Engineered immune cells targeting cd30 and bcma

Abstract

This invention provides a dual-target engineered immune cell capable of simultaneously targeting CD30 and BCMA to reduce tumor cell escape and recurrence rate. Specifically, this invention provides an engineered immune cell comprising a chimeric antigen receptor targeting BCMA and CD30, wherein the chimeric antigen receptor comprises: (1) an antigen-binding region comprising an antibody targeting BCMA and an antibody targeting CD30; (2) a transmembrane domain; and (3) a primary signal transduction domain. This invention also provides an engineered immune cell comprising: (1) a first chimeric antigen receptor targeting BCMA, comprising an antibody targeting BCMA, a transmembrane domain, and a primary signal transduction domain; and (2) a second chimeric antigen receptor targeting CD30, comprising an antibody targeting CD30, a transmembrane domain, and a primary signal transduction domain.

Description

Technical Field

[0001] This invention belongs to the field of immunotherapy. More specifically, this invention relates to chimeric antigen receptors targeting CD30 and BCMA, and their use in treating diseases. Background Technology

[0002] In recent years, cancer immunotherapy technology has developed rapidly, especially chimeric antigen receptor T cell (CAR-T) related immunotherapy. As a novel adoptive immunotherapy technology, it has shown very significant clinical efficacy in the treatment of various solid tumors and hematological malignancies.

[0003] CD30 is a type I transmembrane protein that is generally expressed in activated B cells and T cells. CD30 expression has been observed in various non-malignant diseases, such as lymphomatoid papulosis, and in B cells and T cells infected with viruses. CD30 expression has also been observed in various malignant tumors, such as Hodgkin's lymphoma, anaplastic large cell lymphoma (ALCL), immunoblastic lymphoma, multiple myeloma, adult T-cell lymphoma, leukemia, mycosis fungoides, germ cell malignancies, and thyroid cancer.

[0004] BCMA is an extremely important B-cell biomarker, mainly expressed in plasma cells and mature B cells, and widely present on the surface of multiple myeloma cells. It is a very popular immunotherapy target for multiple myeloma and other hematologic malignancies.

[0005] Currently, CAR-T therapies targeting CD30 or BCMA alone exist. However, single-target therapy easily leads to relapse after tumor cells downregulate antigen expression. Therefore, this invention aims to provide a dual-target engineered immune cell that can simultaneously target CD30 and BCMA to reduce tumor cell escape and lower the relapse rate. Summary of the Invention

[0006] In one aspect, the present invention provides an engineered immune cell comprising a chimeric antigen receptor targeting BCMA and CD30, wherein the chimeric antigen receptor comprises:

[0007] (1) Antigen-binding region, containing antibodies targeting BCMA and antibodies targeting CD30;

[0008] (2) Transmembrane domains; and

[0009] (3) Primary signal transmission structure domain.

[0010] In one embodiment, the antibody targeting BCMA and the antibody targeting CD30 are connected via a linker.

[0011] In one embodiment, the adapter comprises (G4S)n, where n is 1, 2, 3, 4, 5, or 6, or the adapter comprises or is composed of the amino acid sequence (EAAAK)n, where n is 1, 2, 3, 4, 5, or 6.

[0012] The present invention also provides an engineered immune cell comprising:

[0013] (1) The first chimeric antigen receptor targeting BCMA, comprising an antibody targeting BCMA, a transmembrane domain, and a primary signal transduction domain; and

[0014] (2) A second chimeric antigen receptor that targets CD30, comprising an antibody that targets CD30, a transmembrane domain and a primary signal transduction domain.

[0015] In one embodiment, the first chimeric antigen receptor and the second chimeric antigen receptor are located in the same or different carriers.

[0016] The present invention also provides a composition comprising:

[0017] (1) A first engineered immune cell population expressing a first chimeric antigen receptor, wherein the first chimeric antigen receptor comprises an antibody targeting BCMA, a transmembrane domain, and a primary signal transduction domain; and

[0018] (2) A second engineered immune cell population expressing a second chimeric antigen receptor, wherein the second chimeric antigen receptor contains an antibody targeting CD30, a transmembrane domain and a primary signal transduction domain.

[0019] In one embodiment, the chimeric antigen receptor of the present invention includes a transmembrane domain selected from the transmembrane domains of the following proteins: TCRα chain, TCRβ chain, TCRγ chain, TCRδ chain, CD3ζ subunit, CD3ε subunit, CD3γ subunit, CD3δ subunit, CD45, CD4, CD5, CD8α, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.

[0020] In one embodiment, the chimeric antigen receptor of the present invention includes a primary signal transduction domain selected from the intracellular regions of the following proteins: FcRγ, FcRβ, CD3γ, CD3δ, CD3ε, CD3ζ, CD22, CD79a, CD79b, and CD66d.

[0021] In one embodiment, the chimeric antigen receptor of the present invention further comprises one or more co-stimulatory domains selected from the intracellular regions of the following proteins: CD94, LTB, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD8, CD18, CD27, CD28, CD30, CD40, CD54, CD83, CD134 (OX40), CD137 (4-1BB), CD270 (HVEM), CD272 (BTLA), CD276 (B7-H3), CD278 (ICOS), CD357 (GITR), DAP10, DAP12, LAT, NKG2C, SLP76, PD-1, LIGHT, TRIM, ZAP70, and combinations thereof.

[0022] In one embodiment, the chimeric antigen receptor of the present invention comprises an antibody selected from Fab, Fab', F(ab')2, Fd, Fd′, Fv, scFv, sdFv, single-domain antibodies, and nanobodies; preferably selected from scFv, single-domain antibodies, and nanobodies.

[0023] In one embodiment, the antibody targeting CD30 of the present invention comprises: (1) CDR1 as shown in SEQ ID NO: 1, CDR2 as shown in SEQ ID NO: 2, and CDR3 as shown in SEQ ID NO: 3 or 4; (2) CDR1 as shown in SEQ ID NO: 5, CDR2 as shown in SEQ ID NO: 6, and CDR3 as shown in SEQ ID NO: 7; (3) CDR1 as shown in SEQ ID NO: 8, CDR2 as shown in SEQ ID NO: 9, and CDR3 as shown in SEQ ID NO: 10; (4) CDR1 as shown in SEQ ID NO: 11, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 13; (5) CDR1 as shown in SEQ ID NO: 14, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 15; (6) CDR1 as shown in SEQ ID NO: 16, CDR2 as shown in SEQ ID NO: 17, and CDR3 as shown in SEQ ID NO: 18; (7) as shown in SEQ ID NO: 10, CDR1 as shown in SEQ ID NO: 11, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 13; (8) CDR1 as shown in SEQ ID NO: 14, CDR2 as shown in SEQ ID NO: 15, and CDR3 as shown in SEQ ID NO: 16; (9) CDR1 as shown in SEQ ID NO: 16, CDR2 as shown in SEQ ID NO: 17, and CDR3 as shown in SEQ ID NO: 18; (10) CDR1 as shown in SEQ ID NO: 11, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: (8) CDR1 as shown in SEQ ID NO: 19, CDR2 as shown in SEQ ID NO: 20, and CDR3 as shown in SEQ ID NO: 21; or (9) CDR1 as shown in SEQ ID NO: 22, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 23; or (10) CDR1 as shown in SEQ ID NO: 24, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 25.

[0024] In one embodiment, the antibody targeting CD30 of the present invention has at least 90% identity with the amino acid sequence selected from SEQ ID NO: 26-72. More preferably, the antibody targeting CD30 of the present invention is selected from SEQ ID NO: 26-72.

[0025] In one embodiment, the antibody targeting BCMA of the present invention comprises: (1) CDR1 as shown in SEQ ID NO: 73, CDR2 as shown in SEQ ID NO: 74, and CDR3 as shown in SEQ ID NO: 75; (2) CDR1 as shown in SEQ ID NO: 76 or SEQ ID NO: 79, CDR2 as shown in SEQ ID NO: 77, and CDR3 as shown in SEQ ID NO: 78; (3) CDR1 as shown in SEQ ID NO: 104, CDR2 as shown in SEQ ID NO: 107, and CDR3 as shown in SEQ ID NO: 111; (4) CDR1 as shown in SEQ ID NO: 105, CDR2 as shown in SEQ ID NO: 108, and CDR3 as shown in SEQ ID NO: 112; (5) CDR1 as shown in SEQ ID NO: 105, CDR2 as shown in SEQ ID NO: 109, and CDR3 as shown in SEQ ID NO: 113; (6) CDR1 as shown in SEQ ID NO: 106, and CDR3 as shown in SEQ ID NO: 78. (7) CDR1 as shown in SEQ ID NO: 110, CDR2 as shown in SEQ ID NO: 120, and CDR3 as shown in SEQ ID NO: 121; (8) CDR1 as shown in SEQ ID NO: 119, CDR2 as shown in SEQ ID NO: 120, and CDR3 as shown in SEQ ID NO: 121; (9) CDR1 as shown in SEQ ID NO: 123, CDR2 as shown in SEQ ID NO: 124, and CDR3 as shown in SEQ ID NO: 125; (10) CDR1 as shown in SEQ ID NO: 126, CDR2 as shown in SEQ ID NO: 127, and CDR3 as shown in SEQ ID NO: 128; (11) CDR1 as shown in SEQ ID NO: 131, CDR2 as shown in SEQ ID NO: 132, and CDR3 as shown in SEQ ID NO: 133; (12) CDR1 as shown in SEQ ID NO: 131, CDR2 as shown in SEQ ID NO: 132, and CDR3 as shown in SEQ ID NO: 133; (13) CDR1 as shown in NO: 134, CDR2 as shown in SEQ ID NO: 135, and CDR3 as shown in SEQ ID NO: 136; (14) CDR1 as shown in SEQ ID NO: 137, CDR2 as shown in SEQ ID NO: 138, and CDR3 as shown in SEQ ID NO: 139; (15) CDR1 as shown in SEQ ID NO: 140, CDR2 as shown in SEQ ID NO: 141, and CDR3 as shown in SEQ ID NO: 142;(15) CDR1 as shown in SEQ ID NO: 143, CDR2 as shown in SEQ ID NO: 144, and CDR3 as shown in SEQ ID NO: 145; (16) CDR1 as shown in SEQ ID NO: 146, CDR2 as shown in SEQ ID NO: 147, and CDR3 as shown in SEQ ID NO: 148; (17) CDR1 as shown in SEQ ID NO: 149, CDR2 as shown in SEQ ID NO: 150, and CDR3 as shown in SEQ ID NO: 151; (18) CDR1 as shown in SEQ ID NO: 159, CDR2 as shown in SEQ ID NO: 160, and CDR3 as shown in SEQ ID NO: 161; (19) CDR1 as shown in SEQ ID NO: 163, CDR2 as shown in SEQ ID NO: 164, and CDR3 as shown in SEQ ID NO: 165; (20) CDR1 as shown in SEQ ID NO: 167, and CDR3 as shown in SEQ ID NO: 148. CDR2 as shown in NO: 168, CDR3 as shown in SEQ ID NO: 169; or (21) CDR1 as shown in SEQ ID NO: 171, CDR2 as shown in SEQ ID NO: 172, CDR3 as shown in SEQ ID NO: 173 or 175.

[0026] In one embodiment, the antibody targeting BCMA of the present invention has at least 90% identity with the amino acid sequence selected from SEQ ID NO: 80-103, 115-118, 122, 129-130, 152-158, 162, 166, 170, 174, and 176. More preferably, the antibody targeting CD30 of the present invention is selected from SEQ ID NO: 80-103, 115-118, 122, 129-130, 152-158, 162, 166, 170, 174, and 176.

[0027] In one embodiment, the engineered immune cells of the present invention are B cells, T cells, macrophages, dendritic cells, monocytes, NK cells, or NKT cells.

[0028] In one embodiment, the engineered immune cells of the present invention are derived from stem cells.

[0029] In another aspect, the present invention also provides a pharmaceutical composition comprising the engineered immune cells or composition of the present invention, and one or more pharmaceutically acceptable excipients. Invention Details

[0031] Unless otherwise stated, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0032] Chimeric antigen receptor

[0033] As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificially constructed hybrid polypeptide that typically includes an antigen-binding domain (e.g., an antibody or its antigen-binding moiety), a transmembrane domain, an optional co-stimulatory domain, and a primary signaling domain, all connected by a linker. CARs can utilize the antigen-binding properties of antibodies to specifically and reactively redirect T cells and other immune cells to selected targets in a non-MHC-restricted manner. This non-MHC-restricted antigen recognition endows CAR-expressing immune cells with the ability to recognize antigens independently of antigen processing, thus bypassing the main mechanisms of tumor escape.

