Anti-CD3 binding domain and antibody containing said domain, as well as methods for producing and using them.

Abstract

Anti-CD3 binding domain and antibodies containing said domain, and their effects To provide a manufacturing method and a method of use. [Solution] An anti-CD3 binding domain and an antibody containing the same, which is particularly desirable for T cell activity It possesses sexualization ability, (re)targeted target cell killing ability, and development potential, and a profile. Antibodies containing multispecific antibodies, and methods for identifying, isolating, and producing them, A method for preparing and using the same is provided. It contains a CD3 binding domain and the said domain. Reagents for identifying, isolating, selecting, preparing, and characterizing antibodies are also provided.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 503,315, filed on May 8, 2017. This is the case, and the application is incorporated by reference in its entirety.

[0002] Sequence List This application was filed electronically in ASCII format and is incorporated herein by reference in its entirety. Includes a sequence list. This ASCII copy was created on April 7, 2017, and is named 2009186-0189_SL.TXT Its name is [name], and its size is 2,923,505 bytes.

[0003] The present invention particularly concerns the anti-surface antigen classification (Cluster of Differentiation) 3 (CD3) binding domain. This relates to antibodies containing the domain, and the antibodies have multispecificity (mult This includes i-specific antibodies and bispecific antibodies, as well as their functional fragments, and This relates to methods and reagents for the identification, isolation, preparation, and use of these. To identify, isolate, select, produce, and characterize antibodies containing the domain. Reagents for the eye are also provided. [Background technology]

[0004] All references cited herein, but not limited to, are referenced throughout this specification. This includes patents, patent applications, and non-patent references, as well as published documents, for all purposes, The entirety is explicitly incorporated herein by reference.

[0005] The body's immune system plays a role in protecting against infection, injury, and cancer. The humoral and cellular immune systems, though separate, are interrelated systems that work together to defend the body. It is controlled. The humoral immune system is mediated by soluble factors, so-called antibodies. Depending on the body, external factors... Antibodies neutralize products that are recognized as sexual. In contrast, the cellular immune system includes, for example, T cells and It contains cells such as macrophages, which remove and neutralize foreign invaders.

[0006] T cell activation is important for stimulating the immune response. T cells exhibit immune specificity and contribute to cellular immunity. They control most of the reaction. T cells do not secrete antibodies, but B lymphocytes do. It is essential. T cell activation requires, for example, the T cell receptor complex and the CD4 molecule or CD8 molecule. The involvement of many cell surface molecules such as the antigen-specific T cell receptor (TcR) is required. Having a chain of α and β or gamma and δ It is a membrane glycoprotein composed of disulfide-linked heterodimers. TcR is C It is non-covalently bound to a complex of unchanging proteins designated as D3.

[0007] TcRs provide antigen specificity, and the CD3 structure transmits activation signals to T cells. The CD3 complex, It contains four subunits. The CD3 complex consists of two zeta subunits and one epsilon subunit. It contains a subunit and either a gamma subunit or a delta subunit. Antigen binding can lead to crosslinking and activation of the TCR complex. Signaling involves the activation of T cells, the production of IL-2, and other complex processes. It causes the production of tokines.

[0008] TcR ligands are MHC peptide complexes on the surface of target cells, such as virus-infected cells. This is a fusion. After recognizing the MHC-peptide on the target cell, the T cell fused with the target cell. It may have cytotoxic or apoptotic effects, especially on cytotoxic T cells (CD8-positive T cells). ) may have the beneficial effect of directly removing virus-infected cells. This weapon, in particular, is very useful in fighting viral infections and eliminating tumor cells. It is essential.

[0009] Activation of cytotoxic T cells occurs without recognition of the MHC-peptide complex by TcRs, and CD3 This can occur through direct binding of the antigen. This alternative activation pathway involves anti-CD3 antibodies. This can be done. Non-human monoclonal antibodies against a portion (subunit) of the CD3 chain have been developed. Examples include mouse antibodies OKT3, SP34, UCHT1, or 64.1. (e.g., June, et al., J. Immunol. 136:3945-3952 (1986); Yang, et al., J. Immunol. See 137:1097-1100 (1986) and Hayward, et al., Immunol. 64:87-92 (1988). (Refer to the above). Other CD3 antibodies have also been disclosed, for example, U.S. Patent No. 5,585,097, No. 5,929. No. 212, No. 5,968,509, No. 6,706,265, No. 6,750,325, No. 7,381,803, No. 7,728,114 This is disclosed in [publication name]. Bispecific antibodies having CD3 binding specificity are also disclosed, for example in the United States This is disclosed in Japanese Patent Nos. 7,262,276, 7,635,472, and 7,862,813.

[0010] Many of these anti-CD3 antibodies bind to the epsilon chain, generating highly activated T cells. In most cases, cancer immunotherapy using conventional monoclonal antibodies does not adequately stimulate T lymphocytes. Without activation, meaningful targeted pharmacological activity against target cell types or target tissues is not attracted. I won't be woken up.

[0011] For example, a bispecific antibody (bsA) that redirects effector T cells to target and kill tumor cells. The development and use of multispecific antibodies such as b) have become quite significant in preclinical and clinical settings in recent years. It has been shown to be desirable (e.g., Topp et al, 2012, Blood 120:5185-87; B See Argou et al, 2008, Science 321:974-77). To date, the following have been developed. Many of these bispecific antibodies are CD3-specific, and are the primary target for T cell recruitment and activation. It contains a binding site and a second binding site for a target disease-related antigen, such as CD19 (Bass an, 2012, Blood 120:5094-95). The bispecific antibody is CD3 + T cells and target disease cells directly It is thought that contact induces cell-mediated cytotoxic activity (Bassan, 2012). The bispecific anti-CD3x and anti-CD19 antibodies are MRD + Complete and persistent in approximately 70% of adult patients with ALL It has been reported that it can induce molecular remission at very low concentrations (Topp et al, 2012). Blood 120:5185-87). Bispecific antibodies that recognize gliomas and CD3 epitopes on T cells. It has been used successfully in the treatment of brain tumors in human patients (Nitta, et al. Lancet 1990; 355:368-371). Furthermore, CD3xCD20 bispecific antibodies (US2015 / 0166661 and US2017 / 0202194). ) and CD3xCLL-1 (US2016 / 0368994) are being manufactured for clinical trials.

[0012] Leukocyte redirection bsAb is not limited to T cells. NK cell antigen CD16 and tumor-associated antigens (for example) Two-specificity killer engine (BiKE:bispe) equipped with scFv for CD19, CD22, CD33 (Cific killer engager) also shows potent anticancer activity (e.g., Miller, Hematology) (Soc Hematol Educ Program 2013:247-53). Other examples include anti-CD16x anti-CD 19x anti-CD22 and other trispecific killer agents (TriKE: trispecific killer engagement) (er) can be cited (Miller, 2013; Gleason et al, 2012, Mol Cancer Ther 11: 2674-84). AML and myelodysplastic syndromes are being treated with anti-CD16x anti-CD33 BiKE. (Miller, 2013; Wiernik et al, 2013, Clin Cancer Res 19:3844-55). incurable In sexual AML, CD16xCD33 BiTE is associated with potent tumor cell killing by NK cells and cytokines. Inhibition of ADAM17 enhanced the CD16xCD33 BiKE reaction (Miller, 2013). ). Other trivalent constructs for other triple specificities, such as CD16 / CD19 / HLA-DR, have also been reported (Sc hubert et al, 2012, mAbs 4:45-56).

[0013] Many methods for producing bispecific antibodies are known (e.g., U.S. 7,405,320 (See issue number). Bispecific antibodies can be produced by the quadroma method. This method produces two different monoclonal antibodies that recognize different antigen sites. This includes the fusion of hybridomas (Milstein and Cuello, Nature 1983; 305:537-5 40). The fused hybridoma synthesizes two different heavy chains and two different light chains. These can form and then randomly associate to create a heterogeneous group of 10 different antibody structures. Only one of these is bispecific, accounting for 1 / 8 of the total antibody molecules. Therefore, this antibody is effective against other types. The body must be further refined. Fusion hybridomas are often different from their parent hybridomas. Furthermore, it has low cytogenetic stability, and therefore the generations of producing cell lines often experience problems. stomach.

[0014] Another method for producing bispecific antibodies involves using a heterobifunctional crosslinking agent to create two different antibodies. It binds to noclonal antibodies, and the resulting hybrid conjugate is two Binds to different targets (Staerz, et al. Nature 1985; 314:628-631; Perez, et al. Nature 1985; 316:354-356). The bispecific antibodies produced by this method are essentially It is essentially a heteroconjugate of two IgG molecules, which diffuse slowly and rapidly within the tissue. It is excluded from circulation. Also, the bispecific antibody is one of the two parent monoclonal antibodies. It is reduced to half its molecule, then combined and re-oxidized to form a hybrid structure. It can also be manufactured by obtaining the necessary materials (Staerz and Bevan. Proc Natl Acad Sci). (USA 1986; 83: 1453-1457). Another method involves using two or three separate purified Fab' fragments. This includes chemically crosslinking using an appropriate linker. All these chemical methods It has high manufacturing costs, is a laboratory-based manufacturing process, involves extensive purification steps, and has a low yield. Due to its low (less than 20%) and non-uniform nature, it is not suitable for development intended for commercial sale. That's not good.

[0015] The VH domain and VL domain of antibodies produced by recombinant DNA are paired together. This may be done to form a dimer (recombinant Fv fragment) that has binding ability (USA) (Nos. 4,642,334). However, such non-covalent molecules are not very stable under physiological conditions. Rather, it is not suitable for practical use. The same type of VH domain and VL domain are given appropriate composition and length. The peptide linker (usually composed of more than 12 amino acid residues) is used to bind the molecules, and the binding activity is improved. It is also possible to form a single-strand Fv (scFv) by changing the linker length. A method for preparing polyvalent and multispecific scFv-based agents is provided under U.S. Patent No. 5,844,094. These are disclosed in U.S. Patent No. 5,837,242 and WO98 / 44001. Common challenges are found in many places. This relates to the production of synthetic, polyvalent, and multispecific scFv-based agents, and the low expression levels. , heterogeneous products, formation of aggregates due to instability in solution, instability in serum, and This is a weakening of infinity.

[0016] Several bispecific antibodies targeting CD3 and CD19 are at various stages of development, Approved as a bispecific antibody construct based on scFv. It is known as (Bispecific T-cell Engager), and has two antigen-binding specificities. It employs a single polypeptide. Each specificity is linked in tandem via a flexible linker. This is given by the related VH and VL (for example, Nagarsen et al, 2 009, Leukemia & Lymphoma 50:886-91; Amann et al, 2009, J Immunother 3 See 2:453-64; Baeuerle and Reinhardt, 2009, Cancer Res 69:4941-44. Another bispecific antibody is called DART(registered trademark) (Dual-Affinity Re-Targeting). Therefore, it utilizes a disulfide-stabilized diabody design (e.g., Moore et al., 2011, Blood 117:4542-51; Veri et al, 2010, Arthritis Rheum 62: 1933- See 43). Both BITE® and DART® are small size Because it is (approximately 55 kDa), it exhibits rapid blood clearance. Therefore, this bispecific antibody The body requires frequent administration to maintain a therapeutic level.

[0017] SCORPION Therapeutics (Emergent Biosolutions, Inc., Seattle, Washington) This is a platform technology that combines two antigen-binding domains in a single-chain protein. One binding domain is an effector domain base on the immunoglobulin Fc region. The first binding domain is located at the C-terminus, and the second binding domain is located at the N-terminus.

[0018] The tetravalent and bispecific antibody-like protein is DVD-Ig, which is a two-monoclonal protein. It was produced from antibodies (Wu, C. et al., Nature Biotechnology, 25, p (1290-1297, 2007). To construct the DVD-Ig molecule, the V domains of two mAbs were shortened. The first antibody light chain (VL) is fused in tandem with Kerr (TVAAP) (SEQ ID NO: 6714) The DVD-Ig protein light chain is formed with the 'n' at the N-terminus, followed by the VL and Ck of the other antibody. Similarly, the variable region of the heavy chain (VH) of two mAbs is controlled by a short linker (ASTKGP) (SEQ ID NO: 671). 5) The antibodies are fused in tandem, with the first antibody at the N-terminus, followed by the other antibody and the heavy chain constant domain. Then, the DVD-Ig protein heavy chain (VH1 / VL1) is formed. All light and heavy chains are stationary. The main data is saved during the DVD-Ig design. The reason is that they are perfectly disulfide bonded. This is because it is important for the formation of IgG-like molecules. The expression vector encoding the light and heavy chains of DVD-Ig By co-transfecting mammalian cells using this method, a molecular weight of approximately 200 kDa is obtained. The secretion of a single type of IgG-like molecule occurs. This molecule has four binding sites, two from each mAb. They are doing it.

[0019] Bispecific antibodies show significant advantages over monospecific antibodies in the treatment and detection of cancer. The widespread commercial application of bispecific antibodies is hampered by the lack of efficient / low-cost production methods. This is inhibited by the lack of stability of the sex polypeptide and its short half-life in humans. Many methods for producing bispecific monoclonal antibodies (BsMABs) have been developed over the past several decades. It is being developed.

[0020] However, many clinical candidate antibodies and therapeutic antibodies are in the early stages of development and prototyping. Despite exhibiting sufficient selectivity and high potential for their target, these antibodies The majority of these will be developed through subsequent downstream development and clinical efficacy activity, for example, the following desired outcomes It has been found that it suffers from undesirable characteristics: randomness of bonding, polyspecific bonding (polyspec (also referred to as "polyspecificity" throughout this specification) ), off-target binding; non-specific binding; for example, mammalian host cells and yeast cells. Poor expression levels or expression profiles in eukaryotic host cells; poor chemical properties and physical properties, such as poor stability during storage (e.g., poor / short "storage period") Stability, poor (low) solubility, poor (high) viscosity, tendency to aggregate, etc.; and poor clinical Physical and biophysical profiles, e.g., poor pharmacokinetic profiles, poor drug potency This includes a pharmacokinetic profile, fast or poor in vivo clearance rate, and short circulating half-life. These factors will force the termination of further therapeutic development of the candidate antibody. Antibodies derived from play technology have historically been a minority among all clinical and commercially available antibodies. Yes, at least partially, this is due to coupling disorder, poor PK profile, and poor CMC characteristics. A tendency has been observed where many people believe that these disorders are sex-related, When screening antibodies using display technology, it is difficult to detect antibodies that cannot be developed. The lack of suitable means and methods to which one can / or alternatively choose is a major issue. It is further hypothesized that this is the cause (e.g., Meninger 2012; available at hyper-text transfer protocol: proteins-congress.com / wordpress / wp-content / uplo ads / 2012 / 01 / Trends-in-Therapeutic-Monoclonal-Antibody-Discovery-Technology.pdf (See reference).

[0021] In this field, antibodies developed during downstream development activities (post-discovery antibodies) are considered to be the most effective. Regarding ), technologies and assays have been developed to evaluate many of the aforementioned development possibilities. For example, CIC, SIC, BVP-ELISA, TMA, and other assays. However, Such assays are often performed using high-sloop technologies such as antibody display platforms. Integrating the TT into early polypeptide development platforms and antibody development platforms Not suitable for mixing. Furthermore, these characteristic assessments are often based on quantities in milligrams to grams. The protein is needed, and therefore often can be considered a pragmatic target for development. This effectively imposes a limit on the number of commands. And as a result, the success of the program... The probability decreases. As a result, vast resources are often used to modify lead candidates with poor characteristics. The effort was spent on attempts to do so, and there were hardly any available backups in the later stages of development. It ends up in a bad state.

[0022] In recognizing this bottleneck, we developed an assay that requires less material, and the development process Many attempts are being made to bring development feasibility assessment to an even earlier stage in the process (Esfa ndiary et al., 2013, Protein Eng Des Sel 26 (10): 663-670, 2013; hish et al., 2013, Nat Rev Drug Discov. 12(4):306-24). Such as Many of these attempts aim to predict the antibody solubility and aggregation characteristics of identified lead candidates. Self-interaction chromatography (SIC) and Cross-interaction chromatography (CIC) is a column-based chromatography system. This is a low to medium throughput assay that correlates with antibody solubility at relatively low concentrations. , predict (Ahamed et al., 2005, J Biol Chem 280(37):32090-100; Jacobs et al., Pharm Res 27:65-71, 2010; Spencer et al., Mabs 4(3)319-325, 2 012). When the retention time on this SIC or CIC column increases, the antibody bound to the column An interaction with is suggested, and it correlates with poor solubility (Jacobs et al., 2010). Sule et al. developed a medium-throughput gold nanoparticle assay to predict solubility at very low concentrations. They have reported and further expanded the assay range to accommodate complex cell culture media. (Sule et al., Biophys J 101(7):1749-1757, 2011; Mol Pharmaceutics 10(4 (1322-1331, 2013).

[0023] As mentioned above, polyspecificity is a highly undesirable characteristic associated with poor antibody pharmacokinetics. (Wu et al., J Mol Biol 368:652-665, 2007; Hotzel et al., 2012, MAbs 4(6):753-760). Medium-through immunohistochemistry for a wide range of panel tissues. A multispecific assay that can serve as a put test alternative has been reported in this field. (Wardeman) n et al. tested the polyreactivity of the natural antibody repertoire during the process of B cell maturation, LPS, This report describes an enzyme-linked immunosorbent assay (ELISA) using insulin, dsDNA, and ssDNA. (Wardemann et al., 2003, Science 301(5638):1374-7). Protein diversity A set of protein biotin for high-throughput ELISA is arranged on an array. The app is a different type of screening tool. (Protagen, Dortmund, Germany) The chip, which contains approximately 400 different human proteins, was analyzed using IHC staining (Lueking et al. l., 2008, Bio Techniques 45(4):Pi-Pv), and clinically approved TNF-alpha inhibitors. Method for measuring off-target binding of harmful agents (Feyen et al., Anal Bioanal Chem 391:1713) It has been reported to be comparable to (1720, 2008). More recently, Frese et al. have reported that 32 subjects They reported a 384-well assay for measuring the multireactivity of proteins, and Protein Panel P This is called rofiling or 3P (Frese et al., 2013, MAbs 5:2, 279-28) 7) Using this assay, the authors found that FDA-approved therapeutic antibodies were found to be effective against 32 test proteins. It exhibits a high specificity profile for quality, and this assay is used in the phage selection process. We demonstrated its application to screening candidates from these specific highly reactive profiles. Illing assays do not yet correlate with downstream development issues such as solubility, expression, and stability. No. Recent advances in this field can be seen in Hotzel et al. 2012 MAbs 4(6):753- It has been reported in 760) that baculovirus particle (BVP) ELISA is an in vivo antimicrobial agent. Predicting early clearance of non-target-mediated processes in the body, while also considering conventional biophysical properties For example, size exclusion chromatography retention time, hydrophobic interaction chromatography solution The emergence time, Fv charge, and pI were not predicted (Hotzel, et al., 2012MAb). (s 4(6):753-760). More recently, for example, the evaluation of therapeutic antibodies that can be developed from antibody libraries. To predict, select, and enrich, and ultimately produce and obtain developable antibodies. Reagents, methods, and means for doing so are disclosed (see, for example, WO2014 / 179363). thing). CD3 targeting methods have been shown to be very promising. On the other hand, specific T cell immunostimulation A common side effect of the therapy is the production of related cytokines. This often leads to cytotoxicity. Insectoid crisis, also known as an insectoid crisis, is a toxic cytokine release crisis. Infusion release syndrome (CRS) occurs. The anti-CD3 binding domain of the bispecific antibody binds to all T cells. To meet, a subset of highly cytokine-producing CD4+ T cells is recruited. The CD4+ T cell subset also includes regulatory T cells. Recruitment and expansion of regulatory T cells are It may potentially cause immunosuppression and negatively impact long-term tumor suppression. ru. For example, cell proliferation disorders such as cancer are characterized by unregulated proliferation of cell subgroups. Sexual dysfunction is a leading cause of death in developed countries and the second leading cause of death in developing countries. Every year, more than 12 million new cases of cancer are diagnosed, and 7 million people die from cancer. The National Cancer Institute reports that more than 500,000 Americans died from cancer in 2013, making it the deadliest year in the country. It is estimated that this accounts for nearly one in four people. As the elderly population increases, so does the incidence of cancer. It sometimes rises. This is because the likelihood of developing cancer more than doubles after the age of 70. Therefore, cancer Treatment is a serious and ever-increasing social burden. Therefore, for example, T cells Binding specificity to CD3 expressed above, T cell activation, (re)direction of activated T cells and Killing target cells, and while doing so, cytokine release syndrome (cytokines) Reduces the risk of triggering a storm (also known as a cytokine release crisis). Desirable development potential profile and / or CRS risk in reducing, etc. It exhibits a profile that is safe and effective, and the CD3 binding domain and this There is a need for the provision of antibodies (including multispecific antibodies). [Prior art documents] [Patent Documents]

[0024] [Patent Document 1] U.S. Patent No. 5,585,097 [Patent Document 2] U.S. Patent No. 5,929,212 [Patent Document 3] U.S. Patent No. 5,968,509 [Patent Document 4] U.S. Patent No. 6,706,265 [Patent Document 5] U.S. Patent No. 6,750,325 [Patent Document 6] U.S. Patent No. 7,381,803 [Patent Document 7] U.S. Patent No. 7,728,114 [Patent Document 8] U.S. Patent No. 7,262,276 [Patent Document 9] U.S. Patent No. 7,635,472 [Patent Document 10] U.S. Patent No. 7,862,813 [Patent Document 11] U.S. Patent Application Publication No. 2015 / 0166661 [Patent Document 12] U.S. Patent Application Publication No. 2017 / 0202194 Specification [Patent Document 13] U.S. Patent Application Publication No. 2016 / 0368994 [Patent Document 14] U.S. Patent No. 7,405,320 [Patent Document 15] U.S. Patent No. 4,642,334 [Patent Document 16] U.S. Patent No. 5,844,094 [Patent Document 17] U.S. Patent No. 5,837,242 [Patent Document 18] International Publication No. 98 / 44001 [Non-patent literature]

[0025] [Non-Patent Document 1] NJune, et al., J. Immunol. 136:3945-3952 (1986) [Non-Patent Document 2] Yang, et al., J. Immunol. 137:1097-1100 (1986) [Non-Patent Document 3] Hayward, et al., Immunol. 64:87-92 (1988)

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[0026] A series of CD3-binding domains and antibodies containing them, as well as methods for producing and using them A method has been found and is disclosed throughout this specification. This series of CD3-bound domains The members of IN collectively have a broad range of desirable characteristics, such as a broad range of CD3 epsilon properties. Affinity, exchange for both human CD3 (Hu CD3) and cynomolgus monkey CD3 (Cy CD3). Differential responsiveness, as well as the desirable development potential profile and / or cytokine release disorders. It exhibits a Congenital Risk Profile (CRS). These desirable characteristics are disclosed herein. Regarding many CD3 binding domains, other anti-CD3 antibodies (e.g., as specified herein and Yang et al.) ., J Immunol, Vol 137, pp. 1097-1100 (August 4, 1986); US 2014 / 008295; oy I2C; SP34; 38E4; CAB21609_A01, CAB21609_B01, CAB as disclosed in WO2015 / 095392 It was found to be superior to the development feasibility profiles of 21609_C01 and CAB21609_D01. Yes, they are.

[0027] Beneficial in nature, the CD3-binding domain is essentially an immunoglobulin form (e.g., IgG, IgM, I). Includes gA, IgE, and their isotypes, and multispecific forms (including bispecific forms). It can be incorporated into all antibody forms. Multiplexing suitable for incorporation into the CD3-binding domain of the present invention. Examples of specific forms include: Fab-Fc-scFv (bottle-opener) (XE NCOR Corporation), Mab-scFv (XENCOR Corporation), Mab-Fv (XENCOR Corporation), Dual scFv (XENC OR Corporation), central Fv (XENCOR Corporation), central scFv (XENCOR Corporation), one-arm central s cFv (one-arm central scFv) (XENCOR), Fab-Fab (XENCOR), Fab-Fv (XENCOR) ), mAb-Fv (XENCOR), mAb-Fab (XENCOR), DART (MACROGENICS), BiTE (Amge n / Micromet, KiTE, Common Light Chain-IgG (Genentech), TandAb (Affimed) Cross-Mab (Roche), SEED (EMD Serono), BEAT (Glenmark), TrioMab (Trion Pharma / These include FresEnius Biotech, DuetMab (MedImmune), and others, for example. (WO 95 / 09917; WO 2008 / 119566; WO 2008 / 119567; WO2011 / 121110; WO 2010 / 0 37835; WO 2007 / 042261; WO 2007 / 110205; WO 2011 / 121110; WO 2012 / 055961; WO 2012 / 16067; WO 2016 / 086189; WO 2016 / 182751; WO 2015 / 006749; WO 2014 / 049003; WO 2013 / 177101; WO 2015 / 128509; US 7,951,917; US 2009 / 0252729; US 2014 / 0348839; US 7,183,076; Mazor et al., Mabs, Vol. 7, pages 377-389 Ji (2015); Muda et al., Protein Engineering, Designe, & Selection, Vol. . 24, pp. 447-454 (2011); and Del Bano et al., Antibodies, Vol. 5, This is disclosed on pages 1-23 (2016).

[0028] The CD3-binding domain of the present invention and antibodies containing it collectively bind to CD3 expressed on the cell surface. Broad affinity to, broad T cell activation ability and (re)targeted target cell killing It possesses the ability, and furthermore, it essentially has any multiple singularity of any value of the object (including two singularities). (m) Suitable for antibody format. Therefore, the CD3 antibody of the present invention is suitable for almost all cell types and tissue types. And selected and incorporated into therapeutic molecules designed to target physiological fractions. This allows for treatment, and therefore, it is a therapeutic product designed to address almost all disease types or conditions. It can serve as a component of a child.

[0029] In certain embodiments, the present invention binds to CD3 (e.g., CD3ε and / or CD3γ). The present invention provides a CD3-binding domain and an antibody containing the same.

[0030] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are other CD3-binding It exhibits an enhanced development potential profile compared to the domain (or antibody containing it). Provided as follows. In certain embodiments, the CD3-binding domain of the present invention and the antibody containing the same are provided. As shown in Table 2, trastuzumab (Herceptin®), lintuzumab, bri Natumomab (Blincyto®), and Mab 364, Mab 366, Mab 367, Mab 368, Enhanced development capabilities compared to one or more of Mab 369, Mab 370, or Mab 22. It is provided with a capability profile.

[0031] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are approximately 0 MFI to approximately 5 00MFI, approximately 0MFI to approximately 450MFI, approximately 0MFI to approximately 400MFI, approximately 0MFI to approximately 350MFI, approximately 0MFI to approximately 300MFI, Approximately 0MFI to approximately 250MFI, approximately 0MFI to approximately 200MFI, approximately 0MFI to approximately 150MFI, approximately 0MFI to approximately 100MFI, approximately 0MFI to approximately 100MFI Approx. 50MFI, Approx. 200 MFI and 500MFI, Approx. 200MFI ~ Approx. 450MFI, Approx. 200MFI ~ Approx. 400MFI, Approx. 200M FI ~ approx. 350MFI, approx. 200MFI ~ approx. 300MFI, approx. 200MFI ~ approx. 250MFI, approx. 100MFI ~ approx. 450MFI, approx. 100M FI ~ approx. 400MFI, approx. 100MFI ~ approx. 350MFI, approx. 100MFI ~ approx. 300MFI, approx. 100MFI ~ approx. 250MFI, approx. 100M It exhibits a development feasibility score of approximately FI to 200MFI, or approximately 100MFI to 150MFI.

[0032] In other embodiments, the CD3-binding substance of the present invention and the antibody containing the same are approximately 0.0 to approximately 0.6, approximately 0 0.0 to approximately 0.57, approximately 0.0 to approximately 0.55, approximately 0.0 to approximately 0.53, approximately 0.0 to approximately 0.51, approximately 0.0 to approximately 0.49, approximately 0.0 to Approximately 0.47, approximately 0.0 to approximately 0.45, approximately 0.0 to approximately 0.43, approximately 0.0 to approximately 0.41, approximately 0.0 to approximately 0.39, approximately 0.0 to approximately 0.3 7. Approximately 0.0 to 0.35, approximately 0.0 to 0.33, approximately 0.0 to 0.31, approximately 0.0 to 0.29, approximately 0.0 to 0.27, approximately 0.0 to approximately 0.25, approximately 0.0 to approximately 0.23, approximately 0.0 to approximately 0.21, approximately 0.0 to approximately 0.19, approximately 0.0 to approximately 0.17, approximately 0.0 to Approximately 0.15, approximately 0.0 to approximately 0.13, approximately 0.0 to approximately 0.11, approximately 0.0 to approximately 0.09, approximately 0.0 to approximately 0.07, or approximately 0.0 It exhibits a standardization feasibility score of approximately 0.05.

[0033] In certain embodiments, the potential for development of the CD3-binding substance of the present invention and antibodies containing it Profile and / or development potential score are obtained from PSR assay, SCP assay, AS-CINS BVP assay, ELISA, DSF assay, Tm assay, HIC assay, CIC assay, or It is obtained by performing those combinations.

[0034] In other embodiments, the CD3-binding domain of the present invention and antibodies containing it exhibit potent T cell activation. It can induce sexualization or T-cell killing, while simultaneously inducing cytokine release syndrome. It exhibits a reduced tendency to induce cytokine production down to a certain level. In certain embodiments, Even if only one cytokine is present, a site can induce cytokine release syndrome. Cytokine production levels were measured to assess the tendency to induce levels of cytokine production. The at least one cytokine is selected from the following group: interleuk IL-6, interleukin-12, tumor necrosis factor alpha (TNFα), (TGFb) Interleukin-2 (IL-2) and interferon-gamma (IFNg).

[0035] In certain embodiments, the CD3-binding domain of the present invention and antibodies containing it activate T cells. Alternatively, as shown in Table 2, trastuzumab (Herceptin) induces T cell killing. (Registered Trademark)), lintuzumab, blinatumomab (Blincyto®), and Mab 364 , or one of the following: Mab 366, Mab 367, Mab 368, Mab 369, Mab 370 or Mab 22 Compared to the trends observed in multiple studies, this is at a level that can induce cytokine release. Up to a certain point, it exhibits a reduced tendency to induce cytokine production. In certain embodiments, at One cytokine can induce cytokine release syndrome. Cytokine production levels were measured to assess the tendency to induce live levels, and the low levels At least one cytokine is selected from the following group: interleukin-6(IL- 6) Interleukin-12 (IL-12), tumor necrosis factor alpha (TNFα), (TGFb), inter - Leukin-2 (IL-2) and interferon-gamma (IFNg).

[0036] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are used in cytokinesiology. Cytokine release syndrome (CRS) risk profile shows a reduced risk of developing cytokine release syndrome (CRS). The file is presented. In other embodiments, the CD3-binding domain of the present invention and antibodies containing it are used. As shown in Table 2, trastuzumab (Herceptin®), lintuzumab, and br Rinatumomab (Blincyto®), and Mab 364, Mab 366, Mab 367, Mab 368 cytokines evaluated using one or more of Mab 369, Mab 370, or Mab 22. Compared to the release syndrome risk profile, the risk of triggering cytokine release syndrome (CRS) It exhibits a cytokine release syndrome risk profile that shows a decrease in saturation.

[0037] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH3 selected from the group consisting of 63 and 371-405, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRH3 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRH3 is Mab223, 364, 365, as shown in Table 2. It is assumed that any of the CDRH3s 366, 367, 368, 369, or 370 are not 100% identical. ru.

[0038] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH2 selected from the group consisting of 63 and 371-405, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRH2 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRH2 is Mab223, 364, 365, as shown in Table 2. It is assumed that any of the CDRH2s 366, 367, 368, 369, or 370 are not 100% identical. ru.

[0039] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH1 selected from the group consisting of 63 and 371-405, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRH1 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRH1 is Mab223, 364, 365, as shown in Table 2. It is assumed that any of the CDRH1s 366, 367, 368, 369, or 370 are not 100% identical. ru.

[0040] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL3 selected from the group consisting of 63 and 371-405 CDRL3, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRL3 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRL3 is Mab223, 364, 365, as shown in Table 2. CDRL3 366, 367, 368, 369, or 370 is not 100% identical. ru.

[0041] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL2 selected from the group consisting of 63 and 371-405 CDRL2, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRL2 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRL2 is Mab223, 364, 365, as shown in Table 2. CDRL2 366, 367, 368, 369, or 370 is not 100% identical. ru.

[0042] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL1 selected from the group consisting of 63 and 371-405 CDRL1, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRL1 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRL1 is Mab223, 364, 365, as shown in Table 2. CDRL1 366, 367, 368, 369, or 370 is not 100% identical. ru.

[0043] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For HCs selected from the group consisting of 63 and 371-405 heavy chains (HCs), 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, few At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, few It contains HC that is at least 83% identical, at least 82% identical, or at least 80% identical. Antibodies are provided, however, the HCs are Mab223, 364, 365, 366, as shown in Table 2. It shall not be 100% identical to any of HC 367, 368, 369, or 370.

[0044] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For LCs selected from the group consisting of 63 and 371-405 light chains, 100% identical, small At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, few At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, few It contains LC that is at least 83% identical, at least 82% identical, or at least 80% identical. Antibodies are provided, however, the LCs are Mab223, 364, 365, 366, as shown in Table 2. It shall not be 100% identical to any of LC 367, 368, 369, or 370.

[0045] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH3 selected from the group consisting of 63 and CDRH3 from 371 to 405, it is 100% identical. , at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, At least 93% identical, at least 92% identical, at least 91% identical, at least At least 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at least They are 84% identical, at least 83% identical, at least 82% identical, or less CDRH3, which is at least 80% identical, is shown in Table 2 as follows: Mab 1-21, 23-222, 224-363, And for CDRH2 selected from the group consisting of 371-405 CDRH2, there are a small number that are 100% identical. At least 99% identical, at least 98% identical, at least 97% identical, at least They are at least 96% identical, at least 95% identical, at least 94% identical, at least Both are 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at 87% identical, at least 86% identical, at least 85% identical, at least 84% identical % identical, at least 83% identical, at least 82% identical, or at least CDRH2, which is 80% identical, and Mab 1-21, 23-222, 224-36, as shown in Table 2. 3, and CDRH1 selected from the group consisting of CDRH1s 371-405, are 100% identical. They are at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, at least At least 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at 84% identical, at least 83% identical, at least 82% identical, or less We provide antibodies containing CDRH1 which is 80% identical to CDRH3, CDRH2, and And each of the CHRH1s is shown in Table 2 as Mab223, 364, 365, 366, 367, 36 Not 100% identical to any of CHRH3, CDRH2, or CDRH1 of 8, 369, or 370 Let's assume that.

[0046] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL3 selected from the group consisting of 63 and CDRL3s 371-405, it is 100% identical. , at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, At least 93% identical, at least 92% identical, at least 91% identical, at least At least 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at least They are 84% identical, at least 83% identical, at least 82% identical, or less CDRL3, which is at least 80% identical, is shown in Table 2 as follows: Mabs 1-21, 23-222, 224-363, And for CDRL2 selected from the group consisting of 371-405 CDRL2, there are few that are 100% identical. At least 99% identical, at least 98% identical, at least 97% identical, at least They are at least 96% identical, at least 95% identical, at least 94% identical, at least Both are 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at 87% identical, at least 86% identical, at least 85% identical, at least 84% identical % identical, at least 83% identical, at least 82% identical, or at least CDRL2, which is 80% identical, and Mabs 1-21, 23-222, 224-36, as shown in Table 2. 3, and a CDRL1 selected from the group consisting of CDRL1s 371-405, which is 100% identical. They are at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, at least At least 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at 84% identical, at least 83% identical, at least 82% identical, or less We provide antibodies containing CDRL1 which is 80% identical to CDRL3, CDRL2, etc. And each of CHRL1 is as shown in Table 2: Mab223, 364, 365, 366, 367, 36 Not 100% identical to CHRL3, CDRL2, or CDRL1 of any of 8, 369, or 370 Let's assume that.

[0047] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH3 selected from the group consisting of 63 and CDRH3 from 371 to 405, it is 100% identical. , at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, At least 93% identical, at least 92% identical, at least 91% identical, at least At least 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at least They are 84% identical, at least 83% identical, at least 82% identical, or less CDRH3, which is at least 80% identical, is shown in Table 2 as follows: Mab 1-21, 23-222, 224-363, And for CDRH2 selected from the group consisting of 371-405 CDRH2, there are a small number that are 100% identical. At least 99% identical, at least 98% identical, at least 97% identical, at least They are at least 96% identical, at least 95% identical, at least 94% identical, at least Both are 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at 87% identical, at least 86% identical, at least 85% identical, at least 84% identical % identical, at least 83% identical, at least 82% identical, or at least CDRH2, which is 80% identical, is shown in Table 2 as follows: Mab 1-21, 23-222, 224-363, and For CDRH1 selected from the group consisting of CDRH1 371-405, at least one that is 100% identical. They are 99% identical, at least 98% identical, at least 97% identical, at least They are 96% identical, at least 95% identical, at least 94% identical, at 93% identical, at least 92% identical, at least 91% identical, at least 90% identical % identical, at least 89% identical, at least 88% identical, at least 87% They are identical, at least 86% identical, at least 85% identical, at least 84% identical It is one, at least 83% identical, at least 82% identical, or at least 80% identical. CDRH1, which is % identical, is shown in Table 2 as follows: Mabs 1-21, 23-222, 224-363, and 371 For a CDRL3 selected from the group consisting of ~405 CDRL3s, at least 99 are 100% identical. % identical, at least 98% identical, at least 97% identical, at least 96% They are identical, at least 95% identical, at least 94% identical, at least 93% identical One, at least 92% identical, at least 91% identical, at least 90% identical They are, at least 89% identical, at least 88% identical, at least 87% identical. Yes, at least 86% identical, at least 85% identical, at least 84% identical They are at least 83% identical, at least 82% identical, or at least 80% identical. CDRL3, as shown in Table 2, is represented by Mabs 1-21, 23-222, 224-363, and 371-405. For a CDRL2 selected from the group consisting of the following CDRL2s, it is 100% identical, or at least 99% identical. It is one, at least 98% identical, at least 97% identical, at least 96% identical They are, at least 95% identical, at least 94% identical, at least 93% identical. Yes, at least 92% identical, at least 91% identical, at least 90% identical They are at least 89% identical, at least 88% identical, at least 87% identical. , at least 86% identical, at least 85% identical, at least 84% identical, They are at least 83% identical, at least 82% identical, or at least 80% identical. CDRL2, as well as Mabs 1-21, 23-222, 224-363, and 371- as shown in Table 2. For a CDRL1 selected from a group consisting of 405 CDRL1s, 100% identical, or at least 99% identical. They are identical, at least 98% identical, at least 97% identical, at least 96% identical It is one, at least 95% identical, at least 94% identical, at least 93% identical They are, at least 92% identical, at least 91% identical, at least 90% identical. Yes, at least 89% identical, at least 88% identical, at least 87% identical They are at least 86% identical, at least 85% identical, at least 84% identical. , at least 83% identical, at least 82% identical, or at least 80% identical We provide antibodies containing a certain CDRL1, however, CDRH3, CDRH2, CDRH1, CDRL3, CDH Both L2 and CHRL1 are as shown in Table 2: Mab223, 364, 365, 366, 3 CDRH3, CDRH2, CDRH1, CDRL3, CDHL2, or CHRL, either 67, 368, 369, or 370. It is assumed that they are not 100% identical to 1.

