WO2021050948A1

WO2021050948A1 - Compositions and methods for tcr reprogramming using fusion proteins

Info

Publication number: WO2021050948A1
Application number: PCT/US2020/050503
Authority: WO
Inventors: Patrick Baeuerle; Robert Hofmeister; Daniel Getts; Dario Gutierrez; Philippe KIEFFER-KWON; Julie DONAGHEY
Original assignee: TCR2 Therapeutics Inc.
Priority date: 2019-09-12
Filing date: 2020-09-11
Publication date: 2021-03-18
Also published as: KR20220078607A; AU2020344628A1; JP2022548866A; EP4028033A4; IL291236A; EP4028033A1; MX2022002984A; CA3154287A1; CN114828862A; BR112022004458A2

Abstract

Provided herein are recombinant nucleic acids encoding T cell receptor (TCR) fusion proteins (TFPs) and a TCR constant domain, modified T cells expressing the encoded molecules, and methods of use thereof for the treatment of diseases, including cancer. Described herein are modified T cells comprising fusion proteins of TCR subunits, including CD3 epsilon, CD3gamma, CD3 delta, TCR gamma, TCR delta, TCR alpha and TCR beta chains with binding domains specific for cell surface antigens that have the potential to overcome limitations of existing approaches.

Description

C OMPO SITIONS AND METHODS FOR TCR REPROGRAMMING USING FUSION PROTEINS

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 62/899,563, filed on September 12, 2019, and U.S. Provisional Application No. 62/971,682, filed on February 7, 2020, each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Most patients with hematological malignancies or with late-stage solid tumors are incurable with standard therapy. In addition, traditional treatment options often have serious side effects. Numerous attempts have been made to engage a patient’s immune system for rejecting cancerous cells, an approach collectively referred to as cancer immunotherapy. However, several obstacles make it rather difficult to achieve clinical effectiveness. Although hundreds of so-called tumor antigens have been identified, these are often derived from self and thus can direct the cancer immunotherapy against healthy tissue, or are poorly immunogenic. Furthermore, cancer cells use multiple mechanisms to render themselves invisible or hostile to the initiation and propagation of an immune attack by cancer immunotherapies.

[0003] Recent developments using chimeric antigen receptor (CAR) modified autologous T cell therapy, which relies on redirecting genetically engineered T cells to a suitable cell-surface molecule on cancer cells, show promising results in harnessing the power of the immune system to treatB cell malignancies (see, e.g., Sadelain et ah, Cancer Discovery 3:388-398 (2013)). The clinical results with CD19-specific CAR T cells (called CTL019) have shown complete remissions in patients suffering from chronic lymphocytic leukemia (CLL) as well as in childhood acute lymphoblastic leukemia (ALL) (see, e.g., Kalos et ah, Sci Transl Med 3:95ra73 (2011), Porter et ah, NEJM 365:725-733 (2011), Grupp et ah, NEJM 368:1509-1518 (2013)). An alternative approach is the use of T cell receptor (TCR) alpha and beta chains selected for a tumor-associated peptide antigen for genetically engineering autologous T cells. These TCR chains will form complete TCR complexes and provide the T cells with a TCR for a second defined specificity. Encouraging results were obtained with engineered autologous T cells expressing NY-ESO-1 -specific TCR alpha and beta chains in patients with synovial carcinoma. [0004] Besides the ability for genetically modified T cells expressing a CAR or a second TCR to recognize and destroy respective target cells in vitro/ex vivo , successful patient therapy with engineered T cells may require the T cells to be capable of strong activation, expansion, persistence over time, and, in case of relapsing disease, to enable a ‘memory’ response. High and manageable clinical efficacy of CAR T cells is currently limited to CD19-positive B cell malignancies and to NY-ESO-1 -peptide expressing synovial sarcoma patients expressing HLA- A2.

SUMMARY OF THE INVENTION

[0005] There is a clear need to improve genetically engineered T cells to more broadly act against various human malignancies.

[0006] Described herein are modified T cells comprising fusion proteins of TCR subunits, including CD3 epsilon, CD3gamma, CD3 delta, TCR gamma, TCR delta, TCR alpha and TCR beta chains with binding domains specific for cell surface antigens that have the potential to overcome limitations of existing approaches. Additionally, these modified T cells may have functional disruption of an endogenous TCR (e.g., TCR alpha, beta or both). These modified T cells may have the ability to kill target cells more efficiently than CARs, but release comparable or lower levels of pro-inflammatory cytokines. These modified T cells and methods of their use may represent an advantage for these cells relative to CARs because elevated levels of these cytokines have been associated with dose-limiting toxicities for adoptive CAR T therapies.

[0007] Provided herein are modified T cells comprising T-cell receptor (TCR) fusion protein (TFP) and a TCR constant domain, methods of producing the modified T cells, and methods of use thereof for the treatment of diseases. The TCR constant domain described herein can be a TCR alpha constant domain, a TCR beta constant domain, a TCR alpha constant domain and a TCR beta constant domain, a TCR gamma constant domain, a TCR delta constant domain, or a TCR gamma constant domain and a TCR constant domain. The TFP described herein can comprise a TCR subunit and an antibody or fragment thereof. The TFP described herein can comprise a TCR subunit and a binding ligand or fragment thereof. The TCR subunit can be derived from any of the TCR chains such as TCR alpha chain, TCR beta chain, TCR gamma chain, TCR delta chain, CD3 epsilon, CD3 delta, or CD3 gamma. The antibody or fragment thereof can be murine, human, or humanized.

[0008] In an aspect, the present disclosure provides a recombinant nucleic acid comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a TCR extracellular domain, and a transmembrane domain, and an antibody comprising an antigen binding domain; and a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain, or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0009] In another aspect, the present disclosure provides a recombinant nucleic acid comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a TCR extracellular domain, a transmembrane domain, and a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain, or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0010] In some embodiments, the TCR subunit further comprises an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta. In some embodiments, the TCR constant domain is a TCR delta constant domain. In some embodiments, the TCR delta constant domain comprises SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the intracellular domain is an intracellular domain of TCR gamma. In some embodiments, the sequence encoding the TCR delta constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR delta constant domain. In some embodiments, the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP. In some embodiments, the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR delta constant domain via a linker. In some embodiments, the TCR constant domain is a TCR gamma constant domain. In some embodiments, the TCR gamma constant domain comprises SEQ ID NO:21 or SEQ ID NO: 155, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the intracellular domain is an intracellular domain of TCR delta. In some embodiments, the sequence encoding the TCR gamma constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR gamma constant domain. In some embodiments, the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP. In some embodiments, the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR gamma constant domain via a linker.

[0011] In some embodiments, the recombinant nucleic acid comprises a sequence encoding a TCR gamma constant domain and a TCR delta constant domain. In some embodiments, the TCR gamma constant domain comprises SEQ ID NO:21 or SEQ ID NO: 155, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the sequence encoding the TCR gamma constant domain further encodes a TCR gamma variable domain, thereby encoding a full TCR gamma domain. In some embodiments, the full TCR gamma domain is gamma 9 or gamma 4. In some embodiments, the full TCR gamma domain comprises SEQ ID NO:255, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR delta constant domain comprises SEQ ID NO: 20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the sequence encoding the TCR delta constant domain further encodes a TCR delta variable domain, thereby encoding a full TCR delta domain. In some embodiments, the full TCR delta domain is delta 2 or delta 1. In some embodiments, the full TCR delta constant domain comprises SEQ ID NO:256, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the intracellular signaling domain is CD3 epsilon, CD3 gamma, or CD3 delta. In some embodiments, the intracellular signaling domain is CD3 epsilon. In some embodiments, the recombinant nucleic acid further comprises at least one leader sequence and at least one linker. In some embodiments, the recombinant nucleic acid further comprises a portion of a TCR alpha constant domain, a portion of a TCR beta domain, or both. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRGC gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker sequence, and a TRGC gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, an antigen binding domain sequence, a first linker sequence, a TRDC gene sequence, a cleavable linker, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, and a TRGC gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, a TRDC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRGC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, a first antigen binding domain sequence, a first linker sequence, a TRDC gene sequence or fragment thereof, a TRAC gene sequence or fragment thereof, a cleavable linker sequence, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, a TRGC gene sequence or fragment thereof, and a TRBC gene sequence or fragment thereof.

[0012] In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO: 1. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:2. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:3. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:4. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:5. In some embodiments, the sequence encodes a sequence of SEQ ID NO:242. In some embodiments, the sequence encodes a sequence of SEQ ID NO:244. In some embodiments, the sequence encodes a sequence of SEQ ID NO:245. In some embodiments, the sequence encodes a sequence of SEQ ID NO:246. In some embodiments, the sequence encodes a sequence of SEQ ID NO:248. In some embodiments, the sequence encodes a sequence of SEQ ID NO:250. In some embodiments, the sequence encodes a sequence of SEQ ID NO:252. In some embodiments, the sequence encodes a sequence of SEQ ID NO:257. In some embodiments, the sequence encodes a sequence of SEQ ID NO:263. In some embodiments, the sequence encodes a sequence of SEQ ID NO:264. [0013] In some embodiments, the binding ligand is capable of binding an Fc domain of the antibody. In some embodiments, the binding ligand is capable of selectively binding an IgGl antibody. In some embodiments, the binding ligand is capable of specifically binding an IgG4 antibody. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen. In some embodiments, the antibody or fragment thereof is murine, human or humanized. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some embodiments, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the binding ligand does not comprise an antibody or fragment thereof. In some embodiments, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some embodiments, the binding ligand comprises a CD 16-binding polypeptide. In some embodiments, the binding ligand is human or humanized. In some embodiments, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some embodiments, the antibody or fragment thereof is capable of being secreted from a cell.

[0014] In another aspect, the present disclosure provides a recombinant nucleic acid comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a TCR extracellular domain, and a transmembrane domain, and an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain; or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0015] In some embodiments, the TCR subunit further comprises an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta. In some embodiments, the recombinant nucleic acid further comprises at least a partial sequence encoding a TCR alpha constant domain, a TCR beta constant domain, or a partial sequence of both a TCR alpha constant domain and a TCR beta constant domain. In some embodiments, the antigen binding domain comprises a ligand. In some embodiments, the ligand binds to the receptor of a cell. In some embodiments, the ligand binds to the polypeptide expressed on a surface of a cell. In some embodiments, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some embodiments, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some embodiments, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some embodiments, the antigen binding domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof. In some embodiments, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the ligand or fragment thereof is a monomer or a dimer. In some embodiments, the antigen binding domain does not comprise an antibody or fragment thereof. In some embodiments, the antigen binding domain does not comprise a variable region. In some embodiments, the antigen binding domain does not comprise a CDR. In some embodiments, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof.

In some embodiments, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some embodiments, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within a same nucleic acid molecule. In some embodiments, the encoded TFP and the encoded TCR constant domains are operatively linked by a first linker sequence. In some embodiments, the first linker comprises a protease cleavage site. In some embodiments, the protease cleavage site is a 2A, e.g., a T2A or a P2A cleavage site. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within different nucleic acid molecules. In some embodiments, the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof of the TFP are operatively linked by a second linker sequence. In some embodiments, the second linker sequence comprises (G4S)n, wherein n=l to 4. In some embodiments, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR delta, or TCR gamma. In some embodiments, the intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha, TCR beta, TCR gamma, or TCR delta. In some embodiments, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit. In some embodiments, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain of a TCR gamma chain or a TCR delta chain. In some embodiments, the TCR extracellular domain comprises the extracellular portion of a constant domain of a TCR gamma chain or a TCR delta chain, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications In some embodiments, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a delta constant domain, or a fragment thereof. In some embodiments, the delta constant domain has the sequence of SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprising (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a gamma constant domain. In some embodiments, the gamma constant domain has the sequence of SEQ ID NO:21 or SEQ ID NO: 155, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the extracellular domain of the TFP does not comprise the variable domain of a gamma chain or a delta chain. In some embodiments, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto. In some embodiments, the TCR subunit of the TFP comprises the extracellular, transmembrane and intracellular domain of CD3 epsilon. In some embodiments, the TCR subunit of CD3 epsilon comprises the sequence of SEQ ID NO:258, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

[0016] In some embodiments, the TFP, the TCR gamma constant domain, the TCR delta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide. In some embodiments, the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR delta,

CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR gamma, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof. In some embodiments, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP. In some embodiments, the antibody is an antibody fragment In some embodiments, the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain. In some embodiments, an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, an anti-B-cell maturation antigen (BCMA) binding domain, an anti-mesothelin (MSLN) binding domain, an anti-CD20 binding domain, an anti-CD70 binding domain, an anti-79b binding domain, an anti- HER2 binding domain, an anti-PMSA binding domain, an anti-MUC16 binding domain, an anti- CD22 binding domain, an anti-PD-Ll binding domain, an anti BAFF or BAFF receptor binding domain, an anti-Nectin-4 binding domain, an anti-TROP-2 binding domain, an anti-GPC3 binding domain, and an anti-ROR-1 binding domain. In some embodiments, the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:60, a CDR2 of SEQ ID NO:61, and a CDR3 of SEQ ID NO:62. In some embodiments, the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:63, a CDR2 of SEQ ID NO:64, and a CDR3 of SEQ ID NO:65. In some embodiments, the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:66, a CDR2 of SEQ ID NO:67, and a CDR3 of SEQ ID NO:68. In some embodiments, the anti-MSLN binding domain comprises a sequence with at least about 80% sequence identity to a sequence of SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:71. In some embodiments, the anti-CD19 binding domain comprises a CDR1 of SEQ ID NO:73, a CDR2 of SEQ ID NO:75, and a CDR3 of SEQ ID NO:77. In some embodiments, the anti-CD19 binding domain comprises a CDR1 of SEQ ID NO: 79, a CDR2 of SEQ ID NO: 81, and a CDR3 of SEQ ID NO: 83. In some embodiments, the anti-CD19 binding domain comprises a sequence with at least about 80% sequence identity to a sequence of SEQ ID NO:85 and/or SEQ ID NO:87. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR beta transmembrane domain. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain.

[0017] In another aspect, the present disclosure provides a recombinant nucleic acid comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and a murine TCR alpha or murine TCR beta transmembrane domain, and an antibody or fragment thereof comprising an antigen binding domain; and a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0018] In another aspect, the present disclosure provides a recombinant nucleic acid comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and a murine TCR alpha or murine TCR beta transmembrane domain, and a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0019] In some embodiments, the TCR subunit comprises an intracellular domain of murine TCR alpha or murine TCR beta. In some embodiments, the TCR constant domain is a TCR alpha constant domain. In some embodiments, the TCR alpha constant domain comprises SEQ ID NO: 17, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, or SEQ ID NO:207, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR alpha constant domain comprises a murine TCR alpha constant domain. In some embodiments, the murine TCR alpha constant domain comprises amino acids 2-137 of the murine TCR alpha constant domain. In some embodiments, the murine TCR alpha constant domain comprises amino acids 2-137 of SEQ ID NO: 146. In some embodiments, the murine TCR alpha constant domain comprises a sequence of SEQ ID NO:207. In some embodiments, the murine TCR alpha constant domain comprises amino acids 82-137 of SEQ ID NO: 146. In some embodiments, the murine TCR alpha constant domain comprises a sequence of SEQ ID NO: 17. In some embodiments, the intracellular domain is an intracellular domain of TCR beta. In some embodiments, the sequence encoding the TCR alpha constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR alpha constant domain. In some embodiments, the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP. In some embodiment, the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR alpha constant domain via a linker. In some embodiments, the TCR constant domain is a TCR beta constant domain. In some embodiments, the TCR beta constant domain comprises SEQ ID NO: 18, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, or SEQ ID NO:209, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, TCR beta constant domain comprises a murine TCR beta constant domain. In some embodiments, murine TCR beta constant domain comprises amino acids 2-173 of the murine TCR beta constant domain. In some embodiments, murine TCR beta constant domain comprises amino acids 2-173 of SEQ ID NO: 152. In some embodiments, murine TCR beta constant domain comprises SEQ ID NO:209.

