10% FBS + 1% Penicillin-Streptomycin for 24 hours, and then analyzed by flow cytometry in the same manner as above. As shown in Figure 8, it was found that the group reacted with T-4 antibodies on DBCO-modified cells exhibited stronger fluorescence compared to the group reacted with non-DBCO-modified cells, allowing for antibody binding with higher efficiency. Furthermore, after 24 hours, while the fluorescence of the mixture of non-DBCO-modified cells and T-4 antibodies was lost in most cells, the fluorescence of most cells in the group reacted with T-4 antibodies on DBCO-modified cells was maintained, suggesting that the formation of a covalent bond between the DBCO group on the cell surface and the azide group of the antibody may contribute to the high stability of the antibody modification. Example 3 Synthesis of Cy5 antibody-cell conjugate and evaluation of HER2 binding ability Example 3-1 Synthesis of antibody-cell conjugates 2×10 HEL cells with the cell surface modified with DBCO 6Cells were aliquoted and suspended in 200 μL of D-MEM / F12 medium. 1 μM of T-5 was added, and the mixture was incubated at 37°C for 1 hour. After centrifuging to remove the supernatant, 1 mL of PBS was added for washing, and the process of centrifuging to remove the supernatant was repeated twice to obtain antibody-cell complexes. Example 3-2 Evaluation of HER2 binding of antibody-cell conjugates 0.3×10 6 Cells were provided for HER2 binding evaluation, and the remaining cells were cultured in 200 μL of D-MEM / F12 + 10% FBS + 1% Penicillin-Streptomycin for 48 hours, after which the same HER2 binding evaluation as above was performed. 0.3×10 6 For the cells, 45 μL of FACS buffer (PBS + 1% FBS) containing 2% Human TruStain FcX Fc Receptor Blocking Solution (BioLegend) was added, and the mixture was incubated on ice for 10 minutes. Human recombinant HER2-Fc (R&D Systems), biotinated with Biotin Labeling Kit - NH2 (Dojin Kagaku Kenkyusho), was added to the cells to a concentration of 10 μg / mL, and the mixture was incubated on ice for 20 minutes. The cells were washed three times with FACS buffer, and 100 μL of FACS buffer containing 20 μg / mL of Streptavidin-Alexa Fluor 488 (Thermo Fisher Scientific) was added, and the mixture was incubated on ice for 20 minutes. The cells were washed three times with FACS buffer and suspended in 500 μL of FACS buffer. The amount of antibodies bound to cells and the amount of HER2-Fc bound were evaluated by performing flow cytometry analysis using an Attune NxT Flow Cytometer (Thermo Fisher Scientific). In addition, cells treated with the same HER2 binding were observed using a fluorescence microscope with a BZ-X700 (Keyence). As shown in Figure 9, for cells conjugated with T-5 antibodies, fluorescence derived from Cy5 and Streptavidin-Alexa 488 modified by the antibody was detected from the cells, confirming that the cells were modified by the antibody and that human recombinant HER2-Fc was bound. On the other hand, in cells modified with DBCO and unmodified cells, neither type of fluorescence was detected, and it was found that HER2-Fc was not bound. From the above results, it was revealed that the T-5-cell conjugate acquired antibody-derived HER2 binding ability. Furthermore, it was confirmed that HER2 binding ability was maintained even after 48 hours. In addition, as shown in Figure 10, it was confirmed that HER2 bound to the antibody conjugated to the cell from the fact that fluorescence derived from Alexa Fluor 488 was detected on the cell membrane of the cell conjugated with the T-5 antibody during fluorescence microscopy observation. Example 4 Comparison of conjugated and non-conjugated forms of antibodies and cells Example 4-1 Synthesis of antibody-cell conjugate and preparation of non-conjugate body The synthesis of the antibody-cell conjugate was carried out as follows. 2 × 10⁶ HEL cells with the cell surface modified with DBCO. 6Cells were aliquoted and suspended in 200 μL of D-MEM / F12 medium. 1 μM was added and incubated at 37°C for 1 hour. After centrifuging to remove the supernatant, the process of adding 1 mL of PBS to wash and centrifuging to remove the supernatant was repeated twice to obtain antibody-cell complexes. The beaconjugate was prepared by performing the above operation on HEL cells that were not modified on the cell surface with DBCO. Example 4-2 Evaluation of HER2 binding of antibody-cell conjugates and non-conjugates In the same manner as in the previous method, the HER2 binding ability of each antibody-cell conjugate was evaluated by flow cytometry analysis. As shown in Figure 11, the proportion of cells exhibiting Streptavidin-Alexa Fluor 488 fluorescence was higher in the antibody-cell conjugate group compared to the beconjugate group. Furthermore, the amount of HER2 binding per antibody bound to a cell was calculated by determining (fluorescence intensity of Streptavidin-Alexa Fluor 488) / (fluorescence intensity of Cy5) for each group. As a result, the conjugate group showed a value more than six times higher. From this, it was revealed that conjugating the antibody to the cell maintains a high antigen-binding ability of the antibody against the beconjugate body. Example 5 Comparison of various azide-modified antibody-cell conjugates Example 5-1 Synthesis of antibody-cell conjugates 2×10 HEL cells with the cell surface modified with DBCO 6 Cells were aliquoted and suspended in 200 μL of D-MEM / F12 medium. 0.3 μM or 1 μM of T-5, T-8, or T-9 was added, and the mixture was incubated at 37°C for 1 hour. After centrifuging to remove the supernatant, 1 mL of PBS was added for washing, and the process of centrifuging to remove the supernatant was repeated twice to obtain conjugates of the antibody and cells. Example 5-2 Evaluation of HER2 binding of antibody-cell conjugates In the same manner as in the tactic, HER2 binding evaluation of each antibody-cell conjugate was performed using flow cytometry. As shown in Fig. 12A, for cells conjugated with all modification antibodies, fluorescence derived from Cy5 and Streptavidin-Alexa 488 modified by the antibody was detected from the cells. From this result, it was confirmed that the cells were modified by the antibody and that human recombinant HER2-Fc was bound. For each group, the amount of HER2 binding per antibody bound to the cell was calculated by calculating (fluorescence intensity of Streptavidin-Alexa Fluor 488) / (fluorescence intensity of Cy5). As a result, as shown in Fig. 12B, the antibody-cell conjugate modified with T-5 exhibited a value more than six times higher than that of the antibody-cell conjugate modified with T-8 or T-9. From this, it was revealed that by conjugating a site-specifically modified antibody to a cell, an antibody-cell conjugate with a higher antigen-binding ability is obtained compared to antibody-cell conjugates synthesized using an antibody modified with a randomly modified lysine residue or an antibody modified with a sulfhydryl group generated by reducing a disulfide bond on the antibody. Example 6 Synthesis of Cy5 antibody-T cell conjugate and evaluation of HER2 binding ability Example 6-1 Culture of T cells DPBS supplemented with 5 μg / mL anti-CD3 antibody (Thermo Fisher Scientific) and 25 μg / mL RetroNectin (Takara Bio) was coated onto a 24-well plate. The plate was washed three times with DPBS, and 6×10⁶ were placed in a medium supplemented with Optimizer (Thermo Fisher Scientific) and IL-2 (PeproTech). 