[0048] In certain embodiments, the present invention relates to ADI-15512, ADI-15516, and as shown in Table 2. It contains a CD3-binding domain selected from the group consisting of the CD3-binding domains of ADI-16513 and ADI-16513. We provide antibodies.

[0049] In certain embodiments, the present invention relates to ADI-18562; ADI-18564; A, as shown in Table 2. DI-18565; ADI-18566; ADI-18567; ADI-18568; ADI-18570; ADI-18571; ADI-18572 ; ADI-18573; ADI-18563; ADI-18569; ADI-18574; ADI-18575; ADI-18576; ADI-1 8578; ADI-18579; ADI-18580; ADI-18581; ADI-18582; ADI-18584; ADI-18585; A DI-18577; ADI-18583; ADI-18588; ADI-18589; ADI-18590; ADI-18591; ADI-18593 ; ADI-18594; ADI-18595; ADI-18596; ADI-18597; ADI-18592; ADI-18587; ADI-1 8586, and an antibody comprising a CD3 binding domain selected from the group consisting of the CD3 binding domain of ADI-16606 is provided.

[0050] In certain embodiments, the present invention provides, as presented in Table 2, ADI-18576; ADI-20820; A DI-20578; ADI-20571; ADI-21097; ADI-20577; ADI-20576; ADI-20568; ADI-20582 ; ADI-20575; ADI-20567; ADI-20574; ADI-20573; ADI-20579; ADI-18565; ADI-2 0818; ADI-20587; ADI-20588; ADI-20589; ADI-20590; ADI-20594; ADI-20596; A DI-20599; ADI-20605; ADI-20607; ADI-20608, and an antibody comprising a CD3 binding domain selected from the group consisting of the CD3 binding domain of ADI-20609 is provided.

[0051] In certain embodiments, the present invention, as presented in Table 2, includes ADI-16606; ADI-20587; A DI-20607; ADI-20590; ADI-28708; ADI-28709; ADI-28710; ADI-21943; ADI-28711 ; ADI-28712; ADI-28713; ADI-28714; ADI-28715; ADI-21944; ADI-28716; ADI-2 1945; ADI-21946; ADI-28717; ADI-21947; ADI-28718; ADI-28719; ADI-28720; A DI-28721; ADI-28722; ADI-28723; ADI-28724; ADI-28725; ADI-28726; ADI-28727 ; ADI-28728; ADI-28729; ADI-28730; ADI-28731; ADI-28732; ADI-28733; ADI-2 8734; ADI-28735; ADI-28736; ADI-28737; ADI-28738; ADI-28739; ADI-28740; A DI-28741; ADI-28742; ADI-28743; ADI-21948; ADI-21949; ADI-28744; ADI-21950 ; ADI-28745; ADI-28746; ADI-28747; ADI-28748; ADI-21951; ADI-21952; ADI-2 8749; ADI-28750; ADI-28751; ADI-21953; ADI-28752; ADI-21954; ADI-28753; A DI-28754; ADI-28755; ADI-28756; ADI-28757; ADI-28758; ADI-28759; ADI-28760 ; ADI-28761; ADI-28762; ADI-28763; ADI-28764; ADI-28765; ADI-28766; ADI-2 8767; ADI-28768; ADI-21955; ADI-28769; ADI-28770; ADI-21956; ADI-28771; A From the group consisting of the CD3 binding domains of DI-28772; ADI-28773; ADI-28774; and ADI-28775 We provide antibodies containing a selected CD3-binding domain.

[0052] In certain embodiments, the present invention relates to ADI-21959; ADI-21963 as shown in Table 2. ; ADI-21965; ADI-21967; ADI-21970; ADI-21971; ADI-21972; ADI-21973; ADI-2 1974; ADI-21975; ADI-21976; ADI-21977; ADI-21978; ADI-21979; ADI-21943; A DI-21944; ADI-21945; ADI-21946; ADI-21947; ADI-21948; ADI-21949; ADI-21950 ; ADI-21951; ADI-21952; ADI-21953; ADI-21954; ADI-21955; and ADI-21956 We provide an antibody containing a CD3-binding domain selected from the group consisting of CD3-binding domains.

[0053] In certain embodiments, the present invention relates to ADI-21952; ADI-22523; A, as shown in Table 2. DI-24403; ADI-24404; ADI-24405; ADI-24407; ADI-24408; ADI-24409; ADI-24410 ; ADI-24411; ADI-24412; ADI-24413; ADI-24414; ADI-24415; ADI-24416; ADI-2 4417; ADI-24418; ADI-24434; ADI-24435; ADI-24436; ADI-24437; ADI-24438; A DI-24439; ADI-24440; ADI-24441; ADI-24442; ADI-24443; ADI-24444; ADI-24445 ; ADI-24446; ADI-24449; ADI-24388; ADI-24389; ADI-24390; ADI-24391; ADI-2 4392; ADI-24393; ADI-24394; ADI-24395; ADI-24396; ADI-24397; ADI-24398; A DI-24399; ADI-24400; ADI-24401; ADI-24402; ADI-24419; ADI-24420; ADI-24421 ; ADI-24422; ADI-24423; ADI-24424; ADI-24425; ADI-24426; ADI-24427; ADI-2 4428; ADI-24429; ADI-24430; ADI-24431; ADI-24432; ADI-24433; ADI-24447, It contains a CD3-binding domain selected from the group consisting of the CD3-binding domains of ADI-24448 and ADI-24448. We provide antibodies.

[0054] In certain embodiments, the present invention relates to ADI-22523; ADI-23652; A, as shown in Table 2. DI-23653; ADI-23654; ADI-23655; ADI-23656; ADI-23657; ADI-23658; ADI-23651 ; ADI-23644; ADI-23645; ADI-23646; ADI-23647; ADI-23648; ADI-23649; ADI-2 3650; ADI-23667; ADI-23668; ADI-23669; ADI-23670; ADI-23671; ADI-23672; A DI-23673; ADI-23659; ADI-23660; ADI-23661; ADI-23663; ADI-23664; ADI-23639 ; ADI-23641; ADI-23642; ADI-23640; ADI-23643; ADI-21952; ADI-23633; ADI-2 3634; ADI-23635; ADI-23636; ADI-23637; ADI-23638; ADI-23632, and ADI-2362 We provide an antibody containing a CD3-binding domain selected from a group consisting of 9 CD3-binding domains. ru.

[0055] In certain embodiments, the present invention relates to ADI-22523; ADI-26906; A, as shown in Table 2. DI-26907; ADI-26908; ADI-26909; ADI-26910; ADI-26912; ADI-26913; ADI-26915 ; ADI-26916; ADI-26917; ADI-26918; ADI-26919; ADI-26920; ADI-26921; ADI-2 6924; ADI-26925; ADI-26927; ADI-26928; ADI-26929; ADI-26930; ADI-26932; A DI-26933; ADI-26938; ADI-26939; ADI-26940; ADI-26941; ADI-26942; ADI-26943 ; ADI-26944; ADI-26945; ADI-26950; ADI-26954; ADI-23672; ADI-23673; ADI-2 3664; ADI-26955; ADI-26956; ADI-26957; ADI-26958; ADI-26959; ADI-26960; A DI-26962; ADI-26963; ADI-26964; ADI-26965; ADI-26966; ADI-26968; ADI-26969 ; ADI-26971; ADI-26972; ADI-26973; ADI-26974; ADI-26975; ADI-26976; ADI-2 6977; ADI-26978; ADI-26979; ADI-26980; ADI-26981; ADI-26982; ADI-26983; A DI-26984; ADI-26985; ADI-26986; ADI-26987; ADI-26988; ADI-26989; ADI-26990 ; ADI-26991; ADI-26992; ADI-26993; ADI-26994, and the CD3 binding domain of ADI-26995 To provide an antibody containing a CD3 binding domain selected from the group consisting of domains.

[0056] In certain embodiments, the invention is as presented in Table 2, of ADI-22523; ADI-26906 ; ADI-26907; ADI-26908; ADI-26910; ADI-26913; ADI-26915; ADI-26919; ADI-2 6920; ADI-26921; ADI-26943; ADI-26954; ADI-21952; ADI-26955; ADI-26956; A DI-26962; ADI-26978; ADI-26983, and the CD3 binding domains of ADI-26994 from the group consisting of We provide antibodies containing a selected CD3-binding domain.

[0057] In certain embodiments, the present invention includes a CD3-binding domain selected from the group consisting of the following: The antibodies provided are: ADI-15512, ADI-16513, ADI-15516, ADI-18565, ADI-18589, ADI -18585, ADI-18590, ADI-18576, ADI-20568, ADI-20580, ADI-21978, ADI-22523, ADI-25 133, and ADI-26906.

[0058] In certain embodiments, the present invention includes a CD3-binding domain selected from the group consisting of the following: The antibodies provided are: ADI-16606, ADI-29601, ADI-29602, ADI-29603, ADI-20587, ADI -20607, ADI-20590, ADI-21952, ADI-23633, ADI-26955, ADI-26956, ADI-26957, ADI-26 958, ADI-26959, ADI-26960, ADI-26961, ADI-26962, ADI-26963, ADI-26964, ADI-26965 , ADI-26966, ADI-26967, ADI-26968, ADI-26969, ADI-26970, ADI-26971, ADI-26972, A DI-26973, ADI-26974, ADI-26975, ADI-26976, ADI-26977, ADI-26978, ADI-26979, ADI- 26980, ADI-26981, ADI-26982, ADI-26983, ADI-26984, ADI-26985, ADI-26986, ADI-269 87, ADI-26988, ADI-26989, ADI-26990, ADI-26991, ADI-26992, ADI-26993, and ADI- 26994.

[0059] In any particular embodiment, either alone or in combination with other embodiments of the present invention, The CD3-binding domain of the invention and the antibody containing it are shown in Table 2, and are trastuzma Herceptin (registered trademark), lintuzumab, blinatumomab (Blincyto (registered trademark)), Also known as Mab 364, Mab 366, Mab 367, Mab 368, Mab 369, Mab 370 or Mab 22 It exhibits a reduced tendency to decompose compared to one or more of the other.

[0060] In any particular embodiment, either alone or in combination with other embodiments of the present invention, The CD3-binding domain of the invention and the antibody containing it are shown in Table 2, and are trastuzma Herceptin (registered trademark), lintuzumab, blinatumomab (Blincyto (registered trademark)), Also known as Mab 364, Mab 366, Mab 367, Mab 368, Mab 369, Mab 370 or Mab 22 It exhibits a reduced CRS risk profile compared to one or more of the other conditions.

[0061] In any particular embodiment, either alone or in combination with other embodiments of the present invention, the table As presented in section 2, trastuzumab (Herceptin®), lintuzumab, blina Momab (Blincyto®), and Mab 364, Mab 366, Mab 367, Mab 368, Mab It exhibits a reduced resolution tendency compared to one or more of the following: 369, Mab 370, or Mab 22. A CD3-binding domain and an antibody containing the same are provided.

[0062] A particular embodiment, and / or any of the embodiments disclosed throughout this Spec. In combination with the above, a CD3-binding domain and a humanized antibody containing it are provided. In certain embodiments, such CD3-binding domains include the CDR of such other embodiments. And furthermore, accept human frameworks, such as human immunoglobulin frameworks. Includes a work or human consensus framework.

[0063] A particular embodiment, and / or any of the embodiments disclosed throughout this Spec. In combination with the CD3 binding domain, and throughout this specification VH in any of the embodiments presented, and the embodiments presented throughout this specification An antibody containing a VL in either state is provided, in this case the variable domain sequence One or both of these include translation modification.

[0064] In a further embodiment of the present invention, the CD3 binding domain and the entire Spec. The same epitope as the CD3-binding domain provided in other embodiments disclosed therethrough A binding antibody is provided.

[0065] In certain embodiments, the antibody containing the CD3-binding domain and / or thereof is ≤1 μM. ≤100nM, ≤10nM, ≤1nM, ≤0.1nM, ≤0.01nM, or ≤0.001nM (e.g., 10 -8 M or below, for example ba10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 It has the CD3 dissociation constant (Kd) of M).

[0066] In a further aspect of the present invention, a CD3-binding domain and an antibody comprising the same are multispecific antibodies. The body includes. In a further aspect of the present invention, the CD3-binding domain and the antibody containing the same are two-part specially selected. Contains heterozygous antibodies.

[0067] In a further aspect of the present invention, the CD3-binding domain and the antibody comprising it are used to target oncological targets. immuno-oncological targets, neurodegenerative disease targets, autoimmune disease targets, infectious disease targets, metabolic Few molecules specifically bind to disease targets, cognitive impairment targets, blood-brain barrier targets, or blood disorder targets. It also contains a second antigen-binding domain.

[0068] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are, for example, type 2. This includes multispecific antibodies such as heterozygous antibodies, and in this case, the multispecific antibodies are as follows: It contains a second binding domain that has specificity for a second antigen selected from the following group: 0772P (CA125, MUC16; Genbank accession number AF36148); adipophilin (perilip in-2, Adipose differentiation-related protein, ADRP, ADFP, MGC10598; NCBI reference Reference array: NP-001113.2); AIM-2 (Absent In Melanoma 2, PYHIN4, Interferon-Indu Cible Protein AIM2; NCBI reference sequence: NP-004824.1); ALDH1 A1 (Aldehyde Deh hydrogenase 1 Family, Member A1, ALDH1, PUMB1, Retinaldehyde Dehydrogenase 1, ALDC, ALDH-E1, ALHDII, RALDH 1, EC 1.2.1.36, ALDH11, HEL-9, HEL-S-53e, HEL1 2, RALDH1, Acetaldehyde Dehydrogenase 1, Aldehyde Dehydrogenase 1, Soluble , Aldehyde Dehydrogenase, liver cytosolic, ALDH Class 1, Epididymis Lumina l Protein 12, Epididymis Luminal Protein 9, Epididymis Secretory Sperm B inding Protein Li 53e, Retinal Dehydrogenase 1, RaIDH1, Aldehyde Dehydroge nase Family 1 Member A1, Aldehyde Dehydrogenase, Cytosolic, EC 1.2.1; NC BI reference sequence: NP - 000680.2); alpha - actinin - 4 (ACTN4, Actinin, Alpha 4, FSGS1 , Focal Segmental Glomerulosclerosis 1, Non - Muscle Alpha - Actinin 4, F - Actin Cross - Linking Protein, FSGS, ACTININ - 4, Actinin Alpha4 Isoform, alpha - actin in - 4; NCBI reference sequence: NP - 004915.2); alpha - fetoprotein (AFP, HPAFP, FETA, alp ha - 1 - fetoprotein, alpha - fetoglobulin, Alpha - 1 - fetoprotein, Alpha - fetoglobulin, H P; GenBank: AAB58754.1); Amphiregulin (AREG, SDGF, Schwannoma - Derived Growt h Factor, Colorectum Cell - Derived Growth Factor, AR, CRDGF; GenBank: AAA51 781.1); ARTC1 (ART1、ADP-Ribosyltransferase 1、Mono(ADP-Ribosyl)Transferase 1、ADP-Ribosyltransferase C2 And C3 Toxin-Like 1、ART2、CD296、RT6、ADP-Rib osyltransferase 2、GPI-Linked NAD(P)(+)-Arginine ADP-Ribosyltransferase 1、E C 2.4.2.31、CD296 Antigen; NP); ASLG659; ASPHD1 (Aspartate Beta-Hydroxyla se Domain Containing 1、Aspartate Beta-Hydroxylase Domain-Containing Prote in 1、EC 1.14.11.、GenBank: AAI44153.1); B7-H4 (VTCN1、V-Set Domain Conta ining T Cell Activation Inhibitor 1、B7H4、B7 Superfamily Member 1、Immu ne Costimulatory Protein B7-H4、B7h.5、T-Cell Costimulatory Molecule B7x、 B7S1、B7X、VCTN1、H4, B7 Family Member、PRO1291、B7 Family Member, H4、T Cell Costimulatory Molecule B7x、V-Set Domain-Containing T-Cell Activation Inhibitor 1、Protein B7S1; GenBank: AAZ17406.1); BAFF-R (TNFRSF13C、Tumo r坏死因子受体超家族,成员13C、BAFFR、B细胞激活 因子受体、BAFF受体、BLyS受体3、CVID4、BROMIX、CD268、B 细胞激活因子受体、prolixin、肿瘤坏死因子受体 超家族成员13C、BR3、CD268抗原;NCBI参考序列:NP - 443177.1); BAGE - 1; BCLX (L); BCR - ABL融合蛋白(b3a2); β - 连环蛋白(CTNNB1、Ca 连环蛋白(钙黏蛋白相关蛋白)、β1、88 kDa、CTNNB、MRD19、连环蛋白 (钙黏蛋白相关蛋白)、β1(88kD)、犰狳蛋白、连环蛋白β - 1; Ge nBank: CAA61107.1); BING - 4 (WDR46、WD重复结构域46、C6orf11、BING4、WD 重复含蛋白BING4、6号染色体开放阅读框11、FP 221、UTP7、WD重复含蛋白46; NP); BMPR1 B(骨形态发生 蛋白受体IB型、Genbank登录号NM - 00120; NP); B - RA F(短蛋白聚糖(BCAN、BEHAB、Genbank登录号AF22905); 短蛋白聚糖(BCAN , Chondroitin Sulfate Proteoglycan 7, Brain-Enriched Hyaluronan-Binding Pro tein, BEHAB, CSPG7, Brevican Proteoglycan, Brevican Core Protein, Chondroitin Sulfate Proteoglycan BEHAB; GenBank: AAH27971.1); CALCA (Calcitonin-Rela ted Polypeptide Alpha, CALC1, Calcitonin 1, calcitonin, Alpha-Type CGRP, Ca lcitonin Gene-Related Peptide I, CGRP-I, CGRP, CGRP1, CT, KC, Calcitonin / Calc itonin-Related Polypeptide, Alpha, katacalcin; NP); CASP-5 (CASP5, Caspase 5, Apoptosis-Related Cysteine Peptidase, Caspase 5, Apoptosis-Related Cyst eine Protease, Protease ICH-3, Protease TY, ICE(rel)-111, ICE(rel)III, ICEREL -III, ICH-3, caspase-5, TY Protease, EC 3.4.22.58, ICH3, EC 3.4.22; NP); CA SP-8; CD19 (CD19-B-lymphocyte antigen CD19 isoform 2 precursor, B4, CVID3 [Homo sapiens], NCBI reference sequence: NP-001761.3); CD20 (CD20-B-lymphocyte ant igen CD20, membrane-spanning 4-domains, subfamily A, member 1, B1, Bp35, C D20, CVID5, LEU-16, MS4A2, S7; NCBI reference sequence: NP-690605.1); CD21 (CD21 (CR 2 (Complement receptor or C3DR (C3d / Epstein-Barr virus receptor) or Hs .73792 Genbank accession number M2600); (CD22 (B-cell receptor CD22-B isof orm, BL-CAM, Lyb-8, LybB, SIGLEC-2, FLJ22814, Genbank accession number AK02646); CD22; CD33 (CD33 molecule, CD33antigen(Gp67), Sialic Acid Binding Ig-Lik e Lectin 3, Sialic Acid-Binding Ig-Like Lectin 3, SIGLEC3, gp67, SIGLEC-3 , Myeloid Cell Surface Antigen CD33, p67, Siglec-3, CD33 antigen; GenBank: AAH28152.1); CD45; CD70 (CD70-tumor necrosis factor (ligand) superfamil y, member 7; surface antigen CD70; Ki-24 antigen; CD27 ligand; CD27-L; tumor necrosis factor ligand superfamily member 7; against Homo sapiens species NCBI reference sequence: NP-001243.1); CD72 (CD72 (B-cell differentiation antig en CD72, Lyb-; 359 aa, μl: 8.66, MW: 40225, TM: 1 [P] gene chromosome: 9p 13.3, Genbank accession number NP-001773.); CD79a (CD79a (CD79A, CD79a, immune Ig globulin-associated alpha covalently interacts with Ig beta (CD79B) to form IgM molecules. Together, they form a complex on the surface and transmit B cell-specific signals involved in B cell differentiation. Protein), μl: 4.84, MW: 25028 TM: 2 [P] Gene chromosome: 19q13.2, Genban k Accession number NP-001774.1); CD79b (CD79b (CD79B, CD79b, IGb (immunoglob (ulin-associated beta), B29, Genbank accession number NM-000626 or 1103867); Cdc27 (Cell Division Cycle 27, D0S1430E, D17S978E, Anaphase Promoting Comp lex Subunit 3, Anaphase-Promoting Complex Subunit 3, ANAPC3, APC3, CDC27Hs , H-NUC, CDC27 Homolog, Cell Division Cycle 27 Homolog (S.Cerevisiae), HNU C, NUC2, Anaphase-Promoting Complex, Protein 3, Cell Division Cycle 27 Ho molog, Cell Division Cycle Protein 27 Homolog, Nuc2 Homolog; GenBank: AA H11656.1); CDK4 (Cyclin-Dependent Kinase 4, Cell Division Protein Kinase 4, PSK-J3, EC 2.7.11.22, CMM3, EC 2.7.11; NCBI reference sequence: NP-000066.1); C DKN2A (Cyclin-Dependent Kinase Inhibitor 2A, MLM, CDKN2, MTS1, Cyclin-Dependent ent Kinase Inhibitor 2A (Melanoma, P16, Inhibits CDK4), Cyclin-Dependent Kinase 4 Inhibitor A, Multiple Tumor Suppressor 1, CDK4I, MTS-1, CMM2, P 16, ARF, INK4, INK4A, P14, P14ARF, P16-INK4A, P16INK4, P16INK4A, P19, P19ARF, TP 16, CDK4 inhibitor P16-INK4, Cell Cycle Negative Regulator Beta, p14ARF, p 16-INK4, p16-INK4a, p16INK4A, p19ARF; NP); CEA; CLL1 (CLL-1 (CLEC12A, MICL , and DCAL, many C-type lectin / C-type lectin-like domain (CTL / CTLD) superfamilies —. Members of this family share a common protein folding, and are attached, fine It plays a role in cell-cell signaling, glycoprotein turnover, and inflammatory and immune responses. It has diverse functions such as cleavage. The protein encoded by this gene is involved in granulocytes and monocytes. It is a negative regulator of function. Alternative splice transcription variants of this gene are also Several have been reported, but the properties of some of these variants in terms of length are not yet known. No. This gene is located in the natural killer gene complex region on chromosome 12p13 and contains other CTLs / CTLs. Closely related to the D superfamily (Drickamer, K Curr. Opin. Struct. Bio). l. 9:585-90

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[2006] ; Bakker AB, et al Cancer Res. 64:8443-50