In some embodiments, the TCR beta constant domain comprises amino acids 123-173 of SEQ ID NO: 152. In some embodiments, the TCR beta constant domain comprises SEQ ID NO: 18. In some embodiments, the intracellular domain is an intracellular domain of TCR alpha. In some embodiments, the sequence encoding the TCR beta constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR beta constant domain. In some embodiments, the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP. In some embodiment, the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR beta constant domain via a linker. In some embodiments, the recombinant nucleic acid comprise sequence encoding a TCR alpha constant domain and a TCR beta constant domain. In some embodiments, the TCR alpha constant domain comprises SEQ ID NO: 17, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, or SEQ ID NO:207, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR beta constant domain comprises SEQ ID NO: 18, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, or SEQ ID NO:209, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the intracellular signaling domain is CD3 epsilon, CD3 gamma, or CD3 delta. In some embodiments, the intracellular signaling domain is CD3 epsilon.

[0020] In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker, and a TRBC gene sequence. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker, and a TRBC gene sequence. In some embodiments, the sequence comprises, from 5’-3’, a first leader sequence, a TRAC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRBC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO: 10. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:204. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:206. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:210. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:211. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:217. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:218. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:219. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:220. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:259. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:261. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:262. In some embodiments, the recombinant nucleic acid further comprises at least one leader sequence and at least one linker. In some embodiments, the binding ligand is capable of binding an Fc domain of the antibody. In some embodiments, the binding ligand is capable of selectively binding an IgGl antibody. In some embodiments, the binding ligand is capable of specifically binding an IgG4 antibody. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen. In some embodiments, the antibody or fragment thereof is murine, human or humanized. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some embodiments, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the binding ligand does not comprise an antibody or fragment thereof. In some embodiments, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some embodiments, the binding ligand comprises a CD 16- binding polypeptide. In some embodiments, the binding ligand is human or humanized. In some embodiments, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some embodiments, the antibody or fragment thereof is capable of being secreted from a cell.

[0021] In another aspect, the present disclosure provides a recombinant nucleic acid comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and a murine TCR alpha or murine TCR beta transmembrane domain, and an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0022] In some embodiments, the TCR subunit comprises an intracellular domain of murine TCR alpha or murine TCR beta. In some embodiments, the extracellular domain comprises the extracellular portion of a TCR alpha constant domain or TCR beta constant domain, or a fragment thereof. In some embodiments, the recombinant nucleic acid further comprises at least a partial sequence encoding a TCR gamma constant domain, a TCR delta constant domain, or a partial sequence of both a TCR gamma constant domain and a TCR delta constant domain. In some embodiments, the antigen binding domain comprises a ligand. In some embodiments, the ligand binds to the receptor of a cell. In some embodiments, the ligand binds to the polypeptide expressed on a surface of a cell. In some embodiments, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some embodiments, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some embodiments, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some embodiments, the antigen binding domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof. In some embodiments, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the ligand or fragment thereof is a monomer or a dimer. In some embodiments, the antigen binding domain does not comprise an antibody or fragment thereof In some embodiments, the antigen binding domain does not comprise a variable region. In some embodiments, the antigen binding domain does not comprise a CDR. In some embodiments, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof. In some embodiments, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some embodiments, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within a same nucleic acid molecule. In some embodiments, the TFP and the TCR constant domains are operatively linked by a first linker sequence. In some embodiments, the first linker comprises a protease cleavage site. In some embodiments, the protease cleavage site is a 2A, e.g., a T2A or a P2A cleavage site. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within different nucleic acid molecules. In some embodiments, the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof of the TFP are operatively linked by a second linker sequence. In some embodiments, the second linker sequence comprises (G4S)n, wherein n=l to 4. In some embodiments, the transmembrane domain is a TCR transmembrane domain from TCR alpha or TCR beta, e.g., murine TCR alpha or TCR beta. In some embodiments, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, of TCR alpha or TCR beta. In some embodiments, the TCR extracellular domain comprises the extracellular portion of a constant domain TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a TCR intracellular domain of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, or an amino acid sequence having at least one modification thereto. In some embodiments, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises an alpha constant domain. In some embodiments, the alpha constant domain has the sequence of SEQ ID NO : 17, SEQ ID NO : 142, SEQ ID NO : 143 , SEQ ID NO: 146, or SEQ ID NO:207 functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the encoded TCR comprising (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a beta constant domain. In some embodiments, the beta constant domain has the sequence of SEQ ID NO: 18, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, or SEQ ID NO:209, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the extracellular domain of the TCR subunit does not comprise the variable domain of an alpha chain or a beta chain. In some embodiments, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto. In some embodiments, the TCR subunit of the TFP comprises the extracellular, transmembrane and intracellular domain of CD3 epsilon. In some embodiments, the TCR subunit of CD3 epsilon comprises the sequence of SEQ ID NO:258, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TFP, the TCR alpha constant domain, the TCR beta domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide.

[0023] In some embodiments, the TCR constant domain is a TCR alpha constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof;

[0024] the TCR constant domain is a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or the TCR constant domain is a TCR alpha constant domain and a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0025] In some embodiments, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP. In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain. In some embodiments, an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, an anti-B-cell maturation antigen (BCMA) binding domain, an anti-mesothelin (MSLN) binding domain, an anti-CD20 binding domain, an anti-CD70 binding domain, an anti- 79b binding domain, an anti-HER2 binding domain, an anti-PMSA binding domain, an anti- MUC16 binding domain, an anti-CD22 binding domain, an anti-PD-Ll binding domain, an anti BAFF or BAFF receptor binding domain, an anti-Nectin-4 binding domain, an anti-TROP-2 binding domain, an anti-GPC3 binding domain, and an anti-ROR-1 binding domain. In some embodiments, the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:60, a CDR2 of SEQ ID NO:61, and a CDR3 of SEQ ID NO:62. In some embodiments, the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:63, a CDR2 of SEQ ID NO:64, and a CDR3 of SEQ ID NO:65. In some embodiments, the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO: 66, a CDR2 of SEQ ED NO: 67, and a CDR3 of SEQ ID NO: 68. In some embodiments, the anti-MSLN binding domain comprises a sequence with at least about 80% sequence identity to a sequence of SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:71. In some embodiments, the anti- CD19 binding domain comprises a CDR1 of SEQ ID NO:73, a CDR2 of SEQ ID NO:75, and a CDR3 of SEQ ID NO:77. In some embodiments, the anti-CD19 binding domain comprises a CDR1 of SEQ ID NO:79, a CDR2 of SEQ ID NO:81, and a CDR3 of SEQ ED NO:83 In some embodiments, the anti-CD 19 binding domain comprises a sequence with at least about 80% sequence identity to a sequence of SEQ ID NO:85 and/or SEQ ID NO:87.

[0026] In some embodiments, the nucleic acid is selected from the group consisting of a DNA and an RNA. In some embodiments, the nucleic acid is an mRNA. In some embodiments, the nucleic acid is a circRNA. In some embodiments, the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid. In some embodiments, the nucleic analog is selected from the group consisting of 2 ’-O-methyl, 2 ’-O-m ethoxy ethyl (2’-0-MOE), 2’-0-aminopropyl, 2’-deoxy, T- deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2'-0-dimethylaminoethyl (2’-0-DMAOE), 2’-0- dimethylaminopropyl (2’-0-DMAP), T-O-dimethylaminoethyloxyethyl (2’-0-DMAEOE), 2’-0- N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2’-fluoro N3- P5’-phosphoramidite. In some embodiments, the recombinant nucleic acid further comprises a leader sequence. In some embodiments, the recombinant nucleic acid further comprises a promoter sequence. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a poly(A) tail. In some embodiments, the recombinant nucleic acid further comprises a 3’UTR sequence. In some embodiments, the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid. In some embodiments, the nucleic acid is an in vitro transcribed nucleic acid. In another aspect, the present disclosure provides a vector comprising the recombinant nucleic acid. In some embodiments, the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, an adeno- associated viral vector (AAV), a Rous sarcoma viral (RSV) vector, or a retrovirus vector. In some embodiments, the vector is an AAV6 vector. In some embodiments, the method further comprises a promoter. In some embodiments, the vector is an in vitro transcribed vector.

[0027] In another aspect, the present disclosure provides a modified T cell comprising the recombinant nucleic acid, or the vector, wherein the modified T cell comprises a functional disruption of an endogenous TCR. [0028] In another aspect, the present disclosure provides a modified T cell comprising the sequence encoding the TFP of the nucleic acid or a TFP encoded by the sequence of the nucleic acid encoding the TFP, wherein the modified T cell comprises a functional disruption of an endogenous TCR.

[0029] In another aspect, the present disclosure provides a modified allogenic T cell comprising the sequence encoding the TFP or a TFP encoded by the sequence of the nucleic acid encoding the TFP.

[0030] In some embodiments, the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain. In some embodiments, the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain. In some embodiments, the TCR constant domain, e g., the TCR alpha constant domain, the TCR beta constant domain or the TCR alpha constant domain and the TCR beta constant domain, is a murine TCR constant domain, e.g., a murine TCR alpha constant domain, a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain. In some embodiments, the endogenous TCR that is functionally disrupted is an endogenous TCR alpha chain, an endogenous TCR beta chain, or an endogenous TCR alpha chain and an endogenous TCR beta chain. In some embodiments, the endogenous TCR that is functionally disrupted has reduced binding to MHC -peptide complex compared to that of an unmodified control T cell. In some embodiments, the functional disruption is a disruption of a gene encoding the endogenous TCR. In some embodiments, the disruption of a gene encoding the endogenous TCR is a removal of a sequence of the gene encoding the endogenous TCR from the genome of a T cell. In some embodiments, the T cell is a human T cell selected from CD4 cells, CD8 cells, naive T-cells, memory stem T-cells, central memory T- cells, double negative T-cells, effector memory T-cells, effector T-cells, ThO cells, TcO cells, Thl cells, Tel cells, Th2 cells, Tc2 cells, Thl7 cells, Th22 cells, alpha/beta T cells, gamma/delta T cells, natural killer (NK) cells, natural killer T ( KT) cells, hematopoietic stem cells and pluripotent stem cells. In some embodiments, the T cell is a CD8+ or CD4+ T cell In some embodiments, the T cell is an allogenic T cell. In some embodiments, the method further comprises a nucleic acid encoding an inhibitory molecule that comprises a first polypeptide comprising at least a portion of an inhibitory molecule, associated with a second polypeptide comprising a positive signal from an intracellular signaling domain. In some embodiments, the inhibitory molecule comprises the first polypeptide comprising at least a portion of PD1 and the second polypeptide comprising a costimulatory domain and primary signaling domain.

[0031] In another aspect, the present disclosure provides a pharmaceutical composition comprising: the modified T cells; and a pharmaceutically acceptable carrier.

[0032] In another aspect, the present disclosure provides a method of producing the modified T cell, the method comprising disrupting an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain; thereby producing a T cell containing a functional disruption of an endogenous TCR gene; and transducing the T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid or the vector.

[0033] In some embodiments, the method further comprises disrupting comprises transducing the T cell with a nuclease protein or a nucleic acid sequence encoding a nuclease protein that targets the endogenous gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain.

[0034] In another aspect, the present disclosure provides a method of producing the modified T cell, the method comprising transducing a T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid, or the vector.

[0035] In some embodiments, the T cell containing a functional disruption of an endogenous TCR gene is a T cell containing a functional disruption of an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain.

[0036] In some embodiments, the T cell is a human T cell.

[0037] In some embodiments, the T cell containing a functional disruption of an endogenous TCR gene has reduced binding to MHC -peptide complex compared to that of an unmodified control T cell.

[0038] In some embodiments, the nuclease is a meganuclease, a zinc-finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a CRISPR/Cas nuclease, or a megaTAL nuclease.

[0039] In some embodiments, the sequence comprised by the recombinant nucleic acid or the vector is inserted into the endogenous TCR subunit gene at the cleavage site, and wherein the insertion of the sequence into the endogenous TCR subunit gene functionally disrupts the endogenous TCR subunit.

[0040] In some embodiments, the nuclease is a meganuclease. [0041] In some embodiments, the meganuclease comprises a first subunit and a second subunit, wherein the first subunit binds to a first recognition half-site of the recognition sequence, and wherein the second subunit binds to a second recognition half-site of the recognition sequence. [0042] In some embodiments, the meganuclease is a single-chain meganuclease comprising a linker, wherein the linker covalently joins the first subunit and the second subunit.

[0043] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition.

[0044] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the method described herein; and (b) a pharmaceutically acceptable carrier.

[0045] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the method described herein; and (b) a pharmaceutically acceptable carrier.

[0046] In some embodiments, the modified T cell is an allogeneic T cell. In some embodiments, less cytokines are released in the subject compared a subject administered an effective amount of an unmodified control T cell. In some embodiments, less cytokines are released in the subject compared a subject administered an effective amount of a modified T cell comprising the recombinant nucleic acid, or the vector. In some embodiments, the method comprises administering the pharmaceutical composition in combination with an agent that increases the efficacy of the pharmaceutical composition. In some embodiments, the method comprises administering the pharmaceutical composition in combination with an agent that ameliorates one or more side effects associated with the pharmaceutical composition. In some embodiments, the cancer is a solid cancer, a lymphoma or a leukemia. In some embodiments, the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, cervical cancer, brain cancer, liver cancer, pancreatic cancer, kidney and stomach cancer. In some embodiments, less cytokines are released in the subject compared to a subject administered an effective amount of an autologous T cell expressing the TFP described herein. In some embodiments, the method does not induce graft versus host disease. In some embodiments, the subject has a reduced risk of developing graft versus host disease compared to a subject administered an effective amount of an autologous T cell expressing the TFP described herein. [0047] In another aspect, the present disclosure provides the recombinant nucleic acid, the vector, the modified T cell, or the pharmaceutical composition, for use as a medicament or in the preparation of a medicament.

INCORPORATION BY REFERENCE

[0048] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS [0049] Figure l is a series of graphs showing surface expression of CD3 (SK7) vs TCRa3 (IP26) in TRA-edited (left) and TRB-edited (right) cells. Wild type Jurkat cells were edited at either the TRAC or TRBC genes to disrupt TRA or TRB surface expression. Cells negative for CD3 and TCRap were purified using Magnetic- Activated Cell Sorting (MACS). The gates on the plots were drawn to delineate CD3 and TCRap negative-negative population of cells and the percentages of cells remaining in each quadrant are shown in the corners.

[0050] Figure 2 is a series of graphs showing surface expression of CD3 (SK7) vs TCRap (IP26) in TRA-/- (left) and TRB-/- (right) Jurkat cells. The first panel from the left is a non- transduced negative control. The second panel shows TRB-/- cells transduced with a TCRp Full Length TFP. The third and fourth panels show TRA-/- and TRB-/- transduced with a TCRyd TFP construct.