[0034] In one embodiment, the present invention provides engineered immune cells expressing a chimeric antigen receptor targeting both CD30 and BCMA in a tandem or parallel configuration. In this document, “tandem” means that the CD30-targeting antibody and the BCMA-targeting antibody reside in the same chimeric antigen receptor structure, constituting the antigen-binding region therein. In other words, in the “tandem” configuration, the engineered immune cell expresses a chimeric antigen receptor simultaneously targeting BCMA and CD30, comprising: (1) an antigen-binding region containing the BCMA-targeting antibody and the CD30-targeting antibody; (2) a transmembrane domain; and (3) a primary signaling domain. In this document, “parallel” means that the CD30-targeting antibody and the BCMA-targeting antibody reside in two different chimeric antigen receptor structures, which may reside in the same vector (e.g., by linking the two chimeric antigen receptor structures via a 2A peptide for separate expression) or in different vectors (e.g., each vector contains a chimeric antigen receptor structure targeting either CD30 or BCMA, and then the two vectors are introduced together into the immune cell). In other words, in the "parallel" configuration, the engineered immune cell expresses two chimeric antigen receptors that target BCMA and CD30, respectively. Specifically, the engineered immune cell comprises: (1) a first chimeric antigen receptor targeting BCMA, comprising an antibody targeting BCMA, a transmembrane domain, and a primary signaling domain; and (2) a second chimeric antigen receptor targeting CD30, comprising an antibody targeting CD30, a transmembrane domain, and a primary signaling domain. Optionally, the first and second chimeric antigen receptors are located in the same or different vectors.

[0035] As used herein, the term "antibody" has the broadest meaning as understood by those skilled in the art and includes monoclonal antibodies (including complete antibodies), polyclonal antibodies, multivalent antibodies, and antibody fragments or synthetic polypeptides carrying one or more CDR sequences capable of exhibiting desired biological activity. The antibodies described in this invention can be of any class (e.g., IgG, IgE, IgM, IgD, IgA, etc.) or subclass (e.g., IgG1, IgG2, IgG2a, IgG3, IgG4, IgA1, IgA2, etc.). The antibodies of this invention also include recombinant antibodies, human antibodies, humanized antibodies, camel-derived antibodies, murine antibodies, chimeric antibodies, and their antigen-binding portions.

[0036] As used herein, "antibody fragment" or "antigen-binding portion" refers to a portion of a complete antibody, generally containing the antigen-binding site of the complete antibody and thus retaining the ability to bind antigens. Examples of antibody fragments in this invention include, but are not limited to: Fab, Fab', F(ab')2, Fd fragment, Fd', Fv fragment, scFv, disulfide-linked Fv (sdFv), the heavy chain variable region (VH) or light chain variable region (VL) of an antibody, linear antibodies, "dimers" having two antigen-binding sites, single-domain antibodies, nanobodies, natural ligands of said antigens, or functional fragments thereof, etc. Therefore, the term "antibody" in this invention encompasses antibody fragments or antigen-binding portions of antibodies as defined above.

[0037] Typically, a complete antibody consists of two heavy chains and two light chains linked together by disulfide bonds, each light chain being connected to its respective heavy chain via disulfide bonds, forming a "Y"-shaped structure. Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain variable region contains three complementation-determining regions (CDRs): CDR-H1, CDR-H2, and CDR-H3, and the heavy chain constant region contains three constant structural domains: CH1, CH2, and CH3. Each light chain contains a light chain variable region (VL) and a light chain constant region. The light chain variable region contains three CDRs: CDR-L1, CDR-L2, and CDR-L3, and the light chain constant region contains one constant structural domain, CL. Within the heavy / light chain variable regions, the CDRs are separated by more conserved frame regions (FRs). The variable regions of the heavy / light chains are responsible for the recognition and binding of antigens, while the constant regions mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system.

[0038] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using many numbering schemes well-known in the art, including: Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th edition, Public Health Service, National Institutes of Health, Bethesda, Maryland (“Kabat” numbering scheme); Al-Lazikani et al. (1997) JMB 273, 927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding sitetopography,” J. Mol. Biol. 262, 732-745 (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp. Immunol, January 2003; 27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” JMol Biol, June 8, 2001; 309(3):657-70 (“Aho” numbering scheme); and Martin et al., “Modeling antibody hypervariable loops: a combined algorithm,” PNAS, 1989, 86(23):9268-9272 (“AbM” numbering scheme).

[0039] The boundaries of a given CDR or FR can vary depending on the protocol used for identification. For example, the Kabat protocol is based on structure alignment, while the Chothia protocol is based on structural information. Both the Kabat and Chothia protocols number antibodies based on the length of the most common antibody region sequences, where insertions are indicated by insert letters (e.g., "30a") and deletions occur in some antibodies. These two protocols place certain insertions and deletions ("indels") in different positions, resulting in different numbering. The Contact protocol is based on the analysis of complex crystal structures and is similar to the Chothia numbering protocol in many ways. The AbM protocol is a compromise between the Kabat and Chothia definitions, based on the protocol used by the Oxford Molecular AbM antibody modeling software.

[0040] Therefore, unless otherwise specified, it should be understood that the “CDR” of a given antibody or its region (such as its variable region) encompasses the CDRs defined by any of the above-described protocols or other known protocols. For example, in specifying that a particular CDR (e.g., CDR3) contains a given amino acid sequence, it should be understood that such a CDR may also have the sequence of the corresponding CDR (e.g., CDR3) as defined by any of the above-described protocols or other known protocols. Similarly, unless otherwise specified, it should be understood that the FR of a given antibody or its region (such as its variable region) encompasses the FRs defined by any of the above-described protocols or other known protocols.

[0041] Therefore, in one embodiment, the antibody of the present invention is selected from intact antibodies, Fab, Fab', F(ab')2, Fd, Fd', Fv, scFv, sdFv, single-domain antibodies and nanobodies, preferably selected from Fab, Fab', F(ab')2, scFv, single-domain antibodies and nanobodies, and more preferably selected from scFv, single-domain antibodies and nanobodies.

[0042] A “single-chain antibody” or “scFv” is an antibody composed of a heavy chain variable region (VH) and a light chain variable region (VL) linked together by a linker. The optimal linker length and / or amino acid composition can be selected. The linker length significantly affects the folding and interactions of the variable regions of the scFv. In fact, using a shorter linker (e.g., between 5 and 10 amino acids) can prevent intra-chain folding. For information on the selection of linker size and composition, see, for example, Hollinger et al., 1993 Proc Natl Acad. Sci. USA 90:6444-6448; U.S. Patent Application Publications 2005 / 0100543, 2005 / 0175606, 2007 / 0014794; and PCT Publications WO2006 / 020258 and WO2007 / 024715, the entire contents of which are incorporated herein by reference.

[0043] A "single-domain antibody" or "sdAb" refers to a naturally occurring antibody lacking a light chain. This antibody contains only one heavy chain variable region (VHH) and two conventional CH2 and CH3 regions, and is also called a "heavy chain antibody." The VHH structure, cloned and expressed independently, possesses structural stability and antigen-binding activity comparable to the original heavy chain antibody. It is currently the smallest known unit capable of binding to a target antigen and is also called a nanobody (Nb).

[0044] In one embodiment, the antibody targeting BCMA of the present invention can be derived from any antibody known in the art, such as A7D12.2, C11D5.3, C12A3.2, C13F12.1 (WO2010104949); 320199, 319883, 319952, 320262, 319966, 320111 (WO2019164891); SG1116 (CN112409482A); M1 (WO2021018168); 2A1, 29C12, 11F12, 1E1, 30E1, 32B5, 33C 7. 32H3, 33D4, 35D2, 37B2, 40D7 (US10220090B2); FS-21495, PC-21497, AJ-21508 , NM-21517, TS-21522, RY-21527, PP-21528, RD-21530 (US10689450B2); 15B2GL, I09, L15, M02, N22, P10 (US10988546B2); SCT-Aa01, SCT-Aa02, SCT-Aa03, SCT-Aa 04. SCT-Aa05, SCT-Aa06, SCT-Aa07, SCT-Aa08, SCT-Aa09, SCT-Aa10, SCT-Aa11, SC T-Aa12, SCT-Aa13, SCT-Aa14, SCT-Aa15, SCT-Aa16, SCT-Aa17, SCT-Aa18, SCT-Aa19 (WO2020073917); ET140-42, ET140-47, ET140-30, ET140-22, ET140-7, ET140-3, ET140-51, ET140-17, ET140-13, ET140-57, ET140-15, ET140-38, ET140-46, ET140-54, ET140-40, ET140-37, ET140-24 (US10947314B2); the entire contents of the above references are incorporated herein by reference.

[0045] In one embodiment, the antibody targeting BCMA of the present invention is a nanobody or a single-domain antibody. More preferably, the BCMA-targeting antibody of the present invention comprises: (1) CDR1 as shown in SEQ ID NO: 73, CDR2 as shown in SEQ ID NO: 74, and CDR3 as shown in SEQ ID NO: 75; (2) CDR1 as shown in SEQ ID NO: 76 or SEQ ID NO: 79, CDR2 as shown in SEQ ID NO: 77, and CDR3 as shown in SEQ ID NO: 78; (3) CDR1 as shown in SEQ ID NO: 104, CDR2 as shown in SEQ ID NO: 107, and CDR3 as shown in SEQ ID NO: 111; (4) CDR1 as shown in SEQ ID NO: 105, CDR2 as shown in SEQ ID NO: 108, and CDR3 as shown in SEQ ID NO: 112; (5) CDR1 as shown in SEQ ID NO: 105, CDR2 as shown in SEQ ID NO: 109, and CDR3 as shown in SEQ ID NO: 113; (6) CDR1 as shown in SEQ ID NO: 106, and CDR3 as shown in SEQ ID NO: 78. (7) CDR1 as shown in SEQ ID NO: 110, CDR2 as shown in SEQ ID NO: 120, and CDR3 as shown in SEQ ID NO: 121; (8) CDR1 as shown in SEQ ID NO: 119, CDR2 as shown in SEQ ID NO: 120, and CDR3 as shown in SEQ ID NO: 121; (9) CDR1 as shown in SEQ ID NO: 123, CDR2 as shown in SEQ ID NO: 124, and CDR3 as shown in SEQ ID NO: 125; (10) CDR1 as shown in SEQ ID NO: 126, CDR2 as shown in SEQ ID NO: 127, and CDR3 as shown in SEQ ID NO: 128; (11) CDR1 as shown in SEQ ID NO: 131, CDR2 as shown in SEQ ID NO: 132, and CDR3 as shown in SEQ ID NO: 133; (12) CDR1 as shown in SEQ ID NO: 131, CDR2 as shown in SEQ ID NO: 132, and CDR3 as shown in SEQ ID NO: 133; CDR1 as shown in NO: 134, CDR2 as shown in SEQ ID NO: 135, and CDR3 as shown in SEQ ID NO: 136; (13) CDR1 as shown in SEQ ID NO: 137, CDR2 as shown in SEQ ID NO: 138, and CDR3 as shown in SEQ ID NO: 139;(14) CDR1 as shown in SEQ ID NO: 140, CDR2 as shown in SEQ ID NO: 141, and CDR3 as shown in SEQ ID NO: 142; (15) CDR1 as shown in SEQ ID NO: 143, CDR2 as shown in SEQ ID NO: 144, and CDR3 as shown in SEQ ID NO: 145; (16) CDR1 as shown in SEQ ID NO: 146, CDR2 as shown in SEQ ID NO: 147, and CDR3 as shown in SEQ ID NO: 148; (17) CDR1 as shown in SEQ ID NO: 149, CDR2 as shown in SEQ ID NO: 150, and CDR3 as shown in SEQ ID NO: 151; (18) CDR1 as shown in SEQ ID NO: 159, CDR2 as shown in SEQ ID NO: 160, and CDR3 as shown in SEQ ID NO: 161; (19) CDR1 as shown in SEQ ID NO: 163, and CDR3 as shown in SEQ ID NO: 140, and CDR2 as shown in SEQ ID NO: 142; (20) CDR2 as shown in SEQ ID NO: 164, CDR3 as shown in SEQ ID NO: 165; (21) CDR1 as shown in SEQ ID NO: 167, CDR2 as shown in SEQ ID NO: 168, CDR3 as shown in SEQ ID NO: 169; or (22) CDR1 as shown in SEQ ID NO: 171, CDR2 as shown in SEQ ID NO: 172, CDR3 as shown in SEQ ID NO: 173 or 175.

[0046] In one embodiment, the BCMA-targeting antibody of the present invention has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequences selected from SEQ ID NO: 80-103, 115-118, 122, 129-130, 152-158, 162, 166, 170, 174, and 176. Preferably, the CD30-targeting antibody of the present invention has a conservative modification of no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids compared to SEQ ID NO: 80-103, 115-118, 122, 129-130, 152-158, 162, 166, 170, 174, and 176. More preferably, the antibody targeting CD30 of the present invention is selected from SEQ ID NO: 80-103, 115-118, 122, 129-130, 152-158, 162, 166, 170, 174 and 176.