4T cells were added to the cells / well and cultured. Example 6-2 Synthesis of T antibody-cell conjugate After recovering T cells, the cell count and viability were measured using a Countess Automated Cell Counter (Thermo Fisher Scientific). 2.5×10⁶ 7 T cells were aliquoted from the cells and centrifuged (at 6,000 rpm for 15 seconds), after which the supernatant was removed. 1 mL of PBS was added to the T cells to wash them, and then centrifuged to remove the supernatant. 1 mL of 0.1 mg / mL Traut's reagent (Sigma-Aldrich) / PBS was added to the T cells and incubated at room temperature for 20 minutes. By repeating the process of centrifuging to remove the supernatant, adding 1 mL of PBS to wash, and centrifuging to remove the supernatant twice, T cells modified with sulfhydryl groups on their surface were obtained. Subsequently, 1 mL of 20 μM dibenzocyclooctine (DBCO)-PEG4-maleimide (BroadPharm) / PBS was added to the T cells and incubated at room temperature for 30 minutes. T cells with a cell surface modified with DBCO were obtained by centrifuging to remove the supernatant, washing with 1 mL of PBS, and repeating the process of centrifuging to remove the supernatant twice. T cells with a cell surface modified with DBCO or unmodified T cells are 0.5 × 10⁶ 6 Cells were aliquoted and suspended in 200 μL of T cell medium. 0.33 μM or 1 μM of T-4 was added to each, and the mixture was incubated at 37°C for 1 hour. After centrifuging to remove the supernatant, 1 mL of PBS was added for washing, and the process of centrifuging to remove the supernatant was repeated twice to obtain antibody-cell complexes. Example 6-3 Evaluation of Antibody-Cell Conjugates 0.2×10 6The amount of antibodies bound to the cells was evaluated by performing flow cytometry analysis on the cells using an Attune NxT Flow Cytometer (Thermo Fisher Scientific). As shown in Figure 13, it was found that the group reacted with T-4 antibodies on DBCO-modified cells exhibited stronger fluorescence compared to the group reacted with non-DBCO-modified cells, allowing for higher efficiency in binding antibodies. <Reference Example> Hereinafter, as a reference example, a method for synthesizing a compound containing a bio-orthogonal functional group with said affinity material using an affinity material containing two affinity peptides, and a method for introducing a bio-orthogonal functional group to only one side of a polypeptide derived from a heavy chain normal region constituting the Fc region of an antibody using said compound are described. By using the antibody obtained in this way, in which a bio-orthogonal functional group is introduced to only one side of a polypeptide derived from a heavy chain normal region constituting the Fc region, an Fc-cell complex can be obtained in which the antibody or Fc fusion protein is chemically bound to the cell surface through a linker introduced to a functional group in the side chain of a specific amino acid residue located at one or more positions of one side of the polypeptide derived from a heavy chain normal region constituting the Fc. (Reference Example 1) Design of an affinity substance and secretion expression of the affinity substance in C. glutamicum (1-1) Overview of Affinity Material Design In the present invention, it is necessary to design an affinity material that includes two or more sites capable of binding to an antibody within the molecule. That is, the affinity material is A) A molecule comprising two or more sites capable of binding to an antibody (a linker to connect these sites, if necessary). It is necessary to design it so that it becomes. Next, in the present invention, in order to modify the immunoglobulin unit, it is preferable to bind a compound having a reactive group for the immunoglobulin unit to an affinity substance. In addition, to remove the affinity substance after modification of the immunoglobulin unit, it is desirable to include a cleavable portion between the reactive group and the affinity substance. In addition, to achieve specific binding of a compound to a specific site within an affinity substance, it is desirable to design the affinity substance such that there is only one site capable of reacting with the compound. Therefore, when using an affinity polypeptide as an affinity substance and binding the affinity polypeptide to a compound through the amino group in the side chain of a lysine residue (K) within the affinity polypeptide, it is desirable to design the affinity polypeptide such that there is only one lysine residue within the affinity polypeptide. Accordingly, an affinity polypeptide was designed as follows. B) The polypeptide contains only one residue of K. C) By making the N-terminal amino acid Q (glutamine), pyroglutamylation is performed to convert the N-terminal amino group into an amide. According to the rules of A), B), and C) above, polypeptide-like affinity materials were designed as follows (a) to (h). (1-2) Preparation of affinity substances The following affinity substances were prepared. (a) QET-Z34CM-PA32-Fc3K QET-FNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGG-RGNCAYHKGQIIWCTYH-NH2(Sequence No. 17) (b) QET-Z34CM-PA48-Fc3K QET-FNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGG-RGNCAYHKGQIIWCTYH-NH2(Sequence No. 18) (c) QET-Fc3K-PA32-Z34CM QETRGNCAYHKGQIIWCTYH-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGG-FNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC-NH2 (SEQ ID NO: 19) (d) QET-Fc3K-PA48-Z34CM QETRGNCAYHKGQIIWCTYH-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAPGG-FNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC-NH2 (SEQ ID NO: 20) (e) QET-Fc3K-PA32-ProAR QETRGNCAYHKGQIIWCTYH-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPGG-FNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA-NH2(Sequence No. 21) (f) QET-Fc3K-PA48-ProAR QETRGNCAYHKGQIIWCTYH-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAPGG-FNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA-NH2 (SEQ ID NO: 22) (g) QET-ProAR-PA32-Z34CK QET-FNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGG-FNKQCQRRFYEALHDPNLNEEQRNARIRSIREEC-NH2(Sequence No. 23) (h) QET-ProAR-PA48-Z34CK QET-FNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA-GGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGG-FNKQCQRRFYEALHDPNLNEEQRNARIRSIREEC-NH2(Sequence No. 24) (1-3) Expression of affinity substances The expression of such polypeptide-like affinity substances was examined using Corynex (registered trademark). In expression using Corynex (registered trademark), the CspB fusion method (International Publication No. 2013 / 062029) was utilized, which is a technique that can improve the secretion yield of the target polypeptide by inserting a base sequence encoding an amino acid sequence containing the N-terminal 3 residues Gln-Glu-Thr (QET) of the CspB mature protein between the base sequence encoding the signal peptide and the base sequence encoding the target polypeptide. In addition, since the N-terminus of the CspB tag is Q, there is an advantage that after the signal sequence is cleaved, the first residue Q is pyroglutamylated to protect the