[0051] Figure 3 is a drawing showing various strategies to generate allogeneic TFP T cells. [0052] Figure 4 is a schematic showing elements of the constructs used to generate allogeneic TFP T cells.

[0053] Figure 5 is a series of graphs showing surface expression of CD3 vs TCRaP in T cells transduced with TCRyd TFP constructs after editing the TRAC locus versus wild type cells and TRAC edited, non-transduced T cells. The graphs depict cell populations prior to MACS purification.

[0054] Figure 6 is a series of graphs showing surface expression of CD3 vs TCRaP in T cells transduced with TCRyd TFP constructs after editing the TRAC locus versus wild type cells and TRAC edited, non-transduced T cells. Graphs depict cell populations after MACS purification. [0055] Figure 7 is a series of graphs showing surface expression of allogeneic TFP transduced T cells (TFP+). The left-hand panels show TFP+ percentage of T cells transduced with TCRyd TFP constructs. The right-hand panels show TFP+ percentage of T cells transduced with TCRJ3 full length positive control constructs compared to non-transduced control cells.

[0056] Figure 8 is a series of graphs showing surface expression of CD4 versus CD8 populations within T cells transduced with TCRyd TFP constructs compared to T cells transduced with TCR Full length positive control constructs.

[0057] Figure 9 is a series of graphs showing surface expression of CD45RA versus CCR7 populations in CD4 or CD8 T cells transduced with TCRyd TFP constructs compared to T cells transduced with TCR Full length positive control constructs.

[0058] Figure 10 is two graphs showing Luc-Cyto analysis of allogeneic T effector cells cultured with tumor target cells at 3-to-l, 1-to-l, or l-to-3 and l-to-9 ratios. Target Nalm-6 (CD19 positive) cells are shown in the left panel while CD19 negative cells (K562 cells) are shown in the right panel. The x-axes represent percentage of tumor cell lysis.

[0059] Figure 11 is four graphs showing cytokine secretion (in pg/mL) of supernatants taken from the Nalm-6 co-culture assay in Figure 10. Graphs show cytokine secretion for GM-CSF, IFNy, IL2 and TNFa.

[0060] Figure 12 is a schematic diagram showing TFP constructs in TRAC or TRBC edited cells, and whether or not the TCR is reconstituted with expression of the construct. Figure 12 shows that murine TCRa or TCRP TFP constructs are able to reconstitute the TCR, and human TCRy or TCR5 TFP constructs are able to reconstitute the TCR.

[0061] Figures 13A and 13B show cell surface expression of human TCR TFP constructs. Figures 13A is a schematic diagram showing the constructs expressed in Figure 13B. Human anti-CD19 TCRp TFP and human anti-CD19 TCRP (constant domain) TFP are shown. Figure 13B shows surface expression of CD3 vs TCRc/.b in TRBC knockout Jurkat cells transduced with the constructs of Figure 13 A.

[0062] Figure 14 is a series of graphs showing surface expression of (i) SSC-A versus CD19;

(ii) CD3 versus TCRaP pre-purification and (i) SSC-A versus CD 19; (ii) CD3 versus TCRa ; (iii) CD4 versus CD8; and (iv) CD45RA versus CCR7 post-purification in TRAC knockout T cells transduced with the constructs shown. TRAC was not knocked out in cells transduced with anti-CD 19-CD3s.

[0063] Figure 15 is a series of graphs showing showing Luc-Cyto analysis of TRAC knockout T cells transduced with the constructs shown cultured with tumor target cells at 3-to-l, 1-to-l, or 1- to-3 and l-to-9 ratios from left to right. TRAC was not knocked out in cells transduced with anti-CD19-CD3s. Target Nalm-6 (CD19 positive) cells are shown in the top panel while CD19 negative cells (K562 cells) are shown in the bottom panel. The x-axes represent percentage of tumor cell lysis.

[0064] Figure 16 is a series of four graphs showing cytokine secretion (in pg/mL) of supernatants taken from the Nalm-6 co-culture assay in Figure 15 in which allogeneic T effector cells were cultured with tumor target cells at 3-to-l, 1-to-l, or l-to-3 and l-to-9 ratios from left to right. Graphs show cytokine secretion for GM-CSF, IFNy, IL2 and TNFa.

[0065] Figure 17 is a series of graphs showing secretion (in pg/mL) of GM-CSF and IFNy of the TRAC knockout T cells transduced with the constructs shown without or with (from left to right) non-HLA-matched dendritic cells. TRAC was not knocked out in cells transduced with anti- CD 19-CD3S.

[0066] Figures 18A-18C are a series of graphs showing tumor burden as measured by luminescence in Nalm6-luc tumor mouse model mice injected with the TRAC knockout T cells transduced with the constructs shown. TRAC was not knocked out in cells transduced with anti- CD 19-CD3S.

[0067] Figure 19 shows infiltration of CD7+ cells into the liver of non-tumor bearing mice from the in vivo assay shown in Figure 18 Surface expression of CD45RA versus CD7 in the mouse liver is shown as well as immunohistochemistry of CD7 expression in the murine liver.

[0068] Figure 20 is a series of graphs showing showing Luc-Cyto analysis of TRAC knockout T cells transduced with the constructs shown cultured with tumor target cells at 3-to-l, 1-to-l, or 1- to-3 ratios from left to right. Target Nalm-6 (CD 19 positive) cells are shown in the left panel while CD19 negative cells (K562 cells) are shown in the right panel. The x-axes represent percentage of tumor cell lysis.

[0069] Figure 21 is a series of four graphs showing cytokine secretion (in pg/mL) of supernatants taken from the Nalm-6 co-culture assay in Figure 20 in which allogeneic T effector cells were cultured with tumor target cells at 3-to-l, 1-to-l, or l-to-3 ratios from left to right. Graphs show cytokine secretion for GM-CSF, IFNy, IL2 and TNFa.

[0070] Figure 22 is a series of graphs showing showing Luc-Cyto analysis of TRAC knockout T cells transduced with the constructs shown cultured with tumor target cells at 3-to-l, 1-to-l, or 0.1:1 ratios from left to right. Target Nalm-6 (CD 19 positive) cells are shown in the left panel while CD19 negative cells (K562 cells) are shown in the right panel. The x-axes represent percentage of tumor cell lysis.

[0071] Figure 23 is a series of four graphs showing cytokine secretion (in pg/mL) of supernatants taken from the Nalm-6 co-culture assay in Figure 20 in which allogeneic T effector cells were cultured with tumor target cells at 3-to-l, 1-to-l, or 0.1 : 1 ratios from left to right. Graphs show cytokine secretion for GM-CSF, IFNy, IL2 and TNFa

DETAILED DESCRIPTION OF THE INVENTION [0072] Disclosed herein, in some embodiments, is a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, and (2) a transmembrane domain, and (ii) an antibody comprising an antigen binding domain, and (b) a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain, or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0073] Disclosed herein, in some embodiments, is a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain, or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0074] Disclosed herein, in some embodiments, is a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, and (2) a transmembrane domain, and (ii) an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain; or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0075] Disclosed herein, in some embodiment, is a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and (2) a murine TCR alpha or murine TCR beta transmembrane domain, and (ii) an antibody or fragment thereof comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0076] Disclosed herein is a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and (2) a murine TCR alpha or murine TCR beta transmembrane domain, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0077] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising TCR alpha, TCR beta, TCR gamma, or TCR delta or a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, and (ii) a human or humanized antibody comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR delta constant domain and a TCR gamma constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell. [0078] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising TCR alpha, TCR beta, TCR gamma, or TCR delta or a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta,, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell.

[0079] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising TCR alpha, TCR beta, TCR gamma, or TCR delta or a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, and (ii) an antigen domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell.

[0080] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising TCR alpha, TCR beta, TCR gamma, or TCR delta or a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, , and (ii) a human or humanized antibody comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell.

[0081] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising TCR alpha, TCR beta, TCR gamma, or TCR delta or a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta,, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell.

[0082] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising TCR alpha, TCR beta, TCR gamma, or TCR delta or a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta,, and (ii) an antigen domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell.

[0083] Disclosed herein, in some embodiments, are vectors comprising the recombinant nucleic acid disclosed herein.

[0084] Disclosed herein, in some embodiments, are modified T cells comprising the recombinant nucleic acid disclosed herein, or the vectors disclosed herein; wherein the modified T cell comprises a functional disruption of an endogenous TCR.

[0085] Disclosed herein, in some embodiments, are modified T cells comprising the sequence encoding the TFP of the nucleic acid disclosed herein or a TFP encoded by the sequence of the nucleic acid disclosed herein, wherein the modified T cell comprises a functional disruption of an endogenous TCR.

[0086] Disclosed herein, in some embodiments, are modified allogenic T cells comprising the sequence encoding the TFP disclosed herein or a TFP encoded by the sequence of the nucleic acid disclosed herein.

[0087] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising: (a) the modified T cells of the disclosure; and (b) a pharmaceutically acceptable carrier.

[0088] Disclosed herein, in some embodiments, are methods of producing the modified T cell of the disclosure, the method comprising (a) disrupting an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain; thereby producing a T cell containing a functional disruption of an endogenous TCR gene; and (b) transducing the T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid of the disclosure, or the vectors disclosed herein.

[0089] Disclosed herein, in some embodiments, are methods of producing the modified T cell of the disclosure, the method comprising transducing a T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid disclosed herein, or the vectors disclosed herein.

[0090] Disclosed herein, in some embodiments, are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical compositions disclosed herein.

[0091] Disclosed herein, in some embodiments, are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the methods disclosed herein; and (b) a pharmaceutically acceptable carrier.

Certain terminology

[0092] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0093] The term “a” and “an” refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0094] As used herein, “about” can mean plus or minus less than 1 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or greater than 30 percent, depending upon the situation and known or knowable by one skilled in the art.

[0095] As used herein the specification, “subject” or “subjects” or “individuals” may include, but are not limited to, mammals such as humans or non-human mammals, e.g ., domesticated, agricultural or wild, animals, as well as birds, and aquatic animals. “Patients” are subjects suffering from or at risk of developing a disease, disorder or condition or otherwise in need of the compositions and methods provided herein.

[0096] As used herein, “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of the disease or condition. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. As used herein, “treat or prevent” is sometimes used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and contemplates a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0097] As used herein, “preventing” refers to the prevention of the disease or condition, e.g., tumor formation, in the patient. For example, if an individual at risk of developing a tumor or other form of cancer is treated with the methods of the present disclosure and does not later develop the tumor or other form of cancer, then the disease has been prevented, at least over a period of time, in that individual.

[0098] As used herein, a “therapeutically effective amount” is the amount of a composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. By “therapeutically effective dose” herein is meant a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g. Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)) [0099] As used herein, a “T cell receptor (TCR) fusion protein” or “TFP” includes a recombinant polypeptide derived from the various polypeptides comprising the TCR that is generally capable of i) binding to a surface antigen on target cells and ii) interacting with other polypeptide components of the intact TCR complex, typically when co-located in or on the surface of a T cell.

[0100] The term “stimulation” refers to a primary response induced by binding of a stimulatory domain or stimulatory molecule (e.g., a TCR/CD3 complex) with its cognate ligand thereby mediating a signal transduction event, such as, but not limited to, signal transduction via the TCR/CD3 complex. Stimulation can mediate altered expression of certain molecules, and/or reorganization of cytoskeletal structures, and the like.

[0101] The term “stimulatory molecule” or “stimulatory domain” refers to a molecule or portion thereof expressed by a T cell that provides the primary cytoplasmic signaling sequence(s) that regulate primary activation of the TCR complex in a stimulatory way for at least some aspect of the T cell signaling pathway. In one aspect, the primary signal is initiated by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, and which leads to mediation of a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A primary cytoplasmic signaling sequence (also referred to as a “primary signaling domain”) that acts in a stimulatory manner may contain a signaling motif which is known as immunoreceptor tyrosine-based activation motif or “IT AM”. Examples of an IT AM containing primary cytoplasmic signaling sequence that is of particular use in the invention includes, but is not limited to, those derived from TCR zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (also known as “ICOS”) and CD66d.

[0102] The term “antigen presenting cell” or “APC” refers to an immune system cell such as an accessory cell ( e.g ., a B-cell, a dendritic cell, and the like) that displays a foreign antigen complexed with major histocompatibility complexes (MHC’s) on its surface. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

[0103] “Major histocompatability complex (MHC) molecules are typically bound by TCRs as part of peptide:MHC complex. The MHC molecule may be an MHC class I or II molecule. The complex may be on the surface of an antigen presenting cell, such as a dendritic cell or a B cell, or any other cell, including cancer cells, or it may be immobilized by, for example, coating on to a bead or plate.

[0104] The human leukocyte antigen system (HLA) is the name of the gene complex which encodes major histocompatibility complex (MHC) in humans and includes HLA class I antigens (A, B & C) and HLA class II antigens (DP, DQ, & DR). HLA alleles A, B and C present peptides derived mainly from intracellular proteins, e.g., proteins expressed within the cell.

[0105] During T cell development in vivo, T cells undergo a positive selection step to ensure recognition of self MHCs followed by a negative step to remove T cells that bind too strongly to MHC which present self-antigens. As a consequence, certain T cells and the TCRs they express will only recognize peptides presented by certain types of MHC molecules - i.e. those encoded by particular HLA alleles. This is known as HLA restriction.

[0106] One HLA allele of interest is HLA-A*0201, which is expressed in the vast majority (>50%) of the Caucasian population. Accordingly, TCRs which bind WT1 peptides presented by MHC encoded by HLA-A*0201 (i.e. are HLA-A*0201 restricted) are advantageous since an immunotherapy making use of such TCRs will be suitable for treating a large proportion of the Caucasian population.

[0107] Other HLA- A alleles of interest are HLA-A*0101, HLA-A*2402, and HLA-A*0301. [0108] Widely expressed HLA-B alleles of interest are HLA-B*3501, HLA-B*0702 and HLA- B*3502.

[0109] An “intracellular signaling domain,” as the term is used herein, refers to an intracellular portion of a molecule. The intracellular signaling domain generates a signal that promotes an immune effector function of the TFP containing cell, e.g., a modified T-T cell. Examples of immune effector function, e.g., in a modified T-T cell, include cytolytic activity and T helper cell activity, including the secretion of cytokines. In an embodiment, the intracellular signaling domain can comprise a primary intracellular signaling domain. Exemplary primary intracellular signaling domains include those derived from the molecules responsible for primary stimulation, or antigen dependent simulation. In an embodiment, the intracellular signaling domain can comprise a costimulatory intracellular domain. Exemplary costimulatory intracellular signaling domains include those derived from molecules responsible for costimulatory signals, or antigen independent stimulation.

[0110] A primary intracellular signaling domain can comprise an IT AM (“immunoreceptor tyrosine-based activation motif’). Examples of IT AM containing primary cytoplasmic signaling sequences include, but are not limited to, those derived from CD3 zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, and CD66d DAP10 and DAP12.

[0111] The term “costimulatory molecule” refers to the cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an efficient immune response. Costimulatory molecules include, but are not limited to an MHC class 1 molecule, BTLA and a Toll ligand receptor, as well as 0X40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CD18) and 4-1BB (CD137). A costimulatory intracellular signaling domain can be the intracellular portion of a costimulatory molecule. A costimulatory molecule can be represented in the following protein families: TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4-1BB (CD137), 0X40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, lymphocyte function-associated antigen-1 (LFA- 1), CD2, CD 7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and a ligand that specifically binds with CD83, and the like. The intracellular signaling domain can comprise the entire intracellular portion, or the entire native intracellular signaling domain, of the molecule from which it is derived, or a functional fragment thereof. The term “4- IBB” refers to a member of the TNFR superfamily with an amino acid sequence provided as GenBank Acc. No. AAA62478.2, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like; and a “4-1BB costimulatory domain” is defined as amino acid residues 214-255 of GenBank Acc. No. AAA62478.2, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like.