[0047] In one embodiment, the antibody targeting CD30 of the present invention can be derived from any antibody known in the art, such as HRS-1, HRS-3, and HRS-4 (Pfreundschuh et al., 1988, Anticancer Res. 8: 217-244; Pohlet et al., 1993, Int. J. Cancer 54: 418-25); 5F11, 2H9, and 17G1 (US Patent 7,387,776); AC10 (US Patent Application Publication No. 2005 / 0123536); XmAb2513 (US Patent Application Publication No. 2012 / 0014943); HeFi-1 (Hecht et al., J. Immunol. (1985) 4231-4236); M44 and M67 (Smith et al., Cell 73 (1993) 1349-1360); C10 (Bowen et al., J. Immunol. 151 (1993) 5896-5906), cAC10 (butuximab); Ber-H2 (Schwarting et al., Blood 74(1988)1678-1689); Ki-1, Ki-2, Ki-3, Ki-4, Ki-5, Ki-6 and Ki-7 (Schwaab et al., 1982, 299:65-67; ​​Horn-Lohrens et al., 1995, Int.J. cancer 60:539-544; US Pat. No. 6,033,876); IRac (Hsu et al., 1987, J. Natl. Cancer Inst. 79:1091-1097; Engert et al., 1990, Cancer Res. 50:2929-2935; and T6, T13, T14, T24 and T25 (Nagata, 2002, Clin. Cancer Res. 8:2345-2355), the entire contents of which are incorporated herein by reference.

[0048] In a preferred embodiment, the antibody targeting CD30 of the present invention is a nanobody or a single-domain antibody. Preferably, the antibody targeting CD30 of the present invention comprises: (1) CDR1 as shown in SEQ ID NO: 1, CDR2 as shown in SEQ ID NO: 2, and CDR3 as shown in SEQ ID NO: 3 or 4; (2) CDR1 as shown in SEQ ID NO: 5, CDR2 as shown in SEQ ID NO: 6, and CDR3 as shown in SEQ ID NO: 7; (3) CDR1 as shown in SEQ ID NO: 8, CDR2 as shown in SEQ ID NO: 9, and CDR3 as shown in SEQ ID NO: 10; (4) CDR1 as shown in SEQ ID NO: 11, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 13; (5) CDR1 as shown in SEQ ID NO: 14, CDR2 as shown in SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 15; (6) CDR1 as shown in SEQ ID NO: 16, CDR2 as shown in SEQ ID NO: 17, and CDR3 as shown in SEQ ID NO: 18; (7) as shown in SEQ ID NO: 19, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 13; (8) CDR1 as shown in SEQ ID NO: 14, SEQ ID NO: 15, and CDR3 as shown in SEQ ID NO: 16; (9) CDR1 as shown in SEQ ID NO: 16, SEQ ID NO: 17, and CDR3 as shown in SEQ ID NO: 18; (10) CDR1 as shown in SEQ ID NO: 19, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, and CDR3 as shown in SEQ ID NO: 19; (1 (8) CDR1 as shown in NO: 19, CDR2 as shown in SEQ ID NO: 20 and CDR3 as shown in SEQ ID NO: 21; or (9) CDR1 as shown in SEQ ID NO: 22, CDR2 as shown in SEQ ID NO: 12 and CDR3 as shown in SEQ ID NO: 23; or (10) CDR1 as shown in SEQ ID NO: 24, CDR2 as shown in SEQ ID NO: 12 and CDR3 as shown in SEQ ID NO: 25.

[0049] In one embodiment, the antibody targeting CD30 of the present invention has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence selected from SEQ ID NO: 26-72. Preferably, the antibody targeting CD30 of the present invention has a conserved modification of no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid compared to SEQ ID NO: 26-72. More preferably, the antibody targeting CD30 of the present invention is selected from SEQ ID NO: 26-72.

[0050] The terms "functional variant" or "functional fragment" refer to a variant that substantially contains the amino acid sequence of the parent but contains at least one amino acid modification (i.e., substitution, deletion, or insertion) compared to the parent amino acid sequence, provided that the variant retains the biological activity of the parent amino acid sequence. In one embodiment, the amino acid modification is preferably a conserved modification.

[0051] As used herein, the term "conservative modification" refers to an amino acid modification that does not significantly affect or alter the binding characteristics of an antibody or antibody fragment containing that amino acid sequence. These conserved modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the chimeric antigen receptor of the present invention using standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A conserved amino acid substitution is the substitution of an amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Conservative modifications can be selected, for example, based on the similarity of polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphiphilic properties of the residues involved.

[0052] Therefore, the “functional variant” or “functional fragment” has at least 75%, preferably at least 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the parent amino acid sequence, and retains the biological activity of the parent amino acid sequence, such as binding activity.

[0053] As used herein, the term “sequence identity” refers to the degree to which two (nucleotide or amino acid) sequences have identical residues at the same positions in an alignment, and is typically expressed as a percentage. Preferably, identity is determined over the overall length of the sequences being compared. Thus, two copies having completely identical sequences have 100% identity. Those skilled in the art will recognize that several algorithms can be used to determine sequence identity using standard parameters, such as Blast (Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402), Blast2 (Altschul et al. (1990) J. Mol. Biol. 215: 403-410), Smith-Waterman (Smith et al. (1981) J. Mol. Biol. 147: 195-197), and Clustal W.

[0054] As used herein, the term "transmembrane domain" refers to a polypeptide structure that enables the expression of a chimeric antigen receptor on the surface of immune cells (e.g., lymphocytes, NK cells, or NKT cells) and guides the cellular response of immune cells against target cells. Transmembrane domains can be natural or synthetic and can be derived from any membrane-binding or transmembrane protein. When a chimeric antigen receptor binds to a target antigen, the transmembrane domain enables signal transduction. Transmembrane domains particularly suitable for use in this invention can be derived from, for example, the TCRα chain, TCRβ chain, TCRγ chain, TCRδ chain, CD3ζ subunit, CD3ε subunit, CD3γ subunit, CD3δ subunit, CD45, CD4, CD5, CD8α, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, CD154, and functional fragments thereof. Alternatively, transmembrane domains can be synthetic and may primarily contain hydrophobic residues such as leucine and valine. Preferably, the transmembrane domain is derived from the CD8α chain or CD28, and has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:181 or 183, or its coding sequence has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the nucleotide sequence shown in SEQ ID NO:182 or 184.

[0055] In one embodiment, the chimeric antigen receptor of the present invention may further comprise a hinge region located between the antigen-binding region and the transmembrane domain. As used herein, the term "hinge region" generally refers to any oligopeptide or polypeptide that functions to connect the transmembrane domain to the antigen-binding region. Specifically, the hinge region is used to provide greater flexibility and accessibility to the antigen-binding region. The hinge region may contain up to 300 amino acids, preferably 10 to 100 amino acids, and most preferably 25 to 50 amino acids. The hinge region may be wholly or partially derived from natural molecules, such as the extracellular regions of CD8, CD4, or CD28, or wholly or partially derived from antibody constant regions. Alternatively, the hinge region may be a synthetic sequence corresponding to a naturally occurring hinge sequence, or it may be a fully synthetic hinge sequence. In a preferred embodiment, the hinge region comprises a hinge region portion of the CD8α chain, CD28, FcγRIIIα receptor, IgG4, or IgG1, more preferably a hinge from CD8α, CD28, or IgG4, having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO: 197, 199, or 201, or its coding sequence having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the nucleotide sequence shown in SEQ ID NO: 198, 200, or 202.

[0056] As used herein, the term "primary signal transduction domain" refers to a protein portion that transduces effector functional signals and directs the cell to perform a specific function. Primary signal transduction domains are responsible for intracellular primary signal transduction after antigen binding at the antigen-binding region, leading to the activation of immune cells and the immune response. In other words, primary signal transduction domains are responsible for activating at least one of the normal effector functions of immune cells expressing CARs. For example, the effector functions of T cells can be cytolytic activity or helper activity, including cytokine secretion.

[0057] In one embodiment, the chimeric antigen receptor of the present invention includes a primary signal transduction domain comprising cytoplasmic sequences of a T-cell receptor and a co-receptor, which together function to initiate primary signal transduction upon antigen receptor binding, as well as any derivatives or variants of these sequences and any synthetic sequences having the same or similar functions. The primary signal transduction domain may contain a number of immunoreceptor tyrosine-based activation motifs (ITAMs). Non-limiting embodiments of the primary signal transduction domain of the present invention include, but are not limited to, intracellular regions of FcRγ, FcRβ, CD3γ, CD3δ, CD3ε, CD3ζ, CD22, CD79a, CD79b, and CD66d. In a preferred embodiment, the signal transduction domain of the CAR of the present invention may include an intracellular CD3ζ region having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO: 189 or 191, or its coding sequence having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the nucleotide sequence shown in SEQ ID NO: 190 or 192.

[0058] In one embodiment, the chimeric antigen receptor of the present invention further comprises one or more co-stimulatory domains. The co-stimulatory domain may be an intracellular functional signaling domain derived from a co-stimulatory molecule, comprising the entire intracellular portion of the co-stimulatory molecule or a functional fragment thereof. A “co-stimulatory molecule” refers to a homologous binding partner that specifically binds to a co-stimulatory ligand on a T cell, thereby mediating a co-stimulatory response (e.g., proliferation) of the T cell. Co-stimulatory molecules include, but are not limited to, class 1 MHC molecules, BTLA, and Toll ligand receptors. Non-limiting examples of the co-stimulatory domains of the present invention include, but are not limited to, intracellular regions of the following proteins: TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD8, CD18, CD27, CD28, CD30, CD40, CD54, CD83, CD134 (OX40), CD137 (4-1BB), CD270 (HVEM), CD272 (BTLA), CD276 (B7-H3), CD278 (ICOS), CD357 (GITR), DAP10, DAP12, LAT, NKG2C, SLP76, PD-1, LIGHT, TRIM, CD94, LTB, and ZAP70, and combinations thereof.

[0059] In a preferred embodiment, the co-stimulatory domain comprises one or more intracellular regions selected from the group consisting of DAP10, DAP12, CD27, CD28, CD134, 4-1BB, or CD278. For example, in one embodiment, the co-stimulatory domain comprises an intracellular region of 4-1BB. In one embodiment, the co-stimulatory domain comprises an intracellular region of CD28. In one embodiment, the co-stimulatory domain comprises both an intracellular region of 4-1BB and an intracellular region of CD28.

[0060] In one embodiment, the intracellular region of 4-1BB has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:187, or its coding sequence has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% or 100% sequence identity with the nucleotide sequence shown in SEQ ID NO:188. In one embodiment, the intracellular region of CD28 has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% or 100% sequence identity with the amino acid sequence shown in SEQ ID NO:185, or its coding sequence has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% or 100% sequence identity with the nucleotide sequence shown in SEQ ID NO:186.

[0061] In one embodiment, the CAR of the present invention may further comprise a signal peptide such that, when expressed in cells such as T cells, the nascent protein is directed to the endoplasmic reticulum and subsequently to the cell surface. The core of the signal peptide may contain a long, hydrophobic amino acid segment with a tendency to form a single α-helix. At the terminal end of the signal peptide, there is typically an amino acid segment that is recognized and cleaved by a signal peptidase. The signal peptidase may cleave the peptide during or after translocation to produce a free signal peptide and a mature protein. The free signal peptide is then digested by a specific protease. Signal peptides that can be used in the present invention are well known to those skilled in the art, such as signal peptides derived from CD8α, IgG1, GM-CSFRα, B2M, etc. In one embodiment, the signal peptide used in this invention is derived from B2M or CD8α, having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the amino acid sequence shown in SEQ ID NO: 193 or 195, or its coding sequence having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, 99%, or 100% sequence identity with the nucleotide sequence shown in SEQ ID NO: 194 or 196.

[0062] In some embodiments, the CAR of the present invention further includes a linker for separating any of the domains / regions described herein. For example, the linker may be located between the signal peptide and the antigen-binding region, between the VH and VL regions of the antibody, between the antigen-binding region and the hinge region, between the hinge region and the transmembrane domain, on a side-connected co-stimulatory domain or on the N- or C-region of the co-stimulatory domain, and / or between the transmembrane domain and the primary signaling domain. The linker may be a peptide of about 6 to about 40 amino acids in length, or a peptide of about 6 to about 25 amino acids in length.

[0063] The connector can be easily selected with any suitable length, such as 1 amino acid (e.g., Gly) to 20 amino acids, 2 amino acids to 15 amino acids, 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and can be 1, 2, 3, 4, 5, 6 or 7 amino acids.

[0064] Exemplary connectors include glycine polymers (G)n, glycine-serine polymers (including, for example, (GS)n, (GSGGS)n, (G4S)n, and (GGGS)n, where n is an integer of at least 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), glycine-alanine polymers, alanine-serine polymers, and other flexible connectors known in the art. Exemplary connectors include, but are not limited to, GGSG, GGSGG, GGSGG, GGSGG, GGGSG, GSSSG, (G4S)3, etc.