[2004] ; Marshall AS, et al J. Biol. Chem. 279:14792-80, 2004. CLL-1 is , a single C-type lectin-like domain (predicted to bind to either calcium or sugar) Short strands containing an axial (stalk) region, a transmembrane domain, and an ITIM motif. It has been shown to be a type II transmembrane receptor including a sporangiocarpoid tail; CLPP (Caseinolytic) Mitochondrial Matrix Peptidase Proteolytic Subunit, Endopeptidase Clp, EC 3.4.21.92, PRLTS3, ATP-Dependent Protease ClpAP (E.coli), ClpP (Caseinolyti c Protease, ATP-Dependent, Proteolytic Subunit, E.coli)Homolog, ClpP Casei nolytic Peptidase, ATP-Dependent, Proteolytic Subunit Homolog(E.coli), ClpP Caseinolytic Protease, ATP-Dependent, Proteolytic Subunit Homolog(E.coli) , human, Proteolytic Subunit, ATP-Dependent Protease ClpAP, Proteolytic Subunit, Human, ClpP Caseinolytic Peptidase ATP-Dependent, Proteolytic Su bunit, ClpP Caseinolytic Peptidase, ATP-Dependent, Proteolytic Subunit Hom olog, ClpP Caseinolytic Protease, ATP-Dependent, Proteolytic Subunit Homol og, Putative ATP-Dependent Clp Protease Proteolytic Subunit, Mitochondrial ; NP); COA-1; CPSF; CRIPTO (CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratoca rcinoma-derived growth factor, Genbank accession number NP-003203 or NM-0032 1); Cw6; CXCR5 CXCR5 (Burkitt's lymphoma receptor 1, G protein-coupled receptor It is a chemokine that is activated by CXCL13 and functions in lymphocyte migration and humoral defense. And, regarding HIV-2 infection and possibly the development of AIDS, lymphoma, myeloma, and leukemia (Participates); 372 aa, μl: 8.54 MW: 41959 TM: 7 [P] Gene chromosome: 11q23.3, Genbank accession number NP-001707.); CXORF61 CXORF61-chromosome X open rea ding frame 61[Homo sapiens], NCBI reference sequence: NP-001017978.1); cyclin D1 ( CCND1, BCL1, PRAD1, D11S287E, B-Cell CLL / Lymphoma 1, B-Cell Lymphoma 1 Prot ein, BCL-1 Oncogene, PRAD1 Oncogene, Cyclin D1 (PRAD1: Parathyroid Adenoma tosis 1), G1 / S-Specific Cyclin D1, Parathyroid Adenomatosis 1, U21B31, G1 / S -Specific Cyclin-D1, BCL-1; NCBI reference sequence: NP-444284.1); Cyclin-A1 (CCNA1 , CT146, Cyclin A1; GenBank: AAH36346.1); dek-can fusion protein; DKK1 ( Dickkopf WNT Signaling Pathway Inhibitor 1, SK, hDkk-1, Dickkopf (Xenopus Laevis) Homolog 1, Dickkopf 1 Homolog (Xenopus Laevis), DKK-1, Dickkopf 1 Homolog, Dickkopf Related Protein-1, Dickkopf-1 Like, Dickkopf-Like Pro tein 1, Dickkopf-Rel ated Protein 1, Dickkopf-1, Dkk-1; GenBank: AAQ89364.1); DR1 (Down-Regulat or Of Transcription 1, TBP-Binding (Negative Cofactor 2), Negative Cofact or 2-Beta, TATA-Binding Protein-Associated Phosphoprotein, NC2, NC2-BETA, Pro tein Dr1, NC2-beta, Down-Regulator Of Transcription 1; NCBI Reference Sequence: NP- 001929.1); DR13 (Major Histocompatibility Complex, Class II, DR Beta 1, HLA-DR1B, DRw10, DW2.2 / DR2.2, SS1, DRB1, HLA-DRB, HLA Class II Histocompatibi lity Antigen, DR-1 Beta Chain, Human Leucocyte Antigen DRB1, Lymphocyte A ntigen DRB1, MHC Class II Antigen, MHC Class II HLA-DR Beta 1 Chain, M HC Class II HLA-DR-Beta Cell Surface Glycoprotein, MHC Class II HLA-DRw 10-Beta, DR-1, DR-12, DR-13, DR-14, DR-16, DR-4, DR-5, DR-7, DR-8, DR-9, DR1, DR 12, DR13, DR14, DR16, DR4, DR5, DR7, DRB, DR9, DRw11, DRw8, HLA-DRB2, Clone P2- Beta-3, MHC Class II Antigen DRB1*1, MHC Class II Antigen DRB1*10, MHC Class II Antigen DRB1*11, MHC Class II Antigen DRB1*12, MHC Class II A ntigen DRB1*13, MHC Class II Antigen DRB1*14, MHC Class II Antigen DRB1 *15, MHC Class II Antigen DRB1*16, MHC Class II Antigen DRB1*3, MHC Cla ss II Antigen DRB1*4、MHC Class II Antigen DRB1*7、MHC Class II Antige n DRB1*8、MHC Class II Antigen DRB1*9; NP); E16 (E16 (LAT1、SLC7A5、Gen banking corporate license plate NM-00348); EDAR (EDAR- tumor necrosis factor receptor r superfamily member EDAR precursor、EDA-A1 receptor; downless homolog; ectodysplasin-A receptor; ectodermal dysplasia receptor; anhydrotic ectody splasin receptor 1、DL; ECTD10A; ECTD10B; ED1R; ED3; ED5; EDA-A1R; EDA1 R; EDA3; HRM1 [Homo sapiens]; NCBI Publication Number: NP-071731.1); EFTUD2 (Elon gation Factor Tu GTP Binding Domain Containing 2、Elongation Factor Tu GTP-Binding Domain-Containing Protein 2, hSNU114, SNU114 Homologue, U5 SnRN P-Specific Protein、116 KDa、MFDGA、KIAA0031、116 KD、U5 SnRNP Specific Pr otein、116 KDa U5 Small Nuclear Ribonucleoprotein Component、MFDM、SNRNP11 6, Snrp116, Snu114, U5-116KD, SNRP116, U5-116 KDa; GenBank: AAH02360.1); EGF R (Epidermal Growth Factor Receptor、ERBB、Proto-Oncogene C-ErbB-1、Recept r Tyrosine-Protein Kinase ErbB-1, ERBB1, HER1, EC 2.7.10.1, Epidermal Growt h Receptor Factor (Avian Erythroblastic Leukemia Viral (V-Erb-B) Oncogene and Homolog)、Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog (Avi an)、PlG61、Avian Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog 、Cell Growth Inhibiting Protein 40、Cell Proliferation-Inducing Protein 61、mENA、EC 2.7.10; GenBank: AAH94761.1); EGFR-G719A; EGFR-G719C; EGFR-G7 19S; EGFR-L858R; EGFR-L861Q; EGFR-57681; EGFR-T790M; Elongation factor 2 (EEF2、Eukaryotic Translation Elongation Factor 2、EF2、Polypeptidyl-TRNA Translocase、EF-2、SCA26、EEF-2; NCBI Publication Number: NP-001952.1); ENAH (hMena ) (Enabled Homolog (Drosophila)、MENA、Mammalian Enabled、ENA、NDPP1、Protein n Enabled Homolog; GenBank: AAH95481.1)-“ENAH” and “ENAH (hMena)”. ない; EpCAM (Epithelial Cell Adhesion Molecule、M4S1、MIC18、Tumor-Associat ed Calcium Signal Transducer 1、TACSTD1、TROP1、Adenocarcinoma-Associated A ntigen、Cell Surface Glycoprotein Trop-1、Epithelial Glycoprotein 314、Majo r Gastrointestinal Tumor-Associated Protein GA733-2、EGP314、KSA、DIAR5、HNP CC8、Antigen Identified By Monoclonal Antibody AUA1、EGP-2、EGP40、ESA、KS1 / 4、MK-1、Human Epithelial Glycoprotein-2, Membrane Component, Chromosome 4, Surface Marker (35kD Glycoprotein)、EGP、Ep-CAM、GA733-2、M1S2、CD326 An tigen、Epithelial Cell Surface Antigen、hEGP314、KS 1 / 4 Antigen、ACSTD1; G enBank: AAH14785.1); EphA3 (EPH Receptor A3、ETK1、ETK、TYRO4、HEK、Eph-Lik e Tyrosine Kinase 1、Tyrosine-Protein Kinase Receptor ETK1、EK4、EPH-Like Kinase 4、EC 2.7.10.1、EPHA3、HEK4、Ephrin Type-A Receptor 3、Human Embr yo Kinase 1、TYRO4 Protein Tyrosine Kinase、hEK4、Human Embryo Kinase、Ty rosine-Protein Kinase TYRO4, EC 2.7.10; GenBank: AAH63282.1); EphB2R; Epi regulin (EREG, ER, proepiregulin; GenBank: AAI36405.1); ETBR (EDNRB, Endoth elin Receptor Type B, HSCR2, HSCR, Endothelin Receptor Non-Selective Type 、ET-B, ET-BR, ETRB, ABCDS, WS4A, ETB, Endothelin B Receptor; NP); ETV6-AML1 fusion protein; EZH2 (Enhancer Of Zeste Homolog 2 (Drosophila), Lysine N -Methyltransferase 6, ENX-1, KMT6 EC 2.1.1.43, EZH1, WVS, Enhancer Of Zeste (Drosophila) Homolog 2, ENX1, EZH2b, KMT6A, WVS2, Histone-Lysine N-Methyltr ansferase EZH2, Enhancer Of Zeste Homolog 2, EC 2.1.1; GenBank: AAH10858 .1); FcRH1 (FCRL1, Fc Receptor-Like 1, FCRH1, Fc Receptor Homolog 1, FCR- Like Protein 1, Immune Receptor Translocation-Associated Protein 5, IFGP1 、IRTA5, hIFGP1, IFGP Family Protein 1, CD307a, Fc Receptor-Like Protein 1 、Immunoglobulin Superfamily Fc Receptor, Gp42, FcRL1, CD307a Antigen; GenB ank: AAH33690.1); FcRH2 (FCRL2、Fc Receptor-Like 2、SPAP1、SH2 Domain-Cont aining Phosphatase Anchor Protein 1、Fc Receptor Homolog 2、FcR-Like Pro tein 2、Immunoglobulin Receptor Translocation-Associated Protein 4、FCRH2、 IFGP4、IRTA4、IFGP Family Protein 4、SPAP1A、SPAP1 B、SPAP1C、CD307b、Fc Re ceptor-Like Protein 2、Immune Receptor Translocation-Associated Protein 4 、Immunoglobulin Superfamily Fc Receptor、Gp42、SH2 Domain Containing Phos phatase Anchor Protein 1、FcRL2、CD307b Antigen; GenBank: AAQ88497.1); Fc RH5 (FCRL5、Fc Receptor-Like 5、IRTA2、Fc Receptor Homolog 5、FcR-Like Pr otein 5、Immune Receptor Translocation-Associated Protein 2、BXMAS1、FCRH5 、CD307、CD307e、PRO820、Fc Receptor-Like Protein 5、Immunoglobulin Superfam ily Receptor Translocation Associated 2 (IRTA2)、FCRL5、CD307e Antigen; G enBank: AAI01070.1); FLT3-ITD; FN1(Fibronectin 1、Cold-Insoluble Globulin、 FN, Migration-Stimulating Factor, CIG, FNZ, GFND2, LETS, ED-B, FINC, GFND, MSF 、fibronectin; GenBank: AAI43764.1); G250 (MN, CAIX, Carbonic Anhydrase IX 、Carbonic Dehydratase、RCC-Associated Protein G250、Carbonate Dehydratase IX、Membrane Antigen MN、Renal Cell Carcinoma-Associated Antigen G250、CA- IX, P54 / 58N, pMW1, RCC-Associated Antigen G250, Carbonic Anhydrase 9; NP);- “G250” means “G250 / MN / CAIX”; GAGE-1,2,8; GAGE-3,4,5,6,7; GDNF-Ra1 (GDNF family receptor alpha 1; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1 L; GDNFR-alpha1; GFR-ALPHA-; U95847; BC014962 ; NM-145793 N.S M-005264); GEDA (Genbank database AY26076); GFRA1-GDNF family resp tor alpha-1; GDNF receptor alpha-1; GDNFR-alpha-1; GFR-alpha-1; RET league nd 1; TGF-beta-related neurotrophic factor receptor 1 [Homo sapiens]; P.S rotKB / Swiss-Prot: P56159.2; glypican-3 (GPC3, Glypican 3, SDYS, Glypican Pr oteoglycan 3、Intestinal Protein OCI-5、GTR2-2、MXR7、SGBS1、DGSX、OCI-5. SG B、SGBS、Heparan Sulphate Proteoglycan、Secreted Glypican-3、OCI5; GenBank: AAH35972.1); GnTVf; gp100 (PMEL、Premelanosome Protein、SILV、D12S53E、PME L17、SIL、Melanocyte Protein Pmel 17、Melanocytes Lineage-Specific Antigen GP100、Melanoma-Associated ME20 Antigen、Silver Locus Protein Homolog、ME 20-M、ME20M、P1、P100、Silver (Mouse Homolog) Like、Silver Homolog (マウス) 、ME20、SI、Melanocyte Protein Mel 17、Melanocyte Protein PMEL、Melanosomal Matrix Protein17, Silver, Mouse, Homolog Of; GenBank: AAC60634.1); GPC ; GPNMB (Glycoprotein (Transmembrane) Nmb、Glycoprotein NMB、Glycoprotein Nmb-Like Protein、osteoactivin、Transmembrane Glycoprotein HGFIN、HGFIN、NMB 、Transmembrane Glycoprotein、Transmembrane Glycoprotein NMB; GenBank: AAH3 2783.1); GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D15 Ertd747e); NP-078807.1; NM-024531.3); GPR19 (G protein-coupled receptor 1 9; Mm.478; NP-006134.1; NM-006143.2); GPR54 (KISS1 receptor; KISS1R; GPR 54; HOT7T175; AXOR1; NP-115940.2; NM-032551.4); HAVCR1 (Hepatitis A Viru s Cellular Receptor 1、T-Cell Immunoglobulin Mucin Family Member 1、Kidn ey Injury Molecule 1、KIM-1、KIM1、TIM、TIM-1、TIM1、TIMD-1、TIMD1、T-Cell I mmunoglobulin Mucin Receptor 1、T-Cell Membrane Protein 1、HAVCR、HAVCR-1 、T Cell Immunoglobin Domain And Mucin Domain Protein 1、HAVcr-1、T-Cell Immunoglobulin And Mucin Domain-Containing Protein 1; GenBank: AAH13325 .1); HER2 (ERBB2、V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2、NGL、NEU、Neuro / Glioblastoma Derived Oncogene Homolog、Metastatic Lymph Node Gene 19 Protein、Proto-Oncogene C-ErbB-2、Proto-Oncogene Neu 、Tyrosine Kinase-Type Cell Surface Receptor HER2、MLN 19、p185erbB2、EC 2.7.10.1, V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (Neuro / Glioblastoma Derived Oncogene Homolog), CD340, HER-2, HER-2 / neu, TKR 1, C-Erb B2 / Neu Protein, herstatin, Neuroblastoma / Glioblastoma Derived Oncog ene Homolog, Receptor Tyrosine-Protein Kinase ErbB-2, V-Erb-B2 Erythroblast ic Leukemia Viral Oncogene Homolog 2, Neuro / Glioblastoma Derived Oncogene Homolog, MLN19, CD340 Antigen, EC 2.7.10; NP); HER-2 / neu-the aforementioned alias; HERV -K-MEL; HLA-DOB (MHC cells that bind to peptides and present those peptides to CD4+ T lymphocytes) Las II molecule beta subunit (La antigen); 273 aa, μl: 6.56, MW: 30820.TM: 1 [P] Gene chromosome: 6p21.3, Genbank accession number NP-002111); hsp70-2 (HSPA2, Heat Shock 70kDa Protein 2, Heat Shock 70kD Protein 2, HSP70-3 , Heat Shock-Related 70 KDa Protein 2, Heat Shock 70 KDa Protein 2; enBank: AAD21815.1); IDO1 (Indoleamine 2,3-Dioxygenase 1, IDO, INDO, Indole amine-Pyrrole 2,3-Dioxygenase, IDO-1, Indoleamine-Pyrrole 2,3 Dioxygenase, In dolamine 2,3 Dioxygenase, Indole 2,3 Dioxygenase, EC 1.13.11.52; NCBI Ref erence sequence: NP-002155.1); IGF2B3; IL13Ralpha2 (IL13RA2, Interleukin 13 Recepto r, Alpha 2, Cancer / Testis Antigen 19, Interleukin-13-Binding Protein, IL-13R -alpha-2, IL-13RA2, IL-13 Receptor Subunit Alpha-2, IL-13R Subunit Alpha-2 、CD213A2, CT19, IL- 13R, IL13BP, Interleukin 13 Binding Protein, Interleukin 13 Receptor Alpha 2 Chain, Interleukin-13 Receptor Subunit Alpha-2, IL13R, CD213a2 Antigen; NP); IL20Rα; Intestinal carboxyl esterase; IRTA2 (alias of FcRH5); K allikrein 4 (KLK4, Kallikrein-Related Peptidase 4, PRSS17, EMSP1, Enamel Ma trix Serine Proteinase 1, Kallikrein-Like Protein 1, Serine Protease 17, KLK-L1, PSTS, AI2A1, Kallikrein 4 (Prostase, Enamel Matrix, Prostate), ARM1, EMSP, Androgen-Regulated Message 1, Enamel Matrix Serine Protease 1, kalli krein, kallikrein-4, prostase, EC 3.4.21.-, Prostase, EC 3.4.21; GenBank: AA X30051.1); KIF20A (Kinesin Family Member 20A, RAB6KIFL, RAB6 Interacting, Kinesin-Like (Rabkinesin6), Mitotic a; LAGE-1; LDLR-fucosyltransferase AS fusion protein; Lens Protein With Glutamine Synth etase Domain, GLULD1, Glutamate-Ammonia Ligase Domain-Containing Protein 1 , LGS, Glutamate-Ammonia Ligase (Glutamine Synthetase) Domain Containing 1 , Glutamate-Ammonia Ligase (Glutamine Synthase) Domain Containing 1, Lens Glutamine Synthase-Like; GenBank: AAF61255.1); LGR5 (leucine-rich repeat -containing G protein-coupled receptor 5; GPR49, GPR6; NP-003658.1; NM-00 3667.2; LY64 (Lymphocyte antigen 64 (RP10, leucine-rich repeat (LRR) ph It is a type I membrane protein of the family and regulates B cell activation and apoptosis. Its function The disappearance of [the substance] has been associated with increased disease activity in patients with systemic lupus erythematosus; 66 1 aa, μl: 6.20, MW: 74147 TM: 1 [P] Gene chromosome: 5q12, Genbank access Item number NP-005573; Ly6E (lymphocyte antigen 6 complex, locus E; Ly67, RIG-E,SCA-2, TSA-; NP-002337.1; NM-002346.2); Ly6G6D (lymphocyte antigen 6 complex, locus G6D; Ly6-D, MEGT; NP-067079.2; NM-021246.2); LY6K (lymph cell antigen 6 complex, locus K; LY6K; HSJ001348; FLJ3522; NP-059997.3 ; NM-017527.3); LyPD1-LY6 / PLAUR domain containing 1, PHTS [Homo sapiens] , GenBank: AAH17318.1); MAGE-A1 (Melanoma Antigen Family A, 1 (Directs E xpression Of Antigen MZ2-E, MAGE1, Melanoma Antigen Family A 1, MAGEA1, M elanoma Antigen MAGE-1, Melanoma-Associated Antigen 1, Melanoma-Associated Antigen MZ2-E, Antigen MZ2-E, Cancer / Testis Antigen 1.1, CT1.1, MAGE-1 Anti gen, Cancer / Testis Antigen Family 1, Member 1, Cancer / Testis Antigen Fami ly 1, Member 1、MAGE1A; NCBI reference sequence: NP-004979.3); MAGE-A10 (MAGEA10、 Melanoma Antigen Family A, 10、MAGE10、MAGE-10 Antigen、Melanoma-Associated Antigen 10、Cancer / Testis Antigen 1.10、CT1.10、Cancer / Testis Antigen Fam ily 1, Member 10、Cancer / Testis Antigen Family 1, Member 10; NCBI reference sequence: NP-001238757.1); MAGE-A12 (MAGEA12、Melanoma Antigen Family A, 12、 MAGE12、Cancer / Testis Antigen 1.12、CT1.12、MAGE12F Antigen、Cancer / Testis A ntigen Family 1, Member 12、Cancer / Testis Antigen Family 1, Member 12、 Melanoma-Associated Antigen 12、MAGE-12 Antigen; NCBI reference sequence: NP-0011598 59.1); MAGE-A2 (MAGEA2、Melanoma Antigen Family A, 2、MAGE2、Cancer / Testis Antigen 1.2、CT1.2、MAGEA2A、MAGE-2 Antigen、Cancer / Testis Antigen Family 1, Member 2、Cancer / Testis Antigen Family 1, Member 2、Melanoma Antige n 2、Melanoma-Associated Antigen 2; NCBI reference sequence: NP-001269434.1); MAGE- A3 (MAGEA3, Melanoma Antigen Family A, 3, MAGE3, MAGE-3 Antigen, Antigen MZ2-D, Melanoma-Associated Antigen 3, Cancer / Testis Antigen 1.3, CT1.3, Canc er / Testis Antigen Family 1, Member 3, HIPS, HYPD, MAGEA6, Cancer / Testis An tigen Family 1, Member 3; NCBI reference sequence: NP-005353.1); MAGE-A4 (MAGEA4 、Melanoma Antigen Family A, 4、MAGE4、Melanoma-Associated Antigen 4、Canc er / Testis Antigen 1.4、CT1.4、MAGE-4 Antigen、MAGE-41 Antigen、MAGE-X2 Anti gen、MAGE4A、MAGE4B、Cancer / Testis Antigen Family 1, Member 4、MAGE-41、MAG E-X2、Cancer / Testis Antigen Family 1, Member 4; NCBI reference sequence: NP-001011 550.1); MAGE-A6 (MAGEA6, Melanoma Antigen Family A, 6, MAGE6, MAGE-6 Anti gen、Melanoma-Associated Antigen 6、Cancer / Testis Antigen 1.6、CT1.6、MAGE3B Antigen、Cancer / Testis Antigen Family 1、Melanoma Antigen Family A 6, Member 6、MAGE-3b、MAGE3B、Cancer / Testis Antigen Family 1, Member 6; NCBI Reference sequences: NP-787064.1); MAGE-A9 (MAGEA9, Melanoma Antigen Family A, 9, MAGE9, MAGE-9 Antigen, Melanoma-Associated Antigen 9, Cancer / Testis Antigen 1.9, CT1.9, Cancer / Testis Antigen Family 1, Member 9, Cancer / Testis Anti gen Family 1, Member 9, MAGEA9A; NCBI reference sequence: NP-005356.1); MAGE-C1 ( MAGEC1, Melanoma Antigen Family C, 1, Cancer / Testis Antigen 7.1, CT7.1, MA GE-C1 Antigen, Cancer / Testis Antigen Family 7, Member 1, CT7, Cancer / Testi s Antigen Family 7, Member 1, Melanoma-Associated Antigen C1; NCBI reference sequence: NP-005453.2); MAGE-C2 (MAGEC2, Melanoma Antigen Family C, 2, MAGEE1 、Cancer / Testis Antigen 10, CT10, HCA587, Melanoma Antigen, Family E, 1, C ancer / Testis Specific, Hepatocellular Carcinoma-Associated Antigen 587, MAGE -C2 Antigen, MAGE-E1 Antigen, Hepatocellular Cancer Antigen 587, Melanoma-A ssociated Antigen C2; NCBI reference sequence: NP-057333.1); mammaglobin-A (SCGB2A2 , Secretoglobin, Family 2A, Member 2, MGB1, Mammaglobin 1, UGB2, Mammaglobi n A, mammaglobin-A, Mammaglobin-1, Secretoglobin Family 2A Member 2; NP); MART2 (H HAT, Hedgehog Acyltransferase, SKI1, Melanoma Antigen Recognized By T-Cells 2, Skinny Hedgehog Protein 1, Skn, Melanoma Antigen Recogniz ed By T Cells 2, Protein-Cysteine N-Palmitoyltransferase HHAT, EC 2.3.1.- ; GenBank: AAH39071.1); M-CSF (CSF1, Colony Stimulating Factor 1 (Macrop hage), MCSF, CSF-1, lanimostim, Macrophage Colony-Stimulating Factor 1, Lanim ostim; GenBank: AAH21117.1); MCSP (SMCP, Sperm Mitochondria-Associated Cys teine-Rich Protein, MCS, Mitochondrial Capsule Selenoprotein, HSMCSGEN1, Sper m Mitochondrial-Associated Cysteine-Rich Protein; NCBI reference sequence: NP-109588 .2); XAGE-1b / GAGED2a; WT1 (Wilms Tumor 1, WAGR, GUD, WIT-2, WT33, Amino-Ter minal Domain Of EWS, NPHS4, Last Three Zinc Fingers Of The DNA-Binding Domain Of WT1、AWT1、Wilms Tumor Protein、EWS-WT1; GenBank: AAB33443.1); VEGF; Tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP; NP-000363.1; NM -000372.4; GenBank: AAB60319.1); TrpM4 (BR22450、FLJ20041、TRPM4、TRPM4B、tr ansient receptor potential cation channel、subfamily M, member 4、Genbank accession number NM-01763); TRP2-INT2; TRP-2; TRP-1 / gp75 (Tyrosinase-Relate d Protein 1、5,6-Dihydroxyindole-2-Carboxylic Acid Oxidase、CAS2、CATB、TYRP 、OCAS、Catalase B、b-PROTEIN、Glycoprotein 75、EC 1.14.18.、Melanoma Antige n Gp75、TYRP1、TRP、TYRRP、TRP1、SHEP11、DHICA Oxidase、EC 1.14.18、GP75、EC 1.14.18.1; Triosephosphate isomerase (Triosephosphate isomerase 1、TPID、 Triose-Phosphate Isomerase、HEL-S-49、TIM、Epididymis Secretory Protein Li 49、TPI、Triosephosphate Isomerase、EC 5.3.1.1; TRAG-3 (CSAG Family Member 2、Cancer / Testis Antigen Family 24、CSAG3B, Member 2、CSAG Family Membe r 3B、Cancer / Testis Antigen Family 24 Member 2、Cancer / Testis Antigen 24 .2、Chondrosarcoma-Associated Gene 2 / 3 Protein、Taxol-Resistant-Associated G ene 3 Protein、Chondrosarcoma-Associated Gene 2 / 3 Protein-Like、CT24.2、Tax ol Resistance Associated Gene 3、TRAG-3、CSAG3A、TRAG3;); TMEM46 (shisa h omolog 2 (Xenopus Laevis); SHISA; NP-001007539.1; NM-001007538.1; TMEM118 (ring finger protein、transmembrane2; RNFT2; FLJ1462; NP-001103373.1; NM -001109903.1; TMEFF1 (transmembrane protein with EGF-like and two follis tatin-like domains 1; Tomoregulin-; H7365; C9orf2; C9ORF2; U19878; X8396 1; NM-080655; NM-003692; TGF-betaRII (TGFBR2、Transforming Growth Factor、 Beta Receptor II (70 / 80 kDa)、TGFbeta-RII、MFS2、tbetaR-II、TGFR-2、TGF-Beta Receptor Type IIB、TGF-Beta Type II Receptor、TGF-Beta Receptor Type-2 、EC 2.7.11.30、Transforming Growth Factor Beta Receptor Type IIC、AAT3、 TbetaR-II, Transforming Growth Factor, Beta Receptor II (70-80kD), TGF-Beta Receptor Type II, FAA3, Transforming Growth Factor-Beta Receptor Type I I, LDS1 B, HNPCC6, LDS2B, LDS2, RITC, EC 2.7.11, TAAD2; TENB2 (TMEFF2, tomor egulin, TPEF, HPP1, TR, putative transmembrane proteoglycan, EGF / growth factor helegrinf Associated with family and follistatin; 374 aa, NCBI accession number: AAD5 5776, AAF91397, AAG49451, NCBI reference sequence: NP-057276; NCBI Gene: 23671; OMIM: 6 05734; SwissProt Q9UIK5; Genbank accession number AF179274; AY358907, CAF857 23, CQ782436; TAG-2; TAG-1 (Contactin 2 (Axonal), TAG-1, AXT, Axonin-1 Cel l Adhesion Molecule, TAX, Contactin 2 (transiently Expressed), TAXI, Contac tin-2, Axonal Glycoprotein TAG-1, Transiently-Expressed Axonal Glycoprotein , Transient Axonal Glycoprotein, Axonin-1, TAX-1, TAG1, FAMES; PRF: 444868); SYT-SSX1 or -SSX2 fusion protein; survivin; STEAP2 (HGNC 8639, IPCA-1, PC ANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate ca ncer associated protein 1, six transmembrane epithelial antigen of prost ate 2, six transmembrane prostate protein, Genbank accession number AF4551 3; STEAP1 (six transmembrane epithelial antigen of prostate, Genbank access ion number NM-01244; SSX-4; SSX-2 (SSX2, Synovial Sarcoma, X Breakpoint2, X Breakpoint 2, SSX, X Breakpoint 2B, Cancer / Testis Antigen 5.2, X-Chromos ome-Related 2, Tumor Antigen HOM-MEL-40, CT5.2, HD21, Cancer / Testis Antigen Family 5, HOM-MEL-40, Isoform B, Cancer / Testis Antigen Family 5 member 2a, member 2a, Protein SSX2, Sarcoma, Sarcoma, Synovial, X-Chromosome-Rela ted 2, synovial, Synovial Sarcoma, X Breakpoint 2B, Synovial Sarcomam, S SX2A; Sp17; SOX10 (SRY (Sex Determining Region Y)-Box 10, mouse, PCWH 、DOM、WS4、WS2E、WS4C、Dominant Megacolon, mouse, Human Homolog Of、Domina nt Megacolon、SRY-Related HMG-Box Gene 10, Human Homolog Of、transcriptio n Factor SOX-10; GenBank: CAG30470.1); SNRPD1 (Small Nuclear Ribonucleop rotein D1、Sma ll Nuclear Ribonucleoprotein D1、Polypeptide 16 kDa、Polypeptide (16kD)、S NRPD、HsT2456、Sm-D1、SMD1、Sm-D Autoantigen、Small Nuclear Ribonucleoprotein D1 Polypeptide 16 kDa Pseudogene、SnRNP Core Protein D1、Small Nuclear Ribonucleoprotein Sm D1; SLC35D3 (Solute Carrier Family 35, Member D3 、FRCL1、Fringe Connection-Like Protein 1、bA55K22.3、Frc、Fringe-Like 1、So lute Carrier Family 35 Member D3; NCBI GenBank: NC-000006.11 NC-018917. 2 NT-025741.16); SIRT2 (Sirtuin 2、NAD-Dependent Deacetylase Sirtuin-2、SI RL2、Silent Information Regulator 2、Regulatory Protein SIR2 Homolog 2、S ir2-Related Protein Type 2、SIR2-Like Protein 2、Sirtuin Type 2、Sirtuin (Silent Mating Type Information Regulation 2 Homologue) 2 (S. cerevisiae e)、Sirtuin-2、Sirtuin (Silent Mating Type Information Regulation 2, S. 2). cerevisiae, Homolog)2、EC 3.5.1.、SIR2; GenBank: AAK51133.1); Section 5b ( FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Head, sema domain, seven thrombospondin repeats (type 1 and type 1-like), Transmembrane Domain (TM) and short cytoplasmic domain, (semaphorin) 5B Link AB04087; secernin 1 (SCRN1, SES1, KIAA0193, secerin-1; GenBank: EAL24458.1); SAGE (SAGE1、Sarcoma Antigen 1、Cancer / Testicle Antigen 14、C T14, Putative Tumor Antigen; NCBI Public Number: NP-061136.2); RU2AS (KAAG1、Ki dney Associated Antigen 1, RU2AS, RU2 Antisense Gene Protein, Kidney-Assoc iated Antigen 1; GenBank: AAF23613.1); RNF43-E3 ubiquitin-protein ligase RNF43 precursor [Homo sapiens]、RNF124; URCC; NCBI Public Number: NP-060233.3; RhoC (RGS5 (Regulator Of G-Protein Signaling 5、MSTP032、Regulator Of G-Protein Signalling 5、MSTP092、MST092、MSTP106、MST106、MSTP129、MST129; Ge nBank: AAB84001.1); RET (ret proto-oncogene; MEN2A; HSCR1; MEN2B; MTC1; PTC; CDHF12; Hs.168114; RET51; RET-ELE; NP-066124.1; NM-020975.4); RBAF 600 (UBR4、Ubiquitin Protein Ligase E3 Component N-Recognin 4、Zinc Fing er、UBR1 Type 1、ZUBR1、E3 Ubiquitin-Protein Ligase UBR4、RBAF600、600 KDa Retinoblastoma Protein-Associated Factor、Zinc Finger UBR1-Type Protein 1、EC 6.3.2.、N-recognin-4、KIAA0462、p600、EC 6.3.2、KIAA1307; GenBank: AAL 83880.1); RAGE-1 (MOK、MOK Protein Kinase、Renal Tumor Antigen、RAGE、MAPK / MAK / MRK Overlapping Kinase、Renal Tumor Antigen 1、Renal Cell Carcinoma Antigen、RAGE-1、EC 2.7.11.22、RAGE1; UniProtKB / Swiss-Prot: Q9UQ07.1); RAB 38 / NY-MEL-1 (RAB38、NY-MEL-1、RAB38、Member RAS Oncogene Family、Melanoma A Antigen NY-MEL-1, Rab-Related GTP-Binding Protein, Ras-Related Protein Rab-3 8, rrGTPbp; GenBank: AAH15808.1); PTPRK (DJ480J14.2.1 (Protein Tyrosine P hosphatase, Receptor Type, K R-PTP-KAPPA, Protein Tyrosine Phosphatase Kap pa, Protein Tyrosine Phosphatase Kappa), Protein Tyrosine Phosphatase, Rec eptor Type, K, Protein-Tyrosine Phosphatase Kappa, Protein-Tyrosine Phospha tase, Receptor Type, Kappa, R-PTP-kappa, Receptor-Type Tyrosine-Protein Pho sphatase Kappa, EC 3.1.3.48, PTPK; GenBank: AAI44514.1); PSMA; PSCA hIg(2 700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 g ene, Genbank accession number AY358628); PSCA (Prostate stem cell antigen precursor, Genbank accession number AJ29743; PRDX5 (Peroxiredoxin 5, EC 1. 11.1.15, TPx Type VI, B166, Antioxidant Enzyme B166, HEL-S-55, Liver Tissue 2D-Page Spot 71 B, PMP20, Peroxisomal Antioxidant Enzyme, PRDX6, Thioredo xin Peroxidase PMP20, PRXV, AOEB166, Epididymis Secretory Protein Li 55, A lu Co-Repressor 1, Peroxiredoxin-5, Mitochondrial, Peroxiredoxin V, prx-V, Th ioredoxin Reductase, Prx-V, ACR1, Alu Corepressor, PLP; GenBank: CAG33484.1) ; PRAME (Preferentially Expressed Antigen In Melanoma, Preferentially Exp ressed Antigen Of Melanoma, MAPE, 01P-4, OIPA, CT130, Cancer / Testis Antigen 130, Melanoma Antigen Preferentially Expressed In Tumors, Opa-Interacting Protein 4, Opa-Interacting Protein 01P4; GenBank: CAG30435.1); pml-RARal pha fusion protein; PMEL17 (silver homolog; SILV; D12S53E; PMEL17; SI; SI L); ME20; gp10 BC001414; BT007202; M32295; M77348; NM-006928; PBF (ZNF3 95, Zinc Finger Protein 395, PRF-1, Huntington disease regulatory, HD Gene Regulatory Region-Binding Protein, Region-Binding Protein 2, Protein 2, P apillomavirus Regulatory Factor 1, HD-Regulating Factor 2, Papillomavirus-R egulatory Factor、PRF1、HDBP-2、Si-1-8-14、HDBP2、Huntington'S Disease Gene Regulatory Region-Binding Protein 2、HDRF-2、Papillomavirus Regulatory Fact or PRF-1、PBF; GenBank: AAH01237.1); PAX5 (Paired Box 5、Paired Box Hom eotic Gene 5、BSAP、Paired Box Protein Pax-5、B-Cell Lineage Specific Ac tivator、Paired Domain Gene 5、Paired Box Gene 5 (B-Cell Lineage Specif ic Activator Protein)、B-Cell-Specific Transcription Factor、Paired Box Ge ne 5 (B-Cell Lineage Specific Activator); PAP (REG3A、Regenerating Islet -Derived 3 Alpha、INGAP、PAP-H、Hepatointestinal Pancreatic Protein、PBBCGF 、Human Proislet Peptide、REG-Ill、Pancreatitis-Associated Protein 1、Regi、 Reg III-Alpha、hepatocarcinoma-intestine-pancreas、Regenerating Islet-Derived Protein III-Alpha、Pancreatic Beta Cell Growth Factor、HIP、PAP Homologo us Protein、HIP / PAP、Proliferation-Inducing Protein 34、PAP1、Proliferation-I nducing Protein 42, REG-3-alpha, Regenerating Islet-Derived Protein 3-Alpha , Pancreatitis-Associated Protein; GenBank: AAH36776.1); p53 (TP53, Tumor Protein P53, TPR53, P53, Cellular Tumor Antigen P53, Antigen NY-CO-13, Muta nt Tumor Protein 53, Phosphoprotein P53, P53 Tumor Suppressor, BCC7, Trans formation-Related Protein 53, LFS1, tumor Protein 53, Li-Fraumeni Syndrome , Tumor Suppressor P53; P2X5 (Purinergic receptor P2X ligand-gated ion Channel 5 is an ion channel that opens and closes due to extracellular ATP, and is involved in synaptic transmission and neuronal development. It may be involved in life. Its deficiency may be the cause of the pathophysiology of idiopathic detrusor instability. ); 422 aa), μl: 7.63, MW: 47206 TM: 1 [P] gene chromosome: 17p13.3, Genba nk accession number NP-002552; OGT (0-Linked N-Acetylglucosamine (GlcNAc) Transferase, O-GlcNAc Transferase P110 Subunit, 0-Linked N-Acetylglucosamine (GlcNAc) Transferase (UDP-N-Acetylglucosamine:Polypeptide-N-Acetylglucosamine yl Transferase、UDP-N-Acetylglucosamine-Peptide N-Acetylglucosaminyltransferas e 110 KDa Subunit、UDP-N-Acetylglucosamine:Polypeptide-N-Acetylglucosaminyl Transferase、Uridinediphospho-N-Acetylglucosamine:Polypeptide Beta-N-Acetylgluc osaminyl Transferase、O-GlcNAc Transferase Subunit P110、EC 2.4.1.255、0-Li nked N-Acetylglucosamine Transferase 110 KDa Subunit、EC 2.4.1、HRNT1、EC 2.4.1.186、0-GLCNAC; GenBank: AAH38180.1); 0A1 (Osteoarthritis QTL 1、OA SD; GenBank: CAA88742.1); NY-ESO-1 / LAGE-2 (Cancer / Testis Antigen 1 B、CTA G1 B、NY-ESO-1、LAGE-2、ESO1、CTAG1、CTAG、LAGE2B、Cancer / Testis Antigen 1、A utoimmunogenic Cancer / Testis Antigen NY-ESO-1、Ancer Antigen 3、Cancer / Test is Antigen 6.1、New York Esophageal Squamous Cell Carcinoma 1、L Antige n Family Member 2、LAGE2、CT6.1、LAGE2A; GenBank: AAI30365.1); NY-BR-1 (A NKRD30A、Ankyrin Repeat Domain 30A、Breast Cancer Antigen NY-BR-1、Serolog ically Defined Breast Cancer Antigen NY-BR-1、Ankyrin Repeat Domain-Conta ining Protein 30A; NCBI Reference Sequence: NP-443723.2); N-ras (NRAS、N euroblastoma RAS Viral (V-Ras) Oncogene Homolog、NRAS1、Transforming Prote in N-Ras、GTPase NRas、ALPS4、N-Ras Protein Part 4、NS6、Oncogene Homolog 、HRAS1; GenBank: AAH05219.1); NFYC (Nuclear Transcription Factor Y、Gamm a、HAP5、HSM、Nuclear Transcription Factor Y Subunit C、Transactivator HSM -1 / 2、CCAAT Binding Factor Subunit C、NF-YC、CCAAT Transcription Binding Factor Subunit Gamma、CAAT Box DNA-Binding Protein Subunit C、Histone H1 Transcription Factor Large Subunit 2A、CBFC、Nuclear Transcription Facto r Y Subunit Gamma、CBF-C、Transactivator HSM-1、H1TF2A、Transcription Facto r NF-Y、C Subunit; neo-PAP (PAPOLG、Poly(A) Polymerase Gamma、Neo-Poly(A) Polymerase, Nuclear Poly(A) Polymerase Gamma, Polynucleotide Adenylyltrans ferase Gamma, SRP RNA 3′ Adenylating Enzyme / Pap2, PAP-gamma, Neo-PAP, SRP RNA 3′-Adenylating Enzyme, PAP2, EC 2.7.7.19, PAPG; NCBI Reference Sequ ence: NP-075045.2); NCA (CEACAM6, Genbank accession number M1872); Napi3b ( NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), memb er 2, type II sodium-dependent phosphate transporter 3b, Genbank accession ion number NM-00642); Myosin class I; MUM-3; MUM-2 (TRAPPC1, Trafficking Pro tein Particle Complex 1, BETS, BETS Homolog, MUM2, Melanoma Ubiquitous Mut ated 2, Multiple Myeloma Protein 2, Trafficking Protein Particle Complex Subunit 1; MUM-1f; Mucin (MUC1, Mucin 1, Cell Surface Associated, PEMT 、PUM, CA 15-3, MCKD1, ADMCKD, Medullary Cystic Kidney Disease 1 (autosoma l dominant), ADMCKD1, Mucin 1, Transmembrane, CD227, Breast Carcinoma-Associa ted Antigen DF3、MAM6、Cancer Antigen 15-3、MCD、Carcinoma-Associated Mucin 、MCKD、Krebs Von Den Lungen-6、MUC-1 / SEC、Peanut-Reactive Urinary Mucin、M UC1 / ZD、Tumor-Associated Epithelial Membrane Antigen、DF3 Antigen、Tumor-Ass ociated Mucin, episialin、EMA、H23 Antigen、H23AG、Mucin-1、KL-6、Tumor Asso ciated Epithelial Mucin、MUC-1、Episialin、PEM、CD227 Antigen; UniProtKB / Swi ss-Prot: P15941.3); MUCSAC (Mucin SAC、Oligomeric Mucus / Gel-Forming、Trache obronchial Mucin′ MUC5、TBM、Mucin 5、Subtypes A And C、Tracheobronchial / Gastric、leB、Gastric Mucin、Mucin SAC、Oligomeric Mucus / Gel-Forming Pseudog ene、Lewis B Blood Group Antigen、LeB、Major Airway Glycoprotein、MUC-SAC 、Mucin-5 Subtype AC、Tracheobronchial; MUC1 (Mucin 1、Cell Surface Assoc iated、PEMT、PUM、CA 15-3、MCKD1、ADMCKD、Medullary Cystic Kidney Disease 1 (Autosomal Dominant)、ADMCKD1、Mucin 1、Transmembrane、CD227、Breast Carcin oma-Associated Antigen DF3、MAM6、Cancer Antigen 15-3、MCD、Carcinoma-Associ ated Mucin、MCKD、Cancer of the Lung-6、MUC-1 / SEC、Peanut-Reactive Urine and Mucin、MUC-1 / X、Polymorphic Epithelial Mucin、MUC1 / ZD、Tumor-Associated Ep ithelial Membrane Antigen、DF3 Antigen、Tumor-Associated Mucin、episialin、E MA、h23 Antigen、H23AG、mucin-1、KL-6、Tumor Associated Epithelial Mucin、MU C-1、Epicialin、PEM、CD227 Antigen; MSG783 (RNF124) hypothetical protein FL J20315 Genbank Release Project NM-01776;MRP4 Multidrug Resistance-Associate ed protein 4 isoform 3、MOAT-B; MOATB [Homo sapiens]; NCBI National Designation: NP- 001288758.1; MPF (MPF、MSLN、SMR、megakaryocyte potentiating factor、mesothe lin Genbank Protocol NM-00582; MMP-7 (MMP7, matrilysin, MPSL1, matrin 、Matrix Metalloproteinase 7 (Matrilysin、Uterine)、Uterine Matrilysin、Matr ix Metalloproteinase-7、EC 3.4.24.23、Pump-1 Protease、Matrin、Uterine Metal loproteinase, PUMP1, MMP-7, EC 3.4.24, PUMP-1; GenBank: AAC37543.1); MMP-2 (MMP2, Matrix Metallopeptidase 2 (Gelatinase A, 72 kDa Gelatinase, 72 kDa Type IV Collagenase), MONA, CLG4A, Matrix Metalloproteinase 2 (Gelatinase A, 72kD Gelatinase, 72kD Type IV Collagenase), CLG4, 72kDa Gelatinase, 72 kDa Type IV Collagenase), Matrix Metalloproteinase-2, MMP-II, 72 KDa G elatinase, Collagenase Type IV-A, MMP-2, Matrix Metalloproteinase-II, TBE-1, Neutrophil Gelatinase, EC 3.4.24.24, EC 3.4.24; GenBank: AAH02576.1); and Meloe.

[0069] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are, for example, type 2. This includes multispecific antibodies such as heterozygous antibodies, and in this case, the multispecific antibodies are as follows: It contains a second binding domain that has specificity for a second antigen selected from the following group: 17-IA, 4-1BB, 4Dc, 6-keto-PGFla, 8-iso-PGF2a, 8-oxo-dG, Al adenosine receptor A33, ACE, ACE-2, activin, activin A, activin AB, activin B, A Activin C, Activin RIA, Activin RIA ALK-2, Activin RIB ALK-4, A Cucivin RIIA, Activin RUB, ADAM, ADAM10, ADAM12, ADAM15, ADAM17 / TACE, ADAM 8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5, addressin, aFGF, ALCAM, ALK, ALK-1, ALK-7, Alpha-L-antitrypsin, alpha-V / beta-1 antagonist, ANG, Ang, APAF-1 APE, APJ, APP, APRIL, AR, ARC, ART, Artemin, anti-Id, ASPARTIC, atrial sodium Diuretic factor, av / b3 integrin, Axl, b2M, B7-1, B7-2, B7-H, B-lymphocyte stimulating factor ( BlyS), BACE, BACE-1, Bad, BAFF, BAFF-R, Bag-1, BAK, Bax, BCA-1, BCAM, Bel, BCMA , BDNF, b-ECGF, bFGF, BID, Bik, BIM, BLC, BL-CAM, BLK, BMP, BMP-2 BMP-2a, BMP-3 Osteogenin, BMP-4, BMP-2b, BMP-5, BMP-6, Vgr-1, BMP-7 (OP-1), BMP-8 (BMP -8a, OP-2), BMPR, BMPR-IA (ALK-3), BMPR-IB (ALK-6), BRK-2, RPK-1, BMPR-II (BR K-3), BMPs, β-NGF, BOK, bombesin, bone-derived neurotrophic factor, BPDE, BPDE-DNA, BTC, Complement factor 3 (C3), C3a, C4, C5, C5a, CIO, CA125, CAD-8, calcitonin, cAMP, fetal cancer Antigen (CEA), tumor-associated antigen, cathepsin A, cathepsin B, cathepsin C / DPPI, cathepsin D Cathepsin E, Cathepsin H, Cathepsin L, Cathepsin O, Cathepsin S, Cathepsin V, Cathepsin X / Z / P, CBL, CCI, CCK2, CCL, CCLl, CCLll, CCL12, CCL13, CCL 14, CCL15 , CCL16, CCLl 7, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9 / 10, CCR, CCR1, CCR 10. CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD1, CD2, CD4, CD5, C D6, CD7, CD8, CD10, CDlla, CDllb, CDllc, CD13, CD14, CD15, CD16, CD18, CD19, CD2 0. CD21, CD22, CD23, CD25, CD27L, CD28, CD29, CD30, CD30L, CD32, CD33 (p67タン パクquality), CD34, CD38, CD40, CD40L, CD44, CD45, CD46, CD49a, CD52, CD54, CD55, CD5 6. CD61, CD64, CD66e, CD74, CD80 (B7-1), CD89, CD95, CD123, CD137, CD138, CD140 a. CD146, CD147, CD148, CD152, CD164, CEACAM5, CFTR, cGMP, CINC, ボツリヌス virus Toxin, Welsh toxin, CKb8-l, CLC, CMV, CMV UL, CNTF, CNTN-1, COX, C-Ret, CRG-2 , CT-1, CTACK, CTGF, CTLA-4, CX3CL1, CX3CR1, CXCL, CXCLl, CXCL2, CXCL3, CXCL4, C XCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15 , CXCL16, CXCR, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, サイトケラチン tumor association Antigen, DAN, DCC, DcR3, DC-SIGN, degradation-promoting factor, des(l-3)-IGF-I (brain IGF-1), Dhh, d Goxin, DNAM-1, Dnase, Dpp, DPPIV / CD26, Dtk, ECAD, EDA, EDA-A1, EDA-A2, EDAR, EGF, EGFR (ErbB-1), EMA, EMMPRIN, EN A, endothelin receptor, enkephalinase eNOS, Eot, eotaxin, EpCAM, Ephrin B2 / EphB4, EPO, ERCC, E-selectin, ET-1 Factor Ila, Factor VII, Factor VIIIc, Factor IX, Fibroblast-Activating Protein (FAP), Fas, FcRl, FEN-1, ferritin, FGF, FGF-19, FGF-2, FGF-3, FGF-8, FGFR, FGFR-3, Fib rin, FL, FLIP, Flt-3, Flt-4, follicle-stimulating hormone, fractalkine, FZD1, FZD2, FZD 3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, G250, Gas 6, GCP-2, GCSF, GD2, GD 3, GDF, GDF-1, GDF-3 (Vgr-2), GDF-5 (BMP-14, CDMP- 1), GDF-6 (BMP-13, CDMP-2 ), GDF-7 (BMP-12, CDMP-3), GDF-8 (myostatin), GDF-9, GDF-15 (MIC-1), GDN F, GDNF, GFAP, GFRa-1, GFR-Alpha I, GFR-Alpha II, GFR-Alpha III, GITR, Gurkha Gon, Glut 4, Glycoprotein Ilb / IIIa (GP Ilb / IIIa), GM-CSF, gpl30, gp72, GRO, Growth hormone-releasing factor, hapten (NP-cap or NIP-cap), HB-EGF, HCC, HCMV gB enzyme Envelope glycoprotein, HCMV) gH Envelope glycoprotein, HCMV UL, hematopoietic growth factor Child (HGF: Hemopoietic growth factor), Hep B gpl20, heparanase, Her2, Her2 / ne u (ErbB-2), Her3 (ErbB-3), Her4 (ErbB-4), Herpes simplex virus (HSV) gB sugar Protein, HSV gD glycoprotein, HGFA, high molecular weight melanoma-associated antigen (HMW-MAA: High molecular weight melanoma-associated antigen), HIV gpl20, HIV IIIB gp 1 20 V3 loop, HLA, HLA-DR, HM1.24, HMFG PEM, HRG, Hrk, human cardiac myosin, human Cytomegalovirus (HCMV), Human Growth Hormone (HGH), HVEM, 1-309, IAP, ICAM, ICA M-1, ICAM-3, ICE, ICOS, IFNg, Ig, IgA receptor, IgE, IGF, IGF-binding protein, IG F-1R, IGFBP, IGF-I, IGF-II, IL, IL-1, IL-1R, IL-2, IL-2R, IL-4, IL-4R, IL-5, IL- 5R, IL-6, IL-6R, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-18R, IL-23 Interferon (INF)-alpha, INF-beta, INF-gamma, inhibin, iNOS, Insulin A-chain, insulin B-chain, insulin-like growth factor 1, integrin ALF A2, Integrin Alpha3, Integrin Alpha4, Integrin Alpha4 / Beta Integrin, Alpha 4 / Beta 7, Integrin Alpha 5 (Alpha V), Integrin Alpha 5 / Beta I, Integrin Alpha 5 / Beta 3, Integrin Alpha 6, Inte Grinbeta I, Integrinbeta II, Interferon Gamma, IP-10, 1-TAC, JE, Ca Kallikrein 2, Kallikrein 5, Kallikrein 6, Kallikrein 11, Kallikrein 12, Kallikrein 14, Kallikrein 15, Kallikrein LI, Kallikrein L2, Kallikrein L3, Lyrein L4, KC, KDR, Keratinocyte Growth Factor (KGF), Laminin 5, LAMP, LAP, LAP ( TGF-1), latent TGF-1, latent TGF-1 bpl, LBP, LDGF, LECT2, lefty, Lewis-Y Antigen, Lewis-Y related antigen, LFA-1, LFA-3, Lfo, LIF, LIGHT, lipoprotein, LIX, LKN Lptn, L-selectin, LT-a, LT-b, LTB4, LTBP-1, pulmonary surfactant, progesterone Lymphotoxin beta receptor, Mac-1, MAdCAM, MAG, MAP2, MARC, MCAM, MCAM, MCK-2 MCP, M-CSF, MDC, Mer, metalloproteinase, MGDF receptor, MGMT, MHC (HLA-DR), MIF MIG, MIP, MIP-1-Alpha, MK, MMAC1, MMP, MMP-1, MMP-10, MMP-11, MMP-12, MMP-1 3, MMP-14, MMP-15, MMP-2, MMP-24, MMP-3, MMP-7, MMP-8, MMP-9, MPIF, Mpo, MSK, MSP, mucin (Mucl), MUC18, Müllerian duct inhibitor, Mug, MuSK, NAIP, NAP, NCAD, N-cad Herin, NCA 90, NCAM, NCAM, Neprilysin, Neurotrophin-3,-4, or-6 Neurturin, nerve growth factor (NGF), NGFR, NGF-beta, nNOS, NO, NOS, Npn, NRG-3 , NT, NTN, OB, OGG1, OPG, OPN, OSM, OX40L, OX40R, pl50, p95, PADPr, Parathyroid hormone, PARC, PARP, PBR, PBSF, PCAD, P-cadherin, PCNA, PDGF, PDK-1, P ECAM, PEM, PF4, PGE, PGF, PGI2, PGJ2, PIN, PLA2, Placental Alkaline Phosphatase (PLAP) ), P1GF, PLP, PP14, proinsulin, prorelaxin, protein C, PS, PSA, PSCA, Prostate-specific membrane antigen (PSMA), PTEN, PTHrp, Ptk, PTN, R51, RANK, RANKL, RANTES, RANTE S, relaxin A-chain, relaxin B-chain, renin, respiratory syncytial virus (RSV) F, RSV Fgp, Ret, rheumatoid factor, RLIP76, RPA2, RSK, S100, SCF / KL, SDF-1, SERINE, serum alcohol Bumin, sFRP-3, Shh, SIGIRR, SK-1, SLAM, SLPI, SMAC, SMDF, SMOH, SOD, SPARC, Sta t, STEAP, STEAP-II, TACE, TACI, TAG-72 (tumor-associated glycoprotein-72), TARC, TCA-3, T cell receptors (e.g., T cell receptor alpha / beta), TdT, TECK, TEM1, TEM5, TEM7, TEM8 TERT, testicular PLAP-like alkaline phosphatase, TfR, TGF, TGF-alpha, TGF-beta, TG F-beta pan-specific, TGF-beta RI (ALK-5), TGF-beta RII, TGF -Beta Rllb, TGF-Beta RIII, TGF-Beta I, TGF-Beta 2, TGF-Beta 3, TGF-Beta T4, TGF-Beta5, Thrombin, Thymus CK-1, Thyroid-stimulating hormone, Tie, TIMP, TIQ, Tissue Recombinant TMEFF2, Tmpo, TMPRSS2, TNF, TNF-catalyst, TNF-catalyst 2, TNFc, TNF-RI, TNF-RII, TNFRSF10A (TRAIL Rl Apo-2, DR4), TNFRSFIOB (TRAIL R2 DR5、KILLER、TRICK-2A、TRICK-B)、TNFRSF10C (TRAIL R3 DcRl、LIT、TRID)、 TNFRSF10D (TRAIL R4 DcR2、TRUNDD)、TNFRSF11A (RANK ODF R、TRANCE R)、TNFR SFllB (OPG OCIF、TR1)、TNFRSF12 (TWEAK R FN14)、TNFRSF13B (TACI)、TNFRSF13 C (BAFF R)、TNFRSF14 (HVEM ATAR、HveA、LIGHT R、TR2)、TNFRSF16 (NGFR p75N). TR)、TNFRSF17 (BCMA)、TNFRSF18 (GITR AITR)、TNFRSF19 (TROY CROWN、TRADE)、TNF RSF19L (RELT)、TNFRSFIA (TNF RI CD120a、p55-60)、TNFRSFIB (TNF RII CD120b). p75-80, TNFRSF26 (TNFRH3), TNFRSF3 (LTbR TNF RIII, TNFC R), TNFRSF4 (OX 40 ACT35, TXGP1 R, TNFRSF5 (CD40 p50), TNFRSF6 (Fas Apo-1, APT1, CD95), T NFRSF6B (DcR3 M68、TR6)、TNFRSF7(CD27)、TNFRSF8(CD30)、TNFRSF9 (4-lBB CD 137. ILA, TNFRSF21 (DR6), TNFRSF22 (DcTRAIL R2 TNFRH2), TNFRST23 (DcTRAIL Rl TNFRH1), TNFRSF25 (DR3 Apo-3, LARD, TR-3, TRAMP, WSL-1), TNFSF10 (TRAIL Apo-2 ligand (TL2), TNFSF11 (TRANCE / RANK ligand ODF, OPG ligand), TNFSF12 (TWEAK Apo-3 ligand, DR3 ligand), TNFSF13 (APRIL TALL2), TNFSF13B (BAFF B LYS, TALL1, THANK, TNFSF20), TNFSF14 (LIGHT HVEM ligand, LTg), TNFSF15 (TL1A / VEGI), TNFSF18 (GITR ligand, AITR ligand, TL6), TNFSFIA (TNF-α Conectin, D IF, TNFSF2), TNFSF1B (TNF-b LTa, TNFSF1), TNFSF3 (LTb TNFC, p33), TNFSF4 (O X40 ligand (gp34, TXGP1), TNFSF5 (CD40 ligand CD154, gp39, HIGM1, IMD3, TRAP ), TNFSF6 (Fas ligand, Apo-1 ligand, APT1 ligand), TNFSF7 (CD27 ligand, CD 70), TNFSF8 (CD30 ligand CD153), TNFSF9 (4-IBB ligand CD137 ligand), TP-1 t-PA, Tpo, TRAIL, TRAIL R, TRAIL-R1, TRAIL-R2, TRANCE, transfer receptor ( (transfer receptor), TRF, Trk, TROP-2, TSG, TSLP, tumor-associated antigen CA125, Louis Tumor-associated antigens expressing Y-related sugars, TWEAK, TXB2, Ung, uPAR, uPAR-1, urokinase, V CAM, VCAM-1, VECAD, VE-cadherin, VE-cadherin-2, VEFGR-1 (flt-1), VEGF, VEGF R, VEGFR-3 (flt-4), VEGI, VIM, viral antigen, VLA, VLA-1, VLA-4, VNR integrin , von Willebrand factor, WIF-1, WNT1, WNT2, WNT2B / 13, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9A, WNT9B, WNT10A, WNT 10B, WNT11, WNT16, XCL1, XCL2, XCR1, XCR1, XEDAR, XIAP, XPD, CTLA4 (cytotoxic Tocyte lymph antigen-4), PD1 (programmed cell death protein 1), PD-L1 (p rogrammed cell death ligand 1), LAG-3 (lymphocyte activation gene-3), TIM -3 (T cell immunoglobulin and mucin protein-3), hormone receptor, and long factor.