[0112] The term “antibody,” as used herein, refers to a protein, or polypeptide sequences derived from an immunoglobulin molecule, which specifically binds to an antigen. Antibodies can be intact immunoglobulins of polyclonal or monoclonal origin, or fragments thereof and can be derived from natural or from recombinant sources.

[0113] The terms “antibody fragment” refers to at least one portion of an antibody, or recombinant variants thereof, that contains the antigen binding domain, i.e., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen and its defined epitope. Examples of antibody fragments include, but are not limited to, Fab, Fab’, F(ab’)2, and Fv fragments, single-chain (sc)Fv (“scFv”) antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi-specific antibodies formed from antibody fragments.

[0114] The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single polypeptide chain, and wherein the scFv retains the specificity of the intact antibody from which it is derived.

[0115] “Heavy chain variable region” or “VH” with regard to an antibody refers to the fragment of the heavy chain that contains three CDRs interposed between flanking stretches known as framework regions, these framework regions are generally more highly conserved than the CDRs and form a scaffold to support the CDRs. A camelid “VHH” domain is a heavy chain comprising a single variable antibody domain.

[0116] Unless specified, as used herein a scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.

[0117] The portion of the TFP composition of the disclosure comprising an antibody or antibody fragment thereof may exist in a variety of forms where the antigen binding domain is expressed as part of a contiguous polypeptide chain including, for example, a single domain antibody fragment (sdAb), a single chain antibody (scFv) derived from a murine, humanized or human antibody (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y.; Harlow et al, 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, N.Y.; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). In one aspect, the antigen binding domain of a TFP composition of the disclosure comprises an antibody fragment. In a further aspect, the TFP comprises an antibody fragment that comprises a scFv or a sdAb.

[0118] The term “recombinant antibody” refers to an antibody that is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage or yeast expression system. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using recombinant DNA or amino acid sequence technology which is available and well known in the art.

[0119] The term “antigen” or “Ag” refers to a molecule that is capable of being bound specifically by an antibody, or otherwise provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both.

[0120] The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present disclosure includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to encode polypeptides that elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample, or might be macromolecule besides a polypeptide. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a fluid with other biological components.

[0121] As used herein, the term “CD19” refers to the Cluster of Differentiation 19 protein, which is an antigenic determinant detectable on B cell leukemia precursor cells, other malignant B cells and most cells of the normal B cell lineage.

[0122] As used herein, the term “BCMA” refers to the B-cell maturation antigen also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17) and Cluster of Differentiation 269 protein (CD269) is a protein that in humans is encoded by the TNFRSF17 gene. TNFRSF17 is a cell surface receptor of the TNF receptor superfamily which recognizes B- cell activating factor (BAFF) (see, e.g ., Laabi et al., EMBO 11 (11): 3897-904 (1992). This receptor is expressed in mature B lymphocytes, and may be important for B-cell development and autoimmune response.

[0123] As used herein, the term “CD 16” (also known as Fc /RIII) refers to a cluster of differentiation molecule found on the surface of natural killer cells, neutrophil polymorphonuclear leukocytes, monocytes and macrophages. CD16 has been identified as Fc receptors FcyRIIIa (CD16a) and FcyRIIIb (CD16b), which participate in signal transduction.

CD 16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC).

[0124] “NKG2D,” as used herein, refers to a transmembrane protein belonging to the CD94/NKG2 family of C-type lectin-like receptors. In humans, NKG2D is expressed by NK cells, gd T cells and CD8+ ab T cells. KG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

[0125] Mesothelin (MSLN) refers to a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium. Mesothelin is over expressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. [0126] Tyrosine-protein kinase transmembrane receptor ROR1, also known as neurotrophic tyrosine kinase, receptor-related 1 (NTRKR1) is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. It plays a role in metastasis of cancer.

[0127] The term “MUC16”, also known as “mucin 16, cell-surface associated” or “ovarian cancer-related tumor marker CA125” is a membrane-tethered mucin that contains an extracellular domain at its amino terminus, a large tandem repeat domain, and a transmembrane domain with a short cytoplasmic domain. Products of this gene have been used as a marker for different cancers, with higher expression levels associated with poorer outcomes.

[0128] The term “CD22,” also known as sialic acid binding Ig-like lectin 2, SIGLEC-2, T cell surface antigen leu-14, and B cell receptor CD22, is a protein that mediates B cell/B cell interactions, and is thought to be involved in the localization of B cells in lymphoid tissues, and is associated with diseases including refractory hematologic cancer and hairy cell leukemia. A fully human anti-CD22 monoclonal antibody (“M971”) suitable for use with the methods disclosed herein is described, e g., in Xiao et al., MAbs. 2009 May-Jun; 1(3): 297-303. [0129] Programmed cell death protein 1, also known as “PD-1” and CD279 (cluster of differentiation 279), is a protein on the surface of cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells. PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells). PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.

[0130] Programmed death-ligand 1 (“PD-L1”) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif. This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.

[0131] The “CD79a” and “CD79P” genes encode proteins that make up the B lymphocyte antigen receptor, a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta (encoded by CD79a and its paralog CD79p, respectively) which are necessary for expression and function of the B-cell antigen receptor. Functional disruption of this complex can lead to, e g., human B-cell chronic lymphocytic leukemias.

[0132] B cell activating factor, or “BAFF” is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptors TNFRSF13B/TACI,

TNFRSF 17 BCMA, and TNFRSF13C BAFF-R. This cytokine is expressed in B cell lineage cells, and acts as a potent B cell activator. It has been also shown to play an important role in the proliferation and differentiation of B cells.

[0133] The term “anti-tumor effect” refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, decrease in tumor cell proliferation, decrease in tumor cell survival, or amelioration of various physiological symptoms associated with the cancerous condition. An “anti-tumor effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the present disclosure in prevention of the occurrence of tumor in the first place.

[0134] The term “autologous” refers to any material derived from the same individual to whom it is later to be re-introduced into the individual.

[0135] The term “allogeneic” or, alternatively, “allogenic,” refers to any material derived from a different animal of the same species or different patient as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic material from individuals of the same species may be sufficiently unlike genetically to interact antigenically.

[0136] The term “xenogeneic” refers to a graft derived from an animal of a different species. [0137] The term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like.

[0138] The term “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides ( e.g ., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene, cDNA, or RNA, encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0139] Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain one or more introns. [0140] The term “effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological or therapeutic result. [0141] The term “endogenous” refers to any material from or produced inside an organism, cell, tissue or system.

[0142] The term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue or system.

[0143] The term “expression” refers to the transcription and/or translation of a particular nucleotide sequence driven by a promoter.

[0144] The term “functional disruption” refers to a physical or biochemical change to a specific (e.g., target) nucleic acid (e.g., gene, RNA transcript, of protein encoded thereby) that prevents its normal expression and/or behavior in the cell. In one embodiment, a functional disruption refers to a modification of the gene via a gene editing method. In one embodiment, a functional disruption prevents expression of a target gene (e.g., an endogenous gene).

[0145] The term “transfer vector” refers to a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “transfer vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to further include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, a polylysine compound, liposome, and the like. Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like.

[0146] The term “expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, including cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno- associated viruses) that incorporate the recombinant polynucleotide.

[0147] The term “lentivirus” refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.

[0148] The term “lentiviral vector” refers to a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that may be used in the clinic, include but are not limited to, e.g., the LENTIVECTOR™ gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen, and the like. Nonclinical types of lentiviral vectors are also available and would be known to one skilled in the art.

[0149] The term “homologous” or “identity” refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g, 9 of 10), are matched or homologous, the two sequences are 90% homologous.

[0150] “Humanized” forms of non-human (e.g, murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’)₂ or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies and antibody fragments thereof are human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, a humanized antibody/antibody fragment can comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications can further refine and optimize antibody or antibody fragment performance. In general, the humanized antibody or antibody fragment thereof will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or a significant portion of the FR regions are those of a human immunoglobulin sequence. The humanized antibody or antibody fragment can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 321: 522- 525, 1986; Reichmann et al., Nature, 332: 323-329, 1988; Presta, Curr. Op. Struct. Biol., 2: 593- 596, 1992.

[0151] “Human” or “fully human” refers to an immunoglobulin, such as an antibody or antibody fragment, where the whole molecule is of human origin or consists of an amino acid sequence identical to a human form of the antibody or immunoglobulin.

[0152] The term “isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0153] In the context of the present disclosure, the following abbreviations for the commonly occurring nucleic acid bases are used. “A” refers to adenosine, “C” refers to cytosine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine.

[0154] The term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the present disclosure by standard techniques known in the art, such as site- directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with 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, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g, threonine, valine, isoleucine) and aromatic side chains (e.g, tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within a TFP of the present disclosure can be replaced with other amino acid residues from the same side chain family and the altered TFP can be tested using the functional assays described herein.

[0155] The term “operably linked” or “transcriptional control” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other and, e.g., where necessary to join two protein coding regions, are in the same reading frame.

[0156] The term “parenteral” administration of an immunogenic composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrastemal injection, intratumoral, or infusion techniques.

[0157] The term “nucleic acid” or “polynucleotide” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[0158] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination thereof. [0159] The term “promoter” refers to a DNA sequence recognized by the transcription machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence.

[0160] The term “promoter/regulatory sequence” refers to a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner.

[0161] The term “constitutive” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.

[0162] The term “inducible” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell.

[0163] The term “tissue-specific” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.

[0164] The terms “linker” and “flexible polypeptide linker” as used in the context of a scFv refers to a peptide linker that consists of amino acids such as glycine and/or serine residues used alone or in combination, to link variable heavy and variable light chain regions together. In one embodiment, the flexible polypeptide linker is a Gly/Ser linker and comprises the amino acid sequence (Gly-Gly-Gly-Ser)_n, where n is a positive integer equal to or greater than 1. For example, n=l, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9 and n=10. In one embodiment, the flexible polypeptide linkers include, but are not limited to, (Gly4Ser)4 or (Gly4Ser)3. In another embodiment, the linkers include multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser). Also included within the scope of the present disclosure are linkers described in WO2012/138475 (incorporated herein by reference). In some instances, the linker sequence comprises (G4S)_n, wherein n=2 to 5. In some instances, the linker sequence comprises (G4S)_n, wherein n=l to 3. [0165] As used herein, a 5’ cap (also termed an RNA cap, an RNA 7-methylguanosine cap or an RNA m7G cap) is a modified guanine nucleotide that has been added to the “front” or 5’ end of a eukaryotic messenger RNA shortly after the start of transcription. The 5’ cap consists of a terminal group which is linked to the first transcribed nucleotide. Its presence is critical for recognition by the ribosome and protection from RNases. Cap addition is coupled to transcription, and occurs co-transcriptionally, such that each influences the other. Shortly after the start of transcription, the 5’ end of the mRNA being synthesized is bound by a cap- synthesizing complex associated with RNA polymerase. This enzymatic complex catalyzes the chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi-step biochemical reaction. The capping moiety can be modified to modulate functionality of mRNA such as its stability or efficiency of translation.

[0166] As used herein, “in vitro transcribed RNA” refers to RNA, preferably mRNA, which has been synthesized in vitro. Generally, the in vitro transcribed RNA is generated from an in vitro transcription vector. The in vitro transcription vector comprises a template that is used to generate the in vitro transcribed RNA.

[0167] As used herein, a “poly(A)” is a series of adenosines attached by polyadenylation to the mRNA. In the preferred embodiment of a construct for transient expression, the polyA is between 50 and 5000, preferably greater than 64, more preferably greater than 100, most preferably greater than 300 or 400. Poly(A) sequences can be modified chemically or enzymatically to modulate mRNA functionality such as localization, stability or efficiency of translation.

[0168] As used herein, “polyadenylation” refers to the covalent linkage of a polyadenylyl moiety, or its modified variant, to a messenger RNA molecule. In eukaryotic organisms, most messenger RNA (mRNA) molecules are polyadenylated at the 3’ end. The 3’ poly(A) tail is a long sequence of adenine nucleotides (often several hundred) added to the pre-mRNA through the action of an enzyme, polyadenylate polymerase. In higher eukaryotes, the poly(A) tail is added onto transcripts that contain a specific sequence, the polyadenylation signal. The poly(A) tail and the protein bound to it aid in protecting mRNA from degradation by exonucleases. Polyadenylation is also important for transcription termination, export of the mRNA from the nucleus, and translation Polyadenylation occurs in the nucleus immediately after transcription of DNA into RNA, but additionally can also occur later in the cytoplasm. After transcription has been terminated, the mRNA chain is cleaved through the action of an endonuclease complex associated with RNA polymerase. The cleavage site is usually characterized by the presence of the base sequence AAUAAA near the cleavage site. After the mRNA has been cleaved, adenosine residues are added to the free 3’ end at the cleavage site.

[0169] As used herein, “transient” refers to expression of a non-integrated transgene for a period of hours, days or weeks, wherein the period of time of expression is less than the period of time for expression of the gene if integrated into the genome or contained within a stable plasmid replicon in the host cell.

[0170] The term “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. The phrase “cell surface receptor” includes molecules and complexes of molecules capable of receiving a signal and transmitting signal across the membrane of a cell.

[0171] The term “subject” is intended to include living organisms in which an immune response can be elicited ( e.g ., mammals, human).

[0172] The term, a “substantially purified” cell refers to a cell that is essentially free of other cell types. A substantially purified cell also refers to a cell which has been separated from other cell types with which it is normally associated in its naturally occurring state. In some instances, a population of substantially purified cells refers to a homogenous population of cells. In other instances, this term refers simply to cell that have been separated from the cells with which they are naturally associated in their natural state. In some aspects, the cells are cultured in vitro. In other aspects, the cells are not cultured in vitro.

[0173] The term “therapeutic” as used herein means a treatment. A therapeutic effect is obtained by reduction, suppression, remission, or eradication of a disease state.

[0174] The term “prophylaxis” as used herein means the prevention of or protective treatment for a disease or disease state.

[0175] In the context of the present disclosure, “tumor antigen” or “hyperproliferative disorder antigen” or “antigen associated with a hyperproliferative disorder” refers to antigens that are common to specific hyperproliferative disorders. In certain aspects, the hyperproliferative disorder antigens of the present disclosure are derived from, cancers including but not limited to primary or metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, NHL, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and the like.

[0176] The term “transfected” or “transformed” or “transduced” refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0177] The term “specifically binds,” refers to an antibody, an antibody fragment or a specific ligand, which recognizes and binds a cognate binding partner (e.g., CD 19) present in a sample, but which does not necessarily and substantially recognize or bind other molecules in the sample. [0178] As used herein, the term "meganuclease" refers to an endonuclease that binds double- stranded DNA at a recognition sequence that is greater than 12 base pairs. Preferably, the recognition sequence for a meganuclease of the present disclosure is 22 base pairs. A meganuclease can be an endonuclease that is derived from I-Crel and can refer to an engineered variant of I-Crel that has been modified relative to natural I-Crel with respect to, for example, DNA-binding specificity, DNA cleavage activity, DNA-binding affinity, or dimerization properties. Methods for producing such modified variants of I-Crel are known in the art (e.g.,

WO 2007/047859). A meganuclease as used herein binds to double-stranded DNA as a heterodimer or as a "single-chain meganuclease" in which a pair of DNA-binding domains are joined into a single polypeptide using a peptide linker. The term "homing endonuclease" is synonymous with the term "meganuclease." Meganucleases of the present disclosure are substantially non-toxic when expressed in cells, particularly in human T cells, such that cells can be transfected and maintained at 37°C without observing deleterious effects on cell viability or significant reductions in meganuclease cleavage activity when measured using the methods described herein.