[0065] In other embodiments, the connector comprises (EAAAK)n, where n is an integer of at least 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0066] In one embodiment, the CAR of the present invention may further include a switch structure to regulate the expression time of the CAR. For example, the switch structure may be in the form of a dimerizing domain that, through binding to its corresponding ligand, causes a conformational change, exposing the extracellular antigen-binding region for binding to the targeted antigen, thereby activating the signal transduction pathway. Alternatively, the switch structure may be used to connect the antigen-binding region and the signal transduction domain separately, such that the antigen-binding region and the signal transduction domain are only connected together via dimerization when the switch structures are interdependent (e.g., in the presence of an inducing compound), thereby activating the signal transduction pathway. The switch structure may also be in the form of a masking peptide. The masking peptide can mask the extracellular antigen-binding region, preventing its binding to the targeted antigen. When the masking peptide is cleaved, for example, by a protease, the extracellular antigen-binding region can be exposed, making it a "normal" CAR structure. Various switch structures known to those skilled in the art can be used in the present invention.

[0067] In one embodiment, the CAR of the present invention may further comprise a suicide gene, i.e., express a cell death signal induced by an exogenous substance to eliminate CAR cells when needed (e.g., in the event of severe toxic side effects). For example, the suicide gene may be in the form of an inserted epitope, such as the CD20 epitope, RQR8, etc., which can be eliminated by adding antibodies or reagents targeting these epitopes when needed. The suicide gene may also be herpes simplex virus thymidine kinase (HSV-TK), which induces cell death upon ganciclovir treatment. The suicide gene may also be iCaspase-9, which can be induced to dimerize by chemically inducing agents such as AP1903, AP20187, etc., thereby activating downstream Caspase3 molecules and leading to apoptosis. Various suicide genes known to those skilled in the art can be used in the present invention.

[0068] Nucleic acid and vector

[0069] The present invention also provides a nucleic acid that encodes the chimeric antigen receptor of the present invention.

[0070] The present invention also provides a vector comprising one or more nucleic acids as described in the present invention.

[0071] The present invention also provides a vector system comprising a first nucleic acid sequence encoding a chimeric receptor polypeptide and a second nucleic acid sequence encoding an Fc fusion polypeptide; the first nucleic acid sequence and the second nucleic acid sequence are located in the same vector or in different vectors.

[0072] As used herein, the term "vector" is a medium nucleic acid molecule used to transfer (exogenous) genetic material into a host cell, in which the nucleic acid molecule may, for example, be replicated and / or expressed.

[0073] Vectors generally include targeting vectors and expression vectors. A “targeting vector” is a medium for delivering isolated nucleic acids into the cell via, for example, homologous recombination or the use of a hybrid recombinase with a specific target site sequence. An “expression vector” is a vector used for the transcription of heterologous nucleic acid sequences (e.g., those encoding the Fc fusion polypeptide or chimeric receptor polypeptide of the present invention) in suitable host cells, as well as the translation of their mRNA. Suitable vectors for use in the present invention are known in the art and many are commercially available. In one embodiment, the vectors of the present invention include, but are not limited to, linear nucleic acid molecules (e.g., DNA or RNA), plasmids, viruses (e.g., retroviruses, lentiviruses, adenoviruses, vaccinia virus, Raul's sarcoma virus (RSV, polyomaviruses, and adeno-associated virus (AAV) etc.), bacteriophages, phage particles, granules, and artificial chromosomes (including BAC and YAC). The vector itself is typically a nucleotide sequence, usually a DNA sequence containing an insert (transgenic) and a larger sequence serving as the vector's "backbone." Engineered vectors typically also include an origin of autonomous replication in the host cell (if stable expression of the polynucleotide is required), a selection marker, and a restriction enzyme cleavage site (e.g., a multiple cloning site, MCS). The vector may additionally include elements such as a promoter, polyA tail, 3'UTR, enhancer, terminator, insulator, operon, selection marker, reporter gene, target sequence, and / or protein purification tag. In one specific embodiment, the vector is an in vitro transcription vector.

[0074] In one implementation, in a parallel configuration, the first nucleic acid sequence encoding a first chimeric antigen receptor polypeptide targeting BCMA and the second nucleic acid sequence encoding a second chimeric antigen receptor targeting CD30 reside in the same vector. For example, by inserting a nucleic acid encoding a 2A peptide between the two nucleic acid sequences, the two chimeric antigen receptor structures can be expressed independently without affecting each other. As used herein, the term "2A peptide" is a cis-hydrolase element (CHYSEls) originally discovered in foot-and-mouth disease virus (FMDV). The average length of a 2A peptide is 18–22 amino acids. During protein translation, the 2A peptide can cleave from its C-terminus via ribosome hopping. Specifically, the peptide bond cluster between glycine and proline is impaired at the 2A site, triggering ribosome hopping and translation from the second codon, thereby allowing independent expression of two proteins within a single transcription unit. This 2A peptide-mediated cleavage is widespread in eukaryotic cells. The high cleavage efficiency and ability of 2A peptides to promote balanced expression of upstream and downstream genes can improve the expression efficiency of heterologous multiproteins (such as cell surface receptors, cytokines, and immunoglobulins). Common 2A peptides include P2A, T2A, E2A, and F2A. In another embodiment, the first nucleic acid sequence encoding a first chimeric antigen receptor polypeptide targeting BCMA and the second nucleic acid sequence encoding a second chimeric antigen receptor targeting CD30 are located in different vectors.

[0075] Engineered immune cells

[0076] The present invention also provides an engineered immune cell that expresses the chimeric antigen receptor described herein.

[0077] The present invention also provides a composition comprising: (1) a first engineered immune cell population expressing a first chimeric antigen receptor, the first chimeric antigen receptor comprising an antibody targeting BCMA, a transmembrane domain, and a primary signal transduction domain; and (2) a second engineered immune cell population expressing a second chimeric antigen receptor, the second chimeric antigen receptor comprising an antibody targeting CD30, a transmembrane domain, and a primary signal transduction domain. In this embodiment, the first and second engineered immune cell populations may be administered to a subject simultaneously or sequentially.

[0078] As used herein, the term "immune cell" refers to any cell of the immune system that has one or more effector functions (e.g., cytotoxic cell-killing activity, secretion of cytokines, induction of ADCC and / or CDC). For example, immune cells can be B cells, T cells, macrophages, dendritic cells, monocytes, NK cells and / or NKT cells, or immune cells derived from stem cells, such as adult stem cells, embryonic stem cells, umbilical cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells, totipotent stem cells, or hematopoietic stem cells. Preferably, the immune cell is a T cell. T cells can be any type of T cell, such as cultured T cells, such as primary T cells, or T cells derived from cultured T cell lines such as Jurkat, SupT1, etc., or T cells obtained from a subject. Examples of subjects include humans, dogs, cats, mice, rats, and their transgenic species. T cells can be obtained from a variety of sources, including peripheral blood monocytes, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. T cells can also be concentrated or purified. T cells can be at any developmental stage, including but not limited to CD4+ / CD8+ T cells, CD4+ helper T cells (e.g., Th1 and Th2 cells), CD8+ T cells (e.g., cytotoxic T cells), tumor-infiltrating cells, memory T cells, naive T cells, γδ-T cells, αβ-T cells, etc. In a preferred embodiment, the immune cells are human T cells. A variety of techniques known to those skilled in the art, such as Ficoll, can be used to separate the subject's blood to obtain T cells.

[0079] Nucleic acid sequences encoding chimeric antigen receptor polypeptides and, optionally, NK repressor molecules can be introduced into immune cells using conventional methods known in the art (such as transduction, transfection, transformation, etc.). "Transfection" is the process of introducing nucleic acid molecules or polynucleotides (including vectors) into target cells. An example is RNA transfection, the process of introducing RNA (such as in vitro transcribed RNA, ivtRNA) into host cells. This term is primarily used for non-viral methods in eukaryotic cells. The term "transduction" is generally used to describe the transfer of virus-mediated nucleic acid molecules or polynucleotides. Transfection of animal cells typically involves opening transient pores or "holes" in the cell membrane to allow material uptake. Transfection can be performed using calcium phosphate, via electroporation, via cell extrusion, or by mixing cationic lipids with the material to create liposomes that fuse with the cell membrane and deposit their carriers inside. Exemplary techniques for transfecting eukaryotic host cells include lipid vesicle-mediated uptake, heat shock-mediated uptake, calcium phosphate-mediated transfection (calcium phosphate / DNA coprecipitation), microinjection, and electroporation. The term "transformation" is used to describe the non-viral transfer of nucleic acid molecules or polynucleotides (including vectors) into bacteria and also into non-animal eukaryotic cells (including plant cells). Therefore, transformation is a genetic alteration in bacteria or non-animal eukaryotic cells that occurs through direct uptake from their surroundings via the cell membrane and subsequent incorporation of exogenous genetic material (nucleic acid molecules). Transformation can be achieved artificially. For transformation to occur, the cell or bacteria must be in a competent state. For prokaryotic transformation, techniques may include heat shock-mediated uptake, fusion with bacterial protoplasts of intact cells, microinjection, and electroporation.

[0080] After introducing nucleic acids or vectors into immune cells, those skilled in the art can amplify and activate the resulting immune cells using conventional techniques.

[0081] Pharmaceutical Composition

[0082] The present invention also provides a pharmaceutical composition comprising the engineered immune cells described herein as an active agent, and one or more pharmaceutically acceptable excipients.

[0083] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient (i.e., capable of eliciting the desired therapeutic effect without causing any undesirable local or systemic effects), which is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Examples of pharmaceutically acceptable excipients include, but are not limited to, fillers, binders, disintegrants, coatings, adsorbents, anti-adhesion agents, flow aids, antioxidants, flavoring agents, coloring agents, sweeteners, solvents, co-solvents, buffers, chelating agents, surfactants, diluents, wetting agents, preservatives, emulsifiers, coating agents, isotonic agents, absorption delay agents, stabilizers, and tension modifiers. Those skilled in the art know how to select suitable excipients to prepare the desired pharmaceutical compositions of the present invention. Exemplary excipients used in the pharmaceutical compositions of the present invention include saline, buffered saline, glucose, and water. Typically, the selection of a suitable excipient depends in particular on the active agent used, the disease to be treated, and the desired dosage form of the pharmaceutical composition.

[0084] The pharmaceutical compositions according to the invention are suitable for administration via a variety of routes. Typically, administration is performed via parenteral delivery. Parenteral delivery methods include local, intra-arterial, intramuscular, subcutaneous, intramedullary, intrathecal, intravenous, intraperitoneal, intrauterine, intravaginal, sublingual, or intranasal administration.

[0085] The pharmaceutical compositions according to the invention can also be prepared in various forms, such as solid, liquid, gaseous, or lyophilized forms, particularly as ointments, creams, transdermal patches, gels, powders, tablets, solutions, aerosols, granules, pills, suspensions, emulsions, capsules, syrups, elixirs, extracts, tinctures, or fluid extracts, or in forms particularly suitable for the desired method of administration. Processes known in this invention for manufacturing pharmaceuticals may include, for example, conventional mixing, dissolving, granulation, coating, grinding, emulsification, encapsulation, embedding, or lyophilization processes. Pharmaceutical compositions containing, for example, immune cells as described herein, are generally provided in solution form and preferably contain pharmaceutically acceptable buffers.

[0086] The pharmaceutical compositions according to the invention can also be administered in combination with one or more other pharmaceutical agents suitable for treating and / or preventing the disease to be treated. Preferred examples of pharmaceutical agents suitable for combination include known anticancer drugs, such as cisplatin, maytansine derivatives, rachelmycin, calicheamicin, docetaxel, etoposide, gemcitabine, ifosfamide, irinotecan, melphalan, mitoxantrone, sorfimer sodium photofrin II, temozolomide, topotecan, trimetreate glucuronate, and orlistatine E. E) vincristine and doxorubicin; peptide cytotoxins, such as ricin, diphtheria toxin, Pseudomonas aeruginosa exotoxin A, DNases and RNases; radionuclides, such as iodine-131, rhenium-186, indium-111, iridium-90, bismuth-210 and 213, actinium-225 and astatine-213; prodrugs, such as antibody-directed enzyme prodrugs; immunostimulants, such as platelet factor 4, melanoma growth stimulating protein, etc.; antibodies or fragments thereof, such as anti-CD3 antibodies or fragments thereof, complement activators, heterologous protein domains, homologous protein domains, viral / bacterial protein domains, and viral / bacterial peptides. Furthermore, the pharmaceutical compositions of the present invention can also be used in combination with one or more other treatment methods, such as chemotherapy and radiotherapy.

[0087] Therapeutic applications

[0088] The present invention also provides a method for treating a subject suffering from a disease associated with CD30 and / or BCMA expression, comprising administering to the subject an effective amount of the immune cells or pharmaceutical composition according to the present invention. Therefore, the present invention also covers the use of the engineered immune cells and pharmaceutical composition in the preparation of a medicament for treating diseases associated with CD30 and / or BCMA expression.

[0089] In one embodiment, the immune cells are autologous or allogeneic cells, preferably B cells, T cells, macrophages, dendritic cells, monocytes, NK cells and / or NKT cells, more preferably T cells, NK cells or NKT cells.