[0070] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are, for example, type 2. This includes multispecific antibodies such as heterozygous antibodies, and in this case, the multispecific antibodies are as follows: It contains a second binding domain that has specificity for a second antigen selected from the following group: BCMA, CTLA4 (cytotoxic T lymphocyte antigen-4), PD1 (programmed cell death) protein 1), PD-L1 (programmed cell death ligand 1), LAG-3 (lymphocyte activation gene-3), TIM-3, CD20, CD2, CD19, Her2, EGFR, EpCAM, FcyRIIIa (CD16 ), FcyRIIa (CD32a), FcyRIIb (CD32b), FcyRI (CD64), Toll-like receptors (TLRs), TLR4 , TLR9, cytokines, IL-2, IL-5, IL-13, IL-6, IL-17, IL-12, IL-23, TNFa, TGFb, Cytokine receptors, IL-2R, chemokines, chemokine receptors, growth factors, VEGF and HGF .

[0071] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are antigen-specific. It comprises at least a second antigen-binding domain that binds to the target, and in this case, the antibody is The following are examples of multispecific forms selected from the group: Fab-Fc-scFv, “bottle-opener -”, Mab-scFv, Mab-Fv, dual scFv, central Fv, central scFv, one-arm central scFv, Fab-Fab Fab-Fv, mAb-Fv, mAb-Fab, DART, BiTE, Common Light Chain-IgG, TandAb, Cross-Mab, SEED, BE AT, TrioMab, and DuetMab.

[0072] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are encoded. The nucleic acid sequence is provided.

[0073] In certain embodiments, the present invention encodes a CD3-binding domain and an antibody containing it. An expression vector containing a nucleic acid sequence is provided.

[0074] In certain embodiments, the present invention encodes a CD3-binding domain and an antibody containing it. Host cells that have been transfected, transformed, or transduced with nucleic acid sequences It will be provided.

[0075] In certain embodiments, the CD3-binding domain of the present invention and an antibody containing it are encoded. Host cells that have been transfected, transformed, or transduced by a chemoat are provided. To be served.

[0076] In certain embodiments, one of the CD3-binding domains of the present invention and antibodies containing the same A pharmaceutical composition containing multiple components is provided.

[0077] In certain embodiments, one of the CD3-binding domains of the present invention and antibodies containing the same A pharmaceutical composition comprising or multiple, as well as pharmaceutically acceptable carriers and / or excipients, is proposed. To be served.

[0078] In certain embodiments, one of the CD3-binding domains of the present invention and antibodies containing the same Alternatively, a pharmaceutical composition is provided that contains one or more nucleic acids that encode multiple codes.

[0079] In certain embodiments, one of the CD3-binding domains of the present invention and antibodies containing the same or one or more vectors encoding multiple vectors, and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a batter and / or excipient is provided.

[0080] In certain embodiments, the treatment of a disorder in a mammal requiring such treatment, Alternatively, a method is provided for delaying the progression of a disorder, the method being the CD3 binding domain of the present invention. and administering one or more antibodies including the same, in this case The disease is reduced or improved as a result of the administration. In certain embodiments, the present invention By administering one or more of the CD3 binding domain and antibodies containing it Methods have been proposed to prevent injuries in mammals or to reduce the risk of injuries occurring. Provided, and in this case, the disorder is prevented as a result of the administration. Specific implementation In this context, methods for treating disorders in mammals requiring such treatment are provided. In this case, the disorder is a proliferative disorder, a cancerous disorder, an immuno-cancer disorder, a neurological disorder, This includes neurodegenerative disorders or autoimmune disorders, and the method is the CD3 binding domain of the present invention This includes administering one or more antibodies, including those said herein. The disorder is reduced or improved as a result of the administration. In certain embodiments, the method This further includes administering additional therapeutic agents to the mammal. In certain embodiments, Mammals are humans. In certain embodiments, the first Fc region contains a CD3 epsilon polypeptide. The first polypeptide chain and the second CD3 delta polypeptide fused to the Fc region A heterodimer CD3 fusion protein containing two polypeptide chains is provided. Specific implementation Morphologically, CD3 epsilon polypeptide includes human CD3 epsilon polypeptide, CD The 3-delta polypeptide contains human CD3 delta polypeptide. In certain embodiments, CD 3-epsilon polypeptide is a human CD3 epsilon polypeptide, and CD3 delta-polypeptide The peptide is a human CD3 delta polypeptide. In certain embodiments, CD3 epsilon The polypeptide contains the CD3 epsilon polypeptide of cynomolgus monkeys, and the CD3 delta polypeptide The drug contains CD3 delta polypeptide of cynomolgus monkeys. In certain embodiments, CD3 ipsi The cynomolgus monkey CD3 epsilon polypeptide and CD3 deltapoly The peptide is a CD3 delta polypeptide from cynomolgus monkeys. In certain embodiments, hete The first polypeptide of the ronimeric CD3 fusion protein contains the following amino acid sequence: QDGNE EMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPE DANFYLYLRARVCENCMEMDGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO: 6716). The second polypeptide chain contains the following amino acid sequence: FK IPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDLGKRILDPRGIYRCNGTDIYKDKESTVQVHYRMCQSCVELDGGS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTY RVVSVLTVLHQDWLNGKEYKCKVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence No. 671) 7) In a particular embodiment, the first polypeptide of the heterodimer CD3 fusion protein is The following amino acid sequence is included: QDGNEEMGSITQTPYQVSISGTTVILTCSQHLGSEAQWQHNGKNKEDSGDRLFLPE FSEMEQSGYYVCYPRGSNPEDASHHLYLKARVCENCMEMDGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 6718). The second polypeptide chain is as follows: Contains mino acid sequence: FKIPVEELEDRVFVKCNTSVTWVEGTVGTLLTNNTRLDLGKRILDPRGIYRCNGTDIYKDKE SAVQVHYRMCQNCVELDPGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK (SEQ ID NO: 6719). In certain embodiments, a CD3-binding domain and an antibody containing the same. In the identification, isolation, selection, generation and / or characterization of the heterodimer CD3 fusion, Provides the use of protein. In certain embodiments, for example, the following are provided: (Item 1) FNIKDYYMH (sequence number 6720), YTFTSYTIH (sequence number 6721), or FTFX1TYAMN (sequence number An antibody or antigen-binding polypeptide comprising CDRH1 containing the amino acid sequence of (No. 6722), In the formula, X1 is any amino acid, and the antibody or antigen-binding polypeptide is used. (Item 2) In the formula, X1 is N or D, the antibody or antigen-binding polypeptide as described in item 1. (Item 3) An antibody containing CDRH2 with the amino acid sequence WIDLENX1NTX2YDX3KFOG (SEQ ID NO: 6723) or An antigen-binding polypeptide, wherein X1, X2, and X3 are independently any amino acids. , an antibody or antigen-binding polypeptide. (Item 4) In the formula, X1 is an antibody or antigen-binding polypeptide as described in item 3, not G. (Item 5) In the formula, X2 is V or I, an antibody or antigen-binding compound as described in any one of items 3-4. Lipeptide. (Item 6) In the formula, X3 is not G, and is an antibody or antigen-binding polypeptide as described in any one of items 3-5. Chido. (Item 7) The amino acid sequence of X1QSYSX2RT (sequence number 6724) or X3RDX4YGX5YFYDV (sequence number 6725) An antibody or antigen-binding polypeptide containing CDRH3, wherein X1, X2, X3, X4 and X5 is an independent of any amino acid, an antibody or antigen-binding polypeptide. (Item 8) In the formula, X1 is K or T, an antibody or antigen-binding polypeptide as described in item 7. (Item 9) In the formula, X1 is T, an antibody or antigen-binding polypeptide as described in item 7. (Item 10) In the formula, X2 is R or L, an antibody or antigen-binding compound as described in any one of items 7-9. Lipeptide. (Item 11) In the formula, X3 is A or G, an antibody or antigen-binding compound as described in any one of items 7-9. Lipeptide. (Item 12) In the formula, X4 is not G, but an antibody or antigen-binding polyp used in any one of items 7-11. Petit de. (Item 13) In the formula, X5 is R, A, G, or L, an antibody or antigen as described in any one of items 7-12. Binding polypeptide. (Item 14) An antibody containing CDRL1 with the amino acid sequence X1KSSQX2LLX3X4RTGKX5YLA (SEQ ID NO: 6726) or An antigen-binding polypeptide, wherein X1, X2, X3, X4, and X5 are independently any amino acid. An acid, antibody, or antigen-binding polypeptide. (Item 15) In the formula, X1 is K or R, an antibody or antigen-binding polypeptide as described in item 14. (Item 16) In the formula, X2 is S or N, an antibody or antigen-binding polypeptide as described in item 14. (Item 17) In the formula, X3 is E or N, an antibody or antigen-binding polypeptide as described in item 14. (Item 18) In the formula, X4 is A or S, an antibody or antigen-binding polypeptide as described in item 14. (Item 19) In the formula, X5 is N or S, an antibody or antigen-binding polypeptide as described in item 14. (Item 20) CDRL2 containing the amino acid sequence of WASTRES (SEQ ID NO: 6727) or GTX1KRAP (SEQ ID NO: 6728) An antibody or antigen-binding polypeptide comprising, where X1 is any amino acid, Antibodies or antigen-binding polypeptides. (Item 21) In the formula, X1 is N or D, an antibody or antigen-binding polypeptide as described in item 20. (Item 22) Antibodies or antigen-binding polypropylene containing CDRL3 with the amino acid sequence of KQSYSX1RT (SEQ ID NO: 6729) A peptide, wherein X1 is any amino acid, that is an antibody or antigen-binding peptide. Do. (Item 23) In the formula, X1 is R, an antibody or antigen-binding polypeptide as described in item 22. (Item 24) In the formula, X1 is L or I, an antibody or antigen-binding polypeptide as described in item 22. (Item 25) CDRH1 as described in any one of items 1-2, CDRH2 as described in any one of items 3-6, and Antibodies or antigens containing one or more of the CDRH3s listed in any one of items 7-13 Synthetic polypeptide. (Item 26) CDRL1 as described in any one of items 14-17, CDRL2 as described in any one of items 20-21, An antibody or anti-CDRL3 containing one or more of the CDRL3s listed in any one of items 22-24. Protoconjugated polypeptide. (Item 27) CDRH1 as described in any one of items 1-2, CDRH2 as described in any one of items 3-6, and item 7 CDRH3 as described in any one of items ~13, and CDRL1 as described in any one of items 14~17. CDRL2 as described in any one of items 20-21, and CDRL3 as described in any one of items 22-24. Antibodies or antigen-binding polypeptides. [Brief explanation of the drawing]

[0081] [Figure 1] Not specified [Figure 2] Not specified [Figure 3] Not specified [Figure 4A] Not specified [Figure 4B] Not specified [Figure 5] Not specified [Figure 6-1] Not specified [Figure 6-2] Not specified [Figure 7] Not specified [Figure 8] Not specified [Figure 9] Not specified [Figure 10A-1] Not specified [Figure 10A-2] Not specified [Figure 10B] Not specified [Figure 10C] Not specified [Figure 10D] Not specified [Figure 11A] Not specified [Figure 11B] Not specified [Figure 11C] Not specified [Figure 12A] Not specified [Figure 12B] Not specified [Figure 13-1] Not specified [Figure 13-2] Not specified [Figure 14] Not specified [Figure 15] Not specified [Figure 16] Not specified [Figure 17] Not specified [Figure 18] Not specified [Figure 19] Not specified [Figure 20] Not specified [Figure 21] Not specified [Figure 22] Not specified [Figure 23A] Not specified [Figure 23B] Not specified [Figure 24] Not specified [Figure 25A] Not specified [Figure 25B] Not specified [Figure 25C] Not specified [Figure 25D] Not specified [Figure 26A] Not specified [Figure 26B] Not specified [Figure 26C] Not specified [Figure 26D] Not specified [Figure 26E] Not specified [Figure 26F] Not specified [Figure 26G] Not specified [Figure 27-1] Not specified [Figure 27-2] Not specified [Figure 28A] Not specified [Figure 28B-1] Not specified [Figure 28B-2] Not specified [Figure 28C] Not specified [Figure 28D-1] Not specified [Figure 28D-2] Not specified [Figure 29A] Not specified [Figure 29B] Not specified [Figure 30] Not specified [Figure 31] Not specified [Figure 32] Not specified [Figure 33A] Not specified [Figure 33B] Not specified [Figure 33C] Not specified [Figure 34A] Not specified [Figure 34B] Not specified [Figure 34C]Not specified [Figure 34D] Not specified [Figure 35A-1] Not specified [Figure 35A-2] Not specified [Figure 35B] Not specified [Figure 36A-1] Not specified [Figure 36A-2] Not specified [Figure 36A-3] Not specified [Figure 36B-1] Not specified [Figure 36B-2] Not specified [Figure 36B-3] Not specified [Figure 36C] Not specified [Figure 37-1] Not specified [Figure 37-2] Not specified [Figure 38A] Not specified [Figure 38B] Not specified [Modes for carrying out the invention]

[0082] Unless otherwise specified, all technical and scientific terms used herein are defined as follows: This has the same meaning as universally understood by those skilled in the art to which this invention belongs. When used in a specification, the term "about" is used in relation to a specific enumerated number. If this occurs, it means that the value can change from the listed value to less than 1%. For example, as used herein, the expression “about 100” means 99 and 101, as well as that Includes all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0083] The aspects and embodiments of the present invention described herein include the aspects and embodiments. Please understand that this includes "consisting of" and "essentially consisting of."

[0084] The term "cluster of differentiation 3" or "CD3" generally refers to any native CD3 derived from any vertebrate source, including, for example, mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), and includes, without further indication, for example, CD3ε chain, CD3γ chain, CD3α chain, and CD3β chain. The term encompasses "full-length", unprocessed CD3 (e.g., unprocessed or non-modified CD3ε or CD3γ), as well as any form of CD3 resulting from processing in a cell. The term also encompasses native variants of CD3, such as splice variants or allelic variants. Examples of CD3 include the human CD3ε protein (NCBI reference sequence number NP 000724), which is 207 amino acids in length, and the human CD3γ protein (NCBI reference sequence number NP 000064), which is 182 amino acids in length. The term further refers to either the human or cynomolgus monkey CD3 epsilon protein, the amino acid sequence of which is shown, for example, in FIG. 18 of the present specification. "CD3εN27" and "CD3εN13" each refer to the 27 amino acids at the N-terminus and the 1 3 amino acids at the N-terminus of CD3, optionally containing chemical modifications or linkages made thereto. The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and these _ 000724), and this protein is 207 amino acids in length, and the human CD3γ protein (NCBI reference sequence number NP _ 000064), and this protein is 182 amino acids in length. The term further refers to either the human or cynomolgus monkey CD3 epsilon protein, the amino acid sequence of which is shown, for example, in FIG. 18 of the present specification. "CD3εN27" and "CD3εN13" each refer to the 27 amino acids at the N-terminus and the 1 3 amino acids at the N-terminus of CD3, optionally containing chemical modifications or linkages made thereto.

[0085] Some of these are further subclasses such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. They may be divided into different types (isotypes). They correspond to different classes of immunoglobulins. The heavy chain constant domains are called α, δ, ε, γ, and μ, respectively.

[0086] When used herein, the term "cytotoxic agent" also means an agent that inhibits cellular function. This refers to a substance that hinders and / or causes cell death or destruction. It is not limited to radioactive isotopes (for example, At 211 , I 131 , I 125 , Y 90 Re 186 Re 188 , Sm 153 , Bi 212 , P 32 Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g.) Methotrexate, Adriamycin, Vinca alkaloids (vincristine, vinba Rustine, etoposide, doxorubicin, melphalan, mitomycin C, chloram Bucil, daunorubicin or other inserts; growth inhibitors; enzymes such as nucleases, for example. Elements and their fragments; antibiotics; for example, low molecular weight toxins or bacteria, fungi, plants or animals Toxins, including their fragments and / or variants, such as enzyme-active toxins of origin; disclosed below. Various antitumor or anticancer agents can be cited.

[0087] "Disability" refers to any condition or disease for which treatment would be beneficial, and is not limited to... However, the disorders in question include pathological conditions that make mammals susceptible to chronic and acute conditions. This includes sexual disorders or conditions.

[0088] The terms "proliferative disorder" and "proliferative disorder" refer to a certain degree of abnormal cell proliferation and It refers to related disorders. In one embodiment, cell proliferation disorders include cancer. In this context, cell proliferation disorders include tumors.

[0089] The terms "cancer" and "cancerous" typically refer to uncontrolled cell proliferation, It refers to or describes a physiological condition in mammals. It is not limited to examples of cancer. These include carcinomas, lymphomas, blastomas, sarcomas, and leukemia or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma). Cancer, including small cell lung cancer, non-small cell lung cancer, lung adenoma, squamous cell carcinoma of the lung, peritoneal cancer, hepatic cell carcinoma Gastric cancer including splenic carcinoma, gastrointestinal cancer and gastrointestinal stromal carcinoma, pancreatic cancer, gliablastoma, cervical cancer, ovarian cancer Liver cancer, bladder cancer, urinary tract cancer, liver cancer (hepatoma), breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer Endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer Penile cancer, melanoma, superficial spreading melanoma, malignant lentiginous melanoma, acral lentiginous melanoma Lanoma, nodular melanoma, multiple myeloma, and B-cell lymphoma (low-grade / follicular) Non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, intermediate-grade / follicular NHL, intermediate-grade High-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade Small non-cleaved cell NHL, giant lesion NHL, mantle cell lymphoma, AIDS-associated lymphoma, and Chronic lymphocytic leukemia (CLL), including Valdenström's macroglobulinemia. Acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia, and translocation Post-plant lymphoproliferative disorder (PTLD) and abnormal vascular proliferation and edema associated with nevus disorders (e.g.) Edema associated with brain tumors), Meige syndrome, brain tumors and head and neck cancers, and related Metastasis is one example. In certain embodiments, cancers suitable for treatment with the antibody of the present invention include breast cancer. Cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, gliablastoma, non-Hodgkin lymphoma (NHL), renal cell carcinoma Cancer, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, Examples include ovarian cancer, mesothelioma, and multiple myeloma. In some embodiments, the cancer is small cell lung cancer. Cancer, gliablastoma, neuroblastoma, melanoma, breast cancer, gastric cancer, colorectal cancer (CRC), and hepatocellular carcinoma. The cancer is selected from among non-small cell lung cancer, colorectal cancer, gliablastoma. However, in some embodiments, the cancer is non-small cell lung cancer, colorectal cancer, gliablastoma. and from breast cancer, including and selected metastatic forms of those cancers. In other embodiments, the cancer is Hodg While kin lymphoma is ruled out, germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL are also considered. Follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic Lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), phosphorus Pa's plasmacytic lymphoma (LL), Valdenström macroglobulinemia (WM), central nervous system Neurological lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prelymphocytic leukemia, splenic lymphoma Marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassified, diffuse red pulp of the spleen Small B-cell lymphoma, hairy cell leukemia variant, Valdenström macroglobulin Blood cell myeloma, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, μ heavy chain disease, plasma cell myeloma, isolated bone cell Cytocytoma, extraskeletal plasmacytoma, extranodal marginal zone lymphoma (MALT lymphoma) of mucosa-associated lymphoid tissue Nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicular lymphoma central cell lymphoma, T-cell / histiocyte-enriched large B-cell lymphoma, primary DLBCL of the CNS, Primary cutaneous DLBCL, foot-shaped DLBCL, EBV-positive DLBCL in the elderly, DLBCL associated with chronic inflammation, lymphoma-like Granulomatous disease, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, HHV8-associated multicentric castle lymphoma Large B-cell lymphoma occurring in disease, primary exudative lymphoma: diffuse large B-cell lymphoma An unclassified B-cell lymphoma with features intermediate between lymphoma and Burkitt lymphoma, and It has features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. It is selected from certain types of mature B-cell cancers, including unclassified B-cell lymphomas.

[0090] As used herein, the term “tumor” refers to a malignant or benign tumor. , the growth and proliferation of all newly formed cells, and all precancerous and cancerous cells as well It refers to tissue. This includes terms such as "cancer," "cancerous," "proliferative disorder," "proliferative disorder," and "tumor." The terms, as used herein, are not mutually exclusive.

[0091] As used herein, the term “tumor antigen” refers to the antigen presented on tumor cells. These antigens can be understood as antigens. These antigens are presented on the cell surface in the extracellular portion. The extracellular portion is formed and, in many cases, combined with the transmembrane and cytoplasmic portions of the molecule. These antigens may occasionally be presented only by tumor cells, and never by normal cells. It is not presented. Tumor antigens may be expressed only on tumor cells, or on normal cells. In some cases, these may represent tumor-specific mutations compared to other mutations. In this case, they are called tumor-specific antigens. It will be discovered. Tumor antigens presented by tumor cells and normal cells are more common, and they These are called tumor-associated antigens. Compared to normal cells, tumor cells have different levels of tumor-associated antigens. It can be overexpressed, and antibodies can access it and bind to tumor cells. This is because tumor tissue has a denser structure compared to normal tissue.

[0092] "EC 50 The term "median effective concentration" refers to the biological or biochemical value. This method measures the effectiveness of a compound (e.g., an antibody containing an anti-CD3 binding domain) in relation to its usefulness. Yes, this quantitative measure indicates whether a particular compound or antibody causes a given biological process to reach its maximum reaction. This indicates the amount or concentration required to induce a reduction to half.

[0093] "Effector function" refers to the biological activity originating from the Fc region of an antibody, and the isota of an antibody. It changes depending on the type. Examples of antibody effector functions include: C1q binding Complement-dependent cell-mediated cytotoxicity (CDC), Fc receptor binding, and antibody-dependent cell-mediated cytotoxicity (ADCC) , phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0094] For example, compounds such as the anti-CD3 antibody or its composition (e.g., pharmaceutical composition) of the present invention have "Efficacy" refers to the measurable improvement or prevention of a specific disorder (e.g., cell proliferation disorders such as cancer). and the minimum amount required to achieve the desired therapeutic or preventive outcome. In this specification, the effective amount is determined by, for example, the disease state, the patient's age, sex and weight, etc. Furthermore, it can vary depending on factors such as the ability of the antibody to elicit the desired response in an individual. Efficacy is also defined as the amount in which the therapeutic benefits outweigh any toxic or adverse effects of the treatment. Also, with regard to preventative use, beneficial or desired results include, for example, the elimination of risk. This may include a decrease in the severity of the disease, or a delay in the onset of the disease. The biochemical, histological, and / or behavioral symptoms, their complications, and the manifestations during the development of the disease. Intermediate pathological phenotypes are included. Regarding therapeutic use, beneficial or desired results are not achieved. For example, a reduction in one or more symptoms resulting from a disease, or an improvement in the quality of life of an individual suffering from a disease. Increased dosage, reduced dosage of other medications needed to treat the disease, for example, disease targeting, disease progression This includes enhancing the effects of another drug through delaying the line of action and / or extending survival time. In the case of cancer or tumors, the effective dose of the drug has the effect of reducing the number of cancer cells, tumor size The effect of reducing the number of cells, inhibiting the invasion of cancer cells into peripheral organs (i.e., to some extent). The effect of slowing down, or preferably stopping, tumor growth to a certain extent. The effect of alleviating, to some extent, one or more of the symptoms associated with the disorder. It may have. The effective amount can be administered in one or more doses. The effective amount of the drug, compound, or pharmaceutical composition is directly or indirectly effective in preventing the target. Or it is a sufficient amount to achieve therapeutic action. As understood in clinical practice, the drug The effective amount of an agent, compound, or pharmaceutical composition is used in combination with another agent, compound, or pharmaceutical composition. It may or may not be achieved. Therefore, the "effective quantity" is one Alternatively, it may be considered in situations where multiple therapeutic agents are administered, or in combination with one or more other agents. If the desired result is achieved, or if the desired result is attained, then the single agent is administered in an effective dose. It may be considered to be granted.

[0095] In this specification, the term "Fc region" refers to an imm that includes at least a portion of the constant region. This term is used to define the C-terminal region of the noglobulin heavy chain. The region and variant Fc region are included. In one embodiment, the Fc region of the human IgG heavy chain is Cys This ranges from 226, or Pro230, to the carboxyl terminus of the heavy chain. However, The C-terminal lysine (Lys447) in the Fc region may or may not be present. Unless otherwise specified, the numbering of amino acid residues in the Fc region or constant region The index follows the EU numbering system, also known as the EU index. This system is based on the Kab system. at et al., Sequences of Proteins of Immunological Interest, 5th Ed. P Public Health Service, National Institutes of Health, Bethesda, Md., 199 It is described in 1.

[0096] "Framework" or "FR" refers to variable domains other than complementarity-determining region (CDR) residues. This refers to a residue. The variable domain FR generally consists of the following four FR domains: FR1, FR2 FR3 and FR4. Therefore, the CDR and FR sequences are generally VH (or VL) The following sequence exists: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0097] The terms "full-length antibody," "complete antibody," and "whole antibody" are interchangeable in this specification. Antibodies that can be used and have a structure substantially similar to that of the natural type antibody, or specified herein This refers to antibodies that have a heavy chain containing the Fc region as described above.

[0098] As used herein, "growth inhibitor" means in vitro or in vivo This refers to a compound or composition that inhibits cell proliferation in any way. In one embodiment, proliferation Inhibitors are growth inhibitors that prevent or reduce the proliferation of cells expressing the antigen to which the antibody binds. It is an antibody. In another embodiment, the proliferation inhibitor significantly reduces the proportion of cells in the S phase. It may also be a drug that inhibits growth. Examples of growth inhibitors include those that inhibit the progression of the cell cycle (stages other than the S phase). Examples of interfering agents include those that induce G1 arrest or M-phase arrest. Classical M As for period blockers, vinca compounds (vincristine and vinblastine) and taxanes. And topoisomerase II inhibitors, such as doxorubicin, epirubicin, and da Examples include unorubicin, etoposide, and bleomycin. Agents that stop G1 are also S Effective in stopping DNA rupture, for example, DNA alkylating agents such as tamoxifen and prednisone. dacarbazine, mechloretamine, cisplatin, methotrexate, 5-fluorouracil Examples include ru and ara-C. For further details, see Mendelsohn and Israel, eds., The Molecules. ar Basis of Cancer, Chapter 1, entitled “Cell cycle regulation, oncog enes, and antiplastic drugs” by Murakami et al. (WB Saunders, Ph. For example, it can be found on page 13 of Iladelphia, 1995. Taxanes (Paclitaxes) Both yew and docetaxel are anticancer drugs derived from the yew tree. TAXOTERE (registered trademark, Rhone-Poulenc Rorer) is derived from the European yew, and Pak It is a semi-synthetic analog of ritaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote microtubule assembly from tubulin dimers. This inhibits depolymerization and stabilizes microtubules, thereby inhibiting mitosis in cells.

[0099] Antigens and terms containing the phrase "~positive," such as "HER2-positive," refer to diseases, conditions, etc. Or the disorder is characterized by elevated levels of the antigen or target, in particular, that are above normal levels. This means that it can be detected. In certain embodiments, the antigen or target is detected at a higher level than normal cells. Bell is expressed on cancer cells, or by other means, at higher levels on cancer cells than on normal cells. This includes the part that exists in [the present state].

[0100] The terms "host cell," "host cell line," and "host cell culture" are interchangeable. This refers to cells into which exogenous nucleic acids are used, and also includes the progeny cells of those cells. The host cell is This includes "transformed organisms" and "transformed cells," and these cells, regardless of passage number, are first It includes transformed cells and their offspring cells. The offspring cells have nucleic acids that are different from those of the parent cells. The contents may not be completely identical and may contain mutations. A sudden change having the same function or biological activity as those screened or selected Mutant progeny cells are also included in this specification.

[0101] "Human antibodies" are antibodies produced by humans or human cells, or human antibody repertoires. amino acids of antibodies derived from non-human sources that utilize Lee or other human antibody coding sequences. This is an antibody that possesses the corresponding amino acid sequence. This definition of a human antibody is related to the binding of non-human antigens. Humanized antibodies containing residues are explicitly excluded. Human antibodies are phage display live. It can be manufactured using various techniques known in this field, including the Lari method. enboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. M ol. Biol., 222:581 (1991). Furthermore, methods available for the production of human monoclonal antibodies. Also, Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Lis s, p. 77 (1985); Boerner et al., J. Immunol. 147(1):86-95 (1991) It is stated in van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368. See also -74 (2001). Human antibodies are produced in response to antigen challenge. However, in transgenic animals, the endogenous locus is modified to be rendered incapacitated, for example, immunosuppressants. It can be produced by administering antigens to infected xenomouses, etc. (xenomouse technology) For more information, see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584. Regarding human antibodies produced via human B cell hybridomas, see Li et al., Pro See also c. Natl. Acad. Sci. USA, 103:3557-3562 (2006). When used in this context, the term "human antibody" refers to an immunoglobulin compound of the human germline. The invention is intended to include an antibody having a variable region and a constant region derived from the column. TomAb, for example in CDRs, particularly CDR3, is found in the immunoglobulin sequences of human germline cells. Unencoded amino acid residues (e.g., random or site-directed mutations in vitro) This includes mutations introduced by induction or mutations introduced by in vivo somatic mutations. In some cases, however, as used herein, the term "human antibody" may be used. CDR sequences derived from the germline of another mammalian species (e.g., mouse) are found on human FR sequences. It is not intended to contain transplanted mAbs.

[0102] The "Human Consensus Framework" is a VL or VH framework for human immunoglobulins. This framework represents the most commonly present amino acid residues in the selection of work sequences. Generally, the selection of VL or VH sequences for human immunoglobulins is based on the variable domain sequence. It is from subgroups. Generally, subgroups of sequences are described in Kabat et al., Sequences of Proteins. of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethe These are subgroups as found in sda Md. (1991), vols. 1-3. In one embodiment, regarding VL... The subgroup is subgroup Kappa I, as described by Kabat et al. above. In one embodiment, with respect to VH, The subgroup is subgroup III, as described by Kabat et al. above.

[0103] A "humanized antibody" is an amino acid residue derived from a non-human CDR and an amino acid derived from a human FR. This refers to an antibody containing an acid residue. In certain embodiments, the humanized antibody contains at least one characteristic In terms of type, it contains virtually all of the two variable domains, within which (for example, CDR) All, or virtually all, correspond to those of non-human antibodies, and all, or actual, FRs. Qualitatively, everything corresponds to that of human antibodies. Humanized antibodies are optional and derived from human antibodies. It may contain at least a portion of the antibody constant region. For example, a humanized form of an antibody such as a non-human antibody and This refers to antibodies that have undergone humanization.

[0104] An "immune complex" is a compound formed by one or more heterologous molecules, including, but not limited to, cytotoxic agents. These are immunoassayed antibodies.

[0105] The "subject" or "individual" is a mammal. Mammals include domesticated animals (e.g., cattle). (Sheep, cats, dogs and horses), primates (e.g., humans and non-human primates such as monkeys) This includes, but is not limited to, rabbits and rodents (e.g., mice and rats). Not possible. In certain embodiments, the subject or individual is a human.

[0106] "Isolated antibodies" are antibodies that have been isolated from components of their natural environment. In terms of application methods, antibodies can be detected by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF)), etc. By pyrary electrophoresis or chromatography (e.g., ion exchange or reverse-phase HPLC) When determined, the antibody is purified to a purity of over 95% or 99%. Regarding the evaluation of antibody purity... For a review of the methods, see, for example, Flatman et al., J. Chromatogr. B 848:79- See 87 (2007).

[0107] "Isolated nucleic acid" refers to nucleic acid molecules that have been separated from their natural environment. Acids contain nucleic acid molecules that are normally found in cells containing nucleic acid molecules, but these nucleic acid molecules , located outside the chromosome, or located at a chromosomal position different from its natural chromosomal location. .

[0108] The terms "monoclonal antibody" or "mAb" are used herein in the context of the context of this document. This refers to antibodies obtained from a group of antibodies that are substantially homogeneous. In other words, the individual antibodies that make up the group Each antibody is identical and / or binds to the same epitope. However, for example, To prepare latent variant antibodies or monoclonal antibody preparations containing natural mutations. Potential variant antibodies that develop during the process are excluded. Such variant antibodies are generally present in small amounts. Yes, they exist. They typically contain polychromosomes that include different antibodies directed towards different determinants (epitopes). In contrast to monoclonal antibody preparations, each monoclonal antibody in a monoclonal antibody preparation is It is directed towards a single determinant on the antigen. Therefore, the modifier "monoclonal" is essentially This shows the characteristics of antibodies obtained from a homogeneous group of antibodies, but also the characteristics of antibodies obtained by any specific method. The production of monoclona is not considered necessary. For example, monoclona used in accordance with the present invention Antibodies may be produced using various techniques, and are not limited to such techniques. Hybridoma method, recombinant DNA method, phage display method, and human immunoglobulin One possible method is to use transgenic animals that contain all or part of the phosphorus locus. Such methods and other exemplary methods relating to the production of monoclonal antibodies are described in this book. It will be stated in the details.

[0109] The terms "pharmaceutical preparation" or "pharmaceutical composition" refer to the biological activity of the active ingredients contained therein. This refers to a preparation in a form that enables activity. Examples of the active ingredient include the CD3 bond of the present invention. Domains and antibodies containing them, and such preparations are effective This refers to a preparation in which no additional toxic components unacceptable to the target population are included.

[0110] A "pharmaceutically acceptable carrier" is a pharmaceutical product containing a non-toxic active ingredient other than the active ingredient. This refers to the components. Pharmaceutically acceptable carriers include buffers, excipients, stabilizers, or preservatives. These include, but are not limited to, the following:

[0111] The term "therapeutic dose" refers to the amount administered that produces the desired effect. The exact amount depends on the therapeutic purpose and can be determined by those skilled in the art using known techniques. It is possible to recognize this (for example, Lloyd (1999) The Art, Science and Technology (See gy of Pharmaceutical Compounding).

[0112] As used herein, "immune response" or "immunological response" means an immune response to a subject. In this context, humoral immune response, cellular immune response, or humoral and cellular immune response to an antigen / immunogen. This refers to the manifestation of an epidemic reaction. A "humoral immune response" is at least partially mediated by antibodies. It refers to a reaction. "Cellular immune response" is caused by T lymphocytes or other white blood cells or both. It is an mediated reaction, and the cytokine produced by activated T cells, leukocytes, or both. This includes the production of chemokines and their analogues. The immune response is a standard immunoassay. This can be determined by the I method and the neutralization assay method, and these methods are well known in the art. .