[0179] As used herein, the term "single-chain meganuclease" refers to a polypeptide comprising a pair of nuclease subunits joined by a linker. A single-chain meganuclease has the organization: N-terminal subunit - Linker - C-terminal subunit. The two meganuclease subunits will generally be non-identical in amino acid sequence and will recognize non-identical DNA sequences. Thus, single-chain meganucleases typically cleave pseudo-palindromic or non-palindromic recognition sequences. A single-chain meganuclease may be referred to as a "single-chain heterodimer" or "single-chain heterodimeric meganuclease" although it is not, in fact, dimeric. For clarity, unless otherwise specified, the term "meganuclease" can refer to a dimeric or single-chain meganuclease.

[0180] As used herein, the term "TALEN" refers to an endonuclease comprising a DNA-binding domain comprising 16-22 TAL domain repeats fused to any portion of the Fokl nuclease domain. [0181] As used herein, the term "Compact TALEN" refers to an endonuclease comprising a DNA-binding domain with 16-22 TAL domain repeats fused in any orientation to any catalytically active portion of nuclease domain of the I-Tevl homing endonuclease.

[0182] As used herein, the term "CRISPR" refers to a caspase-based endonuclease comprising a caspase, such as Cas9, and a guide RNA that directs DNA cleavage of the caspase by hybridizing to a recognition site in the genomic DNA. [0183] As used herein, the term "megaTAL" refers to a single-chain nuclease comprising a transcription activator-like effector (TALE) DNA binding domain with an engineered, sequence- specific homing endonuclease.

[0184] As is used herein, the terms “T cell receptor” and “T cell receptor complex” are used interchangeably to refer to a molecule found on the surface of T cells that is, in general, responsible for recognizing antigens. The TCR comprises a heterodimer consisting of a TCR alpha and TCR beta chain in 95% of T cells, whereas 5% of T cells have TCRs consisting of TCR gamma and TCR delta chains. The TCR further comprises one or more of CD3s, CD3y, and CD35. In some embodiments, the TCR comprises CD3e. In some embodiments, the TCR comprises CD3y. In some embodiments, the TCR comprises CD36. In some embodiments, the TCR comprises CD3z. Engagement of the TCR with antigen, e.g., with antigen and MHC, results in activation of its T cells through a series of biochemical events mediated by associated enzymes, co-receptors, and specialized accessory molecules. In some embodiments, the constant domain of human TCR alpha has a sequence of SEQ ID NO: 142. In some embodiments, the constant domain of human TCR alpha has an IgC domain having a sequence of SEQ ID NO: 143, a transmembrane domain having a sequence of SEQ ID NO: 144, and an intracellular domain having a sequence of SS. In some embodiments, the constant domain of murine TCR alpha has a sequence of SEQ ID NO: 147. In some embodiments, the constant domain of murine TCR alpha has a transmembrane domain having a sequence of SEQ ID NO: 144, and an intracellular domain having a sequence of SS. In some embodiments, the constant domain of human TCR beta has a sequence of SEQ ID NO: 148. In some embodiments, the constant domain of human TCR beta has an IgC domain having a sequence of SEQ ID NO: 149, a transmembrane domain having a sequence of SEQ ID NO: 150, and an intracellular domain having a sequence of SEQ ID NO:

151. In some embodiments, the constant domain of murine TCR beta has a sequence of SEQ ID NO: 152. In some embodiments, the constant domain of murine TCR beta has a transmembrane domain having a sequence of SEQ ID NO: 152, and an intracellular domain having a sequence of SEQ ID NO: 153. In some embodiments, the constant domain of human TCR delta has a sequence of SEQ ID NO: 243. In some embodiments, the constant domain of human TCR delta has an IgC domain having a sequence of SEQ ID NO: 265, a transmembrane domain having a sequence of SEQ ID NO: 159, and an intracellular domain having a sequence of L. In some embodiments, the constant domain of human TCR gamma has a sequence of SEQ ID NO: 21. In some embodiments, the constant domain of human TCR gamma has an IgC domain having a sequence of SEQ ID NO: 155, a transmembrane domain having a sequence of SEQ ID NO: 156, and an intracellular domain having a sequence of SEQ ID NO: 157. [0185] In some embodiments, human CD3 epsilon has a sequence of SEQ ID NO: 258. In some embodiments, human CD3 epsilon has an extracellular domain having a sequence of SEQ ID NO: 126, a transmembrane domain having a sequence of SEQ ID NO: 127, and an intracellular domain, e.g., an intracellular signaling domain, having a sequence of SEQ ID NO: 128. In some embodiments, human CD3 delta has a sequence of SEQ ID NO: 136. In some embodiments, human CD3 delta has an extracellular domain having a sequence of SEQ ID NO: 138, a transmembrane domain having a sequence of SEQ ID NO: 139, and an intracellular domain, e.g., an intracellular signaling domain, having a sequence of SEQ ID NO: 140. In some embodiments, human CD3 gamma has a sequence of SEQ ID NO: 130. In some embodiments, human CD3 gamma has an extracellular domain having a sequence of SEQ ID NO: 132, a transmembrane domain having a sequence of SEQ ID NO: 133, and an intracellular domain, e.g., an intracellular signaling domain, having a sequence of SEQ ID NO: 134.

[0186] Ranges: throughout this disclosure, various aspects of the present disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity, includes something with 95%, 96%, 97%, 98% or 99% identity, and includes subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98% and 98-99% identity. This applies regardless of the breadth of the range.

[0187] Provided herein are compositions of matter and methods of use for the treatment of a disease such as cancer, using modified T cells comprising a T cell receptors (TCR) fusion protein (TFP and a TCR constant domain, wherein the modified T cell also has a functionally disrupted endogenous TCR subunit. As used herein, a “T cell receptor (TCR) fusion protein” or “TFP” includes a recombinant polypeptide derived from the various polypeptides comprising the TCR that is generally capable of i) binding to a surface antigen on target cells and ii) interacting with other polypeptide components of the intact TCR complex, typically when co-located in or on the surface of a T cell. As provided herein, TFPs provide substantial benefits as compared to Chimeric Antigen Receptors. The term “Chimeric Antigen Receptor” or alternatively a “CAR” refers to a recombinant polypeptide comprising an extracellular antigen binding domain in the form of, e.g., a single domain antibody or scFv, a transmembrane domain, and cytoplasmic signaling domains (also referred to herein as “intracellular signaling domains”) comprising a functional signaling domain derived from a stimulatory molecule as defined below. Generally, the central intracellular signaling domain of a CAR is derived from the CD3 zeta chain that is normally found associated with the TCR complex. The CD3 zeta signaling domain can be fused with one or more functional signaling domains derived from at least one co-stimulatory molecule such as 4-1BB (i.e., CD137), CD27 and/or CD28.

T cell receptor (TCR) fusion proteins (TFPs)

[0188] The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises a binding domain, e.g., an antibody or antibody fragment, a ligand, or a ligand binding protein, wherein the sequence of the binding domain is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof.

The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to CD 19, e.g., human CD 19, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to mesothelin, e.g., human mesothelin, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to MUC16, e.g., human MUC16, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to CD20, e.g., human CD20, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to CD70, e.g., human CD70, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to CD79B, e.g., human CD79B, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to HER2, e.g., human HER2, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to PSMA, e.g., human PSMA, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to BCMA, e.g., human BCMA, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to ROR1, e.g., human ROR1, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to CD22, e.g., human CD22, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to GPC3, e.g., human GPC3, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to Nectin-4, e.g. , human Nectin-4, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The present disclosure encompasses recombinant DNA constructs encoding TFPs, wherein the TFP comprises an antibody fragment that binds specifically to Trop-2, e.g., human Trop-2, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding a TCR subunit or portion thereof. The TFPs provided herein are able to associate with one or more endogenous (or alternatively, one or more exogenous, or a combination of endogenous and exogenous) TCR subunits in order to form a functional TCR complex.

[0189] In one aspect, the TFP of the present disclosure comprises a target-specific binding element otherwise referred to as an antigen binding domain. The choice of moiety depends upon the type and number of target antigen that define the surface of a target cell. For example, the antigen binding domain may be chosen to recognize a target antigen that acts as a cell surface marker on target cells associated with a particular disease state. Thus, examples of cell surface markers that may act as target antigens for the antigen binding domain in a TFP of the present disclosure include those associated with viral, bacterial and parasitic infections; autoimmune diseases; and cancerous diseases ( e.g ., malignant diseases).

[0190] In one aspect, the TFP-mediated T cell response can be directed to an antigen of interest by way of engineering an antigen-binding domain into the TFP that specifically binds a desired antigen.

[0191] The antigen binding domain can be any domain that binds to the antigen including but not limited to a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of a camelid derived nanobody, and to an alternative scaffold known in the art to function as antigen binding domain, such as a recombinant fibronectin domain, anticalin, DARPIN and the like. Likewise, a natural or synthetic ligand specifically recognizing and binding the target antigen can be used as antigen binding domain for the TFP. In some instances, it is beneficial for the antigen binding domain to be derived from the same species in which the TFP will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the TFP to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment.

[0192] Thus, in one aspect, the antigen-binding domain comprises a humanized or human antibody or an antibody fragment, or a murine antibody or antibody fragment. In one embodiment, the humanized or human anti-TAA binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a humanized or human anti-TAA binding domain described herein, and/or one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a humanized or human anti-CD 19 binding domain described herein, e.g., a humanized or human anti-TAA binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs. In one embodiment, the humanized or human anti-CD19 binding domain comprises one or more (e.g. , all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a humanized or human anti-TAA binding domain described herein, e.g., the humanized or human anti-TAA binding domain has two variable heavy chain regions, each comprising a HC CDR1, a HC CDR2 and a HC CDR3 described herein. In one embodiment, the humanized or human anti-TAA binding domain comprises a humanized or human light chain variable region described herein and/or a humanized or human heavy chain variable region described herein. In one embodiment, the humanized or human anti-TAA binding domain comprises a humanized heavy chain variable region described herein, e.g., at least two humanized or human heavy chain variable regions described herein. In one embodiment, the anti-TAA binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence provided herein. In an embodiment, the anti- =TAA binding domain (e.g, a scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g, substitutions) but not more than 30, 20 or 10 modifications (e.g, substitutions) of an amino acid sequence of a light chain variable region provided herein, or a sequence with 95-99% identity with an amino acid sequence provided herein; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g, substitutions) but not more than 30, 20 or 10 modifications (e.g, substitutions) of an amino acid sequence of a heavy chain variable region provided herein, or a sequence with 95-99% identity to an amino acid sequence provided herein. In one embodiment, the humanized or human anti-TAA binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, is attached to a heavy chain variable region comprising an amino acid sequence described herein, via a linker, e.g, a linker described herein. In one embodiment, the humanized anti-TAA binding domain includes a (Gly4-Ser)_n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 3 or 4. The light chain variable region and heavy chain variable region of a scFv can be, e.g, in any of the following orientations: light chain variable region -linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. In some instances, the linker sequence comprises a long linker (LL) sequence. In some instances, the long linker sequence comprises (G4S)_n, wherein n=2 to 4. In some instances, the linker sequence comprises a short linker (SL) sequence. In some instances, the short linker sequence comprises (G4S)_n, wherein n=l to 3. [0193] In some embodiments, the antigen-binding domain comprises an anti-CD19 humanized or human antibody or an antibody fragment, or a murine antibody or antibody fragment having a light chain CDR1 of SEQ ID NO:73, a CDR2 of SEQ ID NO:75, and a CDR3 of SEQ ID NO:77 and a heavy chain CDR1 of SEQ ID NO: 79, a CDR2 of SEQ ID NO: 81, and a CDR3 of SEQ ID NO: 83. In some embodiments, the anti-CD 19 antibody is a murine scFv. In some embodiments, the anti-CD-19 antibody comprises a VL of SEQ ID NO:85 and a VH of SEQ ID NO:87 [0194] In some embodiments, the antigen-binding domain comprises an anti-mesothelin humanized or human single domain antibody or an antibody fragment having a CDR1 of SEQ ID NO 60, a CDR2 of SEQ ID NO:61, and a CDR3 of SEQ ID NO:62 or a CDR1 of SEQ ID NO 63, a CDR2 of SEQ ID NO: 64, and a CDR3 of SEQ ID NO: 65 or a CDR1 of SEQ ID NO: 66, a CDR2 of SEQ ID NO: 67, and a CDR3 of SEQ ID NO: 68. In some embodiments, the anti-mesothelin antibody has a variable domain of SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:71.

[0195] In some embodiments, the antigen-binding domain comprises an anti-CD70 humanized or human single domain antibody or an antibody fragment having a CDR1 of SEQ ID NO:88, a CDR2 of SEQ ID NO:89, and a CDR3 of SEQ ID NO:90, or a CDR1 of SEQ ID NO:92, a CDR2 of SEQ ID NO:93, and a CDR3 of SEQ ID NO:94, or a CDR1 of SEQ ID NO:96, a CDR2 of SEQ ID NO:97, and a CDR3 of SEQ ID NO:98, or a CDR1 of SEQ ID NO: 100, a CDR2 of SEQ ID NO: 101, and a CDR3 of SEQ ID NO: 102, or a CDR1 of SEQ ID NO: 104, a CDR2 of SEQ ID NO: 105, and a CDR3 of SEQ ID NO: 106, or a CDR1 of SEQ ID NO: 108, a CDR2 of SEQ ID NO: 109, and a CDR3 of SEQ ID NO: 110, or a CDR1 of SEQ ID NO: 112, a CDR2 of SEQ ID NO: 113, and a CDR3 of SEQ ID NO: 114, or a CDR1 of SEQ ID NO 116, a CDR2 of SEQ ID NO: 117, and a CDR3 of SEQ ID NO: 118, or a CDR1 of SEQ ID NO: 120, a CDR2 of SEQ ID NO: 121, and a CDR3 of SEQ ID NO: 122.

[0196] In some aspects, a non-human antibody is humanized, where specific sequences or regions of the antibody are modified to increase similarity to an antibody naturally produced in a human or fragment thereof. In one aspect, the antigen binding domain is humanized.

[0197] A humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference), veneering or resurfacing (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991,

Molecular Immunology, 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering, 7(6):805- 814; and Roguska et al., 1994, PNAS, 91:969-973, each of which is incorporated herein by its entirety by reference), chain shuffling (see, e.g., U.S. Pat. No. 5,565,332, which is incorporated herein in its entirety by reference), and techniques disclosed in, e.g., U.S. Patent Application Publication No. US2005/0042664, U.S. Patent Application Publication No. US2005/0048617, U.S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, International Publication No. WO 9317105, Tan et al., J. Immunol., 169:1119-25 (2002), Caldas et al., Protein Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al., J. Biol. Chem., 272(16): 10678-84 (1997), Roguska et al., Protein Eng., 9(10):895-904 (1996), Couto et al., Cancer Res., 55 (23 Supp):5973s-5977s (1995), Couto et al., Cancer Res., 55(8): 1717-22 (1995), Sandhu J S, Gene, 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol., 235(3):959-73 (1994), each of which is incorporated herein in its entirety by reference. Often, framework residues in the framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, for example improve, antigen binding. These framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions (see, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.)