N-terminal amino group. That is, in addition to the rules of A), B), and C) above, considering the rule of D) below is effective for improving the expression of the affinity polypeptide using Corynex (registered trademark). D) Improvement in secretion efficiency in Corynex (registered trademark) by adding three residues of QET to the N-terminus Below, reference examples of expression review by Corynex (registered trademark) are described. (1-4) Construction of each secretory expression plasmid of QET-Z34CM-PA32-Fc3K, QET-Z34CM-PA48-Fc3K, QET-Fc3K-PA32-Z34CM, QET-Fc3K-PA48-Z34CM, QET-Fc3K-PA32-ProAR, QET-Fc3K-PA48-ProAR, QET-ProAR-PA32-Z34CK, and QET-ProAR-PA48-Z34CK As affinity polypeptides, eight types of amino acid sequences were designed, each including QET-Z34CM-PA32-Fc3K, QET-Z34CM-PA48-Fc3K, QET-Fc3K-PA32-Z34CM, QET-Fc3K-PA48-Z34CM, QET-Fc3K-PA32-ProAR, QET-Fc3K-PA48-ProAR, QET-ProAR-PA32-Z34CK, and QET-ProAR-PA48-Z34CK, and the nucleotide sequences encoding these polypeptides were designed considering the codon usage frequency of C. glutamicum. In addition, the following expression cassettes were designed to enable secretory expression by C. glutamicum. QET-Z34CM-PA32-Fc3K was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and Z34CM-PA32-Fc3K (hereinafter referred to as "CspBss-QET-Z34CM-PA32-Fc3K"). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-Z34CM-PA32-Fc3K are shown in SEQ Nos. 25 and 26, respectively. The base sequence encoding CspBss-QET-Z34CM-PA32-Fc3K atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagaccttcaacatgcagtgccaacggcgcttttacgaagcgctccacgatcccaacctgaacgaggaacagcgtaacgcgcgcattcgc tccatccgtgaggaatgtggcggtgctgcccctgctgccccagcaccggcagcacctgcggcaccagctccggcagctccagctgcaccggcccctgccgctccagcagcgccagctcccggaggtcgaggcaattgcgcctatcacaaggggcagatcatctggtgcacttaccattaa (sequence number 25) Amino acid sequence of CspBss-QET-Z34CM-PA32-Fc3K MFNNRIRTAALAGAIAISTAASGVAIPAFAQETFNMQCQRRFYEALHDPNLNEEQRNARIRSIREECGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGRGNCAYHKGQIIWCTYH (SEQ ID NO: 26) QET-Z34CM-PA48-Fc3K was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and Z34CM-PA48-Fc3K (hereinafter referred to as "CspBss-QET-Z34CM-PA48-Fc3k"). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-Z34CM-PA48-Fc3K are shown in SEQ Nos. 27 and 28, respectively. The base sequence encoding CspBss-QET-Z34CM-PA48-Fc3K atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagaccttta acatgcagtgccaacgtcgtttttacgaagcgctgcacgatcccaacctgaacgaggaacagcgcaatgcgcgaatacgctccattcgcgaggaatgtggcgga gcagctcccgcggctcctgctccagcagcgcctgctgctcctgcccctgcggcacctgcagcacctgcaccagcagctccggcagcaccagctccagctgcac ccgccgccccagctcctgcagcgccagccgctccggccccccggaggtaggggcaactgcgcatatcacaaggggcagataatctggtgcacttatcactaa (sequence number 27) Amino acid sequence of CspBss-QET-Z34CM-PA48-Fc3K MFNNRIRTAALAGAIAISTAASGVAIPAFAQETFNMQCQRRFYEALHDPNLNEEQRNARIRSIREECGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGRGNCAYHKGQIIWCTYH (SEQ ID NO: 28) QET-Fc3K-PA32-Z34CM was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and Fc3K-PA32-Z34CM (hereinafter referred to as “CspBss-QET-Fc3K-PA32-Z34CM”). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-Fc3K-PA32-Z34CM are shown in SEQ Nos. 29 and 30, respectively. The base sequence encoding CspBss-QET-Fc3K-PA32-Z34CM atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagacccgtggcaactgtgcctaccacaagggccagatcatctggtgcacgtaccacggaggtgccgcgcctgccgcacctgctccagct gctcccgctgcccctgcaccagctgcgccagcagcaccagctccagcggcacctgcagcaccggcacctggtggcttcaacatgcagtgccaacgacgcttctacgaggctctgcacgatccgaacctcaacgaggaacagcgcaatgcccgtattcggtccatcagggaggaatgctaa (sequence number 29) Amino acid sequence of CspBss-QET-Fc3K-PA32-Z34CM MFNNRIRTAALAGAIAISTAASGVAIPAFAQETRGNCAYHKGQIIWCTYHGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGFNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC (SEQ ID NO: 30) QET-Fc3K-PA48-Z34CM was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and Fc3K-PA48-Z34CM (hereinafter referred to as “CspBss-QET-Fc3K-PA48-Z34CM”). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-Fc3K-PA48-Z34CM are shown in SEQ Nos. 31 and 32, respectively. The base sequence encoding CspBss-QET-Fc3K-PA48-Z34CM atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagacccgtg gcaattgcgcctatcacaagggtcagatcatttggtgcacctaccatggtggtgcagcaccagctgccccggctccggctgcgcctgctgcacctgcgccagct gcacctgcagcaccggcacctgctgctccagcagcacccgctcctgcagctcccgctgccccagctccagcggcgcctgcggcgccagcacctggagggttca acatgcagtgccaacgtcgcttttacgaggctttgcatgatcctaacttgaacgaggaacagcggaatgcgcggatacgctccatacgcgaagaatgttaa (sequence number 31) Amino acid sequence of CspBss-QET-Fc3K-PA48-Z34CM MFNNRIRTAALAGAIAISTAASGVAIPAFAQETRGNCAYHKGQIIWCTYHGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGFNMQCQRRFYEALHDPNLNEEQRNARIRSIREEC (SEQ ID NO: 32) QET-Fc3K-PA32-ProAR was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and Fc3K-PA32-ProAR (hereinafter referred to as “CspBss-QET-Fc3K-PA32-ProAR”). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-Fc3K-PA32-ProAR are shown in SEQ Nos. 33 and 34, respectively. nucleotide sequence encoding CspBss-QET-Fc3K-PA32-ProAR atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagacc cgcggcaactgtgcctaccacaaggggcagatcatctggtgcacctatcacggtggtgcggctccggctgctccagcgccagcagctcccgctgcacca gccccagcggcacctgccgcacctgcacctgcagctccagcggctcccgcaccgggaggctttaaccgcgaacagcagaacgccttctacgagattctc catctgcccaacctcaacgaggagcaacggaatggcttcatccagagcttgcgtgacgatccgtctcaatccgccaatctgcttgcggaagcctaa (sequence number 33) Amino acid sequence of CspBss-QET-Fc3K-PA32-ProAR MFNNRIRTAALAGAIAISTAASGVAIPAFAQETRGNCAYHKGQIIWCTYHGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGFNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA (SEQ ID NO: 34) QET-Fc3K-PA48-ProAR was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and Fc3K-PA48-ProAR (hereinafter referred to as “CspBss-QET-Fc3K-PA48-ProAR”). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-Fc3K-PA48-ProAR are shown in SEQ Nos. 35 and 36, respectively. nucleotide sequence encoding CspBss-QET-Fc3K-PA48-ProAR atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagacccgtgggaactgc gcgtaccataagggccagatcatctggtgcacctatcatggcggtgctgcgcctgcagctccggctcctgccgctccagccgcgccagccccagcagctccagcagcacct gcacctgctgcaccagcggctccagctcctgcggcacccgctgcaccggcaccagccgctccggctgccccagctccgggtggctttaaccgcgaacagcagaacgccttc tacgagatactccaccttcccaacctgaacgaggagcagcgaaacggcttcatccagtctcttcgcgatgatccatcccagagcgctaacttgcttgcagaagcgtaa (sequence number 35) Amino acid sequence of CspBss-QET-Fc3K-PA32-ProAR MFNNRIRTAALAGAIAISTAASGVAIPAFAQETRGNCAYHKGQIIWCTYHGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGFNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEA (SEQ ID NO: 36) QET-ProAR-PA32-Z34CK was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and ProAR-PA32-Z34CK (hereinafter referred to as “CspBss-QET-ProAR-PA32-Z34CK”). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-ProAR-PA32-Z34CK are shown in SEQ Nos. 37 and 38, respectively. The base sequence encoding CspBss-QET-ProAR-PA32-Z34CK atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagacctttaaccgcgaa cagcagaacgccttctacgagatcctgcatctccccaatctgaacgaagagcagaggaatggctttatccagagccttcgtgacgatccgtcgcaatctgccaacctgttgg cggaagctggaggtgccgcgccagcggcaccagcaccagctgcaccggctgctcccgcacctgccgcaccagccgctcctgccccagcagctccggcagctcctgcacctgg tggcttcaacaagcagtgccaacgtcgcttctatgaagcgctacacgatcccaacctcaacgaggaacagcgcaatgcgcgaatccggtccattcgcgaagagtgttaa (sequence number 37) Amino acid sequence of CspBss-QET-ProAR-PA32-Z34CK MFNNRIRTAALAGAIAISTAASGVAIPAFAQETFNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEAGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGFNKQCQRRFYEALHDPNLNEEQRNARIRSIREEC (SEQ ID NO: 38) QET-ProAR-PA48-Z34CK was secretedly expressed as a fusion protein of the signal peptide 30 amino acid residues of CspB derived from C. glutamicum ATCC13869 strain, the N-terminal 3 amino acid residues QET of the mature CspB protein derived from the same strain, and ProAR-PA48-Z34CK (hereinafter referred to as “CspBss-QET-ProAR-PA48-Z34CK”). The nucleotide sequence and amino acid sequence encoding the designed CspBss-QET-ProAR-PA48-Z34CK are shown in SEQ Nos. 39 and 40, respectively. The base sequence encoding CspBss-QET-ProAR-PA48-Z34CK atgtttaacaaccgtatccgcactgcagctctcgctggtgcaatcgcaatctccaccgcagcttccggcgtagctatcccagcattcgctcaggagacctttaaccgcgaacagcagaacgcc ttctacgagatcctccatctgccaaacctgaacgaagaacagcgcaacggctttatccagtccctcagggacgatccgtctcagtcggccaatttgctagccgaagcgggaggtgctgctccgg cagcacccgcaccagccgcgcccgctgctccagcgccggcagctcctgcggcaccagctccagcagcaccagcggctccagcacctgccgcacctgcagctccggctcctgcagcccccgccgc tcctgcgccgggtggcttcaacaagcagtgccaacgacgcttctatgaggcgcttcacgatcccaacctgaatgaggagcaacggaatgcccgtatccgtagcattcgcgaagaatgttaa (sequence number 39) Amino acid sequence of CspBss-QET-ProAR-PA48-Z34CK MFNNRIRTAALAGAIAISTAASGVAIPAFAQETFNREQQNAFYEILHLPNLNEEQRNGFIQSLRDDPSQSANLLAEAGGAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPAAPAAPAPGGFNKQCQRRFYEALHDPNLNEEQRNARIRSIREEC(서열 번호 40) Eight types of affinity polypeptides formed by linking the promoter of the cspB gene derived from C. glutamicum ATCC13869 strain to the upstream of the nucleotide sequences described in CspBss-QET-Z34CM-PA32-Fc3K, CspBss-QET-Z34CM-PA48-Fc3K, CspBss-QET-Fc3K-PA32-ProAR, CspBss-QET-Fc3K-PA48-ProAR, CspBss-QET-ProAR-PA32-Z34CK, and CspBss-QET-ProAR-PA48-Z34CK, and additionally adding a KpnI site to the 5'-side and a BamHI site to the 3'-side An expression cassette was designed and synthesized in its entirety. By inserting the entirely synthesized DNA fragment (expression cassette of the affinity polypeptide) into the KpnI-BamHI region of pPK4 described in Japanese Patent Publication No. JP 9-322774, the secretory expression plusmids of the affinity polypeptide, pPK4_CspBss-QET-Z34CM-PA32-Fc3K, pPK4_CspBss-QET-Z34CM-PA48-Fc3K, pPK4_CspBss-QET-Fc3K-PA32-Z34CM, pPK4_CspBss-QET-Fc3K-PA48-Z34CM, pPK4_CspBss-QET-Fc3K-PA32-ProAR, pPK4_CspBss-QET-Fc3K-PA48-ProAR, pPK4_CspBss-QET-ProAR-PA32-Z34CK and pPK4_CspBss-QET-ProAR-PA48-Z34CK were constructed, respectively. As a result of sequencing the insertion fragments, it was confirmed that expression cassettes of polypeptides with the same affinity as the design were constructed for each. Sequencing was performed using the BigDye(R) Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems) and the 3500xL Genetic Analyzer (Applied Biosystems). (1-5) Secretory expression of affinity polypeptides in C. glutamicum Using the pPK4_CspBss-QET-Z34CM-PA32-Fc3K, pPK4_CspBss-QET-Z34CM-PA48-Fc3K, pPK4_CspBss-QET-Fc3K-PA32-Z34CM, pPK4_CspBss-QET-Fc3K-PA48-Z34CM, pPK4_CspBss-QET-Fc3K-PA32-ProAR, pPK4_CspBss-QET-Fc3K-PA48-ProAR, pPK4_CspBss-QET-ProAR-PA32-Z34CK, and pPK4_CspBss-QET-ProAR-PA48-Z34CK constructed above, C. glutamicum described in International Publication No. 2016 / 171224 YDK0107 strain was transformed to produce YDK0107 / pPK4_CspBss-QET-Z34CM-PA32-Fc3K strain, YDK0107 / pPK4_CspBss-QET-Z34CM-PA48-Fc3K strain, YDK0107 / pPK4_CspBss-QET-Fc3K-PA32-Z34CM strain, YDK0107 / pPK4_CspBss-QET-Fc3K-PA48-Z34CM strain, YDK0107 / pPK4_CspBss-QET-Fc3K-PA32-ProAR strain, YDK0107 / pPK4_CspBss-QET-Fc3K-PA48-ProAR strain, YDK0107 / pPK4_CspBss-QET-ProAR-PA32-Z34CK and YDK0107 / pPK4_CspBss-QET-ProAR-PA48-Z34CK were obtained. Each obtained transformant was cultured for 72 hours at 30°C in MMTG liquid medium containing 25 mg / L kanamycin (120 g glucose, 3 g magnesium heptahydrate, 30 g ammonium sulfate, 1.5 g potassium dihydrogen phosphate, 0.03 g iron heptahydrate, 0.03 g manganese sulfate heptahydrate, 0.45 mg thiamine hydrochloride, 0.45 mg biotin, 0.15 g DL-methionine, soybean hydrochloride (total nitrogen content 0.2 g), 50 g calcium carbonate, and 1 L of water adjusted to pH 7.0).After the culture was finished, 6.5 μL of the culture supernatant obtained by centrifuging each culture medium was fed to reduced SDS-PAGE using NuPAGE (registered trademark) 12% Bis-Tris Gel (Thermo Fisher Scientific) and then stained with Quick-CBB (Wako).As a result, polypeptide bands presumed to be QET-Z34CM-PA32-Fc3K in the culture supernatant of strain YDK0107 / pPK4_CspBss-QET-Z34CM-PA32-Fc3K (Fig. 14, Lanes 2-5), polypeptide bands presumed to be QET-Z34CM-PA32-Fc3K in the culture supernatant of strain YDK0107 / pPK4_CspBss-QET-Z34CM-PA32-Fc3K (Fig. 14, Lanes 6-9), polypeptide bands presumed to be QET-Fc3K-PA32-Z34CM in the culture supernatant of strain YDK0107 / pPK4_CspBss-QET-Fc3K-PA32-Z34CM (Fig. 14, Lanes 10-13), polypeptide band presumed to be QET-Fc3K-PA48-Z34CM in the culture supernatant of strain YDK0107 / pPK4_CspBss-QET-Fc3K-PA48-Z34CM (Fig. 14, Lanes 14-17), polypeptide band presumed to be QET-Fc3K-PA32-ProAR in the culture supernatant of strain YDK0107 / pPK4_CspBss-QET-Fc3K-PA32-ProAR (Fig. 14, Lanes 18-21), polypeptide band presumed to be QET-Fc3K-PA48-ProAR in the culture supernatant of strain YDK0107 / pPK4_CspBss-QET-Fc3K-PA48-ProAR (Fig. 14, Lanes 22-25), Polypeptide bands presumed to be QET-ProAR-PA32-Z34CK (Fig. 14, Lanes 26-29) and polypeptide bands presumed to be QET-ProAR-PA48-Z34CK were detected in the culture supernatant of YDK0107 / pPK4_CspBss-QET-ProAR-PA32-Z34CK, respectively (Fig. 14, Lanes 30-33). (Reference Example 2) Preparation of a compound having an affinity for an antibody, a cleavable portion, and a reactive group A compound having a cleavable portion and a reactive group was bonded to a purified polypeptide. According to the Gibo (International Publication No. 2019 / 0240287), an affinity reagent (1) was prepared by amidating the affinity material QET-Z34CM-PA32-Fc3K prepared in Reference Example 1-2. [Tue 19] Affinity reagent (1) All of the above amino acid sequences are the amino acid sequences of sequence number 17. MS(ESI) m / z:z=11 885.80[M+3H] 3+ Likewise, an affinity reagent (2) was prepared from the affinity material QET-Z34CM-PA48-Fc3K prepared in Reference Example 1-2. MS(ESI) m / z:z=13 849.35[M+3H] 3+ Likewise, an affinity reagent (3) was prepared from the affinity material QET-Fc3K-PA32-Z34CM prepared in Reference Example 1-2. MS(ESI) m / z:z=11 886.15[M+3H] 3+ Likewise, an affinity reagent (4) was prepared from the affinity material QET-Fc3K-PA48-Z34CM prepared in Reference Example 1-2. MS(ESI) m / z:z=13 849.20[M+3H] 3+ Likewise, an affinity reagent (5) was prepared from the affinity material QET-Fc3K-PA32-ProAR prepared in Reference Example 1-2. MS(ESI) m / z:z=12 885.1[M+3H] 3+ Likewise, an affinity reagent (6) was prepared from the affinity material QET-Fc3K-PA48-ProAR prepared in Reference Example 1-2. MS(ESI) m / z:z=11 1082.00[M+3H] 3+ Likewise, an