[0113] "Immunogenicity," as used herein, refers to bacteria that cause specific diseases or These are proteins or peptides that trigger an immune response specifically directed against viruses. This refers to Do's ability.

[0114] As used herein, "treatment" (and for example, "to treat" or "to cure") Grammatical variations such as "to do" mean to alter the natural course of the individual being treated. This refers to clinical interventions in trials, carried out either for preventive purposes or during the course of a clinicopathological condition. It is possible. The desired effects of treatment are not limited to the onset or recurrence of the disease. Prevention of disease, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention of metastasis, These include a reduction in the rate of disease progression, improvement or alleviation of the disease state, and remission or improved prognosis. In some embodiments, the antibodies of the present invention are used to delay the onset of injury or disease. To slow down the progression of a disability or disease.

[0115] As used herein, “delay in the progression” of a disability or disease means the progression of the disability. or to delay, inhibit, or postpone the onset of a disease (e.g., cell proliferation disorders, e.g., cancer). , to fix, stabilize, and / or postpone. This delay is The length of time may vary depending on the disease and / or the medical history of the individual being treated. As is evident, a sufficient or significant delay effectively means that the individual has the disease. Prevention encompasses the act of preventing the occurrence of a disease, such as metastasis in advanced cancer. These may be delayed.

[0116] "To decrease" or "to inhibit" means, for example, more than 20%, more than 50%, or 75%, 85%, This means the ability to produce an overall reduction of 90%, 95%, or more. In certain embodiments, the reduction Inhibition may refer to the effector function of an antibody mediated by the antibody's Fc region, and so on. Its effector functions include complement-dependent cell-mediated cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity. Examples include ADCC (antibody-dependent cell phagocytosis) and antibody-dependent cell phagocytosis (ADCP).

[0117] As used herein, “prevent,” “prevent,” and “prevention” The term refers to the prevention or inhibition of the onset or development of a disorder or disease.

[0118] As used herein, the terms “improvement” and “reduction” refer to a state or condition. This refers to a reduction or decrease in the severity of any given symptom.

[0119] In this specification, the term "antibody" is used in its broadest sense and refers to various antibody structures. This includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, and multispecific antibodies. (e.g., a bispecific antibody) and antibody fragments insofar as they exhibit the desired antigen-binding activity. Regarding multispecific antibodies, such antibodies have at least two different antigen-binding domains. It contains and recognizes and specifically binds to at least two different antigens. Regarding specific antibodies, such antibodies contain two different antigen-binding domains, and they are few At the very least, it recognizes and specifically binds to two different antigens. "Different antigens" means different Become and / or separate proteins, polypeptides or molecules, as well as different It may refer to a single epitope or a separate epitope, and that epitope is a single protein. Polypeptides, or other molecules that may be contained within them. Unless otherwise indicated, this specification. When used in this context, the term "antibody" refers to two immunoglobulins in addition to the above. An antibody molecule containing a heavy chain and two immunoglobulin light chains (i.e., a "complete antibody molecule") It should also be understood that this includes the antigen-binding fragment. The "antigen-binding portion" of the antibody, the " When used herein, terms such as "antigen-binding fragment" refer to fragments that specifically bind to an antigen. The complex is formed from any of the following: natural, enzymatically obtainable, synthetic, or genetically derived materials. Contains manipulated polypeptides or glycoproteins.

[0120] An "antibody" is a molecule consisting of four polypeptide chains, which are interconnected by disulfide bonds. An immunoglobulin molecule (i.e., "complete") is composed of two heavy chains (H) and two light chains (L). The term "total antibody molecule" may also refer to its multiple forms (e.g., IgM) or their antigen-binding fragments. Yes. Each heavy chain has a variable heavy chain region (VH) and a constant heavy chain region (domain C). H 1. C H 2 and C H 3 Each light chain consists of a variable light chain region (VL) and a constant light chain region (C). It consists of L) and V H Region and V L The domain was further named the Framework Domain (FR). A more conservative region and a highly variable region called the Complementarity Determination Region (CDR) located between them. It can be divided into the realm of sexuality. V H and V LEach consists of three CD-Rs and four FRs, as follows: The order is arranged from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR 3. FR4. In certain embodiments of the present invention, the FR of the antibody (or its antigen-binding fragment) is human. The sequence may be identical to that of the proliferative cell lineage, or it may be natural, or it may be artificial. Modifications are acceptable. The consensus sequence of amino acids is determined by analyzing two or more CDRs side by side. The results may be used to define the CDRs of the heavy chains, respectively: "CHRH1" and "CDRH The CDRs of the light chain are designated as "CDRL1", "CDRL2", and "CDRL3". It is specified as follows.

[0121] An "antibody fragment" is a complete antibody containing the part of the complete antibody that binds to the antigen to which the complete antibody binds. This refers to molecules other than [the specified molecule]. Examples of antibody fragments include Fv, Fab, Fab', Fab'-SH, F(ab') 2, and Dye. Multispecificity formed from antibody bodies, linear antibodies, single-chain antibody molecules (scFv), and antibody fragments. Antibodies are an example, but are not limited to them.

[0122] The "binding domain" or "antigen-binding domain" refers to the target epitope, antigen, or ligand. This refers to the part of an antibody, compound, or molecule that specifically binds to a receptor. Domains include antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies) Antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or parts thereof (e.g., Fab fragments, Fab 2, scFv antibody, Fv fragment, SMIP, domain antibody, diabody, minibody, scFv-Fc, Af Body, nanobody, and VH and / or VL domains of antibodies, receptors, ligans Examples include ions, aptamers, and other molecules with identified binding partners. This is not limited to these.

[0123] "Affinity-matured antibodies" are antibodies that have one or more complementarity-determining regions (CDRs) This refers to an antibody having one or more modifications, compared to a parent antibody that does not have such modifications. The modification improves the antibody affinity to the antigen. One or more CDRs Substitution of residues or omission of one or more CDRs is also possible. Antibodies are described in scientific literature. It is stated that, regarding the combination, one or two CDRs may be omitted. Padlan et al. (1995 FASEB J. 9:133-139) have shown that the contact area between the antibody and its antigen is Based on the publicly released crystal structure, analysis revealed that only about one-fifth to one-third of the CDR residues were actually present. It was concluded that the antigen was in contact with the antibody. Padlan found that in many antibodies, one or two CDRs were present. It was also found that there were no amino acids in contact with the antigen (Vajdos et al. 2002 J See also Mol Biol 320:415-428). CDR residues that are not in contact with the antigen are molecular models. By means of and / or empirically, from the region of KabatCDR that is outside of ChothiaCDR, This can be identified based on past research (for example, residues H60-H65 of CDRH2 are often necessary). (Not considered). If the CDR or its residue is omitted, it is usually not considered in another human antibody sequence. It is replaced by the amino acid at the corresponding position or the consensus of such sequence within the CDR. The position of the substitution and the amino acid to be substituted can also be selected empirically.

[0124] The fully human monoclonal antibodies disclosed herein are based on the sequence of the corresponding germline and In comparison, the frameworks of heavy chain variable domains and light chain variable domains and / or The CDR region includes one or more amino acid substitutions, insertions, and / or deletions. Such mutations can occur. For example, in the publicly available antibody sequence data. This can be easily confirmed by comparing it with the available germline sequences from the database. This is possible. The present invention relates to antibodies derived from any of the amino acid sequences disclosed herein. The antigen-binding fragment thereof, in this case, one or more frameworks and / or one or more amino acids within the CDR region are germline from which the antibody originates. For the corresponding residue, or for the corresponding residue in the sequence of another human germ cell lineage, Alternatively, the mutation is applied to the conserved amino acid substitution of the corresponding residue in the corresponding germline sequence. (Such sequence changes are collectively referred to as "germline mutations" in this specification.) (To be referred to). Those skilled in the art will understand the heavy chain variable region sequence and light chain variable region disclosed herein. Starting with a sequence, one or more individual germline mutations or combinations thereof. Many antibodies and antigen-binding fragments can be readily produced, including in certain embodiments. V H and / or V L The framework within the domain and / or CDR residues are anti The body is mutated back to residues present in the original germline sequence from which it originates. Other embodiments Then, only specific residues are reverse-mutated back to the original germline sequence. For example, the first residue of FR1 Only mutant residues located within the 8 amino acids of, or within the last 8 amino acids of FR4, or CDR1 In other embodiments, One or more of the framework and / or CDR residues are different germline The sequence (i.e., the germline sequence which is different from the germline sequence from which the antibody originally originates) The corresponding residues in the column are mutated. Furthermore, the antibody of the present invention is also a framework and / or The CDR region may contain any combination of two or more germline mutations, for example If a specific individual residue is mutated to the corresponding residue in a specific germline sequence, then the original Certain other residues that are different from the germline sequence are maintained, or different germline sequences The corresponding residues in the column are mutated. At the time of acquisition, one or more germline mutations occur. Antibodies and antigen-binding fragments containing different properties can be easily tested for one or more desired properties. This can be demonstrated. Desired characteristics include, for example, improved binding specificity and binding affinity. Increase, improvement or enhancement of antagonistic or agonistic biological characteristics (in cases) Therefore, (for example) a decrease in immunogenicity may occur. Antibodies obtained by this general method and The antigen-binding fragments are included within the scope of the present invention.

[0125] Furthermore, the present invention relates to a CDR ami having one or more conservative substitutions as disclosed herein. It contains a complete monoclonal antibody containing any variant of the noacid sequence. For example, this The clearing is compared to any of the CDR amino acid sequences disclosed herein, for example, 10 or fewer, 8 Antibody having a CDR amino acid sequence with conservative amino acid substitutions such as one or fewer, six or fewer, or four or fewer amino acids. Including the body.

[0126] "Anti-CD3 antibody," "Anti-CD3 binding domain-containing antibody," "CD3-binding antibody," "CD3 binding" Terms such as "domain" and "antibody containing a CD3-binding domain" require sufficient affinity. It can bind to CD3 and / or has specificity, thereby allowing the antibody to target CD3. This refers to antibodies (or CD3-binding domains) that are useful as diagnostic and / or therapeutic agents. In one embodiment, the degree to which an anti-CD3 antibody binds to an unrelated non-CD3 protein is: For example, one of the affinity measurement techniques and apparatus based on various solutions and surfaces. When measured by such techniques, the binding of antibodies to CD3 is less than 10%. And as for the equipment, for example, biolayer interferometry (BLI), surface plasmon resonance (SPR), Solution equilibrium-based dynamic exclusion assay Based on sion assays, ForteBio instruments and reagents, such as Octet RED 384 and HTX BLI. KinExA direct association assay using the instrument, enzyme-linked immunoassay Examples include immunosorbent assay (ELISA) and radioimmunoassay (RIA) (e.g., Estep et al.) , MAbs, Vol. 5, pages 270-278 (2013); Yu et al., J Biomol Screen, V See ol. 21, pages 88-95 (2016). In certain embodiments, it is coupled to CD3. Antibodies are available in concentrations of <1 mM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 nM). -8 More than M For example, 10 -8 M~10 -13 M, for example, 10 -9M~10 -13 It has a dissociation constant (Kd) of M. In certain embodiments, the anti-CD3 antibody is used to identify the CD3 epitome that is conserved among different species of CD3. Connect to the pu.

[0127] The term “developable” refers to one or more polypeptides among multiple polypeptides. This refers to the degree to which it possesses desirable characteristics such as the following: for example, the desired characteristics in mammalian cells. Expression, solubility, viscosity, aggregation, chemical stability and / or physical stability, desirable "preservation" "Shelf life," melting point, pharmacokinetic profile, circulating half-life, and clearance characteristics. These characteristics indicate that one or more polypeptides have been successfully developed as therapeutic agent candidates, and ultimately Regarding the possibility of becoming an approved drug, it is treated independently as a mark, and the sub-marks of said mark They may be treated as a combination of sets, or as a whole. Therefore, in this field As can be understood, polypeptides that possess the desired development potential characteristics are generally, for example It has relatively high solubility, relatively low viscosity, relatively low tendency to aggregate, and relatively high chemical stability. Relatively high physical stability, relatively long "storage period", relatively high melting point, relatively long It possesses a cyclic half-life and a relatively long clearance time. Polypeptides exhibiting these characteristics include, for example, relatively low solubility, relatively high viscosity, and relatively high aggregation. Tendency, relatively poor chemical stability, relatively poor physical stability, relatively short "storage" "Duration," relatively low melting point, relatively short cyclic half-life, relatively long short clearance time, etc. They own it.

[0128] For example, the CD3 binding domain of the present invention and polypeptides such as antibodies containing it, To what extent does it possess the desired (or, in some cases, undesirable) characteristics of development possibilities? Methods and assays that may be employed for verification are available in this field, for example See also WO 2014 / 179363 and Xu et al., Protein Eng Des Sol, Vol. 26, 663-67. Methods and assays disclosed on page 0 (2013); crossovers such as SMP and SCP assays. Interaction chromatography (CIC); Self-interaction chromatography (SIC); Dynamic light Scattering; Size exclusion chromatography (SEC), Dynamic light scattering (DLS) spectroscopy; Photon correlation spectroscopy Methods; quasi-elastic light scattering, circular dichroism (CD), viscosity measurement; whole-cell binding; tissue microarray techniques Method; BVP ELISA assay; AC-SINS assay (Liu et al; MAbs, Vol. 6, pages 48) 3-492 (2014)); This includes differential scanning calorimetry (e.g., He et al., J. Pharm. S ci., Vol. 100(4), pp. 1330-1340 (2011); Wagner et al., Pharm. Develop. & Technol (posted online 2012; hyper-text transfer protocol: informahe althcare.com / doi / abs / 10.3109 / 10837450.2011.649851); Hotzel et al., mAbs, Vo l. 4(6), pages 753-7601 (2012); Weiqiang et al., J. Pharm. Sci., Vol. 101(5), pp. 1701-1720 (2012); Banks et al., J. Pharm. Sci., Vol. 10 1(8), pp. 2720-2732 (2012); Lie et al., J. Pharm. Sci., Vol. 94(9), pp. 1928–1948 (2005); and Payne et al., Biopolymers, Vol. 85(5), pp. 5 See 27-533 (2006).

[0129] Furthermore, the CD3 interface of the present invention, for example, has been selected or identified as having enhanced development potential. Synthetic domains and polypeptides such as antibodies containing them are referred to as "developable." The development potential has decreased, and the polypeptide detected in accordance with this disclosure and the requested method Chido is detected as such due to its interaction with the disclosed and claimed PSR. Therefore, it is referred to as a "polyspecific" polypeptide. Lipeptides are also relatively "undevelopable" or relatively "undevelopable" polypeptides It is referred to as "Do".

[0130] Any means for detecting interactions between one or more polypeptides, and The part in which one or more polypeptides interact, as disclosed and requested It may be adopted according to the method. An example of such a method is flow cytometry. Methods; Magnetically activated cell sorting (MAGS); Fluorescence-assisted cell sorting (FACS); Immunotherapy Chemical methods; column and / or affinity chromatography or separation; precipitation techniques Methods (e.g., centrifugation); immunoprecipitation; 2-hybrid methods, e.g., mammalian 2-hybrid methods. Methods and yeast 2-hybrid methods; fluorescence resonance energy transfer (FRET) assays; Affinity Examples include dichromatography. In certain embodiments, such interactions For detection, magnetically activated cell sorting (MAGS) and fluorescence-assisted cell sorting (FACS) are used. ; and / or magnetically activated cell sorting (MAGS) and fluorescently activated cell sorting (FA) This includes the use of combinations of CS.

[0131] The "development feasibility score" is also known as the "development feasibility profile," and this specification... As described in the book, and for example, WO 2014 / 179363 and Xu et al., Protein As described in Eng Des Sol, Vol. 26, pages 663-670 (2013), the feasibility of development When evaluation is performed, the CD3 binding domain of the present invention and / or antibodies containing it are assigned This refers to an indicator that can be developed. Therefore, the development feasibility score is for CD3-binding substances and / or this The feasibility of developing antibodies containing this can be evaluated, compared, and / or rated using evaluation scales. It is a degree or evaluation criterion. Such a development feasibility score is used for CD3-binding substances and antibodies containing them. It serves as a measure of the degree of bodily interaction. The degree of interaction is determined by the parts that are connected. This field provides output values ​​that correlate with the strength or affinity of polypeptides relative to minutes. It may be evaluated by any number of means available. Examples of such means include, Low cytometry methods, such as FACS; ELISA; quantitative immunoaffinity assays or immunoassays. Plaque precipitation assay; mammalian 2-hybrid assay or yeast 2-hybrid assay Examples include the method. In the case of FACS, as shown in the examples, multiple polypeptides The degree of interaction between polypeptides and PSRs is determined by the detected polypeptide-PSR interactions. Generate the average fluorescence intensity (MFI) for each element, and then sort the MFIs in either ascending or descending order. The order is determined according to the relative degree of interaction between each polypeptide and PSR detected therein, and multiple This can also be confirmed by classifying the polypeptides within the polypeptide. By assigning ratings to multiple polypeptides, we can identify polypeptides with high development potential. Peptides are easily identified, and polypeptides with low development potential are also easily identified. It is recognized. In certain embodiments, MFIs of 500 or less have high development potential. This is an indicator of the product. In certain embodiments, MFIs of 400 or less have high development potential. This is an indicator of peptides. In certain embodiments, an MFI of 300 or less indicates high development potential. This is an indicator of polypeptides. In certain embodiments, an MFI of 200 or less indicates high development potential. This is an indicator of the polypeptides possessed. In certain embodiments, an MFI of 100 or less indicates high development potential. This is an indicator of polypeptides that possess the potential for low performance. In certain embodiments, an MFI of 1000 or more indicates low performance. This is an indicator of polypeptides that possess development potential. In certain embodiments, there are more than 900 MFIs. This is an indicator of polypeptides with low development potential. In certain embodiments, 800 or The above MFI is an indicator of polypeptides with low development potential. In certain embodiments, A MFI of over 700 is an indicator of polypeptides with low development potential. In this context, an MFI of 600 or less is an indicator of a polypeptide with low development potential.

[0132] Furthermore, the development feasibility score may take the form of a standardized score on a scale of, for example, 0.0 to 1.0. The scores of one or more test CD3-binding substances and / or antibodies containing them are also standard. Alternatively, it was determined by performing an assay using a control polypeptide or antibody. It is standardized against a development feasibility score. Examples of such standard or control antibodies are, for example, This includes lysozyme-conjugated (HEL) antibodies for chicken eggs, such as ADI-03847.

[0133] "Cytokine release syndrome," "cytokine release crisis," or "cytokine" The term "storm" refers to a pro-inflammatory positive feedback loop between cytokines and immune cells. This refers to a loop, which causes excessive or controlled activity of cells within the immune system (e.g., T cells). Uncontrolled release of pro-inflammatory cytokines occurs (e.g., Lee et al., Blood, Vol. 124, pages 188-195 (2014) and Tisoncik et al., Microbiol Mol B See iol Rev, Vol. 76, pages 16-32 (2012). Although we do not want this to happen, when stimulated and activated, immune cells (e.g., T cells) It releases a series of cytokines to levels and degrees that produce harmful biological / physiological effects, Or, for example, redness, swelling or edema, fever, pain and "mechanism" Loss of function: When localized in the skin or other tissues: increased blood flow, white blood Blood cells and plasma proteins can reach the external vascular site of the trauma, above local temperature. The onset of elevation and pain, tissue edema and extravascular pressure, and decreased tissue perfusion; organs and Systemic functional impairment, e.g., cardiac dysfunction, adult respiratory distress syndrome, neurotoxicity, renal failure and / or The severity and severity of acute inflammation, including liver failure and disseminated intravascular coagulation syndrome. It is thought that this alters the series of cytokine releases to the degree of severity. It is thought that IFNγ, IL-6, TNFα, TGFβ, IL-2, and granulocytes are associated with the development of CRS, but IFNγ, IL-6, TNFα, TGFβ, IL-2, and granulocytes are also involved. Clophage colony-stimulating factor (GM-CSF), IL-10, IL-8, IL-5, and / or flux Elevated talcaine levels may be involved as a precursor and / or cause of CRS, This suggests a tendency for CRS to occur upon T cell stimulation. In a specific embodiment of the present invention, CD3 Interruption by T cells incubated with the synthetic domain and antibodies containing it Ikin-6 (IL-6), Interleukin-12 (IL-12), Tumor Necrosis Factor Alpha (TNFa); (TG Fb); interleukin-2 (IL-2); and / or interferon-gamma (IFNg) An increase in production levels predicts a tendency for CRS to occur. In certain embodiments of the present invention, CD3 Interaction by T cells incubated with the binding domain and antibodies containing it Elevated levels of feron-gamma (IFNg) production predict a tendency for CRS to develop.

[0134] The "Cytokine Release Syndrome Risk Score" is the "Cytokine Release Syndrome Risk Profile" Also known as "file," "CRS risk score," or "CRS risk profile." incubate with the CD3-binding domain of the present invention (and / or an antibody containing it). The cytokine production level from T cells that have been treated or come into contact with the target cells is measured in the cytokine It is predicted or expected to be sufficient to induce in-release syndrome, and / Or, when evaluating the tendency to cause it to actually occur to the indicated level, the present invention's CD3 This refers to an index that can be assigned to the binding domain and / or the antibody containing it. The development feasibility score assesses the CRS risk of CD3-binding substances and / or antibodies containing them. such an evaluation scale or criterion that can be compared and / or rated. The CRS risk score is determined by the effectiveness of CD3-binding agents and antibodies containing them in vitro (e.g., in cell systems). Cytokine release is increased either in vivo (e.g., in the subject or patient). When evaluating Sei, the tendency of either an indicator or suggestion that triggers cytokine release It is useful as an evaluation scale. Such assays are available to those skilled in the art, and the invention is specific. In one embodiment, either a cultured cell line or primary cells obtained from a living donor. Including the use of such PBMCs, for example, a CD3-binding domain and an antibody containing it, immobilized, Alternatively, a cell line cytokine release assay performed preferably in the form of a soluble antibody. The ability to induce cytokine production / secretion in this context is evaluated (e.g., Vessillier et al.) See al., J Immunol Methods, Vol. 424, pages 43-52 (2015). Generally, cytokine production levels, which are measured as an indicator or forecast of CRS risk, Cytokine release, as understood by the vendor and / or disclosed in the relevant literature. Measured with known inducers of the syndrome or cytokine storm (i.e., positive control) When the level of the test molecule is lower than the level of the test inducer, CRS is induced by the test inducer. The "square" is an indicator of smallness.

[0135] The term "recombinant" generally refers to any protein created by genetic engineering. This refers to cells that express polypeptides or target genes. (Protein or polypeptide) When used in connection with this, the term "recombinant" refers to the development of recombinant polynucleotides. This refers to polypeptides produced by the present invention. The protein may be isolated from a natural source or produced by genetic engineering.

[0136] In some embodiments, the antibody of the present invention may be a recombinant human antibody. The term "antibody" as used herein refers to an antibody prepared by recombinant means and expressed by recombinant means. Human antibodies or humanized antibodies that have been produced or isolated, for example, when a host cell is subjected to a tidal wave. Antibodies expressed using an infected recombinant expression vector (details below), Antibodies isolated from a replacement combinatorial human antibody library (details below), human Isolation of munoglobulin genes from transgenic animals (e.g., mice) The antibody used (e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) (See reference) or splicing human immunoglobulin gene sequences into other DNA sequences Prepared, expressed, produced, or isolated by any other means including It is intended to include all antibodies, including antibodies. Such recombinant human antibodies are human It has a variable region and a constant region derived from germline immunoglobulin sequences. In certain embodiments, such recombinant human antibodies are subjected to in vitro mutation induction. If transgenic animals are used (or if human Ig sequences are used), (Somatic cell mutation induction occurs), and consequently, the recombinant antibody V H and V L Area Net The no-acid sequence is from the human germline V H and V L Induced from the array, and related, Some antibodies within the vivo human germline repertoire may not exist naturally.

[0137] The terms "specifically bind" or "specifically bind to ~" refer to antibodies or This means that the antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding occurs at least approximately 1 x 10⁻⁶. -6 It can be characterized by an equilibrium dissociation constant of M or less. can (for example K D The smaller the value, the tighter the bond. Methods for determining whether or not this is known in this field include, for example, equilibrium dialysis, surface plasmon resonance, etc. Examples include the FORTEBIO Octet HTX apparatus (Pall Surface imaging techniques such as BIACORE® biolayer interferometry using Life Sciences Inc. Rasmon resonance identifies antibodies that specifically bind to CD3. Furthermore, CD3 and one Alternatively, multispecific antibodies that bind to multiple additional antigens, or CD3 and / or additional antigens Bispecific antibodies that bind to two different regions in different areas are also used herein. This is considered an antibody that "specifically binds". In certain embodiments, as disclosed herein Antibodies are approximately 1 x 10⁶ -6 M, about 1x10 -7 M, about 1x10 -8 M, about 1x10 -9 M, about 1x10 -10 M, about 1x10 -6 M ~ approx. 1 x10 -7 M, about 1x10 -7 M ~ approx. 1x10 -8 M, about 1x10 -8 M ~ approx. 1x10 -9 M, or approximately 1x10 -9 M ~approximately 1x10 -10 It exhibits the equilibrium dissociation constant of M (and the associated singularities).

[0138] The term "high affinity" antibody is used, for example, in the FORTEBIO Octet HTX instrument (Pall L (ife Sciences, Inc.) or using solution affinity ELISA, for example, BIACORE, When measured by surface plasmon resonance such as Olayer interferometry, at least 10 -9 M, preferably 10 -10 M, more comfortable 10 -11 M, more comfortable 10 -12 M's K D year This refers to an mAb that has binding affinity to CD3, represented as such.

[0139] The term "slow off rate" is used, for example, by BIACORE (trademark) or FO. Determined by surface plasmon resonance using instruments such as the RTEBIO Octet HTX (Pall Life Sciences). When this happens, 1x10 -3 s "1 The following is preferably 1x10 -4 s "1 The following rate constant (K off or K D This refers to an antibody that dissociates from CD3.

[0140] Furthermore, regarding antibody fragments, such antibody fragments include Fab fragments, F(ab')2 fragments, The antibody may contain an Fv fragment, a dAb fragment, a fragment containing a CDR, or an isolated CDR. For example, protein digestion, or the variable domain and (optionally) constant domain of an antibody Any appropriate standard techniques, such as genetic engineering methods including the manipulation and expression of the encoding DNA. It may be derived from a complete antibody molecule using such DNA, and / Alternatively, for example, commercially available sources, DNA libraries (including, for example, phage-antibody libraries) DNA can be easily obtained from or synthesized from sources such as [unspecified sources]. Alternatively, the sequences may be analyzed and manipulated using molecular biological techniques, for example. For example, one or more variable domains and / or constant domains can be arranged into an appropriate configuration. It may be placed, or a codon may be introduced, or a cysteine ​​residue may be generated, Modifications are permitted, and amino acids may be added or deleted.

[0141] Non-limiting examples of antigen-binding fragments include (i) Fab fragments, (ii) F(ab')2 fragments, (iii) (iv) Fd fragment, (v) Fv fragment, (v) single-stranded Fv(scFv) molecule, (vi) dAb fragment, and (vii) anti The smallest recognition unit consisting of amino acid residues that mimic the hypervariable regions of the body (e.g., CDR3 peptide) The isolated complementary determination region (CDR) or constrained FR3-CDR3-FR4 peptide Examples include domain-specific antibodies, single-domain antibodies, and domain deletion antibodies. Chimeric antibodies, CDR transplant antibodies, diabodies, triabodies, tetrabodies, minibodies, Nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunotherapies (SMIP: small modular immunopharmaceutical), and shark variable IgNAR domains, etc. Other manipulative molecules, when used herein, may also be referred to as "antigen-binding fragments". It is contained within.

[0142] Antibody antigen-binding fragments will often contain at least one variable domain. The variant domain may be of any size or amino acid composition, and is generally one Alternatively, it may be adjacent to a frame along with multiple framework arrays, or within a frame. It will include at least one CD-R. L V associated with the domain H domain In an antigen-binding fragment having V H Domain and V L Domains are distributed amongst themselves in any appropriate manner. It may be positioned in a certain location. For example, the variable region may be a dimer, V H - V H , V H - V L or V L - V L It may contain a dimer of the antibody. Alternatively, the antigen-binding fragment of the antibody may be a monomer of V H or V L It may contain a domain.

[0143] In certain embodiments, the antigen-binding fragment of the antibody is covalently bound to at least one constant domain. It may contain at least one combined variable domain. Antigen-binding fragment of the antibody of the present invention Non-restrictive configurations of variable domains and stationary domains that may exist within include: (i) V H -C H 1 (ii) V H -C H 2; (iii) V H-C H 3; (iv) V H -C h 1 -C h 2; (V) V H -C h 1-C h 2-C h 3; ( vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1 ; (ix) V L - C H 2; (x) V L -C H 3 ; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L include. In any configuration of the variable domain and the constant domain including any of the above exemplary configurations, the variable domain and the constant domain may be directly coupled to each other, or may be coupled by a complete or partial hinge or linker region. The hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids and this hinge region results in a flexible or semi-flexible bond between adjacent variable domains and / or constant domains in a single polypeptide molecule occurring. Furthermore, the antigen-binding fragments of the antibodies of the present invention are non-covalently bound to each other and / or one or more monomers V Hor V L Non-covalent bonds in the domain (e.g., disulfide bonds) ), homodimer or heterodimer of either the variable domain and the constant domain configuration described above. It may contain a molecule (or other polymer).

[0144] Similar to complete antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). ) may also be the case. Antibody multispecific antigen-binding fragments are often at least two different antigens. It contains variable domains, in which case each variable domain is specific to a different antigen. The ability to bind, or to specifically bind to different epitopes on the same antigen. This is possible. Examples of bispecific antibody forms disclosed herein, including any multiple specific antibody The sex antibody format is obtained by using conventional techniques available in the art to obtain the antigen-binding fragment of the antibody of the present invention. It may be suitable for use as background. Multiple suitable for incorporating the anti-CD3 binding domain of the present invention Non-restrictive examples of heptaspecific and dispecific forms include, for example, Fab-Fc-scFv (bot Lu-Opener (XENCOR), Mab-scFv (XENCOR), Mab-Fv (XENCOR), Dual scFv (Dual scFv) (XENCOR), central Fv (XENCOR), central scFv (XENCOR) XENCOR Corporation, Fab-Fab (XENCOR Corporation) ), Fab-Fv (XENCOR), mAb-Fv (XENCOR), mAb-Fab (XENCOR), DART (MacroGe nics, BiTE (Amgen / Micromet), KiTE, Common Light Chain-IgG (Genentech), TandAb (S FFIMED, Cross-Mab (Roche), SEED (EMD Serono), BEAT (Glenmark), Trio Mab (Trion Pharma / FresEnius Biotech), DuetMab (MedImmune), and others These include, for example (WO 95 / 09917; WO 2008 / 119566; WO 2008 / 119567; WO 2011 / 121110; WO 2010 / 037835; WO 2007 / 042261; WO 2007 / 110205; WO 2011 / 121 110; WO 2012 / 055961; WO 2012 / 16067; WO 2016 / 086189; WO 2016 / 182751; WO 2015 / 006749; WO 2014 / 049003; WO 2013 / 177101; WO 2015 / 128509; US 7,951, 917; US 2009 / 0252729; US 2014 / 0348839; US 7,183,076; Mazor et al., Mab s, Vol. 7, pages 377-389 (2015); Muda et al., Protein Engineering, Desi gne, & Selection, Vol. 24, pp. 447-454 (2011); and Del Bano et al., This is disclosed in Antibodies, Vol. 5, pp. 1-23 (2016).

[0145] In certain embodiments, the antibody or antibody fragment of the present invention may be, for example, an antibiotic, a second anti-CD3 Therapeutic components such as antibodies, vaccines or toxoids, or any other useful therapeutic components They can also be complexed (immune complexes).

[0146] As used herein, "isolated antibody" refers to other antibodies (Ab) that have different antigen specificities. This is intended to refer to antibodies that substantially do not contain (e.g., isolation antibodies that specifically bind to CD3). The antibody, or fragment thereof, substantially does not contain an Ab that specifically binds to antigens other than CD3.

[0147] As used herein, "inhibitory antibody" or "neutralizing antibody" (or CD3 activity) The antibody that neutralizes the antibody may, in some cases, bind to CD3, as disclosed herein. However, it is intended to refer to antibodies that cause inhibition of at least one biological activity of CD3.

[0148] As used herein, the term "surface plasmon resonance" is, for example, BIAC ORE (trademark) system (Pharmacia Biosensor AB, Sweden, Uppsala, and N Using proteins in a biosensor matrix (Piscataway, New Jersey) By detecting changes in concentration, it is possible to analyze biomolecular interactions in real time. It refers to optical phenomena.

[0149] When used herein, "K D The term refers to a specific antibody-antigen interaction. This is intended to refer to the equilibrium dissociation constant.

[0150] The term "epitope" refers to the identification of a variable region within an antibody molecule, known as a paratope. This refers to antigenic determinants that interact with the antigen-binding site. A single antigen may have multiple epitopes. It is also possible that different antibodies can bind to different regions on the antigen. It can have such biological effects. The term "epitope" also refers to B cells and / Alternatively, it refers to the site on the antigen that T cells react to. Furthermore, it also refers to the region of the antigen to which the antibody binds. Epitopes can be defined structurally or functionally. Functional epitopes are generally structural. A subset of epitopes containing residues that directly contribute to the affinity of interactions. Epitopes may also be three-dimensional structures, that is, they may be composed of nonlinear amino acids. In certain embodiments, the epitope may be, for example, an amino acid, a sugar side chain, or a phosphoryl It may also include determinants, which are chemically active surface groups of molecules such as groups or sulfonyl groups. In certain embodiments, the epitope has specific three-dimensional structural properties and / or specific charge It may have certain characteristics.

[0151] When referring to nucleic acids or fragments thereof, or amino acid sequences or fragments thereof, the term "substance" is used. The terms "substantially identical" or "substantially identical" refer to a nucleic acid sequence or amino acid sequence that is substantially identical to another nucleic acid sequence or amino acid sequence. In some cases, they are optimally positioned with appropriate insertions or deletions (or complementary strands). When this happens, and when sequences such as FASTA, BLAST, or GAP are identical, as will be considered below, for example, When measured by any known algorithm for sex, at least about 100%, at least At least approximately 99%, at least approximately 98%, at least approximately 97%, at least approximately 96%, at least approximately 95% , at least about 94%, at least about 93%, at least about 92%, at least about 91%, at least Approximately 90%, at least approximately 89%, at least approximately 88%, at least approximately 87%, at least approximately 86%, less At least approximately 85%, at least approximately 84%, at least approximately 83%, at least approximately 82%, at least approximately 80% This demonstrates the existence of sequence identity. Therefore, sequences exhibiting a specific proportion of "identity" The columns share the same proportion and / or are "identical" to one another in that proportion.

[0152] In certain embodiments, the disclosed CD3-binding domain, and / or individual heavy chains (HC) ) sequence, light chain (LC) sequence, CDRH3 sequence, CDRH2 sequence, CHRH1 sequence, CDRL3 sequence, CDRL2 sequence, C The DRL1 sequence and / or framework sequence are independent of other sequences and are at least Also about 100%, at least about 99%, at least about 98%, at least about 97%, at least about 96%, less At least approximately 95%, at least approximately 94%, at least approximately 93%, at least approximately 92%, at least approximately 91% %, at least about 90%, at least about 89%, at least about 88%, at least about 87%, and at least Approximately 86%, at least approximately 85%, at least approximately 84%, at least approximately 83%, at least approximately 82%, less At least 80% are identical, and / or identical in all proportions in between, in and / or with each other (or with a specific subset of antibody sequences disclosed herein) Share the same proportion.

[0153] In certain embodiments, the amino acid sequence of the antibody of this disclosure is, for example, less than that of other sequences. Both are 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, and less Both are 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, and less Both are 98% identical, at least 99% identical, and / or identical in all proportions in between. and / or each other (or a specific subset of antibody sequences disclosed herein) ) They share the same proportion.

[0154] Preferably, the positions of non-identical residues differ due to conservative amino acid substitutions. A "conservative amino acid substitution" is when an amino acid residue has similar chemical properties (e.g., charge or hydrophobicity). This substitution is one in which a side chain (R group) accompanied by a ) is substituted by another amino acid residue. Generally Conservative amino acid substitutions do not substantially alter the functional properties of a protein. If the amino acid sequences differ from each other due to conservative substitution, the degree or proportion of similarity is determined by the placement of the amino acid sequences. The conversion may be adjusted upward to correct its conservative properties. The means of making this adjustment is This is publicly known to those skilled in the art. (For example, Pearson (1994) Methods Mol. Biol. 24: 307- See 331). Examples of groups of side-chain amino acids with similar chemical properties include: 1) fats 2) Aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) Aliphatic-hydro Xyl side chains: serine and threonine; 3) Amide-containing side chains: asparagine and glutamate 4) Aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) Basic side Chain: lysine, arginine, and histidine; 6) Acidic side chain: aspartic acid and glutamic acid Examples include cinic acid, and 7) sulfur-containing side chains: cysteine ​​and methionine. The conserved amino acid substituents are valine-leucine-isoleucine and phenylalanine-tyrosine. Lysine-arginine, alanine-valine, glutamic acid-aspartic acid and aspartic acid The alternative is lagin-glutamine. Alternatively, a conservative substitution is shown in Gonnet et al. (1992) Scienc. In the PAM250 log-likelihood matrix disclosed in e 256: 1443 45 Any change with a positive value. "Moderately conservative" permutations are defined by the PAM250 log-likelihood matrix. In the context of ks, this is any change that has a non-negative value.

[0155] Polypeptide sequence similarity is often measured using sequence analysis software. The protein analysis software analyzes various substitutions, deletions, and other amino acid substitutions, including conserved ones. Match similar sequences using the similarity scale assigned to other modifiers. Example For example, GCG software includes programs such as GAP and BESTFIT, and these Using the program with default parameters, homologous polypeptides derived from different species can be used to analyze homologous polypeptides from different biological species. Tydo, or homologous polypeptides between wild-type proteins and their mutants, etc. Sequence homology or sequence identity between closely related polypeptides can be determined. For example, See GCG version 6.1. The polypeptide sequence is also a default parameter or FASTA can also be used with recommended parameters and compared; GCG version 6.1 program FASTA (FASTA2 and FASTA3) is a method for determining the area of ​​best overlap between a query and a search sequence. The present invention provides percentages of inment and sequence identity (Pearson (2000), above). Another preference when comparing a sequence to a database containing numerous sequences from different organisms The algorithm is BLAST for computer programs, and in particular, default parameters This is BLASTP or TBLASTN using T. (e.g., Altschul et al. (1990) J.) See Mol. Biol. 215: 403 410 and (1997) Nucleic Acids Res. 25:3389 402. (Referring to Teru).