[0198] A humanized antibody or antibody fragment has one or more amino acid residues remaining in it from a source which is nonhuman. These nonhuman amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. As provided herein, humanized antibodies or antibody fragments comprise one or more CDRs from nonhuman immunoglobulin molecules and framework regions wherein the amino acid residues comprising the framework are derived completely or mostly from human germline. Multiple techniques for humanization of antibodies or antibody fragments are well-known in the art and can essentially be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody, i.e., CDR-grafting (EP 239,400; PCT Publication No. WO 91/09967; and U.S. Pat. Nos. 4,816,567; 6,331,415; 5,225,539; 5,530,101; 5,585,089; 6,548,640, the contents of which are incorporated herein by reference in their entirety). In such humanized antibodies and antibody fragments, substantially less than an intact human variable domain has been substituted by the corresponding sequence from a nonhuman species. Humanized antibodies are often human antibodies in which some CDR residues and possibly some framework (FR) residues are substituted by residues from analogous sites in rodent antibodies. Humanization of antibodies and antibody fragments can also be achieved by veneering or resurfacing (EP 592,106; EP 519,596; Padlan, 1991 , Molecular Immunology, 28(4/5):489-498; Studnicka et al., Protein Engineering, 7(6):805-814 (1994); and Roguska et ah, Proc. Natl. Acad. Sci. USA , 91:969-973 (1994)) or chain shuffling (U.S. Pat. No. 5,565,332), the contents of which are incorporated herein by reference in their entirety.

[0199] The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is to reduce antigenicity. According to the so-called “best-fit” method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences. The human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987), the contents of which are incorporated herein by reference herein in their entirety). Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (see, e.g., Nicholson et al., Mol. Immun. 34 (16-17): 1157-1165 (1997); Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993), the contents of which are incorporated herein by reference herein in their entirety). In some embodiments, the framework region, e.g., all four framework regions, of the heavy chain variable region are derived from a VH4-4-59 germline sequence. In one embodiment, the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence. In one embodiment, the framework region, e.g., all four framework regions of the light chain variable region are derived from a VK3-1.25 germline sequence. In one embodiment, the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence.

[0200] In some aspects, the portion of a TFP composition of the present disclosure that comprises an antibody fragment is humanized with retention of high affinity for the target antigen and other favorable biological properties. According to one aspect of the present disclosure, humanized antibodies and antibody fragments are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind the target antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody or antibody fragment characteristic, such as increased affinity for the target antigen, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.

[0201] A humanized antibody or antibody fragment may retain a similar antigenic specificity as the original antibody, e.g., in the present disclosure, the ability to bind human a tumor associated antigen (TAA). In some embodiments, a humanized antibody or antibody fragment may have improved affinity and/or specificity of binding to, e.g., human CD 19, human BCMA, or another tumor associated antigen.

[0202] In one aspect, the binding domain is characterized by particular functional features or properties of an antibody or antibody fragment. For example, in one aspect, the portion of a TFP composition of the present disclosure that comprises an antigen binding domain specifically binds human CD 19. In one aspect, the antigen binding domain has the same or a similar binding specificity to human CD19 as the FMC63 scFv described in Nicholson et al., Mol. Immun. 34 (16-17): 1157-1165 (1997). In one aspect, the present disclosure relates to an antigen binding domain comprising an antibody or antibody fragment, wherein the antibody binding domain specifically binds to a CD 19 or BCMA protein or fragment thereof, wherein the antibody or antibody fragment comprises a variable light chain and/or a variable heavy chain that includes an amino acid sequence provided herein. In certain aspects, the scFv is contiguous with and in the same reading frame as a leader sequence.

[0203] In one aspect, the anti -tumor-associated antigen binding domain is a fragment, e.g., a single chain variable fragment (scFv). In one aspect, the anti-TAA binding domain is a Fv, a Fab, a (Fab’)2, or a bi-functional (e.g. bi-specific) hybrid antibody (e.g, Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)). In one aspect, the antibodies and fragments thereof of the present disclosure binds a CD 19 protein with wild-type or enhanced affinity. In another aspect, the anti- TAA binding domain comprises a single domain antibody (sdAb or VHH).

[0204] Also provided herein are methods for obtaining an antibody antigen binding domain specific for a target antigen (e.g, CD 19, BCMA or any target antigen described elsewhere herein for targets of fusion moiety binding domains), the method comprising providing by way of addition, deletion, substitution or insertion of one or more amino acids in the amino acid sequence of a VH domain set out herein a VH domain which is an amino acid sequence variant of the VH domain, optionally combining the VH domain thus provided with one or more VL domains, and testing the V_H domain or V_H/V_L combination or combinations to identify a specific binding member or an antibody antigen binding domain specific for a target antigen of interest ( e.g ., MSLN, CD79B, etc.) and optionally with one or more desired properties.

[0205] In some instances, V_H domains and scFvs can be prepared according to method known in the art (see, for example, Bird et al., (1988) Science 242:423-426 and Huston et ah, (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). scFv molecules can be produced by linking V_H and V_L regions together using flexible polypeptide linkers. The scFv molecules comprise a linker (e.g., a Ser-Gly linker) with an optimized length and/or amino acid composition. The linker length can greatly affect how the variable regions of a scFv fold and interact. In fact, if a short polypeptide linker is employed (e.g, between 5-10 amino acids) intra-chain folding is prevented. Inter-chain folding is also required to bring the two variable regions together to form a functional epitope binding site. In some instances, the linker sequence comprises a linker sequence. In some instances, the long linker sequence comprises (G4S)_n, wherein n=2 to 4. In some instances, the linker sequence comprises (G₄S)n, wherein n=l to 3. For examples of linker orientation and size see, e.g., Hollinger et al., 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, U.S. Patent Application Publication Nos. 2005/0100543, 2005/0175606, 2007/0014794, and PCT publication Nos. W02006/020258 and W02007/024715, each of which is incorporated herein by reference. [0206] An scFv can comprise a linker of about 10, 11, 12, 13, 14, 15 or greater than 15 residues between its V_L and V_H regions. The linker sequence may comprise any naturally occurring amino acid. In some embodiments, the linker sequence comprises amino acids glycine and serine. In another embodiment, the linker sequence comprises sets of glycine and serine repeats such as (Gly₄Ser)_n, where n is a positive integer equal to or greater than 1. In one embodiment, the linker can be (Gly4Ser)4 or (Gly4Ser)3. Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies. In some instances, the linker sequence comprises (GiS)_n, wherein n=2 to 4. In some instances, the linker sequence comprises (G4S)_n, wherein n=l to 3.

Stability and Mutations

[0207] The stability of a tumor associated antigen binding domain, e.g., scFv molecules (e.g., soluble scFv) can be evaluated in reference to the biophysical properties (e.g, thermal stability) of a conventional control scFv molecule or a full-length antibody. In one embodiment, the humanized or human scFv has a thermal stability that is greater than about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10 degrees, about 11 degrees, about 12 degrees, about 13 degrees, about 14 degrees, or about 15 degrees Celsius than a parent scFv in the described assays.

[0208] The improved thermal stability of the anti-TAA binding domain, e.g., scFv is subsequently conferred to the entire TAA-TFP construct, leading to improved therapeutic properties of the anti-TAA TFP construct. The thermal stability of the binding domain, e.g., scFv or sdAb, can be improved by at least about 2 °C or 3 °C as compared to a conventional antibody. In one embodiment, the binding domain, has a 1 °C improved thermal stability as compared to a conventional antibody. In another embodiment, the binding domain, has a 2 °C improved thermal stability as compared to a conventional antibody. In another embodiment, the scFv has a 4 °C, 5 °C, 6 °C, 7 °C, 8 °C, 9 °C, 10 °C, 11 °C, 12 °C, 13 °C, 14 °C, or 15 °C improved thermal stability as compared to a conventional antibody. Comparisons can be made, for example, between the scFv molecules disclosed herein and scFv molecules or Fab fragments of an antibody from which the scFv VH and VL were derived. Thermal stability can be measured using methods known in the art. For example, in one embodiment, TM can be measured. Methods for measuring TM and other methods of determining protein stability are described in more detail below.

[0209] Mutations in antibody sequences (arising through humanization or direct mutagenesis of the soluble scFv) alter the stability of the antibody or fragment thereof and improve the overall stability of the antibody and the TFP construct. Stability of the humanized antibody or fragment thereof is compared against the murine antibody or fragment thereof using measurements such as TM, temperature denaturation and temperature aggregation. In one embodiment, the binding domain, e.g., a scFv or sdAb, comprises at least one mutation arising from the humanization process such that the mutated scFv confers improved stability to the anti-TAA TFP construct. In another embodiment, the anti-TAA binding domain, e.g., scFv or sdAb, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mutations arising from the humanization process such that the mutated scFv or sdAb confers improved stability to the TAA-TFP construct.

[0210] In one aspect, the antigen binding domain of the TFP comprises an amino acid sequence that is homologous to an antigen binding domain amino acid sequence described herein, and the antigen binding domain retains the desired functional properties of the anti-tumor-associated antigen antibody fragments described herein. In one specific aspect, the TFP composition of the present disclosure comprises an antibody fragment. In a further aspect, that antibody fragment comprises a scFv.

[0211] In various aspects, the antigen binding domain of the TFP is engineered by modifying one or more amino acids within one or both variable regions (e.g, VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions. In one specific aspect, the TFP composition of the present disclosure comprises an antibody fragment. In a further aspect, that antibody fragment comprises a scFv.

[0212] It will be understood by one of ordinary skill in the art that the antibody or antibody fragment of the present disclosure may further be modified such that they vary in amino acid sequence ( e.g ., from wild-type), but not in desired activity. For example, additional nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues may be made to the protein. For example, a nonessential amino acid residue in a molecule may be replaced with another amino acid residue from the same side chain family. In another embodiment, a string of amino acids can be replaced with a structurally similar string that differs in order and/or composition of side chain family members, e.g., a conservative substitution, in which an amino acid residue is replaced with an amino acid residue having a similar side chain, may be made.

[0213] Families of amino acid residues having similar side chains have been 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), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). [0214] Percent identity in the context of two or more nucleic acids or polypeptide sequences refers to two or more sequences that are the same. Two sequences are “substantially identical” if two sequences have a specified percentage of amino acid residues or nucleotides that are the same (e.g, 60% identity, optionally 70%, 71% , 72%, 73%, 74%, 75%, 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% identity over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists over a region that is at least about 50 nucleotides (or 10 amino acids) in length, or more preferably over a region that is 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length.

[0215] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm ofNeedleman and Wunsch, (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman, (1988) Proc. Natl. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Brent et al., (2003) Current Protocols in Molecular Biology). Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et ah, (1977 )Nuc. Acids Res. 25:3389-3402; and Altschul et ah, (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

[0216] In one aspect, the present disclosure contemplates modifications of the starting antibody or fragment (e.g., scFv) amino acid sequence that generate functionally equivalent molecules. For example, the VH or VL of a binding domain, e.g., scFv, comprised in the TFP can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,

99% identity of the starting VH or VL framework region of the anti-CD 19 binding domain, e.g., scFv. The present disclosure contemplates modifications of the entire TFP construct, e.g., modifications in one or more amino acid sequences of the various domains of the TFP construct in order to generate functionally equivalent molecules. The TFP construct can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,

99% identity of the starting TFP construct.

Extracellular domain

[0217] The extracellular domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any protein, but in particular a membrane-bound or transmembrane protein. In one aspect the extracellular domain is capable of associating with the transmembrane domain. An extracellular domain of particular use in this present disclosure may include at least the extracellular region(s) of e.g., the alpha, beta or zeta chain of the T cell receptor, or CD3 epsilon, CD3 gamma, or CD3 delta, or in alternative embodiments, CD28, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154. In some embodiments, the extracellular domain is a TCR extracellular domain. In some instances, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0218] In some embodiments, the TCR extracellular domain comprises an extracellular domain or portion thereof of a TCR alpha chain, a TCR beta chain, a TCR delta chain, or a TCR gamma chain. In some embodiments, the TCR extracellular domain comprises an IgC domain of a TCR alpha chain, a TCR beta chain, a TCR delta chain, or a TCR gamma chain.

[0219] In some embodiments, the extracellular domain comprises, or comprises at least 5, 6, 7, 8,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,

61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,

87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more consecutive amino acid residues of the extracellular domain of a TCR alpha chain, a TCR beta chain, a TCR delta chain, or a TCR gamma chain. In some embodiments, the extracellular domain comprises a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more sequence identity to a sequence encoding the extracellular domain of a TCR alpha chain, a TCR beta chain, a TCR delta chain, or a TCR gamma chain. In some embodiments, the extracellular domain comprises a sequence encoding the extracellular domain of a TCR alpha chain, a TCR beta chain, a TCR delta chain, or a TCR gamma chain having a truncation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more amino acids at the N- or C-terminus or at both the N- and C-terminus.

[0220] In some embodiments, the extracellular domain comprises, or comprises at least 5, 6, 7, 8,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more consecutive amino acid residues of an IgC domain of TCR alpha, a TCR beta, a TCR delta, or a TCR gamma. In some embodiments, the extracellular domain comprises a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more sequence identity to a sequence encoding an IgC domain of TCR alpha, a TCR beta, a TCR delta, or a TCR gamma. In some embodiments, the extracellular domain comprises a sequence encoding an IgC domain of TCR alpha, TCR beta, TCR delta, or TCR gamma having a truncation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more amino acids at the N- or C-terminus or at both the N- and C-terminus.

[0221] In some embodiments, the extracellular domain comprises, or comprises at least 5, 6, 7, 8,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, _> 65, 66, 67 _{’ ,} 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86

87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more consecutive amino acid residues of the extracellular domain of a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the extracellular domain comprises a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more sequence identity to a sequence encoding the extracellular domain of a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the extracellular domain comprises a sequence encoding the extracellular domain of a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit having a truncation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more amino acids at the N- or C-terminus or at both the N- and C-terminus.

[0222] The extracellular domain can be a TCR extracellular domain. The TCR extracellular domain can be derived from a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit or a CD3 delta TCR subunit. The extracellular domain can be a full-length TCR extracellular domain or fragment (e.g., functional fragment) thereof. The extracellular domain can comprise a variable domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The extracellular domain can comprise a variable domain and a constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. In some cases, the extracellular domain may not comprise a variable domain.

[0223] The extracellular domain can comprise a constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The extracellular domain can comprise a full-length constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The extracellular domain can comprise a fragment (e.g., functional fragment) of the full-length constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. For example, the extracellular domain can comprise at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of the constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain.

[0224] The TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain described herein can be derived from various species. The TCR chain can be a murine or human TCR chain. For example, the extracellular domain can comprise a constant domain of a murine TCR alpha chain, a murine TCR beta chain, a human TCR gamma chain or a human TCR delta chain.