[0090] As used in this article, the term "self" refers to any material derived from an individual that will later be reintroduced into the same individual.

[0091] As used herein, the term "allogeneic" refers to any material derived from a different animal or patient of the same species as the individual to whom the material was introduced. Two or more individuals are considered allologous to each other when their genes differ at one or more loci. In some cases, allologous material from individuals of the same species may have genetic differences sufficient to cause antigen-antigen interactions.

[0092] As used herein, the term "subject" refers to a mammal. A mammal can be a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects representing animal models of cancer. Preferably, the subject is a human.

[0093] In one implementation, the disease associated with BCMA expression is an autoimmune disease, including but not limited to systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), ANCA-associated vasculitis, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenic purpura, Chagas' disease, Graves' disease, Wegener's granulomatosis, polyarteritis nodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathy, vasculitis, diabetes mellitus, Reynaud's syndrome, antiphospholipid syndrome, and Goodpasture's disease. Diseases such as Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis.

[0094] In one implementation, the disease associated with BCMA expression is lymphoma, including but not limited to Burkitt lymphoma (e.g., endemic or sporadic Burkitt lymphoma), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), marginal zone lymphoma, splenic lymphoma, nodular monocytic B-cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, pulmonary B-cell angiogenic center lymphoma, small lymphocytic lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL).

[0095] In one implementation, the disease associated with BCMA expression is leukemia, including but not limited to chronic lymphocytic leukemia (CLL), plasma cell leukemia, or acute lymphoblastic leukemia (ALL).

[0096] In one embodiment, the disease associated with BCMA expression is a plasma cell malignancy, including but not limited to multiple myeloma (e.g., non-secreting multiple myeloma, condensing multiple myeloma) or plasmacytoma.

[0097] In one implementation, diseases associated with CD30 expression include, but are not limited to, Hodgkin's lymphoma, anaplastic large cell lymphoma (ALCL), adult T-cell lymphoma, angioimmunoblastic lymphadenopathy (AILD)-like T-cell lymphoma, HIV-associated coelomic lymphoma, embryonal carcinoma, nasopharyngeal undifferentiated carcinoma (such as Schmincke's tumor), Castleman's disease, Kaposi's sarcoma, and other T-cell or B-cell lymphomas. In another implementation, diseases associated with CD30 expression are autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, atopic dermatitis, Graves' disease, Wegener's granulomatosis, Hashimoto's thyroiditis, retinopathy syndrome, chronic renal failure, acute infectious mononucleosis, HIV, and herpesvirus-related diseases.

[0098] The present invention will now be described in detail with reference to the accompanying drawings and examples. It should be noted that those skilled in the art should understand that the drawings and embodiments of the present invention are merely illustrative and do not constitute any limitation on the present invention. Where there is no contradiction, the embodiments and features described in this application can be combined with each other. Attached Figure Description

[0099] Figure 1 The figure shows the expression level of antibodies in CAR-T cells.

[0100] Figure 2 This study demonstrates the killing effect of CAR-T cells on K562-BCMA target cells.

[0101] Figure 3 This demonstrates the killing effect of CAR-T cells on Jurkat target cells.

[0102] Figure 4 The survival curves of K562-BCMA-Luci tumor model mice treated with CAR-T cells are shown.

[0103] Figure 5: In vivo imaging of the Jurkat-Luci tumor model mouse (A) and the inhibitory effect of CAR-T cells on tumors (B). Detailed Implementation

[0104] Example 1. Preparation of CAR T cells

[0105] The sequences encoding the following proteins were synthesized and sequentially cloned into the pLVX vector (Public Protein / Plasmid Library (PPL), catalog number: PPL00157-4a): CD8α signal peptide (SEQ ID NO: 195), anti-CD30 antibody (SEQ ID NO: 54), CD8α hinge region (SEQ ID NO: 197), CD8α transmembrane region (SEQ ID NO: 181), 4-1BB intracellular region (SEQ ID NO: 187), and CD3ζ primary signal transduction domain (SEQ ID NO: 189). The correct insertion of the target sequences was confirmed by sequencing, and the plasmid expressing CD30-CAR was obtained and named BH395.

[0106] The anti-CD30 antibody in the BH395 plasmid was replaced with the anti-BCMA antibody (SEQ ID NO: 89) to obtain a plasmid expressing BCMA-CAR, which was named 60V1.

[0107] The sequences encoding the following proteins were synthesized and sequentially cloned into the pLVX vector (Public Protein / Plasmid Library (PPL), catalog number: PPL00157-4a): CD8α signal peptide (SEQ ID NO: 195), anti-BCMA antibody (SEQ ID NO: 89), adapter (SEQ ID NO: 180), anti-CD30 antibody (SEQ ID NO: 54), CD8α hinge region (SEQ ID NO: 197), CD8α transmembrane region (SEQ ID NO: 181), 4-1BB intracellular region (SEQ ID NO: 187), and CD3ζ primary signal transduction domain (SEQ ID NO: 189). The correct insertion of the target sequences was confirmed by sequencing, and a tandem CAR plasmid targeting CD30 and BCMA was obtained, which was named BH415.

[0108] The sequences encoding the following proteins were synthesized and sequentially cloned into the pLVX vector (Public Protein / Plasmid Library (PPL), catalog number: PPL00157-4a): CD8α signal peptide (SEQ ID NO: 195), anti-CD30 antibody (SEQ ID NO: 54), CD8α hinge region (SEQ ID NO: 197), CD8α transmembrane region (SEQ ID NO: 181), 4-1BB intracellular region (SEQ ID NO: 187), CD3ζ primary signal transduction domain (SEQ ID NO: 189), T2A (SEQ ID NO: 177), CD8α signal peptide (SEQ ID NO: 195), anti-BCMA antibody (SEQ ID NO: 89 ... CD8α primary signal transduction domain (SEQ ID NO: 189), CD8α primary signal transduction domain (SEQ ID NO: 189), CD8α primary signal transduction domain (SEQ ID NO: 189), CD8α primary signal transduction domain (SEQ ID NO: 189), CD8α transmembrane region (SEQ ID NO: 181), CD8α primary signal transduction domain (SEQ ID NO: 189), CD8α primary signal transduction domain (SEQ ID NO: 189), CD8α primary signal transduction domain (SEQ ID NO: 189), and the correct insertion of the target sequence was confirmed by sequencing, and a parallel CAR plasmid targeting CD30 and BCMA was obtained, which was named BH412.

[0109] Add 3 ml of Opti-MEM (Gibco, catalog number 31985-070) to a sterile tube to dilute the plasmid. Then, add the packaging vector psPAX2 (Addgene, catalog number 12260) and the envelope vector pMD2.G (Addgene, catalog number 12259) in a plasmid:viral packaging vector:viral envelope vector ratio of 4:2:1. Next, add 120 μL of X-treme GENE HP DNA transfection reagent (Roche, catalog number 06366236001), mix immediately, and incubate at room temperature for 15 min. Then, add the plasmid / vector / transfection reagent mixture dropwise to a culture flask of 293T cells. Collect the virus at 24 and 48 hours, combine them, and then ultracentrifuge (25000g, 4℃, 2.5 h) to obtain concentrated lentivirus.

[0110] Use DynaBeads CD3 / CD28 CTS TM (Gibco, catalog number 40203D) Wild-type T cells were activated and cultured at 37°C and 5% CO2 for another day. Concentrated lentivirus was added, and the cells were continuously expanded to obtain CAR T cells. On day 12 of culture, MonoRab was used... TMRabbit Anti-Camelid VHH Cocktail [iFluor 488] (GenScript, catalog number A02021) was used to detect the expression level of CAR molecules on corresponding CAR-T cells by flow cytometry. The results are as follows: Figure 1 As shown.

[0111] It can be seen that scFv can be effectively expressed in the CAR T cells prepared by this invention.

[0112] Example 2: Killing effect of CAR T cells on target cells

[0113] To test the killing ability of CAR-T cells against target cells, we first used 1x10 4 K562-BCMA cells expressing BCMA and carrying the luciferin gene, or Jurkat cells expressing CD30, were seeded into 96-well plates. CAR T cells and untransfected T cells (UnT, negative control) were then seeded into the 96-well plates at effector-to-target ratios (i.e., the ratio of effector T cells to target cells) of 5:1, 2.5:1, 1.25:1, 0.625:1, and 0.3125:1 for co-culture. Fluorescence values ​​were measured using a microplate reader after 16-18 hours. The killing efficiency was calculated using the formula: (mean fluorescence value of target cells - mean fluorescence value of sample cells) / mean fluorescence value of target cells × 100%. The results are shown below. Figure 2 and Figure 3 As shown.

[0114] Figure 2 The killing effects of various CAR-T cells on K562-BCMA target cells were demonstrated. It can be seen that, compared with untransfected UnT cells, BH412, BH415, and 60V1 CAR-T cells all produced significant killing effects on target cells. Surprisingly, at a high effector-to-target ratio of 5:1, dual-target CAR-T cells (e.g., BH412 and BH415) showed significantly higher killing effects on K562-BCMA target cells than single-target 60V1 CAR-T cells.

[0115] Figure 3The cytotoxic effects of various CAR-T cells on Jurkat target cells are shown. It can be seen that BH412, BH415, and 60V1 CAR-T cells all exhibited significant cytotoxic effects on target cells compared to untransfected UnT cells. Surprisingly, at higher target-to-cell ratios (e.g., 5:1 and 2.5:1), the cytotoxic effects of dual-target BH412 and BH415 CAR-T cells on Jurkat target cells were comparable to those of single-target BH395 CAR-T cells, while at lower target-to-cell ratios (e.g., 1.25:1, 0.625:1, 0.3125:1), the cytotoxic effects of dual-target CAR-T cells were significantly higher than those of single-target CAR-T cells.

[0116] The above results indicate that the design of dual-target CAR-T cells produced a synergistic effect, and its killing effect on target cells was superior to that of single-target CAR-T cells.

[0117] Example 3. In vivo tumor-suppressive effect of CAR T cells

[0118] 3.1 In vivo inhibitory effect on K562-BCMA-Luci tumors

[0119] Twenty-five healthy female NPI mice aged 6-8 weeks were randomly divided into five groups of five mice each: PBS group, UnT group (negative control), BH412 CAR-T cell group, BH415 CAR-T cell group, and 60V1 CAR-T cell group (positive control). On day 0, each mouse was injected via tail vein with 8 × 10⁸ CAR-T cells. 6 K562-BCMA-luci cells. After 14 days, each mouse was injected via tail vein with PBS solution (2 x 10⁻⁶ cells). 6 One UnT cell or 2x10 6 Each corresponding CAR-T cell was used. Mouse status and survival were assessed weekly.

[0120] The survival curve of mice is as follows Figure 4 As shown in the figure, in the PBS and UnT groups, the tumor burden in mice progressed rapidly, and mice died one by one. Mice treated with CAR-T cells showed slower tumor burden progression, with the BH412 CAR group showing the best effect, with all mice surviving after 58 days of tumor bearing; the BH415 CAR group showed the second best effect, with a survival rate of 60%; while the 60V1 CAR group had a survival rate of 40%. These results indicate that, compared with 60V1 CAR-T cells targeting only BCMA, dual-target CAR-T cells (BH412 and BH415) targeting both BCMA and CD30 can significantly increase the inhibitory effect on tumors and improve mouse survival rates.

[0121] 3.2 In vivo inhibitory effect on Jurkat-Luci tumors

[0122] Twenty-five healthy female NPI mice aged 6-8 weeks were randomly divided into five groups of five mice each: PBS group, UnT group (negative control), BH395 CAR-T cell group (positive control), BH412 CAR-T cell group, and BH415 CAR-T cell group. On day 0, each mouse was injected via tail vein with 2 × 10⁻⁶ cells. 6 Jurkat-luci cells. Six days later, according to the grouping, each mouse was injected via tail vein with PBS solution, 2 x 10⁻⁶ cells. 6 One UnT cell or 2x10 6 Each corresponding CAR-T cell was used. Changes in mouse status and tumor burden were assessed weekly.

[0123] Tumor burden changes in each group of mice were assessed using in vivo optical imaging techniques. The results are as follows: Figure 5A As shown in the figure. Tumor burden in mice was measured at 12, 21, 26, and 33 days after cell therapy and expressed as Photons / s. The results are shown in the figure. Figure 5B As shown in the results, tumor burden in mice progressed rapidly in both the PBS and UnT groups. In contrast, CAR-T cell treatment significantly inhibited tumor growth. Specifically, BH412 CAR-T cells showed slightly better tumor-suppressing effects than BH395 CAR-T cells, while BH415 CAR-T cells exhibited the best tumor-suppressing effect, significantly superior to the aforementioned two groups of CAR-T cells. This indicates that for CD30-positive tumors, dual-target CAR-T cells are more effective than single-target CAR-T cells.