[0156] In certain embodiments, the antibody or antibody fragment for use in the method of the present invention is unique It may be sex-specific, bispecific, or multispecific. A multispecific antibody targets one target polyp The peptide may be specific to different epitopes, or to multiple target polypeptides. It may contain an antigen-binding domain specific to the epitope of the drug. An example of a bispecific antibody form that can be used is the first immunoglobulin (Ig) C H Approximately 3 domains and the second IgC H This includes the use of three domains, in which case the first and second IgC H 3 degrees The main one is that at least one amino acid is different from the others, and in this case at least Another difference in amino acids is that, compared to bispecific antibodies that do not have this amino acid difference, the proteo This reduces the binding of bispecific antibodies to in A. In one embodiment, first IgC H The 3 domains bind to protein A, and the second IgC H 3 domains are, for example, H95R (IMGT Based on Xon numbering; EU numbering reduces protein A binding such as H435R modification. Contains mutations that are reduced or eliminated. Second C H 3 is Y96F modified (according to IMGT; in the EU, Y 436F) may also be included. Second C H Further modifications that may exist within 3 include the following: In the case of IgG1 mAb, D16E, L18M, N44S, K52N, V57M, and V82I (IMGT According to the EU, D356E, L358M, N384S, K392N, V397M, and V422I; in the case of IgG2 mAb , N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I in the EU); and IgG4 For mAb, these include Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (according to IMGT; EU (These are Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I). The above bispecific antibodies. Variations in form are also anticipated within the scope of the present invention.

[0157] Examples of anti-CD3 binding domains and antibodies containing them

[0158] As described above, in certain embodiments of the present invention, a series of CD3-binding domains and including Antibodies, as well as methods for producing and using them, are provided. Furthermore, this series of CD3-binding domains collectively exhibit desirable properties, for example, CD3 type Broad affinity for silon, human CD3 (Hu CD3) and cynomolgus monkey CD3 (Cy CD3). Cross-response to both, as well as the desired development potential profile and / or One example is the risk profile of itokine release syndrome (CRS). In certain embodiments, The CD3-binding domain of the present invention and antibodies containing it have potential for development of other anti-CD3 antibodies. Development potential profiles and / or CRS risk profiles are superior to the CRS risk profiles. / or exhibits a CRS risk profile. In certain embodiments, the CD3-bound domain of the present invention Antibodies containing the same are disclosed herein, for example, as well as Yang et al., J Immunol, Vol 137, pp. 1097–1100 (August 4, 1986), US 2014 / 008295 and WO 20 I2C, SP34, 38E4, CAB21609_A01, CAB21609_B01, CAB21609_C01, disclosed in 15 / 095392 and / or CAB21609_D01 development feasibility profile and / or CRS risk profile It exhibits a superior development potential profile and / or CRS risk profile compared to the file. do.

[0159] In certain embodiments, the present invention binds to CD3 (e.g., CD3ε and / or CD3γ). The present invention provides a CD3-binding domain and an antibody containing the same.

[0160] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are other CD3-binding It exhibits an enhanced development potential profile compared to the domain (or antibody containing it). Provided as follows. In certain embodiments, the CD3-binding domain of the present invention and the antibody containing the same are provided. As shown in Table 2, trastuzumab (Herceptin®), lintuzumab, bri Natumomab (Blincyto®), and Mab 364, Mab 366, Mab 367, Mab 368, Enhanced development capabilities compared to one or more of Mab 369, Mab 370, or Mab 22. It is provided with a capability profile.

[0161] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are approximately 0 MFI to approximately 5 00MFI, approximately 0MFI to approximately 450MFI, approximately 0MFI to approximately 400MFI, approximately 0MFI to approximately 350MFI, approximately 0MFI to approximately 300MFI, Approximately 0MFI to approximately 250MFI, approximately 0MFI to approximately 200MFI, approximately 0MFI to approximately 150MFI, approximately 0MFI to approximately 100MFI, approximately 0MFI to approximately 100MFI Approx. 50MFI, Approx. 200 MFI and 500MFI, Approx. 200MFI ~ Approx. 450MFI, Approx. 200MFI ~ Approx. 400MFI, Approx. 200M FI ~ approx. 350MFI, approx. 200MFI ~ approx. 300MFI, approx. 200MFI ~ approx. 250MFI, approx. 100MFI ~ approx. 450MFI, approx. 100M FI ~ approx. 400MFI, approx. 100MFI ~ approx. 350MFI, approx. 100MFI ~ approx. 300MFI, approx. 100MFI ~ approx. 250MFI, approx. 100M It exhibits a development feasibility score of approximately FI to 200MFI, or approximately 100MFI to 150MFI.

[0162] In other embodiments, the CD3-binding substance of the present invention and the antibody containing the same are approximately 0.0 to approximately 0.6, approximately 0 0.0 to approximately 0.57, approximately 0.0 to approximately 0.55, approximately 0.0 to approximately 0.53, approximately 0.0 to approximately 0.51, approximately 0.0 to approximately 0.49, approximately 0.0 to Approximately 0.47, approximately 0.0 to approximately 0.45, approximately 0.0 to approximately 0.43, approximately 0.0 to approximately 0.41, approximately 0.0 to approximately 0.39, approximately 0.0 to approximately 0.3 7. Approximately 0.0 to 0.35, approximately 0.0 to 0.33, approximately 0.0 to 0.31, approximately 0.0 to 0.29, approximately 0.0 to 0.27, approximately 0.0 to approximately 0.25, approximately 0.0 to approximately 0.23, approximately 0.0 to approximately 0.21, approximately 0.0 to approximately 0.19, approximately 0.0 to approximately 0.17, approximately 0.0 to Approximately 0.15, approximately 0.0 to approximately 0.13, approximately 0.0 to approximately 0.11, approximately 0.0 to approximately 0.09, approximately 0.0 to approximately 0.07, or approximately 0.0 It exhibits a standardization feasibility score of approximately 0.05.

[0163] In certain embodiments, the potential for development of the CD3-binding substance of the present invention and antibodies containing it Profile and / or development potential score are obtained from PSR assay, SCP assay, AS-CINS BVP assay, ELISA, DSF assay, Tm assay, HIC assay, CIC assay, or It is obtained by performing those combinations.

[0164] In other embodiments, the CD3-binding domain of the present invention and antibodies containing it exhibit potent T cell activation. It can induce sexualization or T-cell killing, while simultaneously inducing cytokine release syndrome. It exhibits a reduced tendency to induce cytokine production down to a certain level. In certain embodiments, Even if only one cytokine is present, a site can induce cytokine release syndrome. Cytokine production levels were measured to assess the tendency to induce levels of cytokine production. The at least one cytokine is selected from the following group: interleuk IL-6, interleukin-12, tumor necrosis factor alpha (TNFα), (TGFb) Interleukin-2 (IL-2) and interferon-gamma (IFNg).

[0165] In certain embodiments, the CD3-binding domain of the present invention and antibodies containing it activate T cells. Alternatively, as shown in Table 2, trastuzumab (Herceptin) induces T cell killing. (Registered Trademark)), lintuzumab, blinatumomab (Blincyto®), and Mab 364 , or one of the following: Mab 366, Mab 367, Mab 368, Mab 369, Mab 370 or Mab 22 Compared to the trends observed in multiple studies, this is at a level that can induce cytokine release. Up to a certain point, it exhibits a reduced tendency to induce cytokine production. In certain embodiments, at One cytokine can induce cytokine release syndrome. Cytokine production levels were measured to assess the tendency to induce live levels, and the low levels At least one cytokine is selected from the following group: interleukin-6(IL- 6) Interleukin-12 (IL-12), tumor necrosis factor alpha (TNFα), (TGFb), inter - Leukin-2 (IL-2) and interferon-gamma (IFNg).

[0166] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are used in cytokinesiology. Cytokine release syndrome (CRS) risk profile shows a reduced risk of developing cytokine release syndrome (CRS). The file is presented. In other embodiments, the CD3-binding domain of the present invention and antibodies containing it are used. As shown in Table 2, trastuzumab (Herceptin®), lintuzumab, and br Rinatumomab (Blincyto®), and Mab 364, Mab 366, Mab 367, Mab 368 cytokines evaluated using one or more of Mab 369, Mab 370, or Mab 22. Compared to the release syndrome risk profile, the risk of triggering cytokine release syndrome (CRS) It exhibits a cytokine release syndrome risk profile that shows a decrease in saturation.

[0167] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH3 selected from the group consisting of 63 and 371-405, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRH3 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRH3 is Mab223, 364, 365, as shown in Table 2. It is assumed that any of the CDRH3s 366, 367, 368, 369, or 370 are not 100% identical. ru.

[0168] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH2 selected from the group consisting of 63 and 371-405, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRH2 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRH2 is Mab223, 364, 365, as shown in Table 2. It is assumed that any of the CDRH2s 366, 367, 368, 369, or 370 are not 100% identical. ru.

[0169] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH1 selected from the group consisting of 63 and 371-405, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRH1 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRH1 is Mab223, 364, 365, as shown in Table 2. It is assumed that any of the CDRH1s 366, 367, 368, 369, or 370 are not 100% identical. ru.

[0170] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL3 selected from the group consisting of 63 and 371-405 CDRL3, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRL3 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRL3 is Mab223, 364, 365, as shown in Table 2. CDRL3 366, 367, 368, 369, or 370 is not 100% identical. ru.

[0171] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL2 selected from the group consisting of 63 and 371-405 CDRL2, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRL2 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRL2 is Mab223, 364, 365, as shown in Table 2. CDRL2 366, 367, 368, 369, or 370 is not 100% identical. ru.

[0172] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL1 selected from the group consisting of 63 and 371-405 CDRL1, 100% identical, less At least 99% identical, at least 98% identical, at least 97% identical, at least 96% identical, and at least At least 95% identical, at least 94% identical, at least 93% identical, at least 92% identical, and at least At least 91% identical, at least 90% identical, at least 89% identical, at least 88% identical, and at least At least 87% identical, at least 86% identical, at least 85% identical, at least 84% identical, and at least Contains CDRL1 that is at least 83% identical, at least 82% identical, or at least 80% identical. The antibody provided is, however, that the CDRL1 is Mab223, 364, 365, as shown in Table 2. CDRL1 366, 367, 368, 369, or 370 is not 100% identical. ru.

[0173] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For HC variable regions selected from the group consisting of 63 and heavy chain (HC) variable regions 371-405 , 100% identical, at least 99% identical, at least 98% identical, at least 97% identical, less Both are 96% identical, at least 95% identical, at least 94% identical, at least 93% identical, and less Both are 92% identical, at least 91% identical, at least 90% identical, at least 89% identical, less Both are 88% identical, at least 87% identical, at least 86% identical, at least 85% identical, less All are 84% identical, at least 83% identical, at least 82% identical, or at least 80% identical. The present invention provides an antibody containing a certain HC variable region, however, the HC variable region is as shown in Table 2. To enable this, one of the HC variable regions of Mab223, 364, 365, 366, 367, 368, 369, or 370 It should be assumed that they are not 100% identical.

[0174] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For LC variable regions selected from the group consisting of 63 and light chain (LC) variable regions 371-405 , 100% identical, at least 99% identical, at least 98% identical, at least 97% identical, less Both are 96% identical, at least 95% identical, at least 94% identical, at least 93% identical, and less Both are 92% identical, at least 91% identical, at least 90% identical, at least 89% identical, less Both are 88% identical, at least 87% identical, at least 86% identical, at least 85% identical, less All are 84% identical, at least 83% identical, at least 82% identical, or at least 80% identical. An antibody containing a certain LC variable region is provided, however, the LC variable region is shown in Table 2. To enable this, 1 They are not 00% identical.

[0175] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH3 selected from the group consisting of 63 and CDRH3 from 371 to 405, it is 100% identical. , at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, At least 93% identical, at least 92% identical, at least 91% identical, at least At least 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at least They are 84% identical, at least 83% identical, at least 82% identical, or less CDRH3, which is at least 80% identical, is shown in Table 2 as follows: Mab 1-21, 23-222, 224-363, And for CDRH2 selected from the group consisting of 371-405 CDRH2, there are a small number that are 100% identical. At least 99% identical, at least 98% identical, at least 97% identical, at least They are at least 96% identical, at least 95% identical, at least 94% identical, at least Both are 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at 87% identical, at least 86% identical, at least 85% identical, at least 84% identical % identical, at least 83% identical, at least 82% identical, or at least CDRH2, which is 80% identical, and Mab 1-21, 23-222, 224-36, as shown in Table 2. 3, and CDRH1 selected from the group consisting of CDRH1s 371-405, are 100% identical. They are at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, at least At least 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at 84% identical, at least 83% identical, at least 82% identical, or less We provide antibodies containing CDRH1 which is 80% identical to CDRH3, CDRH2, and And each of the CHRH1s is shown in Table 2 as Mab223, 364, 365, 366, 367, 36 Not 100% identical to any of CHRH3, CDRH2, or CDRH1 of 8, 369, or 370 Let's assume that.

[0176] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRL3 selected from the group consisting of 63 and CDRL3s 371-405, it is 100% identical. , at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, At least 93% identical, at least 92% identical, at least 91% identical, at least At least 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at least They are 84% identical, at least 83% identical, at least 82% identical, or less CDRL3, which is at least 80% identical, is shown in Table 2 as follows: Mabs 1-21, 23-222, 224-363, And for CDRL2 selected from the group consisting of 371-405 CDRL2, there are few that are 100% identical. At least 99% identical, at least 98% identical, at least 97% identical, at least They are at least 96% identical, at least 95% identical, at least 94% identical, at least Both are 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at 87% identical, at least 86% identical, at least 85% identical, at least 84% identical % identical, at least 83% identical, at least 82% identical, or at least CDRL2, which is 80% identical, and Mabs 1-21, 23-222, 224-36, as shown in Table 2. 3, and a CDRL1 selected from the group consisting of CDRL1s 371-405, which is 100% identical. They are at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, at least At least 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at 84% identical, at least 83% identical, at least 82% identical, or less We provide antibodies containing CDRL1 which is 80% identical to CDRL3, CDRL2, etc. And each of CHRL1 is as shown in Table 2: Mab223, 364, 365, 366, 367, 36 Not 100% identical to CHRL3, CDRL2, or CDRL1 of any of 8, 369, or 370 Let's assume that.

[0177] In certain embodiments, the present invention relates to Maps 1-21, 23-222, 224-3 as shown in Table 2. For CDRH3 selected from the group consisting of 63 and CDRH3 from 371 to 405, it is 100% identical. , at least 99% identical, at least 98% identical, at least 97% identical, At least 96% identical, at least 95% identical, at least 94% identical, At least 93% identical, at least 92% identical, at least 91% identical, at least At least 90% identical, at least 89% identical, at least 88% identical, at least They are 87% identical, at least 86% identical, at least 85% identical, at least They are 84% identical, at least 83% identical, at least 82% identical, or less CDRH3, which is at least 80% identical, is shown in Table 2 as follows: Mab 1-21, 23-222, 224-363, And for CDRH2 selected from the group consisting of 371-405 CDRH2, there are a small number that are 100% identical. At least 99% identical, at least 98% identical, at least 97% identical, at least They are at least 96% identical, at least 95% identical, at least 94% identical, at least Both are 93% identical, at least 92% identical, at least 91% identical, at least They are 90% identical, at least 89% identical, at least 88% identical, at 87% identical, at least 86% identical, at least 85% identical, at least 84% identical % identical, at least 83% identical, at least 82% identical, or at least CDRH2, which is 80% identical, is shown in Table 2 as follows: Mab 1-21, 23-222, 224-363, and For CDRH1 selected from the group consisting of CDRH1 371-405, at least one that is 100% identical. They are 99% identical, at least 98% identical, at least 97% identical, at least They are 96% identical, at least 95% identical, at least 94% identical, at 93% identical, at least 92% identical, at least 91% identical, at least 90% identical % identical, at least 89% identical, at least 88% identical, at least 87% They are identical, at least 86% identical, at least 85% identical, at least 84% identical It is one, at least 83% identical, at least 82% identical, or at least 80% identical. CDRH1, which is % identical, is shown in Table 2 as follows: Mabs 1-21, 23-222, 224-363, and 371 For a CDRL3 selected from the group consisting of ~405 CDRL3s, at least 99 are 100% identical. % identical, at least 98% identical, at least 97% identical, at least 96% They are identical, at least 95% identical, at least 94% identical, at least 93% identical One, at least 92% identical, at least 91% identical, at least 90% identical They are, at least 89% identical, at least 88% identical, at least 87% identical. Yes, at least 86% identical, at least 85% identical, at least 84% identical They are at least 83% identical, at least 82% identical, or at least 80% identical. CDRL3, as shown in Table 2, is represented by Mabs 1-21, 23-222, 224-363, and 371-405. For a CDRL2 selected from the group consisting of the following CDRL2s, it is 100% identical, or at least 99% identical. It is one, at least 98% identical, at least 97% identical, at least 96% identical They are, at least 95% identical, at least 94% identical, at least 93% identical. Yes, at least 92% identical, at least 91% identical, at least 90% identical They are at least 89% identical, at least 88% identical, at least 87% identical. , at least 86% identical, at least 85% identical, at least 84% identical, They are at least 83% identical, at least 82% identical, or at least 80% identical. CDRL2, as well as Mabs 1-21, 23-222, 224-363, and 371- as shown in Table 2. For a CDRL1 selected from a group consisting of 405 CDRL1s, 100% identical, or at least 99% identical. They are identical, at least 98% identical, at least 97% identical, at least 96% identical It is one, at least 95% identical, at least 94% identical, at least 93% identical They are, at least 92% identical, at least 91% identical, at least 90% identical. Yes, at least 89% identical, at least 88% identical, at least 87% identical They are at least 86% identical, at least 85% identical, at least 84% identical. , at least 83% identical, at least 82% identical, or at least 80% identical We provide antibodies containing a certain CDRL1, however, CDRH3, CDRH2, CDRH1, CDRL3, CDH Both L2 and CHRL1 are as shown in Table 2: Mab223, 364, 365, 366, 3 CDRH3, CDRH2, CDRH1, CDRL3, CDHL2, or CHRL, either 67, 368, 369, or 370. It is assumed that they are not 100% identical to 1.

[0178] In certain embodiments, the present invention relates to ADI-15512, ADI-15516, and as shown in Table 2. It contains a CD3-binding domain selected from the group consisting of the CD3-binding domains of ADI-16513 and ADI-16513. We provide antibodies.

[0179] In certain embodiments, the present invention relates to ADI-18562; ADI-18564; A, as shown in Table 2. DI-18565; ADI-18566; ADI-18567; ADI-18568; ADI-18570; ADI-18571; ADI-18572 ; ADI-18573; ADI-18563; ADI-18569; ADI-18574; ADI-18575; ADI-18576; ADI-1 8578; ADI-18579; ADI-18580; ADI-18581; ADI-18582; ADI-18584; ADI-18585; A DI-18577; ADI-18583; ADI-18588; ADI-18589; ADI-18590; ADI-18591; ADI-18593 ; ADI-18594; ADI-18595; ADI-18596; ADI-18597; ADI-18592; ADI-18587; ADI-1 A CD3-binding domain selected from the group consisting of 8586 and the CD3-binding domain of ADI-16606 We provide antibodies that contain this material.

[0180] In certain embodiments, the present invention relates to ADI-18576; ADI-20820; A, as shown in Table 2. DI-20578; ADI-20571; ADI-21097; ADI-20577; ADI-20576; ADI-20568; ADI-20582 ; ADI-20575; ADI-20567; ADI-20574; ADI-20573; ADI-20579; ADI-18565; ADI-2 0818; ADI-20587; ADI-20588; ADI-20589; ADI-20590; ADI-20594; ADI-20596; CD3 binding domains of DI-20599; ADI-20605; ADI-20607; ADI-20608; and ADI-20609 We provide antibodies containing a CD3-binding domain selected from the following groups.

[0181] In certain embodiments, the present invention is, as presented in Table 2, ADI-16606; ADI-20587; A DI-20607; ADI-20590; ADI-28708; ADI-28709; ADI-28710; ADI-21943; ADI-28711 ; ADI-28712; ADI-28713; ADI-28714; ADI-28715; ADI-21944; ADI-28716; ADI-2 1945; ADI-21946; ADI-28717; ADI-21947; ADI-28718; ADI-28719; ADI-28720; A DI-28721; ADI-28722; ADI-28723; ADI-28724; ADI-28725; ADI-28726; ADI-28727 ; ADI-28728; ADI-28729; ADI-28730; ADI-28731; ADI-28732; ADI-28733; ADI-2 8734; ADI-28735; ADI-28736; ADI-28737; ADI-28738; ADI-28739; ADI-28740; A DI-28741; ADI-28742; ADI-28743; ADI-21948; ADI-21949; ADI-28744; ADI-21950 ; ADI-28745; ADI-28746; ADI-28747; ADI-28748; ADI-21951; ADI-21952; ADI-2 8749; ADI-28750; ADI-28751; ADI-21953; ADI-28752; ADI-21954; ADI-28753; A DI-28754; ADI-28755; ADI-28756; ADI-28757; ADI-28758; ADI-28759; ADI-28760 ; ADI-28761; ADI-28762; ADI-28763; ADI-28764; ADI-28765; ADI-28766; ADI-2 8767; ADI-28768; ADI-21955; ADI-28769; ADI-28770; ADI-21956; ADI-28771; A From the group consisting of the CD3 binding domains of DI-28772; ADI-28773; ADI-28774; and ADI-28775 We provide antibodies containing a selected CD3-binding domain.

[0182] In certain embodiments, the present invention relates to ADI-21959; ADI-21963; A, as shown in Table 2. DI-21965; ADI-21967; ADI-21970; ADI-21971; ADI-21972; ADI-21973; ADI-21974 ; ADI-21975; ADI-21976; ADI-21977; ADI-21978; ADI-21979; ADI-21943; ADI-2 1944; ADI-21945; ADI-21946; ADI-21947; ADI-21948; ADI-21949; ADI-21950; A CD3 connection of DI-21951; ADI-21952; ADI-21953; ADI-21954; ADI-21955, and ADI-21956 The present invention provides an antibody containing a CD3-binding domain selected from the group consisting of binding domains.

[0183] In certain embodiments, the present invention relates to ADI-21952; ADI-22523; A, as shown in Table 2. DI-24403; ADI-24404; ADI-24405; ADI-24407; ADI-24408; ADI-24409; ADI-24410 ; ADI-24411; ADI-24412; ADI-24413; ADI-24414; ADI-24415; ADI-24416; ADI-2 4417; ADI-24418; ADI-24434; ADI-24435; ADI-24436; ADI-24437; ADI-24438; A DI-24439; ADI-24440; ADI-24441; ADI-24442; ADI-24443; ADI-24444; ADI-24445 ; ADI-24446; ADI-24449; ADI-24388; ADI-24389; ADI-24390; ADI-24391; ADI-2 4392; ADI-24393; ADI-24394; ADI-24395; ADI-24396; ADI-24397; ADI-24398; A DI-24399; ADI-24400; ADI-24401; ADI-24402; ADI-24419; ADI-24420; ADI-24421 ; ADI-24422; ADI-24423; ADI-24424; ADI-24425; ADI-24426; ADI-24427; ADI-2 4428; ADI-24429; ADI-24430; ADI-24431; ADI-24432; ADI-24433; ADI-24447, It contains a CD3-binding domain selected from the group consisting of the CD3-binding domains of ADI-24448 and ADI-24448. We provide antibodies.

[0184] In certain embodiments, the present invention relates to ADI-22523; ADI-23652; A, as shown in Table 2. DI-23653; ADI-23654; ADI-23655; ADI-23656; ADI-23657; ADI-23658; ADI-23651 ; ADI-23644; ADI-23645; ADI-23646; ADI-23647; ADI-23648; ADI-23649; ADI-2 3650; ADI-23667; ADI-23668; ADI-23669; ADI-23670; ADI-23671; ADI-23672; A DI-23673; ADI-23659; ADI-23660; ADI-23661; ADI-23663; ADI-23664; ADI-23639 ; ADI-23641; ADI-23642; ADI-23640; ADI-23643; ADI-21952; ADI-23633; ADI-2 3634; ADI-23635; ADI-23636; ADI-23637; ADI-23638; ADI-23632, and ADI-2362 We provide an antibody containing a CD3-binding domain selected from a group consisting of 9 CD3-binding domains. ru.

[0185] In certain embodiments, the present invention relates to ADI-22523; ADI-26906; A, as shown in Table 2. DI-26907; ADI-26908; ADI-26909; ADI-26910; ADI-26912; ADI-26913; ADI-26915 ; ADI-26916; ADI-26917; ADI-26918; ADI-26919; ADI-26920; ADI-26921; ADI-2 6924; ADI-26925; ADI-26927; ADI-26928; ADI-26929; ADI-26930; ADI-26932; A DI-26933; ADI-26938; ADI-26939; ADI-26940; ADI-26941; ADI-26942; ADI-26943 ; ADI-26944; ADI-26945; ADI-26950; ADI-26954; ADI-23672; ADI-23673; ADI-2 3664; ADI-26955; ADI-26956; ADI-26957; ADI-26958; ADI-26959; ADI-26960; A DI-26962; ADI-26963; ADI-26964; ADI-26965; ADI-26966; ADI-26968; ADI-26969 ; ADI-26971; ADI-26972; ADI-26973; ADI-26974; ADI-26975; ADI-26976; ADI-2 6977; ADI-26978; ADI-26979; ADI-26980; ADI-26981; ADI-26982; ADI-26983; A DI-26984; ADI-26985; ADI-26986; ADI-26987; ADI-26988; ADI-26989; ADI-26990 CD3-bound domerants for ADI-26991, ADI-26992, ADI-26993, ADI-26994, and ADI-26995 We provide an antibody containing a CD3-binding domain selected from the group consisting of 'in'.

[0186] In certain embodiments, the present invention relates to ADI-22523, ADI-26906, ADI as shown in Table 2. -26907, ADI-26908, ADI-26910, ADI-26913, ADI-26915, ADI-26919, ADI-26920, ADI-26 921, ADI-26943, ADI-26954, ADI-21952, ADI-26955, ADI-26956, ADI-26962, ADI-26978 A CD3 binding domain selected from the group consisting of the CD3 binding domains of ADI-26983 and ADI-26994 We provide antibodies containing yin.

[0187] In certain embodiments, the present invention includes a CD3-binding domain selected from the group consisting of the following: The antibodies provided are: ADI-15512, ADI-16513, ADI-15516, ADI-18565, ADI-18589, ADI -18585, ADI-18590, ADI-18576, ADI-20568, ADI-20580, ADI-21978, ADI-22523, ADI-25 133, and ADI-26906.

[0188] In certain embodiments, the present invention relates to ADI-16606; ADI-29601; ADI-29602; ADI-29603; ADI-20587; ADI-20607; ADI-20590; ADI-21952; ADI-23633; ADI-26955; ADI-2695 6; ADI-26957; ADI-26958; ADI-26959; ADI-26960; ADI-26961; ADI-26962; ADI- 26963; ADI-26964; ADI-26965; ADI-26966; ADI-26967; ADI-26968; ADI-26969; ADI-26970; ADI-26971; ADI-26972; ADI-26973; ADI-26974; ADI-26975; ADI-2697 6; ADI-26977; ADI-26978; ADI-26979; ADI-26980; ADI-26981; ADI-26982; ADI- 26983; ADI-26984; ADI-26985; ADI-26986; ADI-26987; ADI-26988; ADI-26989; Select from the group consisting of ADI-26990; ADI-26991; ADI-26992; ADI-26993; and ADI-26994. We provide antibodies containing a selected CD3-binding domain:

[0189] In certain embodiments, the present invention relates to ADI-32238, ADI-32241, ADI-32244, ADI-32247, ADI-32250, ADI-32253, ADI-32256, ADI-32259, ADI-32239, ADI-32242, ADI-3224 5, ADI-32248, ADI-32251, ADI-32254, ADI-32257, ADI-32260, ADI-32240, ADI- 32243, ADI-32246, ADI-32249, ADI-32252, ADI-32255, ADI-32258 and ADI-32261 We provide antibodies containing a CD3-binding domain selected from the group consisting of:

[0190] In certain embodiments, the present invention includes a CD3-binding domain selected from the group consisting of the following: The antibodies provided are: ADI-29295, ADI-32249, ADI-29298, ADI-29300, and ADI-2691. 5.

[0191] In any particular embodiment, either alone or in combination with other embodiments of the present invention, The CD3-binding domain of the invention and the antibody containing it are shown in Table 2, and are trastuzma Herceptin (registered trademark), lintuzumab, blinatumomab (Blincyto (registered trademark)), Also known as Mab 364, Mab 366, Mab 367, Mab 368, Mab 369, Mab 370 or Mab 22 It exhibits a reduced tendency to decompose compared to one or more of the other.

[0192] In any particular embodiment, either alone or in combination with other embodiments of the present invention, The CD3-binding domain of the invention and the antibody containing it are shown in Table 2, and are trastuzma Herceptin (registered trademark), lintuzumab, blinatumomab (Blincyto (registered trademark)), Also known as Mab 364, Mab 366, Mab 367, Mab 368, Mab 369, Mab 370 or Mab 22 It exhibits a reduced CRS risk profile compared to one or more of the other conditions.

[0193] A particular embodiment, and / or any of the embodiments disclosed throughout this Spec. In combination with the above, a CD3-binding domain and a humanized antibody containing it are provided. In certain embodiments, such CD3-binding domains include the CDR of such other embodiments. And furthermore, accept human frameworks, such as human immunoglobulin frameworks. Includes a work or human consensus framework.

[0194] A particular embodiment, and / or any of the embodiments disclosed throughout this Spec. In combination with the CD3 binding domain, and throughout this specification VH in any of the embodiments presented, and the embodiments presented throughout this specification An antibody containing a VL in either state is provided, in this case the variable domain sequence One or both of these include translation modification.

[0195] In a further embodiment of the present invention, the CD3 binding domain and the entire Spec. The same epitope as the CD3-binding domain provided in other embodiments disclosed therethrough A binding antibody is provided.

[0196] In certain embodiments, the antibody containing the CD3-binding domain and / or thereof is ≤1 μM. ≤100nM, ≤10nM, ≤1nM, ≤0.1nM, ≤0.01nM, or ≤0.001nM (e.g., 10 -8 M or below, for example ba10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 It has the CD3 dissociation constant (Kd) of M).

[0197] In certain embodiments, Kd is used in biolayer interferometry (BLI) and surface plasmon resonance (SPR). ), solution equilibrium-based dynamic exclusion assay ( ForteBio instruments and reagents (e.g., xclusion assay), such as Octet RED 384 and HTX BLI. KinExA direct association assay using the based instrument, enzyme-binding immunoassay It is measured by immunosorbent assay (ELISA) and radioimmunoassay (RIA). Specific implementations In this configuration, Kd measurement is performed using the CD3 binding domain of the present invention or the Fab type of an antibody containing it. For example, the solution-binding affinity of Fab to an antigen is determined by the presence of the unlabeled antigen in the titration system. Under these conditions, Fab was equilibrated using the minimum concentration of (125I)-labeled antigen, and then anti-Fab anti It is measured by capturing antigens bound to a plate covered with body tissue (e.g., Chen et al.) See al., J. Mol. Biol. 293:865-881 (1999). Establish assay conditions. To do this, use the MICROTITER® multiwell plate (Thermo Scientific). Using a 5 μg / ml capture anti-Fab antibody (Cappel Labs) solution in 50 mM sodium carbonate (pH 9.6) The coating was left overnight. Then, it was treated with a PBS solution of 2% (w / v) bovine serum albumin for 2-5 minutes. Blocking was performed for 2 hours at room temperature (approximately 23°C). Non-adsorbent plate (Nunc #269620) In this process, a 100 pM or 26 pM [125I]-antigen is mixed with serial dilutions of the target Fab (for example). Presta et al., Cancer Res. 57:4593-4599 (1997) describes the anti-VEGF antibody Fab-12. (Matches the evaluation). Then, incubate the target Fab overnight. However, incubation The mixture may be continued for a longer period (for example, about 65 hours) to ensure equilibrium is reached. After that, the mixture Transfer the mixture to an incubation capture plate at room temperature (e.g., 1 hour). Next, remove the solution and apply 0.1% polysorbate 20 (TWEEN-20®) to the plate. The plates were washed eight times with PBS solution. When drying the plates, 150 μl / well of scintillating solution was added. Add scintillant (MICROSCINT-20 (trademark); Packard Company) and TOPCOUN Count for 10 minutes on a T(trademark) gamma counter (Packard). Less than 20% of the maximum bindings. The concentration of each Fab added is selected for use in the competitive binding assay.

[0198] In other embodiments, Kd uses the BIACORE® surface plasmon resonance assay. It is measured. For example, BIACORE(registered trademark)-2000, or BIACORE(registered trademark)-3000(BIA Assays using CORE, Inc. (Piscataway, New Jersey) are performed in approximately 10 reaction units. The procedure is performed at 25°C using a CM5 chip immobilized with response units (RU). One implementation method In this context, carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) ) is N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide salt, as per the vendor's instructions. It is activated using salts (EDC) and N-hydroxysuccinimide (NHS). The antigen is 10 mM Dilute to 5 μg / ml (approximately 0.2 μM) using sodium acetate, pH 4.8, and then flow at 5 μl / min. Rapid injection was performed, yielding approximately 10 reaction units (RUs) of binding protein. Following antigen injection... Then, 1M ethanolamine was injected to block unreacted groups. For dynamic measurements, In PBS (PBST) containing 0.05% polysorbate 20 (TWEEN-20®) surfactant, twice the amount of compound Further diluted Fab (0.78 nM to 500 nM) is injected at 25°C at a flow rate of approximately 25 μl / min. (Association) Speed ​​(K on ) and dissociation rate (KO) are based on the 1:1 Langmuir coupling model (B Using IACORE® Evaluation Software version 3.2, the association and dissociation of cells It is calculated by simultaneously fitting the sensorgram. The equilibrium dissociation constant (Kd) is kon / koff. It is calculated as a ratio. For example, Chen et al., J. Mol. Biol. 293:865-881 (1 See 999). The association rate by the above surface plasmon resonance assay is 10⁶ M⁻¹s⁻¹. If it exceeds a certain value, the association rate can be determined using fluorescence quenching techniques. This technology involves increasing the fluorescence emission intensity of a 20 nM anti-antigen antibody (Fab type) in a PBS solution at pH 7.2. Addition or reduction can be performed, for example, with a spectrophotometer equipped with stop-flow (Aviv Instruments). Or, in spectrometers such as the 8000-series SLM-AMINC spectrophotometer (ThermoSpectronic), stirring While measuring using a mixing cuvette, the antigen concentration is increased and measured at 25°C (excitation = 29 (5nm, emission = 340nm, 16nm bandpass).

[0199] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are used to bind an antibody fragment Includes, but is not limited to, antibody fragments such as Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv. Examples include fragments, as well as other fragments described throughout this specification. Specific antibody fragments For a review, see, for example, Hudson et al. Nat. Med. 9:129-134 (2003). Regarding the review of scFv fragments, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-V See Erlag, New York, pp. 269–315 (1994). Also see WO 93 / 16185 and See also U.S. Patent Nos. 5,571,894 and 5,587,458. Salvage receptor-binding epidural For Fab and F(ab')2 fragments containing tope residues and exhibiting extended in vivo half-lives, See National Patent No. 5,869,046.

[0200] The diabody is an antibody fragment having two antigen-binding sites, which may be bivalent or bispecific. For example, EP 404,097, WO 1993 / 01161, Hudson et al. Nat. Med. 9:129- 134 (2003), and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 64 See 44-6448 (1993). Triabodies and tetrabodies are also discussed by Hudson et al. This is described in Nat. Med. 9:129-134 (2003).

[0201] A single-domain antibody may have all or part of the heavy chain variable domain of the antibody, or the light chain variable domain. An antibody fragment containing all or part of a domain. In certain embodiments, a single domain A single-domain antibody is a human single-domain antibody (e.g., Domantis, Inc., Waltham, Mass., for example). (See U.S. Patent No. 6,248,516B1).

[0202] Antibody fragments can be produced by various techniques, but are not limited to those described herein. Thus, complete proteolytic digestion of antibodies, as well as recombinant host cells (e.g., large intestine) Production by bacteria or phages is one example.

[0203] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are chimeric antibodies. Includes. Specific chimeric antibodies are, for example, U.S. Patent No. 4,816,567; and Morrison et al. It is described in l. Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In the example, chimeric antibodies have non-human variable regions (e.g., mouse, rat, hamster, rabbit). Or, for example, a variable region derived from non-human primates such as monkeys, and a human constant region. In the example, a chimeric antibody is one in which the class or subclass has changed from that of the parent antibody. It is an "itch" antibody. A chimeric antibody contains its antigen-binding fragment.

[0204] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are used as a humanized antibody. It contains a chimeric antibody. Typically, the non-human antibody has the specificity of the parent's non-human antibody and It is humanized to reduce immunogenicity to humans while maintaining its affinity. Generally, humanized antibodies contain one or more variable domains, and within those variable domains, CDR (or part thereof) originates from non-human antibodies, while FR (or part thereof) originates from human antibody sequences. Derived from. Humanized antibodies are optional and also contain at least a portion of the human constant region. Partial implementation Morphologically, some FR residues in humanized antibodies originate from non-human antibodies (e.g., CDR residues). Substitution with a corresponding residue derived from the antibody, for example, antibody specificity, affinity, immunity The lack of epidemicogenicity, stability, development potential profile, and CRS risk have been recovered or improved. ru.

[0205] Humanized antibodies and methods for producing humanized antibodies are described, for example, by Almagro and Fransson, F. An abstract is published in ront. Biosci. 13:1619-1633 (2008), and also, for example, Riechmann et al. al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Nos. 5,821,337, 7,527,791, 6,982, Issue 321, and issues 7,087,409, Kashmiri et al., Methods 36:25-34 (2005) (Personal This document describes sex determination region (SDR) transplantation; Padlan, Mol. Immunol. 28:489-498 (1 991) (Describe "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describes "FR shuffling"); and Osbourn et al., Meth ods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (200 0) This is described in detail in (the "guided selection" method for FR shuffling).

[0206] The following are some examples of human framework domains that can be used for humanization, although they are not limited to these. ru: Framework regions selected using the "best fit" method (e.g., Sims et See al. J. Immunol. 151:2296 (1993); the light chain variable region of a specific subgroup. or framework regions derived from the human antibody consensus sequence in the heavy chain variable region (for example) For example, Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Pr See esta et al. J. Immunol., 151:2623 (1993); human maturation (somatic cells (A matured framework region in human germline) See, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008). ); and framework areas induced by screening FR libraries (e.g.) For example, Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al. See al., J. Biol. Chem. 271:22611-22618 (1996).