Transmembrane Domain

[0225] In general, a TFP sequence contains an extracellular domain and a transmembrane domain encoded by a single genomic sequence. In alternative embodiments, a TFP can be designed to comprise a transmembrane domain that is heterologous to the extracellular domain of the TFP. A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid associated with the extracellular region of the protein from which the transmembrane was derived (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more amino acids of the extracellular region) and/or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (e.g., 1, 2, 3,

4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more amino acids of the intracellular region). In some cases, the transmembrane domain can include at least 30, 35, 40, 45, 50, 55, 60 or more amino acids of the extracellular region. In some cases, the transmembrane domain can include at least 30, 35, 40, 45, 50, 55, 60 or more amino acids of the intracellular region. In one aspect, the transmembrane domain is one that is associated with one of the other domains of the TFP is used. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins, e.g., to minimize interactions with other members of the receptor complex. In one aspect, the transmembrane domain is capable of homodimerization with another TFP on the TFP- T cell surface. In a different aspect the amino acid sequence of the transmembrane domain may be modified or substituted so as to minimize interactions with the binding domains of the native binding partner present in the same TFP.

[0226] The transmembrane domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In one aspect the transmembrane domain is capable of signaling to the intracellular domain(s) whenever the TFP has bound to a target. In some instances, the TCR- integrating subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, CD154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0227] In some embodiments, the transmembrane domain comprises, or comprises at least 5, 6,

7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more consecutive amino acid residues of the transmembrane domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the transmembrane domain comprises a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more sequence identity to a sequence encoding the transmembrane domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the transmembrane domain comprises a sequence encoding the transmembrane domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit having a truncation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acids at the N- or C-terminus or at both the N- and C- terminus.

[0228] In some instances, the transmembrane domain can be attached to the extracellular region of the TTP, e.g., the antigen binding domain of the TFP, via a hinge, e.g., a hinge from a human protein. For example, in one embodiment, the hinge can be a human immunoglobulin (Ig) hinge, e.g., an IgG4 hinge, or a CD8a hinge.

Linkers

[0229] Optionally, a short oligo- or polypeptide linker, between 2 and 10 amino acids in length may form the linkage between the binding element and the TCR extracellular domain of the TFP. A glycine-serine doublet provides a particularly suitable linker. In some cases, the linker may be at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more in length. For example, in one aspect, the linker comprises the amino acid sequence of GGGGSGGGGS or a sequence (GGGGS)x wherein X is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more. In some embodiments,

X is 2. In some embodiments, X is 4. In some embodiments, the linker is encoded by a nucleotide sequence of GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC. Cytoplasmic Domain

[0230] The cytoplasmic domain of the TFP can include an intracellular domain. In some embodiments, the intracellular domain is from CD3 gamma, CD3 delta, CD3 epsilon, TCR alpha, TCR beta, TCR gamma, or TCR delta. In some embodiments, the intracellular domain comprises a signaling domain, if the TFP contains CD3 gamma, delta or epsilon polypeptides; TCR alpha, TCR beta, TCR gamma, and TCR delta subunits generally have short (e.g., 1-19 amino acids in length) intracellular domains and are generally lacking in a signaling domain. An intracellular signaling domain is generally responsible for activation of at least one of the normal effector functions of the immune cell in which the TFP has been introduced. While the intracellular domains of TCR alpha, TCR beta, TCR gamma, and TCR delta do not have signaling domains, they are able to recruit proteins having a primary intracellular signaling domain described herein, e.g., CD3 zeta, which functions as an intracellular signaling domain. The term “effector function” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. Thus the term “intracellular signaling domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term intracellular signaling domain is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal.

[0231] Examples of intracellular domains for use in the TFP of the present disclosure include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that are able to act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any recombinant sequence that has the same functional capability. In some embodiments, the intracellular domain comprises the intracellular domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the intracellular domain comprises, or comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 or more consecutive amino acid residues of the intracellular domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, or a TCR delta chain. In some embodiments, the intracellular domain comprises a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more sequence identity to a sequence encoding the intracellular domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, or a TCR delta chain. In some embodiments, the transmembrane domain comprises a sequence encoding the intracellular domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, or a TCR delta chain having a truncation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acids at the N- or C-terminus or at both the N- and C-terminus.

[0232] In some embodiments, the intracellular domain comprises, or comprises at least 5, 6, 7, 8,

61, or 62 or more consecutive amino acid residues of the intracellular domain of a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the intracellular domain comprises a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more sequence identity to a sequence encoding the intracellular domain of a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit. In some embodiments, the intracellular domain comprises a sequence encoding the intracellular domain of a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, or a CD3 delta TCR subunit having a truncation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more amino acids at the N- or C-terminus or at both the N- and C-terminus.

[0233] It is known that signals generated through the TCR alone are insufficient for full activation of naive T cells and that a secondary and/or costimulatory signal is required. Thus, naive T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (secondary cytoplasmic domain, e.g., a costimulatory domain). [0234] A primary signaling domain regulates primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine- based activation motifs (ITAMs).

[0235] Examples of ITAMs containing primary intracellular signaling domains that are of particular use in the present disclosure include those of CD3 zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, and CD66d. In one embodiment, a TFP of the present disclosure comprises an intracellular signaling domain, e.g., a primary signaling domain of CD3 -epsilon. In one embodiment, a primary signaling domain comprises a modified IT AM domain, e.g., a mutated IT AM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain. In one embodiment, a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain, e.g ., an optimized and/or truncated ITAM-containing primary intracellular signaling domain. In an embodiment, a primary signaling domain comprises one, two, three, four or more ITAM motifs.

[0236] The intracellular signaling domain of the TFP can comprise a CD3 signaling domain, e.g., CD3 epsilon, CD3 delta, CD3 gamma, or CD3 zeta, by itself or it can be combined with any other desired intracellular signaling domain(s) useful in the context of a TFP of the present disclosure. For example, the intracellular signaling domain of the TFP can comprise a CD3 epsilon chain portion and a costimulatory signaling domain. The costimulatory signaling domain refers to a portion of the TFP comprising the intracellular domain of a costimulatory molecule. A costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligands that is required for an efficient response of lymphocytes to an antigen. Examples of such molecules include CD27, CD28, 4-1BB (CD137), 0X40, CD30, CD40, PD1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like. For example, CD27 costimulation has been demonstrated to enhance expansion, effector function, and survival of human TFP-T cells in vitro and augments human T cell persistence and antitumor activity in vivo (Song et al., Blood. 2012;

119(3):696-706).

[0237] The intracellular signaling sequences within the cytoplasmic portion of the TFP of the present disclosure may be linked to each other in a random or specified order. Optionally, a short oligo- or polypeptide linker, for example, between 2 and 10 amino acids (e.g., 2, 3, 4, 5, 6, 7, 8,

9, or 10 amino acids) in length may form the linkage between intracellular signaling sequences. [0238] In one embodiment, a glycine-serine doublet can be used as a suitable linker. In one embodiment, a single amino acid, e.g., an alanine, a glycine, can be used as a suitable linker. [0239] In one aspect, the TFP-expressing cell described herein can further comprise a second TFP, e g., a second TFP that includes a different antigen binding domain, e.g., to the same target (e.g., MSLN) or a different target (e.g., CD70, CD19, or MUC16). In one embodiment, when the TFP-expressing cell comprises two or more different TFPs, the antigen binding domains of the different TFPs can be such that the antigen binding domains do not interact with one another. For example, a cell expressing a first and second TFP can have an antigen binding domain of the first TFP, e.g., as a fragment, e.g., a scFv, that does not form an association with the antigen binding domain of the second TFP, e.g., the antigen binding domain of the second TFP is a VHH. [0240] In another aspect, the TFP-expressing cell described herein can further express another agent, e.g., an agent which enhances the activity of a modified T cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., PD1, can, in some embodiments, decrease the ability of a modified T cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and TGFR beta. In one embodiment, the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, LAG3, CTLA4,

CD 160, BTLA, LAIR1, TIM3, 2B4 and TIGIT, or a fragment of any of these (e.g, at least a portion of an extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g, comprising a costimulatory domain (e.g, 4- 1BB, CD27 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD1 or a fragment thereof (e.g, at least a portion of an extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g, a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). PD1 is an inhibitory member of the CD28 family of receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B cells, T cells and myeloid cells (Agata et al., 1996, Ini. Immunol 8:765-75). Two ligands for PD1, PD-L1 and PD-L2, have been shown to downregulate T cell activation upon binding to PD1 (Freeman et al., 2000./. Exp. Med.

192: 1027-34; Latchman et al., 2001 Nat. Immunol. 2:261-8; Carter et al., 2002 Eur. J. Immunol. 32:634-43). PD-L1 is abundant in human cancers (Dong et al., 2003 J. Mol. Med. 81:281-7;

Blank et al., 2005 Cancer Immunol. Immunother. 54:307-314; Konishi et al., 2004 Clin. Cancer Res. 10:5094). Immune suppression can be reversed by inhibiting the local interaction of PD1 with PD-L1.

[0241] In one embodiment, the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., Programmed Death 1 (PD1) can be fused to a transmembrane domain and optionally an intracellular signaling domain such as 4 IBB and CD3 zeta (also referred to herein as a PD1 TFP). In one embodiment, the PD1 TFP, when used in combinations with an anti-TAA TFP described herein, improves the persistence of the T cell. In one embodiment, the TFP is a PD1 TFP comprising the extracellular domain of PD 1. Alternatively, provided are TFPs containing an antibody or antibody fragment such as a scFv that specifically binds to the Programmed Death-Ligand 1 (PD-L1) or Programmed Death-Ligand 2 (PD-L2).

[0242] In another aspect, the present disclosure provides a population of TFP-expressing T cells, e.g., FFP-T cells. In some embodiments, the population of TFP-expressing T cells comprises a mixture of cells expressing different TFPs. For example, in one embodiment, the population of TFP-T cells can include a first cell expressing a TFP having a binding domain described herein, and a second cell expressing a TFP having a different anti-TAA binding domain, e.g., a binding domain described herein that differs from the binding domain in the TFP expressed by the first cell. As another example, the population of TFP-expressing cells can include a first cell expressing a TFP that includes a first binding domain binding domain, e.g., as described herein, and a second cell expressing a TFP that includes an antigen binding domain to a target other than the binding domain of the first cell (e.g., another tumor-associated antigen).

[0243] In another aspect, the present disclosure provides a population of cells wherein at least one cell in the population expresses a TFP having a domain described herein, and a second cell expressing another agent, e.g., an agent which enhances the activity of a modified T cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., can, in some embodiments, decrease the ability of a modified T cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, PD- L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and TGFR beta. In one embodiment, the agent that inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein.

[0244] Disclosed herein are methods for producing in vitro transcribed RNA encoding TFPs. The present disclosure also includes a TFP encoding RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection can involve in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3’ and 5’ untranslated sequence (“UTR”), a 5’ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length. RNA so produced can efficiently transfect different kinds of cells. In one aspect, the template includes sequences for the TFP.

[0245] In one aspect the anti-TAA TFP is encoded by a messenger RNA (mRNA). In one aspect the mRNA encoding the anti-TAA TFP is introduced into a T cell for production of a TFP-T cell. In one embodiment, the in vitro transcribed RNA TFP can be introduced to a cell as a form of transient transfection. The RNA is produced by in vitro transcription using a polymerase chain reaction (PCR)-generated template. DNA of interest from any source can be directly converted by PCR into a template for in vitro mRNA synthesis using appropriate primers and RNA polymerase. The source of the DNA can be, for example, genomic DNA, plasmid DNA, phage DNA, cDNA, synthetic DNA sequence or any other appropriate source of DNA. The desired template for in vitro transcription is a TFP of the present disclosure. In one embodiment, the DNA to be used for PCR contains an open reading frame. The DNA can be from a naturally occurring DNA sequence from the genome of an organism. In one embodiment, the nucleic acid can include some or all of the 5’ and/or 3’ untranslated regions (UTRs). The nucleic acid can include exons and introns. In one embodiment, the DNA to be used for PCR is a human nucleic acid sequence. In another embodiment, the DNA to be used for PCR is a human nucleic acid sequence including the 5’ and 3’ UTRs. The DNA can alternatively be an artificial DNA sequence that is not normally expressed in a naturally occurring organism. An exemplary artificial DNA sequence is one that contains portions of genes that are ligated together to form an open reading frame that encodes a fusion protein. The portions of DNA that are ligated together can be from a single organism or from more than one organism.

[0246] PCR is used to generate a template for in vitro transcription of mRNA which is used for transfection. Methods for performing PCR are well known in the art. Primers for use in PCR are designed to have regions that are substantially complementary to regions of the DNA to be used as a template for the PCR. “Substantially complementary,” as used herein, refers to sequences of nucleotides where a majority or all of the bases in the primer sequence are complementary, or one or more bases are non-complementary, or mismatched. Substantially complementary sequences are able to anneal or hybridize with the intended DNA target under annealing conditions used for PCR. The primers can be designed to be substantially complementary to any portion of the DNA template. For example, the primers can be designed to amplify the portion of a nucleic acid that is normally transcribed in cells (the open reading frame), including 5’ and 3’ UTRs. The primers can also be designed to amplify a portion of a nucleic acid that encodes a particular domain of interest. In one embodiment, the primers are designed to amplify the coding region of a human cDNA, including all or portions of the 5’ and 3’ UTRs. Primers useful for PCR can be generated by synthetic methods that are well known in the art. “Forward primers” are primers that contain a region of nucleotides that are substantially complementary to nucleotides on the DNA template that are upstream of the DNA sequence that is to be amplified. “Upstream” is used herein to refer to a location 5, to the DNA sequence to be amplified relative to the coding strand. “Reverse primers” are primers that contain a region of nucleotides that are substantially complementary to a double-stranded DNA template that are downstream of the DNA sequence that is to be amplified. “Downstream” is used herein to refer to a location 3’ to the DNA sequence to be amplified relative to the coding strand.

[0247] Any DNA polymerase useful for PCR can be used in the methods disclosed herein. The reagents and polymerase are commercially available from a number of sources.

[0248] Chemical structures with the ability to promote stability and/or translation efficiency may also be used. The RNA preferably has 5’ and 3’ UTRs. In one embodiment, the 5’ UTR is between one and 3000 nucleotides in length. The length of 5’ and 3’ UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5’ and 3’ UTR lengths required to achieve optimal translation efficiency following transfection of the transcribed RNA.

[0249] The 5’ and 3’ UTRs can be the naturally occurring, endogenous 5’ and 3’ UTRs for the nucleic acid of interest. Alternatively, UTR sequences that are not endogenous to the nucleic acid of interest can be added by incorporating the UTR sequences into the forward and reverse primers or by any other modifications of the template. The use of UTR sequences that are not endogenous to the nucleic acid of interest can be useful for modifying the stability and/or translation efficiency of the RNA. For example, it is known that AU-rich elements in 3’UTR sequences can decrease the stability of mRNA. Therefore, 3’ UTRs can be selected or designed to increase the stability of the transcribed RNA based on properties of UTRs that are well known in the art.

[0250] In one embodiment, the 5’ UTR can contain the Kozak sequence of the endogenous nucleic acid. Alternatively, when a 5’ UTR that is not endogenous to the nucleic acid of interest is being added by PCR as described above, a consensus Kozak sequence can be redesigned by adding the 5’ UTR sequence. Kozak sequences can increase the efficiency of translation of some RNA transcripts but do not appear to be required for all RNAs to enable efficient translation. The requirement for Kozak sequences for many mRNAs is known in the art. In other embodiments the 5’ UTR can be 5’UTR of an RNA virus whose RNA genome is stable in cells. In other embodiments various nucleotide analogues can be used in the 3’ or 5’ UTR to impede exonuclease degradation of the mRNA.