[0124] It should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and variations. It is understood by those skilled in the art that any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention. sequence list <110> Nanjing Beiheng Biotechnology Co., Ltd. <120> Engineered immune cells targeting CD30 and BCMA <130> BHCN41 <160> 202 <170> SIPOSequenceListing 1.0 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1 CDR1 <400> 1 Gly Ser Thr Phe Gly Asp Ser 1 5 <210> 2 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1 CDR2 <400> 2 Ser Ser Asp Gly Arg 1 5 <210> 3 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1 CDR3 <400> 3 Asp Leu Arg Gln Tyr Cys Arg Asp Gly Arg Cys Cys Gly Tyr 1 5 10 <210> 4 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑2 CDR3 <400> 4 Asp Leu Arg Leu Asn Cys Arg Asp Gly Arg Cys Cys Gly Tyr 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑3 CDR1 <400> 5 Gly Phe Thr Phe Ala Asn Ser 1 5 <210> 6 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑3 CDR2 <400> 6 Ser Ser His Gly Gly Thr 1 5 <210> 7 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑3 CDR3 <400> 7 Asp Pro Arg Ser Asn Cys Arg Gly Gly Tyr Cys Cys Gly Tyr 1 5 10 <210> 8 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4 CDR1 <400> 8 Gly Phe Thr Phe Ala Asp Ser 1 5 <210> 9 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4 CDR2 <400> 9 Arg Thr Asp Gly Thr 1 5 <210> 10 <211> 16 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4 CDR3 <400> 10 Asp Arg Glu Thr Ser Phe Ile Gly Gly Ser Trp Cys Val Ala Lys Tyr 1 5 10 15 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5 CDR1 <400> 11 Arg Phe Thr Phe Asp Gly Pro 1 5 <210> 12 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5 CDR2 <400> 12 Ser Ala Asp Gly Arg 1 5 <210> 13 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5 CDR3 <400> 13 Asp Pro Arg Arg Asn Cys Arg Gly Gly Tyr Cys Cys Gly Asn 1 5 10 <210> 14 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑6 CDR1 <400> 14 Ala Phe Thr Phe Asp Gly Pro 1 5 <210> 15 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑6 CDR3 <400> 15 Asp Pro Arg Lys Asn Cys Arg Gly Gly Tyr Cys Cys Ala Asn 1 5 10 <210> 16 <211> 4 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑7 CDR1 <400> 16 Gly Tyr Ile Phe 1 <210> 17 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑7 CDR2 <400> 17 Tyr Thr Gly Gly Asp Ser 1 5 <210> 18 <211> 13 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑7 CDR3 <400> 18 Gly Gly Gln Glu Cys Tyr Leu Thr Asn Trp Val Ser Tyr 1 5 10 <210> 19 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8 CDR1 <400> 19 Gly Tyr Ile Tyr Ser Ser Asn 1 5 <210> 20 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8 CDR2 <400> 20 His Thr Gly Ser Gly Ser 1 5 <210> 21 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8 CDR3 <400> 21 Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 1 5 10 <210> 22 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9 CDR1 <400> 22 Gly Phe Thr Asp Asp Gly Pro 1 5 <210> 23 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9 CDR3 <400> 23 Asp Pro Arg Arg Asn Cys Arg Gly Gly Asp Cys Cys Gly Asn 1 5 10 <210> 24 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10 CDR1 <400> 24 Gly Phe Thr Phe Asp Gly Pro 1 5 <210> 25 <211> 13 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10 CDR3 <400> 25 Asp Pro Arg Arg Asn Cys Arg Gly Asn Cys Cys Gly Asn 1 5 10 <210> 26 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1 <400> 26 Gln Val Gln Leu Glu Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Ala Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Val Ser Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Gln Tyr Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 27 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑2 <400> 27 Gln Ile Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Ala Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Val Ser Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Gly Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Leu Asn Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 28 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑3 <400> 28 Gln Val His Leu Met Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ala Asn Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Ala Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser His Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg His Asn Ala Glu Asn Thr Val Tyr 65 70 75 80 Leu Arg Met Thr Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Ala Asp Pro Arg Ser Asn Cys Arg Gly Gly Tyr Cys Cys Gly Tyr 100 105 110 Trp Gly Pro Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 29 <211> 124 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4 <400> 29 Glu Val Gln Leu Val Ala Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ala Asp Ser 20 25 30 Ala Met Gly Trp Tyr Arg Lys Gly Pro Gly Asn Val Cys Asp Leu Val 35 40 45 Ala Ile Ile Arg Thr Asp Gly Thr Thr Tyr Tyr Gly Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95 Ala Asp Arg Glu Thr Ser Phe Ile Gly Gly Ser Trp Cys Val Ala Lys 100 105 110 Tyr Trp Asp Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 30 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5 <400> 30 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Arg Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Asn Ala Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Phe Leu 65 70 75 80 Tyr Leu Asn Ser Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Tyr Cys Cys Gly Asn Trp 100 105 110 Gly Pro Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 31 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑6 <400> 31 Gln Met Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Thr Ser Ala Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Val Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Phe Leu 65 70 75 80 Asn Leu Asn Ser Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Leu Asp Pro Arg Lys Asn Cys Arg Gly Gly Tyr Cys Cys Ala Asn Trp 100 105 110 Gly Pro Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 32 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑7 <400> 32 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Ile Phe Cys Met Gly 20 25 30 Trp Phe Arg Gln Ala Pro Gly Lys Ala Arg Glu Gly Ile Ala Thr Ile 35 40 45 Tyr Thr Gly Gly Asp Ser Thr Tyr Tyr Asp Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Gly 85 90 95 Gly Gln Glu Cys Tyr Leu Thr Asn Trp Val Ser Tyr Trp Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 33 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8 <400> 33 Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val 35 40 45 Ala Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Met Tyr Asp Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 34 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9 <400> 34 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Asp Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Arg Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Phe Leu 65 70 75 80 Tyr Leu Asn Ser Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Asp Cys Cys Gly Asn Trp 100 105 110 Gly Pro Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 35 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10 <400> 35 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ala Ser Gln Asp Asn Ala Lys Asn Thr Val Ser Leu 65 70 75 80 Tyr Leu Lys Ser Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Arg Arg Asn Cys Arg Gly Asn Cys Cys Gly Asn Trp Gly 100 105 110 Pro Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 36 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1‑1 <400> 36 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Gln Tyr Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 37 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1‑2 <400> 37 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Gln Tyr Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 38 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1‑3 <400> 38 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Gln Tyr Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 39 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑1‑4 <400> 39 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Gln Tyr Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 40 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑2‑1 <400> 40 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Leu Asn Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 41 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑2‑2 <400> 41 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Leu Asn Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 42 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑2‑3 <400> 42 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Leu Asn Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 43 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑2‑4 <400> 43 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser Asp Gly Arg Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Arg Leu Asn Cys Arg Asp Gly Arg Cys Cys Gly Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 44 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑3‑1 <400> 44 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asn Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser His Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ala Asp Pro Arg Ser Asn Cys Arg Gly Gly Tyr Cys Cys Gly Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 45 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑3‑2 <400> 45 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asn Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ser His Gly Gly Thr Thr Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ala Asp Pro Arg Ser Asn Cys Arg Gly Gly Tyr Cys Cys Gly Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 46 <211> 124 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4‑1 <400> 46 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Ser 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ala Ile Ile Arg Thr Asp Gly Thr Thr Tyr Tyr Gly Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95 Ala Asp Arg Glu Thr Ser Phe Ile Gly Gly Ser Trp Cys Val Ala Lys 100 105 110 Tyr Trp Asp Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 47 <211> 124 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4‑2 <400> 47 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Ser 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Val Cys Glu Leu Val 35 40 45 Ala Ile Ile Arg Thr Asp Gly Thr Thr Tyr Tyr Gly Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95 Ala Asp Arg Glu Thr Ser Phe Ile Gly Gly Ser Trp Cys Val Ala Lys 100 105 110 Tyr Trp Asp Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 48 <211> 124 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4‑3 <400> 48 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Ser 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ala Ile Ile Arg Thr Asp Gly Thr Thr Tyr Tyr Gly Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95 Ala Asp Arg Glu Thr Ser Phe Ile Gly Gly Ser Trp Cys Val Ala Lys 100 105 110 Tyr Trp Asp Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 49 <211> 124 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑4‑4 <400> 49 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Ser 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Val Cys Glu Leu Val 35 40 45 Ala Ile Ile Arg Thr Asp Gly Thr Thr Tyr Tyr Gly Asp Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95 Ala Asp Arg Glu Thr Ser Phe Ile Gly Gly Ser Trp Cys Val Ala Lys 100 105 110 Tyr Trp Asp Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 50 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5‑1 <400> 50 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Tyr Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 51 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5‑2 <400> 51 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Tyr Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 52 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑5‑3 <400> 52 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Tyr Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 53 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> ACD30‑5‑4 <400> 53 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Tyr Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 54 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑6‑1 <400> 54 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Ala Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Leu Asp Pro Arg Lys Asn Cys Arg Gly Gly Tyr Cys Cys Ala Asn Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 55 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑6‑2 <400> 55 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Ala Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Leu Asp Pro Arg Lys Asn Cys Arg Gly Gly Tyr Cys Cys Ala Asn Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 56 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑7‑1 <400> 56 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Phe Cys Met Gly 20 25 30 Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Ile Ala Thr Ile 35 40 45 Tyr Thr Gly Gly Asp Ser Thr Tyr Tyr Asp Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly 85 90 95 Gly Gln Glu Cys Tyr Leu Thr Asn Trp Val Ser Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 57 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑7‑2 <400> 57 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Phe Cys Met Gly 20 25 30 Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Ile Ala Thr Ile 35 40 45 Tyr Thr Gly Gly Asp Ser Thr Tyr Tyr Asp Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly 85 90 95 Gly Gln Glu Cys Tyr Leu Thr Asn Trp Val Ser Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 58 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑1 <400> 58 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 59 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑2 <400> 59 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 60 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑3 <400> 60 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 61 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑4 <400> 61 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ser Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 62 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑5 <400> 62 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ser Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 63 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑6 <400> 63 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ala Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 64 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑8‑7 <400> 64 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val 35 40 45 Ala Arg Ile His Thr Gly Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys 85 90 95 Ala Ala Gly Arg Val Val Leu Gly Ala Val Val Cys Thr Asn Glu Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 65 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9‑1 <400> 65 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Asp Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Asp Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 66 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9‑2 <400> 66 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Asp Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Asp Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 67 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9‑3 <400> 67 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Asp Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Asp Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 68 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑9‑4 <400> 68 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Asp Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Asp Pro Arg Arg Asn Cys Arg Gly Gly Asp Cys Cys Gly Asn Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 69 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10‑1 <400> 69 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ala Ser Gln Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Arg Arg Asn Cys Arg Gly Asn Cys Cys Gly Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 70 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10‑2 <400> 70 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ala Ser Gln Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Arg Arg Asn Cys Arg Gly Asn Cys Cys Gly Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 71 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10‑3 <400> 71 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ala Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Arg Arg Asn Cys Arg Gly Asn Cys Cys Gly Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 72 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD30‑10‑4 <400> 72 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Gly Pro 20 25 30 Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Cys Glu Leu Val 35 40 45 Ser Ile Ile Ser Ala Asp Gly Arg Thr Tyr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ala Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Arg Arg Asn Cys Arg Gly Asn Cys Cys Gly Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 73 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑1 CDR1 <400> 73 Gly Arg Ala Ile Ser Ser Ile 1 5 <210> 74 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑1 CDR2 <400> 74 Asn Arg Trp Gly Gly Thr 1 5 <210> 75 <211> 10 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑1 CDR3 <400> 75 Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr 1 5 10 <210> 76 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑2 CDR1 <400> 76 Gly Gly Ile Phe Thr Ile Asn 1 5 <210> 77 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑2 CDR2 <400> 77 Ser Arg Ser Gly Ser 1 5 <210> 78 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑2 CDR3 <400> 78 Asp Arg Pro Leu Ser Tyr 1 5 <210> 79 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑3 CDR1 <400> 79 Gly Ile Thr Leu Ser Ser Tyr 1 5 <210> 80 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH59 <400> 80 Gln Glu Val Leu Met Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser His Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Thr Arg Asp His Ala Lys Asn Thr Ile His 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser 115 <210> 81 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60 <400> 81 Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Gln Val Thr Val 100 105 110 Ser <210> 82 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH80 <400> 82 Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser <210> 83 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH81 <400> 83 Gln Val His Leu Val Glu Ser Gly Gly Gly Leu Val Lys Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Ile Thr Leu Ser Ser Tyr 20 25 30 Ser Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Gln Val Thr Val 100 105 110 Ser <210> 84 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH82 <400> 84 Gln Glu Arg Leu Val Glu Ser Gly Gly Gly Ser Val His Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asn Asn Ala Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser <210> 85 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH83 <400> 85 Gln Glu Arg Leu Val Glu Ser Gly Gly Gly Ser Val His Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asn Asn Ala Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Gln Val Thr Val 100 105 110 Ser <210> 86 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH84 <400> 86 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Gln Val Thr Val 100 105 110 Ser <210> 87 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86 <400> 87 Gln Glu Val Leu Met Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asn Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Thr Arg Asp His Ala Lys Asn Thr Ile His 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly His Gly 100 105 110 Thr Gln Val Thr Val Ser 115 <210> 88 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH87 <400> 88 Gln Glu Val Leu Met Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asn Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Thr Arg Asp His Ala Lys Asn Thr Ile His 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser 115 <210> 89 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60V1 <400> 89 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser <210> 90 <211> 114 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60V2 <400> 90 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <210> 91 <211> 114 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60V3 <400> 91 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <210> 92 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60V5 <400> 92 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser <210> 93 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60V6 <400> 93 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Phe Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ser Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser <210> 94 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60_GKV1 <400> 94 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser <210> 95 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH60_GKV2 <400> 95 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Thr Ile Asn 20 25 30 Asp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala His Ile Ser Arg Ser Gly Ser Thr Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn 85 90 95 Ser Ile Asp Arg Pro Leu Ser Tyr Gly Gln Gly Thr Gln Val Thr Val 100 105 110 Ser <210> 96 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86V1 <400> 96 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser 115 <210> 97 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86V2 <400> 97 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Ala Pro Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 98 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86V4 <400> 98 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly His Gly 100 105 110 Thr Leu Val Thr Val Ser 115 <210> 99 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86V5 <400> 99 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asn Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ile His 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser 115 <210> 100 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86V6 <400> 100 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asn Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Ile His 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly His Gly 100 105 110 Thr Leu Val Thr Val Ser 115 <210> 101 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86_GKV1 <400> 101 Gln Glu Val Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp His Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly His Gly 100 105 110 Thr Gln Val Thr Val Ser 115 <210> 102 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86_GKV2 <400> 102 Gln Glu Val Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp His Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Pro Gly 100 105 110 Thr Gln Val Thr Val Ser 115 <210> 103 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BH86_GKV3 <400> 103 Gln Glu Val Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Ile Ser Ser Ile 20 25 30 Val Met Ala Trp Trp Arg Gln Thr Pro Gly Ala Glu Arg Glu Phe Val 35 40 45 Ala Ser Ile Asn Arg Trp Gly Gly Thr Pro Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp His Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Thr Leu Asp Ser Gly Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser 115 <210> 104 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑4 CDR1 <400> 104 Gly Phe Thr Phe Thr Asn His Ala 1 5 <210> 105 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑5 CDR1 <400> 105 Gly Phe Thr Phe Ser Ser His Ala 1 5 <210> 106 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑7 CDR1 <400> 106 Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 <210> 107 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑4 CDR2 <400> 107 Ile Ser Gly Asn Gly Arg Thr Thr 1 5 <210> 108 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑5 CDR2 <400> 108 Ile Ser Gly Ser Gly Asp Phe Thr 1 5 <210> 109 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑6 CDR2 <400> 109 Ile Ser Gly Ser Gly Asp Tyr Thr 1 5 <210> 110 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑7 CDR2 <400> 110 Ile Ser Gly Ser Gly Asp Tyr Ile 1 5 <210> 111 <211> 11 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑4 CDR3 <400> 111 Ala Lys Asp Gly Gly Glu Thr Leu Val Asp Ser 1 5 10 <210> 112 <211> 12 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑5 CDR3 <400> 112 Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly Tyr 1 5 10 <210> 113 <211> 12 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑6 CDR3 <400> 113 Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly His 1 5 10 <210> 114 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑7 CDR3 <400> 114 Ala Lys Glu Gly Thr Gly Ala Asn Ser Ser Leu Ala Asp Tyr 1 5 10 <210> 115 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑4 <400> 115 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn His 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ser Ile Ser Gly Asn Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Leu Asp 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Gly Glu Thr Leu Val Asp Ser Arg Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 116 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑5 <400> 116 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Gly Ser Gly Asp Phe Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Ser 65 70 75 80 Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly Tyr Arg Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 117 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑6 <400> 117 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Asp Tyr Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Glu Asp Gly Gly Ser Leu Leu Gly His Arg Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 118 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑7 <400> 118 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Gly Asp Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu Gly Thr Gly Ala Asn Ser Ser Leu Ala Asp Tyr Arg Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 119 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑8 CDR1 <400> 119 Gly Arg Thr Phe Ser Asp His 1 5 <210> 120 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑8 CDR2 <400> 120 Ser Trp Ser Gly Gly Ser 1 5 <210> 121 <211> 11 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑8 CDR3 <400> 121 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 1 5 10 <210> 122 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑8 <400> 122 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asp His 20 25 30 Thr Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Gly Ala Ile Ser Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Ser Gly Arg Phe Thr Ile Ser Arg Asp Lys Ala Lys Asn Thr Gly Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Asp Asp Arg Tyr Ser Asp Tyr Arg Tyr Trp Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 123 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑9 CDR1 <400> 123 Gly Ser Ile Ser Gly Ile Tyr Ala 1 5 <210> 124 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑9 CDR2 <400> 124 Ile Thr Ser Gly Gly Asp Thr 1 5 <210> 125 <211> 16 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑9 CDR3 <400> 125 Asn Val Ala Pro Trp Gly Asp Tyr Asp Val Arg Ala Asp Phe Gly Ser 1 5 10 15 <210> 126 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑10 CDR1 <400> 126 Gly Ser Ile Leu Ser Ile Tyr Ala 1 5 <210> 127 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑10 CDR2 <400> 127 Ile Asn Ile Ser Ser Asn Thr 1 5 <210> 128 <211> 16 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑10 CDR3 <400> 128 Asn Val Ala Pro Trp Gly Asp Tyr Asp Val Lys Thr Asp Phe Gly Gly 1 5 10 15 <210> 129 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA9 <400> 129 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Ile Leu Ser Ile Tyr 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val 35 40 45 Ala Ala Ile Asn Ile Ser Ser Asn Thr Phe Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn 85 90 95 Val Ala Pro Trp Gly Asp Tyr Asp Val Lys Thr Asp Phe Gly Gly Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 130 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑10 <400> 130 Gln Leu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Ser Gly Ile Tyr 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Arg Leu Val 35 40 45 Ala Ala Ile Thr Ser Gly Gly Asp Thr Phe His Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn 85 90 95 Val Ala Pro Trp Gly Asp Tyr Asp Val Arg Ala Asp Phe Gly Ser Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 131 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑11 CDR1 <400> 131 Gly Arg Thr Val Ser Thr Ala 1 5 <210> 132 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑11 CDR2 <400> 132 Asn Trp Ser Gly Asn Lys 1 5 <210> 133 <211> 17 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑11 CDR3 <400> 133 Gly Pro Asp Leu Asn Tyr Tyr Thr Asn Tyr Asp Ala Arg Arg Tyr Asp 1 5 10 15 His <210> 134 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑12 CDR1 <400> 134 His Thr Thr Ala Ile Asn 1 5 <210> 135 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑12 CDR2 <400> 135 His Asn Asp Gly Ser 1 5 <210> 136 <211> 11 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑12 CDR3 <400> 136 Asp Ser Arg Gly Val Gly Pro Val Trp Ala His 1 5 10 <210> 137 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑13 CDR1 <400> 137 Gly Asn Ile Tyr Ser Ile Asn 1 5 <210> 138 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑13 CDR2 <400> 138 Leu Val Asp Gly Thr 1 5 <210> 139 <211> 21 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑13 CDR3 <400> 139 Glu Gly Asn Arg Ile Asp Tyr Ala Pro Gly Ser Arg Tyr Pro Thr His 1 5 10 15 Ser Tyr Val Glu Leu 20 <210> 140 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑14 CDR1 <400> 140 Gly Ala Ser Phe Asn Asp Tyr 1 5 <210> 141 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑14 CDR2 <400> 141 Ala Arg Tyr Gly Ala Ala 1 5 <210> 142 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑14 CDR3 <400> 142 Asp Arg Ser Asn Tyr Tyr Ile Asp Asn Ala Leu Pro Asp Tyr 1 5 10 <210> 143 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑15 CDR1 <400> 143 Gly Arg Asn Phe Asn Ser Tyr 1 5 <210> 144 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑15 CDR2 <400> 144 Ser Arg Ala Ala Gly Ser 1 5 <210> 145 <211> 19 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑15 CDR3 <400> 145 Glu Ser Trp Thr Pro Thr Thr Gly Trp Pro Pro Thr Lys Ala Asp Glu 1 5 10 15 Phe Asp Tyr <210> 146 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑16 CDR1 <400> 146 Gly Phe Asn Leu Asp Asp Tyr 1 5 <210> 147 <211> 5 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑16 CDR2 <400> 147 Ser Ser Asp Gly Arg 1 5 <210> 148 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑16 CDR3 <400> 148 Glu Arg Thr Ser Arg Leu Cys Ser Phe Leu Ser Tyr Asp Tyr 1 5 10 <210> 149 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑17 CDR1 <400> 149 Gly Arg Thr Phe Ser Asp His 1 5 <210> 150 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑17 CDR2 <400> 150 Ser Trp Ser Gly Gly Ser 1 5 <210> 151 <211> 10 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑17 CDR3 <400> 151 Ala Asp Asp Arg Tyr Ser Asp Tyr Arg Tyr 1 5 10 <210> 152 <211> 126 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑11 <400> 152 Gln Val Leu Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Arg Thr Val Ser Thr Ala 20 25 30 Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Ala Leu Asn Trp Ser Gly Asn Lys Ser Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Glu Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr His Cys 85 90 95 Ala Ala Gly Pro Asp Leu Asn Tyr Tyr Thr Asn Tyr Asp Ala Arg Arg 100 105 110 Tyr Asp His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 153 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑12 <400> 153 Gln Gly Gln Tyr Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Gly Ser His Thr Thr Ala Ile Asn Ala 20 25 30 Ala Gly Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Leu Val Gly 35 40 45 Leu Ile His Asn Asp Gly Ser Thr Gln Tyr Ala Gln Phe Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asp Ala Val Tyr Leu Gln 65 70 75 80 Met Asn Ser Leu Lys Val Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ile 85 90 95 Asp Ser Arg Gly Val Gly Pro Val Trp Ala His Trp Gly Gln Gly Thr 100 105 110 Gln Val Thr Val Ser Ser 115 <210> 154 <211> 129 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑13 <400> 154 Gln Ala Gln Leu Lys Glu Ser Gly Gly Gly Ser Val Arg Thr Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Tyr Ser Ile Asn 20 25 30 Arg Met Ala Trp Tyr Arg Gln Val Ser Gly Met Gln Arg Glu Val Val 35 40 45 Ala Thr Ser Leu Val Asp Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys 50 55 60 Asp Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Lys Met Val Phe Leu 65 70 75 80 Gln Met Asn Ser Leu Glu Pro Ala Asp Thr Gly Val Tyr Tyr Cys Asn 85 90 95 Val Glu Gly Asn Arg Ile Asp Tyr Ala Pro Gly Ser Arg Tyr Pro Thr 100 105 110 His Ser Tyr Val Glu Leu Trp Gly Gln Gly Thr Gln Val Thr Val Ser 115 120 125 Ser <210> 155 <211> 123 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑14 <400> 155 Gln Val Gln Leu Val Glu Asn Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ala Ser Phe Asn Asp Tyr 20 25 30 His Met Gly Trp Phe Arg Gln Ala Pro Gly Gln Glu Arg Lys Phe Val 35 40 45 Ala Gln Ile Ala Arg Tyr Gly Ala Ala Thr Tyr Tyr Ala Arg Ala Val 50 55 60 Gln Gly Arg Phe Thr Ile Ser Val Asp Asp Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Gly Leu Thr Pro Asp Asp Thr Gly Val Tyr Tyr Cys 85 90 95 Thr Ala Asp Arg Ser Asn Tyr Tyr Ile Asp Asn Ala Leu Pro Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 156 <211> 128 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑15 <400> 156 Gln Val Gln Leu Ile Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Thr 1 5 10 15 Ser Leu Thr Leu Ser Cys Ala Ser Ser Gly Arg Asn Phe Asn Ser Tyr 20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Leu 35 40 45 Ala Thr Ile Ser Arg Ala Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Ala 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Arg Lys Glu Phe Ala Tyr 65 70 75 80 Leu Gln Ile His Asp Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Glu Ser Trp Thr Pro Thr Thr Gly Trp Pro Pro Thr Lys Ala 100 105 110 Asp Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 157 <211> 122 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑16 <400> 157 Gln Asp Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Arg Thr Ser Gly Phe Asn Leu Asp Asp Tyr 20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val 35 40 45 Ser Cys Ile Ser Ser Asp Gly Arg Thr Ser His Thr Gly Ser Ala Lys 50 55 60 Gly Arg Phe Thr Ile Arg Ser Ala Asn Ala Arg Asn Thr Val Tyr Leu 65 70 75 80 Gln Leu Asn Arg Leu Thr Pro Glu Asp Ala Gly Val Tyr Phe Cys Ala 85 90 95 Ala Glu Arg Thr Ser Arg Leu Cys Ser Phe Leu Ser Tyr Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 158 <211> 119 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑17 <400> 158 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asp His 20 25 30 Thr Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Gly Ala Ile Ser Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Ser Gly Arg Phe Thr Ile Ser Arg Asp Lys Ala Lys Asn Thr Gly Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Ala Asp Asp Arg Tyr Ser Asp Tyr Arg Tyr Trp Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 159 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑18 CDR1 <400> 159 Gly Phe Arg Phe Ser Asp Tyr 1 5 <210> 160 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑18 CDR2 <400> 160 Asn Thr Asp Gly Gly Arg 1 5 <210> 161 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑18 CDR3 <400> 161 Gly Leu Asp Ser Thr Phe Arg Glu 1 5 <210> 162 <211> 117 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑18 <400> 162 Asp Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Arg Phe Ser Asp Tyr 20 25 30 Tyr Met Lys Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Asn Thr Asp Gly Gly Arg Thr Phe Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Tyr Leu Glu Pro Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Lys Gly Leu Asp Ser Thr Phe Arg Glu Arg Gly Gln Gly Thr Gln 100 105 110 Val Thr Val Ser Ser 115 <210> 163 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑19 CDR1 <400> 163 Gly Arg Met Phe Ser Thr Gly 1 5 <210> 164 <211> 11 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑19 CDR2 <400> 164 Thr Arg Ser Asp Ile Arg Glu Asn Asp Gly Ile 1 5 10 <210> 165 <211> 12 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑19 CDR3 <400> 165 Asp Ala Lys Leu Val Phe Thr Pro Thr Pro Gln Tyr 1 5 10 <210> 166 <211> 126 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑19 <400> 166 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Met Phe Ser Thr Gly 20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Gln Phe Val 35 40 45 Ala Ala Ile Thr Arg Ser Asp Ile Arg Glu Asn Asp Gly Ile Thr Tyr 50 55 60 Tyr Gly Val Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala 65 70 75 80 Gly Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr 85 90 95 Ala Val Tyr Tyr Cys Ala Ala Asp Ala Lys Leu Val Phe Thr Pro Thr 100 105 110 Pro Gln Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Gly 115 120 125 <210> 167 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑20 CDR1 <400> 167 Gly Tyr Ser Asp Ser Asn Tyr Cys 1 5 <210> 168 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑20 CDR2 <400> 168 Ile Asn Gly Asp Gly Val Ile 1 5 <210> 169 <211> 12 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑20 CDR3 <400> 169 Ala Ala Leu Thr Ala Gly Cys Val Arg Tyr Ala Ala 1 5 10 <210> 170 <211> 118 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑20 <400> 170 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Pro Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Ser Asp Ser Asn Tyr 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Ala Arg Gln Gly Val 35 40 45 Ala Phe Ile Asn Gly Asp Gly Val Ile Thr Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Gln Lys Thr Leu Asp Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Leu Thr Ala Gly Cys Val Arg Tyr Ala Ala Trp Gly Gln Gly Thr 100 105 110 Gln Val Thr Val Ser Ser 115 <210> 171 <211> 7 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑21 CDR1 <400> 171 Gly Gly Thr Phe Asn Asn Asp 1 5 <210> 172 <211> 6 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑21 CDR2 <400> 172 Ser Trp Arg Gly Asp Gly 1 5 <210> 173 <211> 12 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑21 CDR3 <400> 173 Gly Asp Gly Ser Arg Trp Arg Gly Ala Tyr Ala Tyr 1 5 10 <210> 174 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑21 <400> 174 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Asn Asn Asp 20 25 30 Asn Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Val Ile Ser Trp Arg Gly Asp Gly Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Tyr Ala Lys Lys Met Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gln Pro Lys Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Val Gly Asp Gly Ser Arg Trp Arg Gly Ala Tyr Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Arg Val Thr Val Ser Ser 115 120 <210> 175 <211> 14 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑22 CDR3 <400> 175 Ala Val Gly Asp Gly Ser Arg Trp His Gly Ala Tyr Ala Tyr 1 5 10 <210> 176 <211> 121 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> BCMA‑22 <400> 176 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Asn Asn Asp 20 25 30 Asn Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Val Ile Ser Trp Arg Gly Asp Gly Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Tyr Ala Lys Lys Met Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gln Pro Lys Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Val Gly Asp Gly Ser Arg Trp His Gly Ala Tyr Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Arg Val Thr Val Ser Ser 115 120 <210> 177 <211> 18 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> T2A <400> 177 Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro 1 5 10 15 Gly Pro <210> 178 <211> 22 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> F2A <400> 178 Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val 1 5 10 15 Glu Ser Asn Pro Gly Pro \(20\) <210> 179 <211> 15 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> linker <400> 179 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 180 <211> 18 <212> PRT Note: In the translation, for the number "20" in line 43, it is presented as "\(20\)" in LaTeX format as it's not clear if it has a specific formatting requirement in the original context. If it's just a regular number, it could be simply "20". Also, "接头" is translated as "linker" which is a common term in relevant fields, but it might need to be adjusted according to the specific domain knowledge. <213> Artificial Sequence(Artificial Sequence) <220> <223> connector <400> 180 Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr 1 5 10 15 Lys Gly <210> 181 <211> 25 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD8α transmembrane domain <400> 181 Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 1 5 10 15 Ser Leu Val Ile Thr Leu Tyr Cys Lys 20 25 <210> 182 <211> 75 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD8α transmembrane domain <400> 182 atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60 accctttact gcaaa 75 <210> 183 <211> 27 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD28 transmembrane domain <400> 183 Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu 1 5 10 15 Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 20 25 <210> 184 <211> 81 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD28 transmembrane domain <400> 184 ttttgggtcc tcgtcgtagt tggaggggta cttgcctgtt atagcctcct ggttaccgta 60 gcatttatta tattctgggt g 81 <210> 185 <211> 41 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD28 costimulatory domain <400> 185 Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser 35 40 <210> 186 <211> 123 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD28 costimulatory domain <400> 186 aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60 gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120 tcc 123 <210> 187 <211> 40 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> 4-1BB costimulatory domain <400> 187 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 1 5 10 15 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 20 25 30 Glu Glu Glu Glu Gly Gly Cys Glu ​​​​​​​​<213> Artificial Sequence(Artificial Sequence) <220> <223> 4‑1BB is not covered <400> 188 cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga tttccagaag aagaagagg aggatgtgaa <210> 189 <211> 113 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD3ζ is also a slightly different type <400> 189 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 1 5 10 15 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 20 25 30 Tyrian Asp Valleu Asp Lys Arg Arg Gly Arg Asp Pro Glu Meth Gly Gly 35 40 45 Light Pro Arg Arg Light Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 50 55 60 Light Asp Light With White Glue White Tire Ser Glue Ile Gly With Light Gly Glue 65 70 75 80 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 85 90 95 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 100 105 110 Arg <210> 190 <211> 339 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD3ζ is the source of the <400> 190 ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60 ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120 ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180 aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240 cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300 acctacgacg cccttcacat gcaggccctg ccccctcgc 339 <210> 191 <211> 114 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD3ζ signal transduction domain mutant <400> 191 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 1 5 10 15 Gly Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 20 25 30 Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 35 40 45 Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 50 55 60 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 65 70 75 80 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser 85 90 95 Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro 100 105 110 Pro Arg <210> 192 <211> 342 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD3ζ signal transduction domain mutant <400> 192 ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60 ctctttaacg agctcaatct aggacgaaga gaggagttcg atgttttgga caagagacgt 120 ggccgggacc ctgagatggg gggaaagccg cagagaagga agaaccctca ggaaggcctg 180 tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 240 gagcgccgga ggggcaaggg gcacgatggc cttttccagg gtctcagtac agccaccaag 300 gacacctttg acgcccttca catgcaggcc ctgccccctc gc 342 <210> 193 <211> 20 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> B2M signal peptide <400> 193 Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser 1 5 10 15 Gly Leu Glu Ala 20 <210> 194 <211> 60 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> B2M signal peptide <400> 194 atgtcccgct ctgttgcttt ggctgtgctg gcccttttgt cccttagcgg actggaggcc 60 <210> 195 <211> twenty one <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD8α signal peptide <400> 195 Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro 20 <210> 196 <211> 63 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD8α signal peptide <400> 196 atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60 ccg 63 <210> 197 <211> 45 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD8α hinge area <400> 197 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 1 5 10 15 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 20 25 30 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 35 40 45 <210> 198 <211> 135 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD8α hinge region <400> 198 accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60 tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120 gacttcgcct gtgat 135 <210> 199 <211> 39 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> CD28 hinge region <400> 199 Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn 1 5 10 15 Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu 20 25 30 Phe Pro Gly Pro Ser Lys Pro 35 <210> 200 <211> 117 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> CD28 switchboard <400> 200 attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc catgtgaag ggaacacct ttgtccaagt cccctatttc ccggaccttc tagccc <210> 201 <211> 12 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> IgG4 switch <400> 201 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 1 5 10 <210> 202 <211> 36 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> IgG4 switch <400> 202 35. acgggccgcc gtgtccaccc tgtccg