[0207] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are used to bind human antibodies. Includes. Human antibodies can be produced using various antibody technologies in this field. van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2 This is outlined in 001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0208] Human antibodies have been modified to produce fully human antibodies, or to respond to antigen challenges. Transgenic animals modified to produce complete antibodies with a human variable region have been given immunity. It may be produced by administering an epidemic agent. Such animals often have endogenous immunosuppressants. All or part of the human immunonoglobulin locus that replaced the noglobulin locus, or stained Human immunoglobulin loci located outside the chromosome, or randomly integrated into animal chromosomes. It contains all or part of the human immunoglobulin loci. In genetic mice, endogenous immunoglobulin loci are generally inactivated. For an overview of methods for obtaining human antibodies from sgenic animals, see Lonberg, Nat. Biot. See ech. 23:1117-1125 (2005), or, for example, the US, which describes xenomouse. This document describes U.S. National Patents No. 6,075,181 and 6,150,584, and the registered trademark HUMAB. U.S. Patent No. 5,770,429, describing the KM MOUSE® technology, is issued in U.S. Patent No. 7,04 U.S. Patent Application Publication No. 1,870, and the VELOCIMOUSE® technology See issue 2007 / 0061900. The complete antibodies derived from such animals. The variable region can be further modified, for example, by combining it with a different human steady-state region. stomach.

[0209] Human antibodies can also be produced using hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for ronal antibody production are described. (For example, Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al.) , Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immu See nol., 147: 86 (1991). Created via human B cell hybridoma technology. For human antibodies, see Li et al., Proc. Natl. Acad. Sci. LISA. 103; 35 It is described in 57-3562 (2006). An additional method is, for example, U.S. Patent No. 7,189,826. No. (Describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (Describes human-human hybridomas) The following are listed. Also, human hybridoma technology (trioma technology) is, Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005 ) and Vollmers and Brandlein, Methods and Findings in Experimental and It is also described in Clinical Pharmacology, 27(3):185-91 (2005).

[0210] Human antibodies are selected from a human-derived phage display library and can be cloned from Fv. It can also be created by isolating the variable domain sequence. Then, such a variable domain sequence It may be combined with a desired human constant domain. Select a human antibody from the antibody library. The technology described is described throughout this specification.

[0211] The present invention relates to antibodies having desired activity, and a combinatorial library is used to select antibodies. They can be isolated by phage display. For example, by preparing a phage display library. To screen such libraries for antibodies that possess the desired binding properties Various methods are known in this field. For example, Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Pr. This is outlined in ess, Totowa, NJ, 2001), and also, for example, McCafferty et al., N Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Me thods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immu Further details can be found in nol. Methods 284(1-2): 119-132(2004).

[0212] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are, for example, WO Libraries disclosed in 2009 / 0363379, WO 2010 / 105256, and WO 2012 / 009568, etc. The antibody may be selected from a yeast-based antibody library. In certain embodiments, the CD3 antibody of the present invention may be selected. The combined domain and the antibody containing it are disclosed throughout this specification, and As disclosed in WO 2009 / 0363379, WO 2010 / 105256 and WO 2012 / 009568, This may be optimized through other technologies available in this field ("affinity matures"). (Also known as...)

[0213] In certain phage display methods, the repertoire of VH and VL genes is polymerized. They are individually cloned by a enzyme chain reaction (PCR) and randomly placed in a phage library. It is then recombined. Subsequently, this library is used by Winter et al., Ann. Rev. Immunol., Screening against antigen-binding phages as described in 12: 433-455 (1994) It is possible. Typically, phages exist as single-stranded Fv (scFv) fragments, or as Fab fragments. The antibody fragment is then presented. The library from the immunized source forms hybridomas. This method provides antibodies with high affinity to the immunogen without the need for construction. As described in Griffiths et al., EMBO J, 12: 725-734 (1993), unseen Cloning the repertoire of works (for example, from humans) and developing a wide range of products without any immunization It can provide a single source of antibodies against both typical non-self antigens and self-antigens. Finally, the unsensitized library is described in Winter, J. Mol. Biol., 227:381-388 (1992). To do this, unreconstructed V gene segments are cloned from stem cells and randomly The hypervariable CDR3 region was encoded using PCR primers containing the sequence, in vitro Human antibody phage libraries can also be synthesized by achieving reconstitution. Examples of patent publications that describe this include U.S. Patent No. 5,750,373, and U.S. Patent Patent applications published 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 20 Examples include 07 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0214] Antibodies or antibody fragments isolated from a human antibody library are referred to herein as human antibodies. Alternatively, it may be considered a human antibody fragment.

[0215] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it exhibit multispecificity. Antibodies, such as bispecific antibodies. Multispecific antibodies are effective against at least two different antigens. Binding specificity, or for at least two different epitopes present on the same antigen It is a monoclonal antibody having binding specificity. In a particular embodiment, the bispecific antibody is It may bind to two different epitopes of CD3 (e.g., CD3ε or CD3γ). In this embodiment, one of the binding specificities is specificity to CD3 (e.g., CD3ε or CD3γ). Yes, and the other can be any other antigen (e.g., a second biomolecule, e.g., a cell surface antigen, e.g., a tumor). This refers to specificity against antigens, etc. Therefore, bispecific anti-CD3 antibodies are specific to CD3 and, for example, Table 1 and the second biomolecule listed in U.S. Patent Application Publication 2010 / 0111856 (e.g., tumor antigen) ) may have binding specificity to a second biomolecule such as ). In certain embodiments, this The CD3-binding domain of this material and antibodies containing it are, for example, multispecific antibodies such as bispecific antibodies. This includes the body, in which case the multispecific antibody is presented on the cell surface by, for example, MHC. It has specificity for a second antigen, such as the human leukocyte antigen (HLA) peptide complex. It includes a second binding domain.

[0216] In certain embodiments, the CD3-binding domain of the present invention and the antibody containing it are, for example, type 2. This includes multispecific antibodies such as heterozygous antibodies, and in this case, the multispecific antibodies are as follows: It contains a second binding domain that has specificity for a second antigen selected from the following group: 0772P (CA125, MUC16; Genbank accession number AF36148); adipophilin (perilip in-2, Adipose differentiation-related protein, ADRP, ADFP, MGC10598; NCBI reference Reference array: NP-001113.2); AIM-2 (Absent In Melanoma 2, PYHIN4, Interferon-Indu cible Protein AIM2; NCBI Reference Sequence: NP-004824.1); ALDH1 A1 (Aldehyde Deh ydrogenase 1 Family, Member A1, ALDH1, PUMB1, Retinaldehyde Dehydrogenase 1, ALDC, ALDH-E1, ALHDII, RALDH 1, EC 1.2.1.36, ALDH11, HEL-9, HEL-S-53e, HEL1 2, RALDH1, Acetaldehyde Dehydrogenase 1, Aldehyde Dehydrogenase 1, Soluble , Aldehyde Dehydrogenase, liver cytosolic, ALDH Class 1, Epididymis Lumina l Protein 12, Epididymis Luminal Protein 9, Epididymis Secretory Sperm B inding Protein Li 53e, Retinal Dehydrogenase 1, RaIDH1, Aldehyde Dehydroge nase Family 1 Member A1, Aldehyde Dehydrogenase, Cytosolic, EC 1.2.1; NC BI Reference Sequence: NP-000680.2); alpha-actinin-4 (ACTN4, Actinin, Alpha 4, FSGS1 , Focal Segmental Glomerulosclerosis 1, Non-Muscle Alpha-Actinin 4, F-Actin Cross-Linking Protein, FSGS, ACTININ-4, Actinin Alpha4 Isoform, alpha-actin in-4; NCBI Reference Sequence: NP-004915.2); alpha-fetoprotein (AFP, HPAFP, FETA, alp ha-1-fetoprotein、alpha-fetoglobulin、Alpha-1-fetoprotein、Alpha-fetoglobulin、H P; GenBank: AAB58754.1); Amphiregulin (AREG、SDGF、Schwannoma-Derived Growt h Factor、Colorectum Cell-Derived Growth Factor、AR、CRDGF; GenBank: AAA51 781.1); ARTC1 (ART1、ADP-Ribosyltransferase 1、Mono(ADP-Ribosyl)Transferase 1、ADP-Ribosyltransferase C2 And C3 Toxin-Like 1、ART2、CD296、RT6、ADP-Rib osyltransferase 2、GPI-Linked NAD(P)(+)-Arginine ADP-Ribosyltransferase 1、E C 2.4.2.31、CD296 Antigen; NP); ASLG659; ASPHD1 (Aspartate Beta-Hydroxyla se Domain Containing 1、Aspartate Beta-Hydroxylase Domain-Containing Prote in 1、EC 1.14.11.-、EC 1.14.11.、GenBank: AAI44153.1); B7-H4 (VTCN1、V-Set Domain Containing T Cell Activation Inhibitor 1、B7H4、B7 Superfamily Member 1、Immune Costimulatory Protein B7-H4、B7h.5、T-Cell Costimulatory Molecule B7x, B7S1, B7X, VCTN1, H4, B7 Family Member, PRO1291, B7 Family M ember, H4, T Cell Costimulatory Molecule B7x, V-Set Domain-Containing T-C ell Activation Inhibitor 1, Protein B7S1; GenBank: AAZ17406.1); BAFF-R ( TNFRSF13C, Tumor Necrosis Factor Receptor Superfamily, Member 13C, BAFFR, B-Cell-Activating Factor Receptor, BAFF Receptor, BLyS Receptor 3, CVID4, B ROMIX, CD268, B Cell-Activating Factor Receptor, prolixin, Tumor Necrosis F actor Receptor Superfamily Member 13C, BR3, CD268 Antigen; NCBI reference sequence: NP-443177.1); BAGE-1; BCLX (L); BCR-ABL fusion protein (b3a2); beta-caten in (CTNNB1, Catenin (Cadherin-Associated Protein), Beta 1, 88 kDa, CTNNB, M RD19, Catenin (Cadherin-Associated Protein), Beta 1 (88kD), armadillo, Caten in Beta-1; GenBank: CAA61107.1); BING-4 (WDR46, WD Repeat Domain 46, C6o rf11, BING4, WD Repeat-Containing Protein BING4, Chromosome 6 Open Reading Frame 11, FP221, UTP7, WD Repeat-Containing Protein 46; NP); BMPR1 B ( bone morphogenetic protein receptor-type IB, Genbank accession number NM-001 20; NP); B-RAF (Brevican (BCAN, BEHAB, Genbank accession number AF22905); B revican (BCAN, Chondroitin Sulfate Proteoglycan 7, Brain-Enriched Hyalurona n-Binding Protein, BEHAB, CSPG7, Brevican Proteoglycan, Brevican Core Protei n, Chondroitin Sulfate Proteoglycan BEHAB; GenBank: AAH27971.1); CALCA (C alcitonin-Related Polypeptide Alpha, CALC1, Calcitonin 1, calcitonin, Alpha- Type CGRP, Calcitonin Gene-Related Peptide I, CGRP-I, CGRP, CGRP1, CT, KC, C alcitonin / Calcitonin-Related Polypeptide, Alpha, katacalcin; NP); CASP-5 (C ASP5, Caspase 5, Apoptosis-Related Cysteine Peptidase, Caspase 5, Apoptosis- Related Cysteine Protease, Protease ICH-3, Protease TY, ICE(rel)-111, ICE(re l)III, ICEREL-III, ICH-3, caspase-5, TY Protease, EC 3.4.22.58, ICH3, EC 3.4. 22; NP); CASP-8; CD19 (CD19-B-lymphocyte antigen CD19 isoform 2 precurs or, B4, CVID3 [Homo sapiens], NCBI reference sequence: NP-001761.3); CD20 (CD20-B-ly mphocyte antigen CD20, membrane-spanning 4-domains, subfamily A, member 1 , B1, Bp35, CD20, CVID5, LEU-16, MS4A2, S7; NCBI reference sequence: NP-690605.1); CD2 1 (CD21 (CR2 (Complement receptor or C3DR (C3d / Epstein-Barr virus rece ptor) or Hs.73792 Genbank accession number M2600); (CD22 (B-cell receptor) CD22-B isoform, BL-CAM, Lyb-8, LybB, SIGLEC-2, FLJ22814, Genbank Accessory (Item code AK02646); CD22; CD33 (CD33 molecule, CD33 antigen (Gp67), Silic Acid) Binding Ig-Like Lectin 3, Sialic Acid-Binding Ig-Like Lectin 3, SIGLEC3, gp67, SIGLEC-3, Myeloid Cell Surface Antigen CD33, p67, Siglec-3, CD33 anti gen; GenBank: AAH28152.1); CD45; CD70 (CD70-tumor necrosis factor (ligan d) superfamily, member 7; surface antigen CD70; Ki-24 antigen; CD27 li gand; CD27-L; tumor necrosis factor ligand superfamily member 7; homosa NCBI reference sequence for Piens species: NP-001243.1); CD72 (CD72 (B-cell differen tiation antigen CD72, Lyb-; 359 aa, μl: 8.66, MW: 40225, TM: 1 [P] Infectious chromosome: 9p13.3, Genbank accession number NP-001773.); CD79a (CD79a (CD79 A, CD79a, immunoglobulin-associated alpha, covalently interacts with Ig beta (CD79B). It acts to form a complex on the surface with IgM molecules and transmits signals involved in B cell differentiation. (B cell-specific protein), μl: 4.84, MW: 25028 TM: 2 [P] Gene chromosome: 19q13.2, Genbank accession number NP-001774.1); CD79b (CD79b (CD79B, CD79b, I Gb (immunoglobulin-associated beta), B29, Genbank accession number NM-000626 (1103867); Cdc27 (Cell Division Cycle 27, D0S1430E, D17S978E, Anaphase) Promoting Complex Subunit 3, Anaphase-Promoting Complex Subunit 3, ANAPC3 , APC3, CDC27Hs, H-NUC, CDC27 Homolog, Cell Division Cycle 27 Homolog (S. Cerevisiae), HNUC, NUC2, Anaphase-Promoting Complex, Protein 3, Cell Divis ion Cycle 27 Homolog, Cell Division Cycle Protein 27 Homolog, Nuc2 Homo log; GenBank: AAH11656.1); CDK4 (Cyclin-Dependent Kinase 4, Cell Division Protein Kinase 4, PSK-J3, EC 2.7.11.22, CMM3, EC 2.7.11; NCBI reference sequence: NP-000066.1); CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A, MLM, CDKN2, M TS1, Cyclin-Dependent Kinase Inhibitor 2A (Melanoma, P16, Inhibits CDK4) , Cyclin-Dependent Kinase 4 Inhibitor A, Multiple Tumor Suppressor 1, CDK 4I, MTS-1, CMM2, P16, ARF, INK4, INK4A, P14, P14ARF, P16-INK4A, P16INK4, P16INK4 A, P19, P19ARF, TP16, CDK4 inhibitor P16-INK4, Cell Cycle Negative Regulato r Beta, p14ARF, p16-INK4, p16-INK4a, p16INK4A, p19ARF; NP); CEA; CLL1 (CLL- 1 (CLEC12A, MICL, and DCAL, many C-type lectins / C-type lectin-like domains (CTLs / CTLDs)) A superfamily. Members of this family share a common protein folding. Sharing, adhesion, cell-cell signaling, glycoprotein turnover, and inflammation and immunity. It has diverse functions, including a role in epidemic responses. The protein encoded by this gene It is a negative regulator of granulocyte and monocyte function. Alternative splice transmutation of this gene Several variants have also been reported, but some of these variants have a total length Its properties are unknown. This gene is located in the natural killer gene complex region on chromosome 12p13. It is closely related to other CTL / CTLD superfamilies in the region (Drickamer, K Curr. Op). in. Struct. Biol. 9):585-90; van Rhenen, A, et al., Blood 110):2659-66; Chen CH, et al. Blood 107):1459-67; Marshall AS, et al. Eur. J. Im munol. 36):2159-69; Bakker AB, et al Cancer Res. 64:8443-50; Marshall AS, et al J. Biol. Chem. 279:14792-80. CLL-1 is a single type C lectin-like domain. (Not expected to bind to either calcium or sugar), stalk region Type II transmembrane receptor containing a region, transmembrane domain, and a short cytoplasmic tail containing the ITIM motif. It has been shown to be a positive condition); CLPP (Caseinolytic Mitochondrial Matrix Pep Tidase Proteolytic Subunit, Endopeptidase Clp, EC 3.4.21.92, PRLTS3, ATP-Dep Endent Protease ClpAP (E.coli), ClpP (Caseinolytic Protease, ATP-Dependent , Proteolytic Subunit, E.Coli)Homolog, ClpP Caseinolytic Peptidase, ATP-De pendent, Proteolytic Subunit Homolog(E.coli), ClpP Caseinolytic Protease, ATP-Dependent, Proteolytic Subunit Homolog(E.coli), Human, Proteolytic Subunit t, ATP-Dependent Protease ClpAP, Proteolytic Subunit, Human, ClpP Caseino lytic Peptidase ATP-Dependent, Proteolytic Subunit, ClpP Caseinolytic Pept idase, ATP-Dependent, Proteolytic Subunit Homolog, ClpP Caseinolytic Prote ase, ATP-Dependent, Proteolytic Subunit Homolog, Putative ATP-Dependent Cl p Protease Proteolytic Subunit, Mitochondrial; NP); COA-1; CPSF; CRIPTO (CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor r, Genbank accession number NP-003203 or NM-0321); Cw6; CXCR5 CXCR5 (Burki tt's lymphoma receptor 1 is a G protein-bound receptor, and is activated by the CXCL13 chemokine. They are activated and function in lymphocyte migration and humoral defense, and in HIV-2 infection, and probably It is involved in the development of AIDS, lymphoma, myeloma, and leukemia; 372 aa, μl: 8.54 M W: 41959 TM: 7 [P] Gene chromosome: 11q23.3, Genbank accession number NP-1707 .); CXORF61 CXORF61-Hromosome X Open Reading Frame 61[Homo sapiens]、NCB I Number: NP-01017978.1); cyclin D1 (CCND1, BCL1, PRAD1, D11S287E, B-Cell CLL / Lymphoma 1、B-Cell Lymphoma 1 Protein、BCL-1 Oncogene、PRAD1 Oncogene e、Cyclin D1 (PRAD1: Parathyroid Adenomatosis 1)、G1 / S-Specific Cyclin D1 、Parathyroid Adenomatosis 1、U21B31、G1 / S-Specific Cyclin-D1、BCL-1; NCBI Number: NP-44284.1); Cyclin-A1 (CCNA1, CT146, Cyclin A1; GenBank: AAH363). 46.1); dec-can fusion protein; DKK1 (Dickkopf WNT Signaling Pathway Inh ibitor 1、SK、hDkk-1、Dickkopf (Xenopus Laevis) Homolog 1、Dickkopf 1 Hom olog (Xenopus Laevis)、DKK-1、Dickkopf 1 Homologue、Dickkopf Related Protein -1、Dickkopf-1 Like、Dickkopf-Like Protein 1、Dickkopf-Related Protein 1、D ickkopf-1、Dkk-1; GenBank: AAQ89364.1); DR1 (Down-Regulator Of Transcripts). on 1、TBP-Binding (Negative Cofactor 2)、Negative Cofactor 2-Beta、TATA-Bi nding Protein-Associated Phosphoprotein, NC2, NC2-BETA, Protein Dr1, NC2-beta , Down-Regulator Of Transcription 1; NCBI Reference Sequence: NP-01929.1); DR13 (M ajor Histocompatibility Complex, Class II, DR Beta 1, HLA-DR1B, DRw10, DW2 .2 / DR2.2, SS1, DRB1, HLA-DRB, HLA Class II Histocompatibility Antigen, DR-1 Beta Chain, Human Leucocyte Antigen DRB1, Lymphocyte Antigen DRB1, MHC Class II Antigen, MHC Class II HLA-DR Beta 1 Chain, MHC Class II HLA- DR-Beta Cell Surface Glycoprotein, MHC Class II HLA-DRw10-Beta, DR-1, DR-1 2, DR-13, DR-14, DR-16, DR-4, DR-5, DR-7, DR-8, DR-9, DR1, DR12, DR13, DR14, DR1 6, DR4, DR5, DR7, DRB, DR9, DRw11, DRw8, HLA-DRB2, Clone P2-Beta-3, MHC Class II Antigen DRB1*1, MHC Class II Antigen DRB1*10, MHC Class II Antigen DRB1*11, MHC Class II Antigen DRB1*12, MHC Class II Antigen DRB1*13, M HC Class II Antigen DRB1*14, MHC Class II Antigen DRB1*15, MHC Class I I Antigen DRB1*16, MHC Class II Antigen DRB1*3, MHC Class II Antigen D RB1*4, MHC Class II Antigen DRB1*7, MHC Class II Antigen DRB1*8, MHC Cl ass II Antigen DRB1*9; NP); E16 (E16 (LAT1, SLC7A5, Genbank accession number NM-00348); EDAR (EDAR- tumor necrosis factor receptor superfamily me mber EDAR precursor, EDA-A1 receptor; downless homolog; ectodysplasin-A r eceptor; ectodermal dysplasia receptor; anhidrotic ectodysplasin receptor 1, DL; ECTD10A; ECTD10B; ED1R; ED3; ED5; EDA-A1R; EDA1R; EDA3; HRM1 [Homo sapiens]; NCBI reference sequence: NP-071731.1); EFTUD2 (Elongation Factor T u GTP Binding Domain Containing 2, Elongation Factor Tu GTP-Binding Dom ain-Containing Protein 2, hSNU114, SNU114 Homolog, U5 SnRNP-Specific Protei n, 116 KDa, MFDGA, KIAA0031, 116 KD, U5 SnRNP Specific Protein, 116 KDa U 5 Small Nuclear Ribonucleoprotein Component, MFDM, SNRNP116, Snrp116, Snu114 , U5-116KD, SNRP116, U5-116 KDa; GenBank: AAH02360.1); EGFR (Epidermal Gro wth Factor Receptor, ERBB, Proto-Oncogene C-ErbB-1, Receptor Tyrosine-Protei n Kinase ErbB-1, ERBB1, HER1, EC 2.7.10.1, Epidermal Growth Factor Recepto r (Avian Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog), Eryth roblastic Leukemia Viral (V-Erb-B) Oncogene Homolog (Avian), PlG61, Avian Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog, Cell Growth I nhibiting Protein 40, Cell Proliferation-Inducing Protein 61, mENA, EC 2.7 .10; GenBank: AAH94761.1); EGFR-G719A; EGFR-G719C; EGFR-G719S; EGFR-L858R; EGFR-L861 Q; EGFR-57681; EGFR-T790M; Elongation factor 2 (EEF2, Eukaryo tic Translation Elongation Factor 2, EF2, Polypeptidyl-TRNA Translocase, EF -2, SCA26, EEF-2; NCBI reference sequence: NP-001952.1); ENAH (hMena) (Enabled Homo log (Drosophila), MENA, Mammalian Enabled, ENA, NDPP1, Protein Enabled Homol og; GenBank: AAH95481.1)-“ENAH”であり“ENAH (hMena)”ではない; EpCAM (Epi thelial Cell Adhesion Molecule、M4S1、MIC18、Tumor-Associated Calcium Signa l Transducer 1、TACSTD1、TROP1、Adenocarcinoma-Associated Antigen、Cell Surf ace Glycoprotein Trop-1、Epithelial Glycoprotein 314、Major Gastrointestina l Tumor-Associated Protein GA733-2、EGP314、KSA、DIAR5、HNPCC8、Antigen Iden tified By Monoclonal Antibody AUA1、EGP-2、EGP40、ESA、KS1 / 4、MK-1、Human E pithelial Glycoprotein-2, Membrane Component, Chromosome 4, Surface Marke r (35kD Glycoprotein)、EGP、Ep-CAM、GA733-2、M1S2、CD326 Antigen、Epithelial Cell Surface Antigen、hEGP314、KS 1 / 4 Antigen、ACSTD1; GenBank: AAH14785 .1); EphA3 (EPH Receptor A3、ETK1、ETK、TYRO4、HEK、Eph-Like Tyrosine Kina se 1、Tyrosine-Protein Kinase Receptor ETK1、EK4、EPH-Like Kinase 4、EC 2 .7.10.1、EPHA3、HEK4、Ephrin Type-A Receptor 3、Human Embryo Kinase 1、TYR O4 Protein Tyrosine Kinase, hEK4, Human Embryo Kinase, Tyrosine-Protein Ki nase TYRO4, EC 2.7.10; GenBank: AAH63282.1); EphB2R; Epiregulin (EREG, ER 、proepiregulin; GenBank: AAI36405.1); ETBR (EDNRB, Endothelin Receptor Ty pe B, HSCR2, HSCR, Endothelin Receptor Non-Selective Type, ET-B, ET-BR, ETRB 、ABCDS, WS4A, ETB, Endothelin B Receptor; NP); ETV6-AML1 fusion protein; EZ H2 (Enhancer Of Zeste Homolog 2 (Drosophila), Lysine N-Methyltransferase 6, ENX-1, KMT6 EC 2.1.1.43, EZH1, WVS, Enhancer Of Zeste (Drosophila) Ho molog 2, ENX1, EZH2b, KMT6A, WVS2, Histone-Lysine N-Methyltransferase EZH2, E nhancer Of Zeste Homolog 2, EC 2.1.1; GenBank: AAH10858.1); FcRH1 (FCRL 1, Fc Receptor-Like 1, FCRH1, Fc Receptor Homolog 1, FcR-Like Protein 1, Immune Receptor Translocation-Associated Protein 5, IFGP1, IRTA5, hIFGP1, IF GP Family Protein 1, CD307a, Fc Receptor-Like Protein 1, Immunoglobulin S uperfamily Fc Receptor、Gp42、FcRL1、CD307a Antigen; GenBank: AAH33690.1); FcRH2 (FCRL2、Fc Receptor-Like 2、SPAP1、SH2 Domain-Containing Phosphatas e Anchor Protein 1、Fc Receptor Homolog 2、FcR-Like Protein 2、Immunoglo bulin Receptor Translocation-Associated Protein 4、FCRH2、IFGP4、IRTA4、IFGP Family Protein 4、SPAP1A、SPAP1 B、SPAP1C、CD307b、Fc Receptor-Like Prote in 2、Immune Receptor Translocation-Associated Protein 4、Immunoglobulin S uperfamily Fc Receptor、Gp42、SH2 Domain Containing Phosphatase Anchor Pr otein 1、FcRL2、CD307b Antigen; GenBank: AAQ88497.1); FcRH5 (FCRL5、Fc Re ceptor-Like 5、IRTA2、Fc Receptor Homolog 5、FcR-Like Protein 5、Immune R eceptor Translocation-Associated Protein 2、BXMAS1、FCRH5、CD307、CD307e、PRO 820、Fc Receptor-Like Protein 5、Immunoglobulin Superfamily Receptor Trans location Associated 2 (IRTA2)、FCRL5、CD307e Antigen; GenBank: AAI01070.1) ; FLT3-ITD; FN1(Fibronectin 1、Cold-Insoluble Globulin、FN、Migration-Stimulator ating Factor, CIG, FNZ, GFND2, LETS, ED-B, FINC, GFND, MSF, fibronectin; GenBa pp: AAI43764.1); G250 (MN, CAIX, Carbonic Anhydrase IX, Carbonic Dehydrata se、RCC-Associated Protein G250、Carbonate Dehydratase IX、Membrane Antigen MN, Renal Cell Carcinoma-Associated Antigen G250, CA-IX, P54 / 58N, pMW1, RC C-Associated Antigen G250、Carbonic Anhydrase 9; NP);- In the case of “G250”. and “G250 / MN / CAIX”; GAGE-1,2,8; GAGE-3,4,5,6,7; GDNF-Ra1 (GDNF father mily receptor alpha 1; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1 L; GD NFR-alpha1; GFR-ALPHA-; U95847; BC014962 ; NM-145793 NM-005264); GEDA (Gen bankアシー。 AY26076); GFRA1-GDNF family receptor alpha-1; GDNF r alpha-1 receptor; GDNFR-alpha-1; GFR-alpha-1; RET ligand 1; TGF-beta-rel ed neurotrophic factor receptor 1 [Homo sapiens]; ProtKB / Swiss-Prot: P56 159.2; glypican-3 (GPC3、Glypican 3、SDYS、Glypican Proteoglycan 3、Intesti nal Protein OCI-5、GTR2-2、MXR7、SGBS1、DGSX、OCI-5. SGB、SGBS、Heparan Sulp hate Proteoglycan、Secreted Glypican-3、OCI5; GenBank: AAH35972.1); GnTVf; gp100 (PMEL、Premelanosome Protein、SILV、D12S53E、PMEL17、SIL、Melanocyte Protein Pmel 17、Melanocytes Lineage-Specific Antigen GP100、Melanoma-Assoc iated ME20 Antigen、Silver Locus Protein Homolog、ME20-M、ME20M、P1、P100、 Silver (Mouse Homolog) Like、Silver Homolog (マウス)、ME20、SI、Melanocyte Protein Mel 17、Melanocyte Protein PMEL、Melanosomal Matrix Protein17, Silver, Mouse, Homolog Of; GenBank: AAC60634.1); GPC; GPNMB (Glycoprotei n (Transmembrane) Nmb、Glycoprotein NMB、Glycoprotein Nmb-Like Protein、ost eoactivin、Transmembrane Glycoprotein HGFIN、HGFIN、NMB、Transmembrane Glycop rotein、Transmembrane Glycoprotein NMB; GenBank: AAH32783.1); GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D15Ertd747e); NP-078807.1 ; NM-024531.3); GPR19 (G protein-coupled receptor 19; Mm.478; NP-006134. 1; NM-006143.2); GPR54 (KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR1; NP-115940.2; NM-032551.4); HAVCR1 (Hepatitis A Virus Cellular Receptor 1、T-Cell Immunoglobulin Mucin Family Member 1、Kidney Injury Molecule 1、KIM-1、KIM1、TIM、TIM-1、TIM1、TIMD-1、TIMD1、T-Cell Immunoglobulin Mucin Receptor 1、T-Cell Membrane Protein 1、HAVCR、HAVCR-1、T Cell Immunoglob in Domain And Mucin Domain Protein 1、HAVcr-1、T-Cell Immunoglobulin And Mucin Domain-Containing Protein 1; GenBank: AAH13325.1); HER2 (ERBB2、V -Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2、NGL、NEU 、Neuro / Glioblastoma Derived Oncogene Homolog、Metastatic Lymph Node Gene 19 Protein, Proto-Oncogene C-ErbB-2, Proto-Oncogene Neu, Tyrosine Kinase-T ype Cell Surface Receptor HER2, MLN 19, p185erbB2, EC 2.7.10.1, V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (Neuro / Glioblastom a Derived Oncogene Homolog), CD340, HER-2, HER-2 / neu, TKR1, C-Erb B2 / Neu Pr otein, herstatin, Neuroblastoma / Glioblastoma Derived Oncogene Homolog, Recept or Tyrosine-Protein Kinase ErbB-2, V-Erb-B2 Erythroblastic Leukemia Viral Oncogene Homolog 2, Neuro / Glioblastoma Derived Oncogene Homolog, MLN19, C D340 Antigen, EC 2.7.10; NP); HER-2 / neu-the aforementioned alternative name; HERV-K-MEL; HLA-DOB (bound to peptide) The beta subunit (LA) of the MHC class II molecule presents the peptide to CD4+ T lymphocytes. Original)); 273 aa, μl: 6.56, MW: 30820.TM: 1 [P] Gene chromosome: 6p21.3, Genb ANK accession number NP-002111); hsp70-2 (HSPA2, Heat Shock 70 kDa Protein) 2, Heat Shock 70kD Protein 2, HSP70-3, Heat Shock-Related 70 KDa Prote in 2, Heat Shock 70 KDa Protein 2; GenBank: AAD21815.1); IDO1 (Indolea mine 2,3-Dioxygenase 1, IDO, INDO, Indoleamine-Pyrrole 2,3-Dioxygenase, IDO-1 , Indoleamine-Pyrrole 2,3 Dioxygenase, Indolamine 2,3 Dioxygenase, Indole 2 ,3 Dioxygenase, EC 1.13.11.52; NCBI reference sequence: NP-002155.1); IGF2B3; IL13R alpha2 (IL13RA2, Interleukin 13 Receptor, Alpha 2, Cancer / Testis Antigen 1 9, Interleukin-13-Binding Protein, IL-13R-alpha-2, IL-13RA2, IL-13 Receptor S ubunit Alpha-2, IL-13R Subunit Alpha-2, CD213A2, CT19, IL-13R, IL13BP, Interl eukin 13 Binding Protein, Interleukin 13 Receptor Alpha 2 Chain, Interle ukin-13 Receptor Subunit Alpha-2, IL13R, CD213a2 Antigen; NP); IL20Rα; I ntestinal carboxyl esterase; IRTA2 (alias of FcRH5); Kallikrein 4 (KLK4 , Kallikrein-Related Peptidase 4, PRSS17, EMSP1, Enamel Matrix Serine Prote inase 1、Kallikrein-Like Protein 1、Serine Protease 17、KLK-L1、PSTS、AI2A1 、Kallikrein 4 (Prostase、Enamel Matrix、Prostate)、ARM1、EMSP、Androgen-Regu lated Message 1、Enamel Matrix Serine Protease 1、kallikrein、kallikrein-4 、prostase、EC 3.4.21.-、Prostase、EC 3.4.21; GenBank: AAX30051.1); KIF20A (Kinesin Family Member 20A、RAB6KIFL、RAB6 Interacting、Kinesin-Like (Rab kinesin6)、Mitotic a; LAGE-1; LDLR-fucosyltransferase AS fusion protein; Lengsin (LGSN、Lengsin、Lens Protein With Glutamine Synthetase Domain、GLU LD1、Glutamate-Ammonia Ligase Domain-Containing Protein 1、LGS、Glutamate-Am monia Ligase (Glutamine Synthetase) Domain Containing 1、Glutamate-Ammonia Ligase (Glutamine Synthase) Domain Containing 1、Lens Glutamine Synthas e-Like; GenBank: AAF61255.1); LGR5 (leucine-rich repeat-containing G prot ein-coupled receptor 5; GPR49、GPR6; NP-003658.1; NM-003667.2; LY64 (Lymp hocyte antigen 64 (RP10, type I membrane protein of the leucine-rich repeat (LRR) family) It is a substance that controls B cell activation and apoptosis. Loss of this function leads to systemic erythema. Associated with increased disease activity in lupus patients; 661 aa, μl: 6.20, M W: 74147 TM: 1 [P] Gene chromosome: 5q12, Genbank accession number NP-005573. Ly6E (lymphocyte antigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-; NP-002337.1; NM-002346.2); Ly6G6D (lymphocyte antigen 6 complex, locus G 6D; Ly6-D, MEGT; NP-067079.2; NM-021246.2); LY6K (lymphocyte antigen 6 c omplex, locus K; LY6K; HSJ001348; FLJ3522; NP-059997.3; NM-017527.3); Ly PD1-LY6 / PLAUR domain containing 1, PHTS [Homo sapiens], GenBank: AAH17318. 1); MAGE-A1 (Melanoma Antigen Family A, 1 (Directs Expression Of Antige n MZ2-E, MAGE1, Melanoma Antigen Family A 1, MAGEA1, Melanoma Antigen MAG E-1, Melanoma-Associated Antigen 1, Melanoma-Associated Antigen MZ2-E, Antig en MZ2-E, Cancer / Testis Antigen 1.1, CT1.1, MAGE-1 Antigen, Cancer / Testis A ntigen Family 1, Member 1, Cancer / Testis Antigen Family 1, Member 1, MA GE1A; NCBI reference sequence: NP-004979.3); MAGE-A10 (MAGEA10, Melanoma Antigen Fa mily A, 10, MAGE10, MAGE-10 Antigen, Melanoma-Associated Antigen 10, Cancer / Testis Antigen 1.10, CT1.10, Cancer / Testis Antigen Family 1, Member 10, Cancer / Testis Antigen Family 1, Member 10; NCBI reference sequence: NP-001238757.1 ); MAGE-A12 (MAGEA12, Melanoma Antigen Family A, 12, MAGE12, Cancer / Testis Antigen 1.12, CT1.12, MAGE12F Antigen, Cancer / Testis Antigen Family 1, M ember 12, Cancer / Testis Antigen Family 1, Member 12, Melanoma-Associated Antigen 12, MAGE-12 Antigen; NCBI reference sequence: NP-001159859.1); MAGE-A2 (MAG EA2, Melanoma Antigen Family A, 2, MAGE2, Cancer / Testis Antigen 1.2, CT1.2 、MAGEA2A、MAGE-2 Antigen、Cancer / Testis Antigen Family 1, Member 2、Cance r / Testis Antigen Family 1, Member 2, Melanoma Antigen 2, Melanoma-Associa ted Antigen 2; NCBI reference sequence: NP-001269434.1); MAGE-A3 (MAGEA3, Melanoma Antigen Family A, 3, MAGE3, MAGE-3 Antigen, Antigen MZ2-D, Melanoma-Assoc iated Antigen 3, Cancer / Testis Antigen 1.3, CT1.3, Cancer / Testis Antigen F amily 1, Member 3, HIPS, HYPD, MAGEA6, Cancer / Testis Antigen Family 1, Me mber 3; NCBI reference sequence: NP-005353.1); MAGE-A4 (MAGEA4, Melanoma Antigen F amily A, 4, MAGE4, Melanoma-Associated Antigen 4, Cancer / Testis Antigen 1. 4, CT1.4, MAGE-4 Antigen, MAGE-41 Antigen, MAGE-X2 Antigen, MAGE4A, MAGE4B, C ancer / Testis Antigen Family 1, Member 4, MAGE-41, MAGE-X2, Cancer / Testis A ntigen Family 1, Member 4; NCBI reference sequence: NP-001011550.1); MAGE-A6 (MAG EA6, Melanoma Antigen Family A, 6, MAGE6, MAGE-6 Antigen, Melanoma-Associat ed Antigen 6, Cancer / Testis Antigen 1.6, CT1.6, MAGE3B Antigen, Cancer / Test is Antigen Family 1, Melanoma Antigen Family A 6, Member 6, MAGE-3b, MA GE3B, Cancer / Testis Antigen Family 1, Member 6; NCBI reference sequence: NP-787064 .1); MAGE-A9 (MAGEA9, Melanoma Antigen Family A, 9, MAGE9, MAGE-9 Antigen , Melanoma-Associated Antigen 9, Cancer / Testis Antigen 1.9, CT1.9, Cancer / Te stis Antigen Family 1, Member 9, Cancer / Testis Antigen Family 1, Member 9, MAGEA9A; NCBI reference sequence: NP-005356.1); MAGE-C1 (MAGEC1, Melanoma Antig en Family C, 1, Cancer / Testis Antigen 7.1, CT7.1, MAGE-C1 Antigen, Cancer / Testis Antigen Family 7, Member 1, CT7, Cancer / Testis Antigen Family 7, Member 1, Melanoma-Associated Antigen C1; NCBI reference sequence: NP-005453.2); MAGE-C2 (MAGEC2, Melanoma Antigen Family C, 2, MAGEE1, Cancer / Testis Antig en 10, CT10, HCA587, Melanoma Antigen, Family E, 1, Cancer / Testis Specific , Hepatocellular Carcinoma-Associated Antigen 587, MAGE-C2 Antigen, MAGE-E1 Antigen、Hepatocellular Cancer Antigen 587、Melanoma-Associated Antigen C 2; NCBI Public Number: NP-057333.1); mammaglobin-A (SCGB2A2、Secretoglobin, Fam ily 2A, Member 2, MGB1, Mammaglobin 1, UGB2, Mammaglobin A, Mammaglobin-A Mammaglobin-1、Secretoglobin Family 2A Member 2; NP); MART2 (H HAT、Hedg ehog Acyltransferase、SKI1、Melanoma Antigen Recognized By T-Cells 2、Skin ny Hedgehog Protein 1、Skin、Melanoma Antigen Recognized By T Cells 2、P rotein-Cysteine ​​N-Palmitoyltransferase HHAT、EC 2.3.1.-; GenBank: AAH39071. 1); M-CSF (CSF1, Colony Stimulating Factor 1 (Macrophage), MCSF, CSF-1 nimostim、Macrophage Colony-Stimulating Factor 1、Lanimostim; GenBank: AAH2 1117.1); MCSP (SMCP、Sperm Mitochondria-Associated Cysteine-Rich Protein、M CS、Mitochondrial Capsule Selenoprotein、HSMCSGEN1、Sperm Mitochondrial-Assoc iated Cysteine-Rich Protein; NCBI Public Number: NP-109588.2); XAGE-1b / GAGED2a; WT1 (Wilms Tumor 1, WAGR, GUD, WIT-2, WT33, Amino-Terminal Domain Of EWS , NPHS4, Last Three Zinc Fingers Of The DNA-Binding Domain Of WT1, AWT1 , Wilms Tumor Protein, EWS-WT1; GenBank: AAB33443.1); VEGF; Tyrosinase (T YR; OCAIA; OCA1A; tyrosinase; SHEP; NP-000363.1; NM-000372.4; GenBank: A AB60319.1); TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor pote ntial cation channel, subfamily M, member 4, Genbank accession number NM-01 763); TRP2-INT2; TRP-2; TRP-1 / gp75 (Tyrosinase-Related Protein 1, 5,6-Dihy droxyindole-2-Carboxylic Acid Oxidase, CAS2, CATB, TYRP, OCAS, Catalase B, b- PROTEIN, Glycoprotein 75, EC 1.14.18., Melanoma Antigen Gp75, TYRP1, TRP, TY RRP, TRP1, SHEP11, DHICA Oxidase, EC 1.14.18, GP75, EC 1.14.18.1; Triosephos phate isomerase (Triosephosphate isomerase 1, TPID, Triose-Phosphate Isomer ase, HEL-S-49, TIM, Epididymis Secretory Protein Li 49, TPI, Triosephosphate Isomerase、EC 5.3.1.1; TRAG-3 (CSAG Family Member 2、Cancer / Testis Anti gen Family 24、CSAG3B, Member 2、CSAG Family Member 3B、Cancer / Testis An tigen Family 24 Member 2、Cancer / Testis Antigen 24.2、Chondrosarcoma-Assoc iated Gene 2 / 3 Protein、Taxol-Resistant-Associated Gene 3 Protein、Chondro sarcoma-Associated Gene 2 / 3 Protein-Like、CT24.2、Taxol Resistance Associat ed Gene 3、TRAG-3、CSAG3A、TRAG3;); TMEM46 (shisa homolog 2 (Xenopus Lae vis); SHISA; NP-001007539.1; NM-001007538.1; TMEM118 (ring finger protein 、transmembrane2; RNFT2; FLJ1462; NP-001103373.1; NM-001109903.1; TMEFF1 ( transmembrane protein with EGF-like and two follistatin-like domains 1; Tomoregulin-; H7365; C9orf2; C9ORF2; U19878; X83961; NM-080655; NM-0036 92; TGF-betaRII (TGFBR2、Transforming Growth Factor、Beta Receptor II (70 / 80 kDa), TGFbeta-RII, MFS2, tbetaR-II, TGFR-2, TGF-Beta Receptor Type IIB, TGF-Beta Type II Receptor, TGF-Beta Receptor Type-2, EC 2.7.11.30, Transfo rming Growth Factor Beta Receptor Type IIC, AAT3, TbetaR-II, Transforming Growth Factor, Beta Receptor II (70-80kD), TGF-Beta Receptor Type II, F AA3, Transforming Growth Factor-Beta Receptor Type II, LDS1 B, HNPCC6, LDS 2B, LDS2, RITC, EC 2.7.11, TAAD2; TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR , presumed transmembrane proteoglycans, EGF / growth factors, the heregulin family and follice Related to Tachin); 374 aa, NCBI accession numbers: AAD55776, AAF91397, AAG494 51. NCBI reference sequence: NP-057276; NCBI Gene: 23671; OMIM: 605734; SwissProt Q9U IK5; Genbank accession number AF179274; AY358907, CAF85723, CQ782436; TAG-2; TAG-1 (Contactin 2 (Axonal), TAG-1, AXT, Axonin-1 Cell Adhesion Molecule , TAX, Contactin 2 (transiently Expressed), TAXI, Contactin-2, Axonal Glycop rotein TAG-1, Transiently-Expressed Axonal Glycoprotein, Transient Axonal G Lycoprotein, Axonin-1, TAX-1, TAG1, FAMES; PRF: 444868); SYT-SSX1 or -SSX2 Fusion protein; survivin; STEAP2 (HGNC 8639, IPCA-1, PCANAP1, STAMP1, STEAP2 ,STMP,prostate cancer associated gene 1,prostate cancer associated pro tein 1, six transmembrane epithelial antigen of prostate 2, six transmem Brane Prost ate protein, Genbank accession number AF45513; STEAP1 (six transmembrane ep Ithelial antigen of prostate, Genbank accession number NM-01244; SSX-4; SS X-2 (SSX2, Synovial Sarcoma, X Breakpoint2, X Breakpoint 2, SSX, X Breakpo int 2B, Cancer / Testis Antigen 5.2, X-Chromosome-Related 2, Tumor Antigen H OM-MEL-40, CT5.2, HD21, Cancer / Testis Antigen Family 5, HOM-MEL-40, Isoform B, Cancer / Testis Antigen Family 5 member 2a, member 2a, Protein SSX2, S arcoma、Sarcoma, Synovial, X-Chromosome-Related 2、synovial, Synovial Sarco ma, X Breakpoint 2B、Synovial Sarcomam, SSX2A; Sp17; SOX10 (SRY (Sex D etermining Region Y)-Box 10, mouse, PCWH、DOM、WS4、WS2E、WS4C、Dominant M egacolon, mouse, Human Homolog Of、Dominant Megacolon、SRY-Related HMG-Box Gene 10, Human Homolog Of、transcription Factor SOX-10; GenBank: CAG30 470.1); SNRPD1 (Small Nuclear Ribonucleoprotein D1、Small Nuclear Ribonuc leoprotein D1、Polypeptide 16 kDa、Polypeptide (16kD)、SNRPD、HsT2456、Sm-D1 、SMD1、Sm-D Autoantigen、Small Nuclear Ribonucleoprotein D1 Polypeptide 1 6 kDa Pseudogene、SnRNP Core Protein D1、Small Nuclear Ribonucleoprotein Sm D1; SLC35D3 (Solute Carrier Family 35, Member D3、FRCL1、Fringe Co nnection-Like Protein 1、bA55K22.3、Frc、Fringe-Like 1、Solute Carrier Fami ly 35 Member D3; NCBI GenBank: NC-000006.11 NC-018917.2 NT-025741.16); SIRT2 (Sirtuin 2, NAD - Dependent Deacetylase Sirtuin - 2, SIRL2, Silent Information Regulator 2, Regulatory Protein SIR2 Homolog 2, Sir2 - Related Protein Type 2, SIR2 - Like Protein 2, Sirtuin Type 2, Sirtuin (Silent Mating Type Information Regulation 2 Homolog) 2 (S. cerevisiae), Sirtuin - 2, Sirtuin (Silent Mating Type Information Regulation 2, S. cerevisiae, Homolog) 2, EC 3.5.1., SIR2; GenBank: AAK51133.1); Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1 - like), Transmembrane Domain(TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession number AB04087; secernin 1 (SCRN1, SES1, KIAA0193, secerin - 1; GenBank: EAL24458.1); SAGE (SAGE1, Sarcoma Antigen 1, Cancer / Testis Antigen 14, CT14, Putative Tumor Antigen; NCBI reference sequence: NP - 061136.2); RU2AS (KAAG1, Kidney Associated An in (Silent Mating Type Information Regulation 2, S. cerevisiae, Homolog ) 2、EC 3.5.1.、SIR2; GenBank: AAK51133.1); Sema 5b (FLJ10372、KIAA1445、 Mm.42015、SEMA5B、SEMAG、Semaphorin 5b Hlog、sema domain, seven thrombospon din repeats (type 1 and type 1 - like), Transmembrane Domain(TM) and sho rt cytoplasmic domain, (semaphorin) 5B、Genbankアクセッション番号 AB04087; secernin 1 (SCRN1、SES1、KIAA0193、secerin - 1; GenBank: EAL24458.1); SAGE (SAGE1、Sarcoma Antigen 1、Cancer / Testis Antigen 14、CT14, Putative Tumo r Antigen; NCBI参照配列: NP - 061136.2); RU2AS (KAAG1、Kidney Associated An Antigen 1, RU2AS, RU2 Antisense Gene Protein, Kidney-Associated Antigen 1; GenBank: AAF23613.1); RNF43 - E3 ubiquitin-protein ligase RNF43 precursor Homo sapiens, RNF124; URCC; NCBI reference sequence: NP - 060233.3; RhoC (RGS5 (Regul ator Of G - Protein Signaling 5, MSTP032, Regulator Of G - Protein Signalling 5, MSTP092, MST092, MSTP106, MST106, MSTP129, MST129; GenBank: AAB84001.1); RET (ret proto - oncogene; MEN2A; HSCR1; MEN2B; MTC1; PTC; CDHF12; Hs.1 68114; RET51; RET - ELE; NP - 066124.1; NM - 020975.4); RBAF600 (UBR4, Ubiquitin Protein Ligase E3 Component N - Recognin 4, Zinc Finger, UBR1 Type 1, ZU BR1, E3 Ubiquitin - Protein Ligase UBR4, RBAF600, 600 KDa Retinoblastoma Pro tein - Associated Factor, Zinc Finger UBR1 - Type Protein 1, EC 6.3.2., N - reco gnin - 4, KIAA0462, p600, EC 6.3.2, KIAA1307; GenBank: AAL83880.1); RAGE - 1 (M OK, MOK Protein Kinase, Renal Tumor Antigen, RAGE, MAPK / MAK / MRK Overlapping Kinase, Renal Tumor Antigen 1, Renal Cell Carcinoma Antigen, RAGE-1, EC 2.7.11.22, RAGE1; UniProtKB / Swiss-Prot: Q9UQ07.1); RAB38 / NY-MEL-1 (RAB38, NY-MEL-1, RAB38, Member RAS Oncogene Family, Melanoma Antigen NY-MEL-1, Rab -Related GTP-Binding Protein, Ras-Related Protein Rab-38, rrGTPbp; GenBank: AAH15808.1); PTPRK (DJ480J14.2.1 (Protein Tyrosine Phosphatase, Receptor Type, K R-PTP-KAPPA, Protein Tyrosine Phosphatase Kappa, Protein Tyrosine Phosphatase Kappa), Protein Tyrosine Phosphatase, Receptor Type, K, Prot ein-Tyrosine Phosphatase Kappa, Protein-Tyrosine Phosphatase, Receptor Type , Kappa, R-PTP-kappa, Receptor-Type Tyrosine-Protein Phosphatase Kappa, EC 3.1.3.48, PTPK; GenBank: AAI44514.1); PSMA; PSCA hIg(2700050C12Rik, C530008 016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628); PSCA (Prostate stem cell antigen precursor, Genbank a Session number AJ29743; PRDX5 (Peroxiredoxin 5, EC 1.11.1.15, TPx Type VI, B166, Antioxidant Enzyme B166, HEL-S-55, Liver Tissue 2D-Page Spot 71 B, PMP20, Peroxisomal Antioxidant Enzyme, PRDX6, Thioredoxin Peroxidase PM P20, PRXV, AOEB166, Epididymis Secretory Protein Li 55, Alu Co-Repressor 1 , Peroxiredoxin-5, Mitochondrial, Peroxiredoxin V, prx-V, Thioredoxin Reductas e, Prx-V, ACR1, Alu Corepressor, PLP; GenBank: CAG33484.1); PRAME (Preferen tially Expressed Antigen In Melanoma, Preferentially Expressed Antigen Of Melanoma, MAPE, 01P-4, OIPA, CT130, Cancer / Testis Antigen 130, Melanoma Ant igen Preferentially Expressed In Tumors, Opa-Interacting Protein 4, Opa-In teracting Protein 01P4; GenBank: CAG30435.1); pml-RARalpha fusion protein; PMEL17 (silver homolog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp10 BC 001414; BT007202; M32295; M77348; NM-006928; PBF (ZNF395, Zinc Finger Pr otein 395、PRF-1、Huntington disease regulatory、HD Gene Regulatory Region -Binding Protein、Region-Binding Protein 2、Protein 2、Papillomavirus Regul atory Factor 1、HD-Regulating Factor 2、Papillomavirus-Regulatory Factor、P RF1、HDBP-2、Si-1-8-14、HDBP2、Huntington'S Disease Gene Regulatory Region-B inding Protein 2、HDRF-2、Papillomavirus Regulatory Factor PRF-1、PBF; Gen Bank: AAH01237.1); PAX5 (Paired Box 5、Paired Box Homeotic Gene 5、BSAP 、Paired Box Protein Pax-5、B-Cell Lineage Specific Activator、Paired Dom ain Gene 5、Paired Box Gene 5 (B-Cell Lineage Specific Activator Prote in)、B-Cell-Specific Transcription Factor、Paired Box Gene 5 (B-Cell Line age Specific Activator); PAP (REG3A、Regenerating Islet-Derived 3 Alpha、 INGAP、PAP-H、Hepatointestinal Pancreatic Protein、PBBCGF、Human Proislet Pe ptide、REG-Ill、Pancreatitis-Associated Protein 1、Regi、Reg III-Alpha、hepat ocarcinoma-intestine-pancreas, Regenerating Islet-Derived Protein III-Alpha, Pancreatic Beta Cell Growth Factor, HIP, PAP Homologous Protein, HIP / PAP, Proliferation-Inducing Protein 34, PAP1, Proliferation-Inducing Protein 42, REG-3-alpha, Regenerating Islet-Derived Protein 3-Alpha, Pancreatitis-Associa ted Protein; GenBank: AAH36776.1); p53 (TP53, Tumor Protein P53, TPR53, P 53, Cellular Tumor Antigen P53, Antigen NY...