affinity reagent (7) was prepared from the affinity material QET-ProAR-PA32-Z34CK prepared in Reference Example 1-2. MS(ESI) m / z:z=15 855.20[M+3H] 3+ Likewise, an affinity reagent (8) was prepared from the affinity material QET-ProAR-PA48-Z34CK prepared in Reference Example 1-2. MS(ESI) m / z:z=17 830.75[M+3H] 3+ [Tue 20] Affinity reagent (2) The above amino acid sequence is the amino acid sequence of sequence number 18. Affinity reagent (3) The above amino acid sequence is the amino acid sequence of sequence number 19. Affinity reagent (4) The above amino acid sequence is the amino acid sequence of sequence number 20. [Tue 21] Affinity reagent (5) The above amino acid sequence is the amino acid sequence of sequence number 21. Affinity reagent (6) The above amino acid sequence is the amino acid sequence of sequence number 22. [Tue 22] Affinity reagent (7) The above amino acid sequence is the amino acid sequence of sequence number 23. Affinity reagent (8) The above amino acid sequence is the amino acid sequence of sequence number 24. (Reference Example 3) Specific modification of the anti-HER2 IgG antibody trastuzumab and synthesis of an ADC mimic (3-1) Specific modification of the anti-HER2 antibody trastuzumab using the affinity reagent (4) 500 μg of anti-HER2 IgG antibody trastuzumab (Chugai Seiyaku) was dissolved in 171 μL of 50 mM sodium acetate buffer (pH 5.5). An N,N'-dimethylformamide solution (10 equivalents) of the affinity reagent (4) synthesized in Reference Example 2 was added to the trastuzumab solution and stirred at room temperature for 1 hour. After removing excess affinity reagent (4) by ultrafiltration, the mass was measured by ESI-TOFMS, and a peak was observed at 148400 for the raw trastuzumab, a peak was observed at 159300 for the product with one introduced binding peptide, and a peak was confirmed at 170390 for the product with two introduced binding peptides. (3-2) Synthesis of Trastuzumab (T-6) with one thiol group introduced By subjecting the antibody obtained above to a cleavage reaction of a thioester group (treatment with hydroxylamine) in accordance with the prior art (International Publication No. 2019 / 240287), a thiol group-introduced antibody derivative (T-1-SH) having the following structural formula with one thiol group introduced was obtained. When the mass was measured by ESI-TOFMS, a peak was identified at 148489, where the cleavage reaction proceeded. [Tue 23] (3-3) Synthesis of a thiol group-introduced antibody derivative by specific modification of the anti-HER2 antibody trastuzumab using an affinity reagent (6) and cleavage of the thioester group Likewise, a modification reaction of trastuzumab was carried out using the affinity reagent (6) synthesized in Reference Example 2. After removing excess affinity reagent (6), the mass was measured by ESI-TOFMS, and a peak was observed at 148227 for the raw material trastuzumab, a peak was observed at 160165 for the product with one binding peptide introduced, and a peak was confirmed at 171953 for the product with two binding peptides introduced. In addition, the results of confirming the peptide / antibody binding ratio using a DAR calculator (Agilent software) are shown in Table 1. By providing the antibody obtained above to a cleavage reaction of a thioester group in accordance with the prior art (International Publication No. 2019 / 0240287), a thiol group-introduced antibody derivative (T-1-SH) was obtained. When the mass was measured by ESI-TOFMS, a peak was identified at 148489, where the cleavage reaction proceeded. (3-4) Peptide mapping by trypsin treatment For the trastuzumab thiol introductory agent (T-1-SH) obtained in (3-2), peptide mapping was performed using the following process. (3-4-1) Trypsin treatment of trastuzumab thiol introducers 10 μL of sample solution, 150 mM Tris hydrochloride buffer (pH 8.0), and 10 μL of 20 mM aqueous solution of dithiothreitol dissolved in 40% trifluoroethanol were added to a 1.5 mL low-adsorption microtest tube and heated at 65°C for 1 hour, then 10 μL of 50 mM aqueous solution of iodoacetamide was added and reacted at room temperature under light protection for 30 minutes. After the reaction, 40 μL of 150 mM Tris hydrochloride buffer (pH 8.0) was added and stirred, and 10 μL of 20 ng / μL aqueous solution of trypsin was added and enzymatic digestion was performed at 37°C for 16 hours. After digestion, 2 μL of a 20% trifluoroacetic acid aqueous solution was added to stop the reaction of the sample solution, which was then diluted 10-fold with a 0.1% formic acid and 2% acetonitrile aqueous solution and provided for LC-MS / MS measurement. (3-4-2) LC-MS / MS measurement of trastuzumab (Analysis device) Nano HPLC: EASY-nLC 1000 (Thermo Fisher Scientific) Mass Spectrometer: Tribrid Mass Spectrometer Orbitrap Fusion (Thermo Fisher Scientific) (HPLC analysis conditions) Trap column: Acclaim PepMap (registered trademark) 100, 75μm×2cm (Thermo Fisher Scientific) Analysis Column: ESI-column(NTCC-360 / 75-3-125, 75μm×12.5cm, 3μm (Nikkyo Technos Co.)) Mobile phase A: 0.1% aqueous formic acid solution Mobile phase B: 0.1% formic acid, acetonitrile solution Loading solution: 0.1% aqueous trifluoroacetic acid solution Flow rate: 300 nL / min Sample injection volume: 0.6μL Gradient condition (B%): 2%(0.0-0.5 min), 2%→50%(0.5-50 min), 50%(50-55.5 min), 50%→95%(55.5-56.5 min), 95%(56.5-60 min) (Mass spectrometer analysis conditions) Ionization method: ESI, Positive mode Scan Type: Data Dependent Aquisition Activation Type: Collision Induced Dissociation (CID) Data acquisition was performed using the accompanying software Xcalibur 4.3 (Thermo Fisher Scientific) and Thermo Orbitrap Fusion Tune Application 3.3 (Thermo Fisher Scientific). Example 7 Preparation of Natural Killer Cell (hereinafter referred to as NK cells)-Antibody Complex Example 7-1 Culture of NK cells CellXVivo TM NK cell culture and NK cell culture plates were prepared using the Human NK Cell Expansion Kit (R&D Systems, Inc.). NK cells (Lonza Co., Ltd.) were cultured on NK cell culture plates using NK cell medium (hereinafter referred to as NK activation medium) supplemented with IL-2 Human Recombinant (PeproTech, Inc.) at a final concentration of 10002 U / mL and recombinant human IL-15 (PeproTech, Inc.) at a final concentration of 2.50 ng / mL. Example 7-2 Preparation of Linker-Modified Antibody Example 7-2-1 Synthesis of Trastuzumab (T-6) with One Molecule of Thiol Group Introduced [Tue 24] According to Reference Example (3-1) and Reference Example (3-2), one molecule of thiol group was introduced into Trastuzumab (T-6). Example 7-2-2 Synthesis of Trastuzumab (T-7) with 1 molecule of Cy5 introduced [Tue 25] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-6) with one thiol group introduced obtained in Example 7-2-1, a dimethylformamide solution of N-(m-PEG4)-N'-(PEG3-Mal)-Cy5 (BroadPharm) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added, and the mixture was shaken at room temperature for 1 hour. The reaction solution was purified using an NAP-25 desalting column (manufactured by Cytiva) to obtain one molecule of the antibody (T-5) with Cy5 introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that Cy5 was introduced. Example 7-2-3 Synthesis of Trastuzumab (T-8) with 1 molecule