Claims

1. An engineered immune cell comprising a chimeric antigen receptor targeting BCMA and CD30, wherein the chimeric antigen receptor comprises: (1) an antigen binding region comprising an antibody targeting BCMA and an antibody targeting CD30; (2) a transmembrane domain; and (3) a primary signaling domain; the antibody targeting BCMA is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 76, a CDR2 as set forth in SEQ ID NO: 77, and a CDR3 as set forth in SEQ ID NO: 78; the antibody targeting CD30 is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 14, a CDR2 as set forth in SEQ ID NO: 12, and a CDR3 as set forth in SEQ ID NO: 15; and the immune cell is a T cell.

2. An engineered immune cell comprising: (1) a first chimeric antigen receptor targeting BCMA comprising an antibody targeting BCMA, a transmembrane domain, and a primary signaling domain; and (2) a second chimeric antigen receptor targeting CD30 comprising an antibody targeting CD30, a transmembrane domain, and a primary signaling domain; the antibody targeting BCMA is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 76, a CDR2 as set forth in SEQ ID NO: 77, and a CDR3 as set forth in SEQ ID NO: 78; the antibody targeting CD30 is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 14, a CDR2 as set forth in SEQ ID NO: 12, and a CDR3 as set forth in SEQ ID NO: 15; and the immune cell is a T cell.

3. The engineered immune cell of claim 1, wherein the antibody targeting BCMA and the antibody targeting CD30 are connected by a linker.

4. The engineered immune cell of claim 3, wherein the linker comprises (G4S)n, wherein n is 1, 2, 3, 4, 5, or 6, or the linker comprises or consists of the amino acid sequence (EAAAK)n, wherein n is 1, 2, 3, 4, 5, or 6.

5. The engineered immune cell of claim 2, wherein the first chimeric antigen receptor and the second chimeric antigen receptor are located on the same or different vectors.

6. The engineered immune cell of claim 1 or 2, wherein the transmembrane domain is selected from the transmembrane domain of the following proteins: TCRa chain, TCRP chain, TCRy chain, TCR5 chain, CD3y subunit, CD3e subunit, CD3y subunit, CD3d subunit, CD45, CD4, CD5, CD8a, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.

7. The engineered immune cell of claim 1 or 2, wherein the primary signaling domain is selected from the intracellular region of the following proteins: FcRy, FcRP, CD3y, CD35, CD3s, CD3z, CD22, CD79a, CD79b, and CD66d.

8. The engineered immune cell of claim 1 or 2, wherein the chimeric antigen receptor further comprises one or more costimulatory domains selected from the intracellular region of the following proteins: CD94, LTB, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD8, CD18, CD27, CD28, CD30, CD40, CD54, CD83, CD134, CD137, CD270, CD272, CD276, CD278, CD357, DAP10, DAP12, LAT, NKG2C, SLP76, PD-1, LIGHT, TRIM, ZAP70, and combinations thereof.

9. The engineered immune cell of claim 1 or 2, wherein the antibody targeting BCMA has at least 90% identity to an amino acid sequence selected from any one of SEQ ID NOs: 81, 82, 84-86, 89-95; and the antibody targeting CD30 has at least 90% identity to an amino acid sequence selected from SEQ ID NOs: 31, 54, or 55.

10. The engineered immune cell of claim 1 or 2, wherein the engineered immune cell is derived from a stem cell.

11. A composition comprising: (1) a first population of engineered immune cells expressing a first chimeric antigen receptor comprising an antibody targeting BCMA, a transmembrane domain, and a primary signaling domain; and (2) a second population of engineered immune cells expressing a second chimeric antigen receptor comprising an antibody targeting CD30, a transmembrane domain, and a primary signaling domain; the antibody targeting BCMA is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 76, a CDR2 as set forth in SEQ ID NO: 77, and a CDR3 as set forth in SEQ ID NO: 78; the antibody targeting CD30 is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 14, a CDR2 as set forth in SEQ ID NO: 12, and a CDR3 as set forth in SEQ ID NO: 15; and the immune cell is a T cell.

12. A pharmaceutical composition comprising the engineered immune cell of any one of claims 1-10 or the composition of claim 11, and one or more pharmaceutically acceptable excipients.

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