Claims

1. A Cluster of Difference (CD3) antibody or an antigen-binding fragment thereof, (A) Heavy chain variable region (VH) polypeptides containing CDRH1, CDRH2 and CDRH3, (B) Light chain variable region (VL) polypeptides including CDRL1, CDRL2 and CDRL3 The amino acid sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 are, (I)(i) The amino acid sequences of CDRH1, CDRH2, and CDRH3 include the heavy chain CDR1, 2, and 3 sequences contained in SEQ ID NO: 4594, and the amino acid sequences of CDRL1, CDRL2, and CDRL3 include the light chain CDR1, 2, and 3 sequences contained in SEQ ID NO: 4602, or (ii) The amino acid sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 each include SEQ ID NOs: 4595, 4597, 4599, 4603, 4605, and 4607, (II) (i) The amino acid sequences of CDRH1, CDRH2, and CDRH3 include the heavy chain CDR1, 2, and 3 sequences contained in SEQ ID NO: 4690, and the amino acid sequences of CDRL1, CDRL2, and CDRL3 include the light chain CDR1, 2, and 3 sequences contained in SEQ ID NO: 4698, or (ii) The amino acid sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 each include SEQ ID NOs: 4691, 4693, 4695, 4699, 4701, and 4703, or (III) (i) The amino acid sequences of CDRH1, CDRH2, and CDRH3 include the heavy chain CDR1, 2, and 3 sequences contained in SEQ ID NO: 4706, and the amino acid sequences of CDRL1, CDRL2, and CDRL3 include the light chain CDR1, 2, and 3 sequences contained in SEQ ID NO: 4714, or (ii) The amino acid sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 each include SEQ ID NOs: 4707, 4709, 4711, 4715, 4717, and 4719, An anti-CD3 antibody or its antigen-binding fragment, including the above.

2. The anti-CD3 antibody or antigen-binding fragment according to Claim 1, (I) wherein (A) the VH polypeptide comprises CDRH1, CDRH2 and CDRH3 and comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 4594, and (B) The VL polypeptide comprises CDRL1, CDRL2, and CDRL3, and includes an amino acid sequence having at least 90% identity with SEQ ID NO: 4602; (II) wherein (A) the VH polypeptide comprises CDRH1, CDRH2 and CDRH3 and comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 4690, and (B) The VL polypeptide comprises CDRL1, CDRL2, and CDRL3, and includes an amino acid sequence having at least 90% identity with SEQ ID NO: 4698; or (III) wherein (A) the VH polypeptide comprises CDRH1, CDRH2 and CDRH3 and comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 4706, (B) The VL polypeptide comprises CDRL1, CDRL2, and CDRL3, and includes an amino acid sequence having at least 90% identity with SEQ ID NO: 4714. Anti-CD3 antibody or its antigen-binding fragment.

3. An anti-CD3 antibody or antigen-binding fragment according to claim 1 or 2, (I) wherein (A) the VH polypeptide comprises CDRH1, CDRH2 and CDRH3 and comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 4594, and (B) The VL polypeptide comprises CDRL1, CDRL2, and CDRL3, and includes an amino acid sequence having at least 95% identity with SEQ ID NO: 4602; (II) wherein (A) the VH polypeptide comprises CDRH1, CDRH2 and CDRH3 and comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 4690, and (B) The VL polypeptide comprises CDRL1, CDRL2, and CDRL3, and includes an amino acid sequence having at least 95% identity with SEQ ID NO: 4698; or (III) wherein (A) the VH polypeptide comprises CDRH1, CDRH2 and CDRH3 and comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 4706, (B) The VL polypeptide comprises CDRL1, CDRL2, and CDRL3, and includes an amino acid sequence having at least 95% identity with SEQ ID NO: 4714. Anti-CD3 antibody or its antigen-binding fragment.

4. An anti-CD3 antibody or antigen-binding fragment according to any one of claims 1 to 3, (I) in (A) the amino acid sequence of the VH polypeptide includes or consists of SEQ ID NO: 4594, and (B) The amino acid sequence of the VL polypeptide includes or consists of SEQ ID NO: 4602; (II) in (A) the amino acid sequence of the VH polypeptide includes or consists of SEQ ID NO: 4690, and (B) The amino acid sequence of the VL polypeptide includes or consists of SEQ ID NO: 4698; or (III) in (A) the amino acid sequence of the VH polypeptide includes or consists of SEQ ID NO: 4706, and (B) The amino acid sequence of the VL polypeptide contains or consists of SEQ ID NO: 4714. Anti-CD3 antibody or its antigen-binding fragment.

5. An anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 4, the following: (a) scFv fragment, diabody, minibody, scFv-Fc, Fab fragment, Fab' fragment, Fab'-SH fragment, F(ab')2 fragment, small modular immunotherapy (SMIP) and / or Fv fragment; (b) (A) (i) the VH polypeptide and (ii) a heavy chain including a heavy chain constant region (CH), and (B) (i) the VL polypeptide and (ii) a light chain comprising a light chain constant region (CL); and / or (c) an immunoglobulin molecule comprising two heavy chains and two light chains interconnected by disulfide bonds, or a polymer of the immunoglobulin molecule, Anti-CD3 antibody or its antigen-binding fragment.

6. An anti-CD3 antibody or antigen-binding fragment according to any one of claims 1 to 5, (i) multispecific antibodies or antibody fragments; (ii) Bispecific antibody or antibody fragment; (iii) At least a second antigen-binding domain that specifically binds to an oncological target; an immuno-oncological target; a neurodegenerative disease target; an autoimmune disorder target; an infectious disease target; a metabolic disease target; a cognitive impairment target; a blood-brain barrier target; or a hematological disease target; (iv) At least a second antigen-binding domain that specifically binds to an antigen selected from the group consisting of: 17-IA, 4-1BB, 4Dc, 6-keto-PGF1a, 8-iso-PGF2a, 8-oxo-dG, A1 adenosine receptor, A33, ACE, ACE-2, activin, activin A, activin AB, activin B, activin C, activin RIA, activin RIA ALK-2, activin RIB ALK-4, activin RIIA, activin RIIB, ADAM, ADAM10, ADAM12, ADAM15, ADAM17 / T ACE, ADAM8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5, Adresin, aFGF, ALCAM, ALK, ALK-1, ALK-7, Alpha-1-Antitrypsin, Alpha-V / Beta-1 Antagonist, ANG, Ang, APAF-1, APE, APJ, APP, APRIL, AR, ARC, ART, Artemin, Anti-Id, ASPARTIC, Atrial Natriuretic factor, av / b3 integrin, Axl, b2M, B7-1, B7-2, B7-H, B-lymphocyte-stimulating factor (BlyS), BACE, BACE-1, Bad, BAFF, BAFF-R, Bag-1, BAK, Bax, BCA-1, BCAM, Bel, BCMA, BDNF, b-ECGF, bFGF, BID, Bik, BFM, BLC, BL-CAM, BLK, BMP, BMP-2, BMP-2a, BMP-3, Osteogenin, BMP-4, BMP-2b, BMP-5, BMP-6Vgr-1, BMP-7 (OP-1), BMP-8 (BMP-8a, OP-2), BMPR, BMPR-IA (ALK-3), BMPR-IB (ALK-6), BRK-2, RPK-1, BMPR-II (BRK-3), BMPs, b-NGF, BOK, bombesin, bone-derived neurotrophic factor, BPDE, BPDE-DNA, BTC, complement factor 3 (C3), C3a, C4, C5, C5a, CIO, CA125, CAD-8, calcitonin, cAMP, carcinoembryonic antigen (CEA), tumor-associated antigen, cathepsin A, Cathepsin B, Cathepsin C / DPPI, Cathepsin D, Cathepsin E, Cathepsin H, Cathepsin L, Cathepsin O, Cathepsin S, Cathepsin V, Cathepsin X / Z / P, CBL, CCI, CCK2, CCL, CCL1, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CC L5, CCL6, CCL7, CCL8, CCL9 / 10, CCR, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD1, CD2, CD4, CD5, CD6, CD7, CD8, CD10 , CD11a, CD11b, CD11c, CD13, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD27L, CD28, CD29, CD30, CD30L, CD32, CD33 (p6 7 proteins), CD34, CD38, CD40, CD40L, CD44, CD45, CD46, CD49a, CD52, CD54, CD55, CD56, CD61, CD64, CD66e, CD74, CD80 (B7-1), CD89, CD95, CD123, CD137, CD138, CD140a, CD146, CD147, CD148, CD152, CD164, CEACAM5, CFTR, cGMP, CINC, botulinum toxin, Clostridium perfringens toxin, CKb8-l, CLC, CMV, CMVUL, CNTF, CNTN-1, COX, C-Ret, CRG-2, CT-1, CTACK, CTGF, CTLA-4, CX3CL1, CX3CR1, CXCL, CXCL1, CXCL2, CXCL3, CXCL 4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCR, CXCR1, CXCR 2. CXCR3, CXCR4, CXCR5, CXCR6, cytokeratin tumor-associated antigen, DAN, DCC, DcR3, DC-SIGN, degradation promoter, des(l-3)-IGF-I (brain IGF-1), Dhh, digoxin, DNAM-1, DNase, Dpp, DPPIV / CD26, Dtk, ECAD, EDA, EDA-A1, EDA-A2, EDAR, EGF, EGFR (ErbB-1), EMA, EMMPRIN, EN A, Endothelin receptor, Enkephalinase, eNOS, Eot, eotaxin, EpCAM, Ephrin B2 / EphB4, EPO, ERCC, E-selectin, ET-1, Factor IIa, Factor VII, Factor VIIIc, Factor IX, Fibroblast-activating protein (FAP), Fas, FcRl, FEN-1, Ferritin, FGF, FGF-19, FGF-2, FGF-3, FGF-8, FGFR, FGFR-3, Fibrin, FL, FLIP, Flt-3, Flt-4, Follicle-stimulating hormone, Fractalkine, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, G250, Gas 6. GCP-2, GCSF, GD2, GD3, GDF, GDF-1, GDF-3 (Vgr-2), GDF-5 (BMP-14, CDMP-1), GDF-6 (BMP-13, CDMP-2), GDF-7 (BMP-12, CDMP-3), GDF-8 (Myostatin), GDF-9, GDF-15 (MIC-1), GDNF, GFAP, GFRa-1, GFR-Alpha-1, GFR-Alpha-2, GFR-Alpha-3, GITR, Glucagon, Glut 4. Glycoprotein IIb / IIIa (GP IIb / IIIa), GM-CSF, gp130, gp72, GRO, growth hormone-releasing factor, hapten (NP-cap or NIP-cap), HB-EGF, HCC, HCMVgB envelope glycoprotein, HCMV gH envelope glycoprotein, HCMV UL, hematopoietic growth factor (HGF), Hep B gp120, heparanase, Her2, Her2 / neu (ErbB-2), Her3 (ErbB-3), Her4 (ErbB-4), herpes simplex virus (HSV) gB glycoprotein, HSV gD glycoprotein, HGFA, high molecular weight melanoma-associated antigen (HMW-MAA), HIV gp120, HIV IIIB gp120 V3 loop, HLA, HLA-DR, HM1.24, HMFG PEM, HRG, Hrk, human cardiac myosin, human cytomegalovirus (HCMV), human growth hormone (HGH), HVEM, I-309, IAP, ICAM, ICAM-1, ICAM-3, ICE, ICOS, IFNg, Ig, IgA receptor, IgE, IGF, IGF-binding protein, IGF-1R, IGFBP, IGF-I, IGF-II, IL, IL-1, IL-1R, IL -2, IL-2R, IL-4, IL-4R, IL-5, IL-5R, IL-6, IL-6R, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-18R, IL-23, Interferon (INF)-alpha, INF-beta, INF-gamma, Inhibin, iNOS, Insulin A-chain, Insulin B-chain, Insulin-like growth factor 1, Integrin Alpha 2, Integrin Alpha 3, Integrin Alpha 4, Integrin Alpha 4 / Beta 1, Integrin Alpha 4 / Beta 7, Integrin Alpha 5 (Alpha V), Integrin Alpha 5 / Beta 1, Integrin Alpha 5 / Beta 3, Integrin Alpha 6, Integrin Beta 1, Integrin Beta 2, Interferon Gamma, IP-10, 1-TAC, JE, Kallikrein 2, Kallikrein 5, Kallikrein 6, Kallikrein 11, Kallikrein 12, Kallikrein 14, Kallikrein 15, Kallikrein L1, Kallikrein L2, Kallikrein L3, Kallikrein L4, KC, KDR, Keratinocyte Growth Factor (KGF), Laminin 5, LAMP, LAP, LAP (TGF-1), Latent TGF-1, Latent TGF-1bpl, LBP, LDGF, LECT2, Lefty, Lewis-Y antigen, Lewis-Y related antigen, LFA-1, LFA-3, Lfo, LIF, LIGHT, lipoprotein, LIX, LKN, Lptn, L-selectin, LT-a, LT-b, LTB4, LTBP-1, pulmonary surfactant, progesterone, lymphotoxin beta receptor, Mac-1, MAdCAM, MAG, MAP2, MARC, MCAM, MCK-2, MCP, M-CSF, MDC, Mer, metalloproteinase, MGD F receptor, MGMT, MHC (HLA-DR), MIF, MIG, MIP, MIP-1-alpha, MK, MMAC1, MMP, MMP-1, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-2, MMP-24, MMP-3, MMP-7, MMP-8, MMP-9, MPIF, Mpo, MSK, MSP, mucin (Mucl), MUC18, Müllerian duct inhibitor, Mug, MuSK, NAIP, NAP, NCAD, N-cadherin, NCA 90, NCAM, Neprilysin, Neurotrophin-3, -4 or -6, Neuroturin, Nerve Growth Factor (NGF), NGFR, NGF-Beta, nNOS, NO, NOS, Npn, NRG-3, NT, NTN, OB, OGG1, OPG, OPN, OSM, OX40L, OX40R, p150, p95, PADPr, Parathyroid hormone, PARC, PARP, PBR, PBSF, PCAD, P-cadherin, PCNA, PDGF, PDK-1, PECAM, PEM, PF4, PGE, PGF, PGI2, PGJ2, PIN, PLA2, placental alkaline phosphatase (PLAP), PIGF, PLP, PP14, proinsulin, prorelaxin, protein C, PS, PSA, PSCA, prostate-specific membrane antigen (PSMA), PTEN, PTHrp, Ptk, PTN, R51, RANK, RANKL, RANTES, relaxin A-chain, relaxin B-chain, renin, respiratory syncytial virus (RSV) F, RSVFgp, Ret, rheumatoid factor, RLIP76, RPA2, RSK, S100, SCF / KL, SDF-1, SERINE, serum albumin, sFRP-3, Shh, SIGIRR, SK-1, SLAM, SLPI, SMAC, SMDF, SMOH, SOD, SPARC, Stat, STEAP, STEAP-II, TACE, TACI, TAG-72 (tumor-associated glycoprotein-72), TARC, TCA-3, T cell receptor (e.g., T cell receptor alpha / beta), TdT, TECK, TEM1, TEM5, TEM7, TEM8, TERT, testicular PLAP-like alkaline phosphatase, TfR, TGF, TGF-alpha, TGF-beta, TGF-beta general-specific, TGF-beta RI (ALK-5), TGF-beta RII, TGF-beta RIIb, TGF-beta RIII, TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta 4, TGF-beta 5, Thrombin, Thymus Ck-1, Thyroid-stimulating hormone, Tie, TIMP, TIQ, TMEFF2, Tmpo, TMPRSS2, TNF, TNF-alpha, TNF-alphabeta, TNF-beta2, TNFc, TNF-RI, TNF-RII, TNF-RSF10A (TRAIL R1 Apo-2, DR4), TNFRSF10B (TRAIL R2 DR5, KILLER, TRICK-2A, TRICK-B), TNFRSF10C (TRAIL R3 DcRl, LIT, TRID), TNFRSF10D (TRAIL R4 DcR2, TRUNDD), TNFRSF11A (RANK ODF R, TRANCE R), TNFRSF11B (OPG OCIF, TR1), TNFRSF12 (TWEAK R FN14), TNFRSF13B (TACI), TNFRSF13C (BAFF R), TNFRSF14 (HVEM ATAR, HveA, LI DASH H、SY2)、SHOSHS16(SYS2) 07SYS、SYSYS17(SYSYS)、SYSYSYS18(JSYS). SHYSY、SYSYS10(SYS3 THIS、HARSHY)、HARSHYS1 (SYS)、SYSYS1(SYS1 H1200、F55606、DWHWHWH H1200、F75806、SHOSH2 6(SYS3)、SYSYS3(SYS THIS SUCH、SHIS S6、SHOSCHS4(SYS)0 SIS33、SHIS1 S) 、WHISCH5(CH040 50)、SWHWH(CH DA11、HAR1、DAY5)、DYSCHYS(DYS3 H68、S6)、S6S67(S027)、 FASHION(SHR30)、SHASHES(400) HR137、HARSH、SHRYSY21 DASH) 、SHASH22(DASH) 2 SHY2)、SHYS23(DYSYS) SHYS1)、SHYSYS25(GY3 FASH3、SHASH、SHASH、SHASH 、SHAKE1)、SHASE100(SHARE). BY22リガンド、DAY2)、SHAS11(SHAS SHASEリガンドDAY、DAYリガンド). DA3リガンド、DAY3リガンド)、DAYDAY13(SYS) LOVE2)、SIGNIFICANCE130 LOVE SY、 LOVE1 LOVE LOVE LOVE LOVE LOVE LOVE LIKEリガンド、THE)、SHASE15(30). 1000000000000000000000000000,000,000,000,000,000,000,000,000,000,000,0 SUBJECTリガンド、CHAS) FASHION、DYS、SYSYS)、SYSYSYS LIKE、SYSYS1)、SYSYS(LOVE THIS、D33) THIS 4(S40リガンドW34、SH1)、SHOSIS5(CHA40リガンドH154、N39、NH10、13 、WATCHES、DAYSJS(THEリガンドDA11リガンド 、DA1リガンド) DASH 7(KS27リガンドCHR706、SHQS8(CHR33リガンドDA153)、DJSJN(401リガンドCD137 ligand), TP-1, t-PA, Tpo, TRAIL, TRAIL R, TRAIL-R1, TRAIL-R2, TRANCE, transfer receptor, TRF, Trk, TROP-2, TSG, TSLP, tumor-associated antigen CA125, Lewis Y-associated sugar-expressing tumor-associated antigen, TWEAK, TXB2, Ung, uPAR, uPAR-1, urokinase, VCAM, VCAM-1, VECAD, VE-cadherin, VE-cadherin-2, VEFGR-1 (flt-1), VEGF, VEGFR, VEGFR-3 (flt-4), VEGI, VFM, viral antigen, VLA, VLA-1, VLA-4, VNR integrin, Von Willebrand factor, WIF-1, WNT1, WNT2, WNT2B / 13, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16, XCL1, XCL2, XCR1, XEDAR, XIAP, XPD, CTLA4 (cytotoxic T lymphocyte antigen-4), PD1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), LAG-3 (lymphocyte activation gene-3), TIM-3 (T cell immunoglobulin and mucin protein-3), hormone receptors and growth factors; (v) At least a second antigen-binding domain that specifically binds to an antigen selected from the group consisting of: BCMA, CTLA4 (cytotoxic T lymphocyte antigen-4), PD1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), LAG-3 (lymphocyte activation gene-3), TIM-3, CD20, CD2, CD19, Her2, EGFR, EpCAM, FcγRIIIIa (CD16), FcγRIIa (CD32a), FcγRIIb (CD32b), FcγRI (CD64), Toll-like receptors (TLRs), TLR4, TLR9, cytokines, IL-2, IL-5, IL-13, IL-6, IL-17, IL-12, IL-23, TNFα, TGFβ, cytokine receptors, IL-2R, chemokines, chemokine receptors, growth factors, VEGF and HGF; and / or (vi) At least a second antigen-binding domain that specifically binds to an antigen, wherein the antibody includes a multispecific form selected from the group consisting of Fab-Fc-scFv, bottle-opener, Mab-scFv, Mab-Fv, double scFv, central Fv, central scFv, one-arm central scFv, Fab-Fab, Fab-Fv, mAb-Fv, mAb-Fab, DART, BiTE, common light chain-IgG, TandAb, Cross-Mab, SEED, BEAT, TrioMab, and DuetMab. An anti-CD3 antibody or its antigen-binding fragment, including the above.

7. An isolated nucleic acid or recombinant nucleic acid encoding an anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 6.

8. An expression vector comprising the isolated nucleic acid or recombinant nucleic acid described in Claim 7.

9. Host cells transfected, transformed, or transduced using the isolated nucleic acid or recombinant nucleic acid described in Claim 7, or the expression vector described in Claim 8.

10. A pharmaceutical composition, (I) (a ) an anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 6, an isolated nucleic acid or recombinant nucleic acid according to claim 7, and / or an expression vector according to claim 8; (b) A pharmaceutically acceptable carrier and / or excipient including, or (II) (a) an anti-CD3 antibody or antigen-binding fragment according to any one of claims 1 to 6, an isolated nucleic acid or recombinant nucleic acid according to claim 7, and / or an expression vector according to claim 8; (b) with a pharmaceutically acceptable carrier and / or excipient; (c) Additional therapeutic agents and A pharmaceutical composition containing the following:

11. A composition for the treatment of a disorder in a mammal requiring treatment, comprising an anti-CD3 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 6.

12. Use of an anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 6 in the manufacture of a pharmaceutical product.

13. The pharmaceutical composition according to claim 10, (i) The additional therapeutic agents are as follows: (i-1) Anti-CD20 monoclonal antibody; (i-2) Alkylating agents; (i-3) BCL-2 inhibitors; (i-4) Phosphoinositide 3-kinase (PI3K) inhibitors; (i-5) Bruton's tyrosine kinase (BTK) inhibitors; (i-6) Thalidomide or its derivatives; (i-7) Apoptotic agents; (i-8) Antitubulin agents; (i-9) Epidermal growth factor receptor (EGFR) antagonists; (i-10) Platelet-derived growth factor inhibitors; (i-11) COX-2 inhibitors; (i-12) Antibodies that bind to ErbB2, ErbB3, ErbB4, PDGFR-beta, BlyS, APRIL, BCMA, VEGF or VEGF receptor, TRAIL, Apo2, PD-1, PD-L1 or PD-L2; and / or (i-13) One or more of the following: cyclophosphamide, doxorubicin, vincristine, and / or prednisolone One or more of the following; (ii) The anti-CD3 antibody or its antigen-binding fragment is a bispecific anti-CD3 and anti-CD20 antibody, and the additional therapeutic agent in the pharmaceutical composition is: (ii-1) Anti-CD20 monoclonal antibody; (ii-2) Chemotherapy agents; (ii-3) Antibody-drug conjugates (ADCs) selected from anti-CD79b ADC; anti-CD19 ADC; anti-CD22 ADC; anti-CD45 ADC; and / or anti-CD32 ADC; (ii-4) BCL-2 inhibitors; (ii-5) Lenalidomide; (ii-6) PI3K-delta inhibitors; (ii-7) PD-1 Antagonist, (ii-8) Agonist antibodies targeting CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127; (ii-9) Antagonist antibodies targeting CTLA4, PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, GITR, or arginase; (ii-10) TGF beta antagonists; and / or (ii-11) T cells expressing chimeric antigen receptors or T cells containing dominant-negative TGF receptors one or more of the following; and / or (iii) A pharmaceutical composition in which the anti-CD3 antibody or its antigen-binding fragment is an anti-CD3 and anti-HER2 bispecific antibody, and the additional therapeutic agent is one or more of trastuzumab, T-DM1 and / or pertuzumab.

14. A composition for treatment according to claim 11, wherein the disorder includes proliferative disorders, cancer, immuno-cancerous disorders, neurological disorders, neurodegenerative disorders, or autoimmune disorders.

15. The use according to claim 12, wherein the pharmacopoeia is for the treatment of a disorder in a mammal requiring treatment, the disorder being a proliferative disorder, cancer, an immuno-cancer disorder, a neurological disorder, a neurodegenerative disorder, or an autoimmune disorder.

16. A composition for use in a method for producing host cells according to claim 9, comprising an isolated nucleic acid or recombinant nucleic acid according to claim 7 or an expression vector according to claim 8, wherein the method comprises introducing the isolated nucleic acid or recombinant nucleic acid or the expression vector into cells.

17. A method for producing an anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 6, wherein the method is (I) A host cell comprising a nucleic acid encoding the anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 6, or the host cell according to claim 9, under conditions suitable for the expression of the anti-CD3 antibody or its antigen-binding fragment, or (II) (i) Culturing a host cell containing a nucleic acid encoding the anti-CD3 antibody or its antigen-binding fragment according to any one of claims 1 to 6, or the host cell according to claim 9, under conditions suitable for the expression of the anti-CD3 antibody or its antigen-binding fragment; (ii) Recovering the anti-CD3 antibody or its antigen-binding fragment from the host cells or culture medium of (i) Methods that include...

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