each of Cy5 and peptide reagent introduced [Tue 26] Trastuzumab (T-7) with one molecule of Cy5 introduced obtained in Example 7-2-2 and reagent P1 described in the record (International Publication No. 2019 / 240287A1) were used to follow the method of International Publication No. 2019 / 240287A1, thereby obtaining (T-8) with one thiol group introduced to T-7. Example 7-2-4 Synthesis of Trastuzumab (T-9) with 1 molecule each of Cy5 and PEG4-benzocyclooctine (DBCO) introduced [Tue 27] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-8) with 1 molecule each of Cy5 and thiol introduced in Example 7-2-3, a dimethylformamide solution of DBCO-PEG4-Maleimide (BroadPharm) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and shaken at room temperature for 1 hour. The reaction solution was purified using a NAP-25 desalting column (manufactured by Cytiva) to obtain Trastuzumab (T-9) with 1 molecule each of Cy5 and PEG4-DBCO introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that PEG4-DBCO was introduced. Example 7-2-5 Synthesis of Trastuzumab (T-10) with 1 molecule each of Cy5 and PEG12-benzocyclooctine (DBCO) introduced [Tue 28] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-8) with 1 molecule each of Cy5 and thiol introduced in Example 7-2-3, a dimethylformamide solution of DBCO-PEG12-Maleimide (BroadPharm) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and shaken at room temperature for 1 hour. The reaction solution was purified using a NAP-25 desalting column (manufactured by Cytiva) to obtain Trastuzumab (T-10) with 1 molecule each of Cy5 and PEG12-DBCO introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that PEG12-DBCO was introduced. Example 7-2-6 Synthesis of Trastuzumab (T-11) with 1 molecule each of Cy5 and PEG24-benzocyclooctine (DBCO) introduced [Tue 29] To a 3 mg / mL PBSE buffer solution (10 mM Phosphate Buffered Saline (PBS), 10 mM EDTA, pH 7.4) of Trastuzumab (T-8) with 1 molecule each of Cy5 and thiol introduced in Example 7-2-3, a dimethylformamide solution of DBCO-PEG24-Maleimide (BroadPharm) (2.5 equivalents to the antibody, dimethylformamide (DMF) (8% v / v) solution) was added and shaken at room temperature for 1 hour. The reaction solution was purified using a NAP-25 desalting column (manufactured by Cytiva) to obtain Trastuzumab (T-11) with 1 molecule each of Cy5 and PEG24-DBCO introduced. HIC-HPLC analysis was performed according to the report (Anal. Chem., 2019, 91, 20, 12724-12732) and it was confirmed that PEG24-DBCO was introduced. Example 7-3 Preparation of antibody-NK cell conjugates using amine-reactive reagents 7-3-1 Synthesis of Peptides The peptide consisting of the amino acid sequences of SEQ Nos. 41 and 42 was synthesized in solid phase according to the method described in International Publication No. 2018 / 199337 (the synthesis of the peptide is the same as below). An azide group was introduced by modifying the N-terminus with 4-Azidobenzoic Acid (Az, Tokyo Kasei Kogyo Co., Ltd.). Sequence No. 41: Az-EEEEC-NH2 SEQ ID NO: 42: Az-EEEEEEEEEEEEEEEEEEEEEEEEEEEEEC-NH2 7-3-2 Preparation of Amine Reactive Reagents Azido-PEG4-NHS ester (BroadPharm), Azido-PEG12-NHS ester (BroadPharm), Azido-PEG24-NHS ester (BroadPharm), DBCO-PEG12-NHS ester (BroadPharm), DBCO-Sulfo-NHS ester (Click Chemistry Tools), and Sulfo DBCO-PEG4-TFP ester (BroadPharm) were used as amine-reactive reagents having bio-orthogonal reactive groups. In addition, Az-EEEEC-NH2 (Sequence 41) and Az-EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEC-NH2 (Sequence No. 42) synthesized in Example (7-3-1) were dissolved in DMSO. Thereby adding NHS-PEG6-Maleimide (Funakoshi Co., Ltd.) at a molar equivalent of 0.77 and reacting at 37°C for 8 hours, a peptide reagent having an amine-reactive group and a bio-orthogonal reactive group at the terminal was synthesized. [Tue 30] [Tue 31] 7-3-3 Production of NK cells with azide groups on the cell surface The number of NK cells cultured according to Example 7-1 was quantified using NucleoCounter (registered trademark) NC-200 (trademark) (ChemoMetec). 1.0 × 10⁶ 6NK cells were separated from the cells and centrifuged (at 4000 rpm for 5 minutes), after which the supernatant was removed. More than 1 mL of PBS was added, and the centrifugation (at 4000 rpm for 5 minutes) and supernatant removal process (hereinafter referred to as the washing process) was repeated twice, after which 1 mL of Azido-PEG24-NHS ester (BroadPharm) of 250 μM (PBS solution) was added. After repeating inversion mixing for 30 minutes using a rotary mixer, centrifugation (at 4000 rpm for 5 minutes) was performed, and then the supernatant was removed. The washing process was then repeated twice, and 200 μL of NK activation medium was added to prepare NK cells having azide groups on the cell surface. 7-3-4 Production of NK cells with bioorthogonal reactors on various cell surfaces As in Example 7-3-3, NK cells having bioorthogonal reactors on the cell surface were produced using the amine-reactive reagent prepared in Example 7-3-2. Production of 7-3-5 antibody-NK cell conjugates Production of antibody-NK cell conjugate (ACC-1) with 7-3-5-1 PEG28 linker To the NK cells having azide on their surface obtained in Example 7-3-3, Trastuzumab, into which one molecule each of Cy5 synthesized in Example (7-2-4) and PEG4-DBCO was introduced to reach a final concentration of 2 μL, was added and incubated in a 37°C incubator for 1 hour. After centrifugation (at 4000 rpm for 5 minutes) and supernatant removal, the washing process was repeated twice, and finally, by adding NK activation medium, an antibody-NK cell conjugate (ACC-1) having a PEG28 linker was synthesized. Production of antibody-NK cell conjugates (ACC-2) with a 7-3-5-2 PEG48 linker To the NK cells having azide on their surface obtained in Example 7-3-3, Trastuzumab, into which one molecule each of Cy5 synthesized in Example (7-2-6) and PEG24-DBCO was introduced to reach a final concentration of 2 μL, was added and incubated in a 37°C incubator for 1 hour. After centrifugation (at 4000 rpm for 5 minutes) and supernatant removal, the washing process was repeated twice, and finally, by adding NK activation medium, an antibody-NK cell conjugate (ACC-2) having a PEG48 linker was synthesized. Evaluation of 7-3-6 antibody-NK cell conjugate By performing flow cytometry analysis on ACC-1 using an Attune NxT Flow Cytometer (Thermo Fisher Scientific), it was observed that the antibody was binding to the cell. By setting the maximum autofluorescence of NK cells without surface modification as the threshold, strong fluorescence derived from Cy5 was observed at the antibody-NK cell conjugate, as shown in Fig. 15. From this, it was confirmed that the antibody was binding to NK cells with high efficiency. Example 7-4 Preparation of antibody-NK cell conjugates using metapolic labeling method 7-4-1 Production of NK cells with azide groups on the cell surface N-azidoacetylmannosamine tetraacylated (Tokyo Kasei Kogyo Co., Ltd.) was added to NK cells cultured according to Example 7-1 to achieve final concentrations of 25 μM, 50 μM, and 100 μM. After incubating overnight at 37°C, the cells were centrifuged (at 4000 rpm for 5 minutes) to remove the supernatant. After washing twice with PBS (adding at least 1 mL of PBS and removing the supernatant by centrifugation), NK cells having azide groups on the cell surface were prepared by adding NK activation medium. Production of 7-4-2 Antibody-NK Cell Conjugates Production of antibody-NK cell conjugates (ACC-3) with a 7-4-2-1 PEG4 linker To the NK cells having azide on their surface obtained in Example 7-4-1, Trastuzumab, into which one molecule each of Cy5 synthesized in Example (7-2-4) and PEG4-DBCO was introduced, was added to a final concentration of 2 μL, and the mixture was left to stand in a 37°C incubator for 1 hour. After centrifugation (at 4000 rpm for 5 minutes) and supernatant removal, the washing process was repeated twice, and finally, by adding NK activation medium, an antibody-NK cell conjugate (ACC-3) having a PEG4 linker was synthesized. Production of antibody-NK cell conjugate (ACC-4) with 7-4-2-2 PEG12 linker To the NK cells having azide on their surface obtained in Example 7-4-1, Trastuzumab, into which one molecule each of Cy5 synthesized in Example 7-2-5 and PEG12-DBCO was introduced to reach a final concentration of 2 μL, was added and left to stand in a 37°C incubator for 1 hour. After centrifugation (at 4000 rpm for 5 minutes) and supernatant removal, the washing process was repeated twice, and finally, by adding NK activation medium, an antibody-NK cell conjugate (ACC-4) having a PEG12 linker was synthesized. Production of antibody-NK cell conjugate (ACC-5) with 7-4-2-3 PEG24 linker To the NK cells having azide on their surface obtained in Example 7-4-1, one molecule each of Cy5 synthesized in Example 7-2-6 and PEG24-DBCO was introduced into Trastuzumab to reach a final concentration of 2 μL, and the mixture was left to stand in a 37°C incubator for 1 hour. After centrifugation (at 4000 rpm for 5 minutes) and supernatant removal, the washing process was repeated twice, and finally, by adding NK activation medium, an antibody-NK cell conjugate (ACC-5) having a PEG24 linker was synthesized. Evaluation of 7-4-3 antibody-NK cell conjugate For the antibody-NK cell conjugate obtained in Example 7-4-2, by performing the same operation as in Example 7-3-6, it was confirmed that the antibody was bound to the cell surface with higher efficiency (Fig. 16). Example 8 Evaluation of the Cell Damage Caused by Antibody-NK Cell Conjugates 8-1 Culture of SK-BR-3 Cells SK-BR-3 (ATCC) was selected as the HER2-positive target cell. SK-BR-3 was cultured in RPMI 1640 Medium supplemented with 10% FBS (Thermo Fisher Scientific) and GlutaMAX (trademark) Supplement Medium (Thermo Fisher Scientific). The above SK-BR-3 culture medium is referred to as RPMI medium below. 8-2 Cell Injury Assessment Assay As a cytotoxicity assessment system, an assay system utilizing the DELFIA EuTDA Cytotoxicity Detection kit (Revvity) (hereinafter referred to as the DELFIA assay) was used. After washing SK-BR-3 cells cultured according to Example 8-1 twice with PBS, TrypLE Select Enzyme (1X) and no phenol red (Thermo Fisher Scientific) were added. The cells were suspended by incubating at 37°C for 3 minutes, centrifuged (at 120g for 5 minutes), and after removing the supernatant, 1 mL of RPMI medium (refer to Example 8-1) was added. The number of cells and viability in the obtained cell suspension were measured using a Countess Automated Cell Counter (Thermo Fisher Scientific), and the result was 2.5 × 10⁶ 6RPMI medium was added until the concentration reached cells / mL. 1 mL of the resulting cell suspension was taken, 5 μL of DELFIA BATDA labeling reagent (included in the DELFIA EuTDA Cytotoxicity Detection kit) was added, and the mixture was incubated at 37°C for 1 hour. After centrifuging to remove the supernatant, 1 mL of PBS was added for washing, and the process of centrifuging to remove the supernatant was repeated twice, after which 500 μL of NK activation medium was added. The number and viability of cells in the resulting cell suspension were measured using a Countess Automated Cell Counter (Thermo Fisher Scientific), and NK activation medium was added until the concentration reached 50,000 cells / mL. The resulting cell suspension was dispensed into a 96-well plate at a rate of 100 μL per well to prepare target cells for the assay. In addition, NK cells prepared according to Example 7-1 and antibody-NK cell conjugates prepared according to Examples 7-3-5 and 7-4-2 were added so that the ratio of NK cells or antibody-NK cell conjugates to SK-BR-3 cells was 6:1, 3:1, 1:1, and 0:1, and the final volume was adjusted to 200 μL / well. At this time, the number of NK cells and antibody-NK conjugates was measured using NucleoCounter (registered trademark) NC-200 (trademark) (ChemoMetec). In addition, instead of effector cells, a well (hereinafter referred to as the 100% kill well) containing 90 μL of NK activation medium and 10 μL of Lysis buffer (included in the DELFIA EuTDA Cytotoxicity Detection kit) and a well containing 100 μL of NK activation medium (hereinafter referred to as the control well) were also prepared. After incubating the above 96-well plate at 37°C for 4 hours, centrifugation (500g, 5 min) was performed, and 20 μL of the supernatant was added to a separately prepared 96-well plate for the DELFIA assay (included with the DELFIA EuTDA Cytotoxicity Detection kit). 200 μL of DELFIA Eu-Solution was added thereto, and after shaking at room temperature for 15 minutes, time-resolved fluorescence measurements were performed on each well using a Revvity Nivo multimode plate reader (Revvity). Based on the obtained intensities, cell damage was measured using the following formula. [Number 1] (Fluorescence intensity of sampling well) - (Fluorescence intensity of control well) Cell damage (%) = 100 × ------------------------------------------------ (Fluorescence intensity of control well) - (Fluorescence intensity of control well) As a result, as shown in Figure 17, antibody-NK cell conjugates synthesized by the modification method using NHS reagents and the metabolic labeling method exhibited high cell damage compared to NK cells. Comparative Example 1 Preparation of an antibody-cell conjugate based on prior art 1-1 Synthesis of Trastuzumab (T-13) with Introduced Single-Stranded DNA Trastuzumab (T-13) with introduced single-stranded DNA was synthesized using Trastuzumab (Chugai Seiyaku) and single-stranded DNA (hereinafter referred to as DNA1, sequence number 43) in accordance with prior art (International Publication No. 2023 / 114719Al, Cytotherapy 22(2020) 135-143). The introduction of DNA was confirmed by performing HIC-HPLC analysis in accordance with the method (Anal. Chem., 2019, 91, 20, 12724-12732). Sequence number 43: s_ccctagagtgagtcgtatga (s=Thiol C6) 1-2 Synthesis of NK cells (C-1) into which single-stranded DNA was introduced NK cells (C-1) modified with single-stranded DNA2 on their surface were prepared using NK cells and single-stranded DNA (hereinafter referred to as DNA2, sequence number 44) in accordance with prior art (International Publication No. 2023 / 114719Al, Langmuir. 2009 June 16; 25 (12): 6985-6991). Sequence number 44: s_tcatacgactcactctaggg (s=Thiol C6) Preparation of antibody-NK cell conjugate (ACC-6) having a 1-3 DNA linker Antibody-NK cell conjugates (ACC-6) were synthesized using Comparative Examples (1-1) and (1-2) in accordance with the prior art (International Publication No. 2023 / 114719Al, Cytotherapy 22(2020) 135-143, Langmuir. 2009 June 16; 25(12): 6985-6991). Comparative Example 2: Comparison of cellular damage with an antibody-NK cell conjugate prepared based on prior art The cellular disruptiveness of the antibody-NK cell conjugate (ACC-6) synthesized based on Comparative Examples 1-3 and the antibody-NK cell conjugate (ACC-3, 4, 5) synthesized in Example 7-4-2 was confirmed according to the method of Example 8-2. As a result, as shown in Fig. 18, ACC-3 and 4, 5 exhibited higher activity than ACC-6. From this, it was shown that the antibody-NK cell conjugate (ACC-3, 4, 5) synthesized in Example 7-4-2 exhibited higher cell damage than the antibody-NK cell conjugate (ACC-6) synthesized in Comparative Example 1-3. Comparative Example 3: Comparison of antigen binding ability with an antibody-NK cell conjugate prepared based on prior art After preparing the antibody-NK cell conjugate (ACC-6) synthesized based on Comparative Examples 1-3 and the NK cell conjugate (ACC-5) synthesized based on Example 7-4-2, they were cultured for 1 day, and their HER2 binding ability was evaluated based on Example 5-2. As a result, as shown in Fig. 19, ACC-5 exhibited higher antigen binding ability than ACC-6.

Claims

Claim 1 An Fc-cell complex comprising a cell and an antibody Fc region bound to the surface of the cell, wherein the antibody Fc region is formed by disulfide bonding of two Fc constituent polypeptides, and the antibody Fc region is chemically bound to the cell surface through a linker introduced into a functional group in the side chain of a specific amino acid residue present at one or more positions of one of the two antibody Fc constituent polypeptides. Claim 2 An Fc-cell complex according to claim 1, wherein the specific amino acid residue is one or more of 14 amino acid residues consisting of asparagine, glutamine, methionine, proline, serine, threonine, tryptophan, tyrosine, aspartic acid, glutamic acid, arginine, histidine, and lysine. Claim 3 In claim 1, the specific amino acid residue is a lysine residue, Fc-cell complex. Claim 4 An Fc-cell complex, wherein the lysine residue is one or more of the lysine residues at positions 246, 248, 274, 288, 290, 317, 320, 322, 360, 414, and 439. Claim 5 In claim 1, the antibody Fc region is an Fc-cell complex in which a functional substance is introduced through a linker introduced into a functional group in the side chain of a specific amino acid residue located at one or more positions of the other of the two Fc constituent polypeptides. Claim 6 In paragraph 5, the functional substance is an Fc-cell complex that is a drug, a labeling substance, an affinity substance, a transport substance, or a stabilizer. Claim 7 In claim 1, the Fc-cell complex, wherein the antibody Fc region comprises an antibody variable region. Claim 8 In claim 1, the antibody Fc region comprises a fusion protein of an antibody Fc constituent polypeptide and a functional polypeptide, an Fc-cell complex. Claim 9 In claim 1, the antibody Fc region is an Fc-cell complex introduced to the cell surface by a reaction between a bio-direct functional group introduced through a linker introduced to a functional group in the side chain of a specific amino acid residue present at one or more positions of one of the two Fc constituent polypeptides, and a group present on the cell surface or reacting with said bio-direct functional group introduced thereto. Claim 10 A method for preparing a cell-Fc region complex, comprising: (I) a process for preparing an antibody Fc region in which two antibody Fc constituent polypeptides are disulfide-bound; (II) a process for reacting a compound represented by the following formula (Ia) or formula (Ib) with the antibody Fc region to form an Fc-compound (Ia) complex or an Fc-compound (Ib) complex; [Chemical 1] [In the formula, R represents a reactive group for the Fc region, L1 represents a first linker, L2 represents a second linker, CLE(B) represents a cleavable portion capable of generating a bio-orthogonal functional group on the reactive group side by cleavage, and A represents an affinity substance comprising an affinity peptide.] [Chem 2] [In the formula, R represents the reactive group, L5 represents the fifth linker, L6 represents the sixth linker, B represents a group containing a bio-orthogonal functional group, CLE represents a cleavable portion, and A represents the affinity substance.] (III) A process of cleaving an Fc-compound (Ia) complex or an Fc-compound (Ib) complex at the cleavable portion to form an Fc region that does not contain the affinity substance and has a bio-orthogonal functional group introduced therein, (IV) A process of preparing a cell having a functional group that reacts with the bio-orthogonal functional group on its surface, (V) A process of introducing the Fc region to the cell surface by reacting the Fc region with the bio-orthogonal functional group and the cell with the bio-orthogonal functional group of the Fc region and the functional group of the cell that reacts with the bio-orthogonal functional group of the cell, the method comprising: (V) Claim 11 In Paragraph 10, A is AP1-L A -AP2(wherein, AP1 represents a first affinity peptide having affinity for the normal region of the heavy chain of the antibody, AP2 represents a second affinity peptide having affinity for the normal region of the heavy chain of the antibody, and L A The method indicated as (representing the linker). Claim 12 In paragraph 10, compound (Ia) is of the following formula (Ia-1): [Chem 3] A method for preparing a cell-Fc region complex represented by [wherein X represents a degreasing agent, W1, W2, and W3 each independently represent an oxygen atom or a sulfur atom, L3 represents a third linker, L4 represents a fourth linker, S represents a sulfur atom, and A represents the affinity substance.] Claim 13 In paragraph 10, compound (Ib) is of the following formula (Ib-1): [Chem 4] A method for preparing a cell-Fc region complex represented by [wherein X represents a degreasing group, W1, W2, and W3 each independently represent an oxygen atom or a sulfur atom, L7 represents a seventh linker, L8 represents an eighth linker, B represents a group containing a bio-orthogonal functional group, V represents an oxygen atom or a sulfur atom, and A represents the affinity substance.] Claim 14 A method for preparing a cell-Fc region complex according to claim 10, wherein the bio-orthogonal functional group is an azide group, an alkyne residue, a tetrazine residue, an alkene residue, a thiol group, a maleimide residue, a furan residue, or a halocarbonyl residue. Claim 15 A method for preparing a cell-Fc region complex according to claim 10, wherein the cell-Fc region complex is an Fc-cell complex described in any one of claims 1 to 9. Claim 16 A method for preparing a cell-Fc region complex according to claim 10, wherein the cell-Fc region complex is the Fc-cell complex described in claim 5, and comprises a process of introducing a functional substance to a functional group in the side chain of a specific amino acid residue present at one or more positions of the other of the two Fc constituent polypeptides in the antibody Fc region.

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