[0251] To enable synthesis of RNA from a DNA template without the need for gene cloning, a promoter of transcription should be attached to the DNA template upstream of the sequence to be transcribed. When a sequence that functions as a promoter for an RNA polymerase is added to the 5’ end of the forward primer, the RNA polymerase promoter becomes incorporated into the PCR product upstream of the open reading frame that is to be transcribed. In one preferred embodiment, the promoter is a T7 polymerase promoter, as described elsewhere herein. Other useful promoters include, but are not limited to, T3 and SP6 RNA polymerase promoters. Consensus nucleotide sequences for T7, T3 and SP6 promoters are known in the art.

[0252] In some embodiments, the mRNA has both a cap on the 5’ end and a 3’ poly(A) tail which determine ribosome binding, initiation of translation and stability mRNA in the cell. On a circular DNA template, for instance, plasmid DNA, RNA polymerase produces a long concatemeric product which is not suitable for expression in eukaryotic cells. The transcription of plasmid DNA linearized at the end of the 3’ UTR results in normal sized mRNA which is not effective in eukaryotic transfection even if it is polyadenylated after transcription.

[0253] On a linear DNA template, phage T7 RNA polymerase can extend the 3 ’ end of the transcript beyond the last base of the template (Schenborn and Mierendorf, Nuc Acids Res. , 13:6223-36 (1985); Nacheva and Berzal-Herranz, Eur. J. Biochem ., 270:1485-65 (2003).

[0254] The conventional method of integration of polyA/T stretches into a DNA template is molecular cloning. However, polyA/T sequence integrated into plasmid DNA can cause plasmid instability, which is why plasmid DNA templates obtained from bacterial cells are often highly contaminated with deletions and other aberrations. This makes cloning procedures not only laborious and time consuming but often not reliable. That is why a method which allows construction of DNA templates with polyA/T 3’ stretch without cloning highly desirable.

[0255] The polyA/T segment of the transcriptional DNA template can be produced during PCR by using a reverse primer containing a poly-T tail, such as 100 T tail (size can be 50-5000 T), or after PCR by any other method, including, but not limited to, DNA ligation or in vitro recombination. Poly(A) tails also provide stability to RNAs and reduce their degradation. Generally, the length of a poly(A) tail positively correlates with the stability of the transcribed RNA. In one embodiment, the poly(A) tail is between 100 and 5000 adenosines.

[0256] Poly(A) tails of RNAs can be further extended following in vitro transcription with the use of a poly(A) polymerase, such as E. coli polyA polymerase (E-PAP). In one embodiment, increasing the length of a poly(A) tail from 100 nucleotides to between 300 and 400 nucleotides results in about a two-fold increase in the translation efficiency of the RNA. Additionally, the attachment of different chemical groups to the 3’ end can increase mRNA stability. Such attachment can contain modified/artificial nucleotides, aptamers and other compounds. For example, ATP analogs can be incorporated into the poly(A) tail using poly(A) polymerase. ATP analogs can further increase the stability of the RNA.

[0257] 5’ caps can also provide stability to RNA molecules. In some embodiments, RNAs produced by the methods disclosed herein include a 5’ cap. The 5’ cap is provided using techniques known in the art and described herein (Cougot, et al., Trends in Biochem. Sci., 29:436-444 (2001); Stepinski, et ah, RNA, 7:1468-95 (2001); Elango, et ah, Biochim. Biophys. Res. Commun ., 330:958-966 (2005)).

[0258] The RNAs produced by the methods disclosed herein can also contain an internal ribosome entry site (IRES) sequence. The IRES sequence may be any viral, chromosomal or artificially designed sequence which initiates cap-independent ribosome binding to mRNA and facilitates the initiation of translation. Any solutes suitable for cell electroporation, which can contain factors facilitating cellular permeability and viability such as sugars, peptides, lipids, proteins, antioxidants, and surfactants can be included.

[0259] RNA can be introduced into target cells using any of a number of different methods, for instance, commercially available methods which include, but are not limited to, electroporation (Amaxa Nucleofector®-II (Amaxa Biosystems, Cologne, Germany)), ECM 830 (BTX) (Harvard Instruments, Boston, Mass.) or the Gene Pulser® II (BioRad, Denver, Colo.), Multiporator® (Eppendorf, Hamburg Germany), cationic liposome mediated transfection using lipofection, polymer encapsulation, peptide mediated transfection, or biolistic particle delivery systems such as “gene guns” (see, for example, Nishikawa, et al. Hum Gene Ther., 12(8):861-70 (2001). Recombinant Nucleic Acid Encoding a TFP and a TCR Constant Domain [0260] Disclosed herein, in some embodiments, are recombinant nucleic acid molecules comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP). The TFP can comprise a TCR subunit comprising at least a portion of a TCR extracellular domain. The TCR subunit can further comprise a transmembrane domain. The TCR subunit can further comprise an intracellular domain of TCR gamma, TCR delta, TCR alpha or TCR beta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta. The TFP can further comprise an antibody (e.g., a human, humanized, or murine antibody) comprising an antigen binding domain. The recombinant nucleic acid molecule can further comprise a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain, a TCR alpha constant domain and a TCR beta constant domain, a TCR gamma constant domain, a TCR delta constant domain, or a TCR gamma constant domain and a TCR delta constant domain. The TCR subunit and the antibody can be operatively linked. The TFP can functionally incorporate into a TCR complex (e g., an endogenous TCR complex) when expressed in a T cell.

[0261] The constant domain can comprise a constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain The constant domain can comprise a full- length constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The constant domain can comprise a fragment (e.g., functional fragment) of the full- length constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. For example, the constant domain can comprise at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of the constant domain of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The sequence encoding the TCR constant domain can further encode the transmembrane domain and/or intracellular region of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The sequence encoding the TCR constant domain can encode a full-length constant region of a TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain. The constant region of a TCR chain can comprise a constant domain, a transmembrane domain, and a intracellular region. The constant region of a TCR chain can also exclude the transmembrane domain and the intracellular region of the TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain.

[0262] The TCR alpha chain, a TCR beta chain, a TCR gamma chain or a TCR delta chain described herein can be derived from various species. The TCR chain can be a murine or human TCR chain. For example, the constant domain can comprise a constant domain of a murine or human TCR alpha chain, TCR beta chain, TCR gamma chain or TCR delta chain.

[0263] The constant domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the constant domain can comprise a truncated version of a constant domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO:143, SEQ ID NO: 146, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:152, SEQ ID NO: 155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of SEQ ID NO 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO:155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265. The constant domain can comprise a sequence or fragment thereof of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO:155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265. The constant domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265. The constant domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265. The constant domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:

20, SEQ ID NO: 21, or SEQ ID NO: 22, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, SEQ ID NO: 155, SEQ ID NO:207, SEQ ID NO:209, SEQ ID NO:243 or SEQ ID NO:265.

[0264] The murine TCR alpha constant domain can comprise positions 2-137 of SEQ ID NO: 146. The murine TCR alpha constant domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the constant domain can comprise a truncated version of a constant domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of positions 2-137 of SEQ ID NO: 146 For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of positions 2-137 of SEQ ID NO: 146. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of positions 2-137 of SEQ ID NO: 146. The constant domain can comprise a sequence or fragment thereof of positions 2-137 of SEQ ID NO: 146. The constant domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of positions 2-137 of SEQ ID NO: 146. The constant domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of positions 2-137 of SEQ ID NO: 146. The constant domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of positions 2-137 of SEQ ID NO: 146.

[0265] The murine TCR beta constant domain can comprise positions 2-173 of SEQ ID NO:152. The murine TCR beta constant domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the constant domain can comprise a truncated version of a constant domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of positions 2-173 of SEQ ID NO: 152. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of positions 2-173 of SEQ ID NO: 152. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of positions 2-173 of SEQ ID NO:152. The constant domain can comprise a sequence or fragment thereof of positions 22-173 of SEQ ID NO: 152. The constant domain can comprise at least 1, 2, 3, 4, 5, 6,

7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of positions 2-173 of SEQ ID NO:152. The constant domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of positions 2-173 of SEQ ID NO:152. The constant domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of positions 2-173 of SEQ ID NO: 152.

[0266] In some instances, the TCR constant domain is a TCR delta constant domain. The TCR delta constant domain can comprise SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID N0 265, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modification. In some embodiments, the TCR delta constant domain can comprise SEQ ID NO:243. The TCR delta constant domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the constant domain can comprise a truncated version of a constant domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of SEQ ID NO:243. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of SEQ ID NO:243. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of SEQ ID NO:243. The constant domain can comprise a sequence or fragment thereof of SEQ ID NO:243. The constant domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of SEQ ID NO:243. The constant domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of SEQ ID NO:243. The constant domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of SEQ ID NO:243.

[0267] The TCR delta constant domain can comprise SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications. In some cases, the sequence encoding a TCR delta constant domain further encodes a TCR delta variable domain, thereby encoding a full TCR delta domain. The full TCR delta domain can be delta 2 or delta 1. The full TCR delta constant domain can comprise SEQ ID NO:256, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0268] The full TCR delta domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the delta domain can comprise a truncated version of a delta domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of SEQ ID NO:256. For example, the delta domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of SEQ ID NO:256. For example, the delta domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of SEQ ID NO:256. The delta domain can comprise a sequence or fragment thereof of SEQ ID NO:256. The delta domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of SEQ ID NO:256. The delta domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8,

7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of SEQ ID NO:256. The delta domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of SEQ ID N0 256 [0269] The TCR gamma constant domain can comprise SEQ ID NO:21. The TCR gamma constant domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the constant domain can comprise a truncated version of a constant domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of SEQ ID NO:21. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of SEQ ID NO:21. For example, the constant domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of SEQ ID NO:21. The constant domain can comprise a sequence or fragment thereof of SEQ ID NO:21. The constant domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or deletions of the sequence of SEQ ID NO:21. The constant domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of SEQ ID NO:21. The constant domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of SEQ ID NO: 243.

[0270] The TCR gamma constant domain can comprise SEQ ID NO:21 or SEQ ID NO:155, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some cases, the sequence encoding the TCR gamma constant domain further encodes a TCR gamma variable domain, thereby encoding a full TCR gamma domain.

The full TCR gamma domain can be gamma 9 or gamma 4. The full TCR gamma domain can comprise SEQ ID NO:255, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0271] The full TCR gamma domain can comprise truncations, additions, or substitutions of a sequence of a constant domain described herein. For example, the gamma domain can comprise a truncated version of a gamma domain described herein having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid residues of SEQ ID NO:255. For example, the gamma domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more additional amino acid residues of SEQ ID NO:255. For example, the gamma domain can comprise a sequence having at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or more amino acid substitutions of SEQ ID NO:255. The gamma domain can comprise a sequence or fragment thereof of SEQ ID NO:255. The gamma domain can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more modifications, mutations or gamma of the sequence of SEQ ED NO:255. The gamma domain can comprise at most 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification, mutations or deletions of the sequence of SEQ ED NO:255. The gamma domain can comprise a sequence having a sequence identity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% to the sequence of SEQ ID NO: 255.

[0272] TCR beta chain (Homo sapiens):

VEDLNK VFPPEVA VFEP SE AEISHT QK ATL V CLAT GFFPDHVEL S WW VN GKEVHS GV S T DPQPLKEQP ALND SRY CLS SRLRVS ATFW QNPRNHFRCQ VQF YGLSENDEWTQDRAKP YTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLYSALVLMAMVKR KDF (SEQ ED NO: 16).

[0273] The murine TCR beta chain constant region canonical sequence is:

EDLRNVTPPK V SLFEP SK AEIANKQK ATL V CL ARGFFPDH VEL S W W VNGKEVHS GV S TD PQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNIS AEAW GRADCGITS ASY QQGVLS ATILYEILLGKATLYAVLVSTLVVMAMVKRKN S (SEQ ID NO: 152).

[0274] TCR alpha constant region (Mus musculus) (or [mm]TRAC(82-137)): ATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 17).

[0275] The murine TCR alpha chain constant (mTRAC) region canonical sequence is: XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSN GAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILL LKVAGFNLLMTLRLW S S (SEQ ID NO: 146).

[0276] TCR beta constant region (Mus musculus) (or [mm]TRBCl(123-173)):

GRADCGITS AS YQQGVLSATILYEILLGKATLY AVLV STLVVMAMVKRKN S (SEQ ID NO: 18).

[0277] The murine TCR beta chain constant region canonical sequence is:

EDLRNVTPPK V SLFEP SK AEIANKQK ATL V CL ARGFFPDHVEL SWW VNGKEVHS GV S TD PQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNIS AEAW GRADCGITS ASY QQGVLS ATILYEILLGKATLYAVLVSTLVVMAMVKRKN S (SEQ ID NO: 152).

[0278] TCR beta chain (Homo sapiens):

PVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVSWYQQSLDQGLQFLIQYYNGEERAK

GNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSPRTGLNTEAFFGQGTRLTVVEDLN KVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPL KEQP ALND SRY CL S SRLRVS ATF W QNPRNHFRC Q VQF YGL SENDEWT QDRAKP VT QIV S AEAWGRADCGFTS V SY QQGVLS ATILYEILLGKATLYAVLV S ALVLMAMVKRKDF (SEQ ID NO: 19)

[0279] TCR delta constant region version 1 (Homo sapiens):

SQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLG K YEDSNS VT C S VQHDNKT VHS TDFEVKTD S TDHVKPKETENTKQP SKS CHKPK AIVHTE KVNMMSLTVLGLRMLFAKTVAVNFLLTAKLFF (SEQ ID NO: 20).

[0280] TCR gamma constant region (Homo sapiens) (or [hs]TRGC(l-173)): DKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGN TMKTNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDN C SKD ANDTLLLQLTNT S A YYM YLLLLLK S V VYF AIITC CLLRRT AF CCN GEK S (SEQ ID NO: 21).

[0281] TCR delta constant region version 2 (Homo sapiens):

SQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLG K YEDSNS VT C S VQHDNKT VHS TDFEVKTD S TDHVKPKETENTKQP SKS CHKPK AIVHTE KVNMMSLTVLGLRMLFAKTVAVNFLLTAK (SEQ ID NO: 22).

[0282] In some instances, the TCR constant domain is a TCR delta constant domain. The sequence encoding the TCR delta constant domain can further encode a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR delta constant domain. The second antigen binding domain or ligand binding domain can be the same or different as the antigen binding domain or ligand binding domain of the TFP.

[0283] In some instances, the TCR constant domain is a TCR gamma constant domain. The sequence encoding the TCR gamma constant domain can further encode a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR gamma constant domain. The second antigen binding domain or ligand binding domain can be the same or different as the antigen binding domain or ligand binding domain of the TFP. [0284] In some instances, the recombinant nucleic acid comprise a sequence encoding a TCR gamma constant domain and a TCR delta constant domain. The TCR gamma constant domain can comprise SEQ ID NO:21 or SEQ ID NO: 155, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The sequence encoding the TCR gamma constant domain can further encode a TCR gamma variable domain, thereby encoding a full TCR gamma domain The TCR gamma domain can be gamma 9 or gamma 4. The full TCR gamma domain comprises SEQ ID NO:255, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The TCR delta constant domain can comprise SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The sequence encoding the TCR delta constant domain can further encode a TCR delta variable domain, thereby encoding a full TCR delta domain. The TCR delta domain can be delta 2 or delta 1. The full TCR delta domain can comprise SEQ ID NO:256, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0285] In some instances, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some instances, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules. The sequence can further encode a cleavage site (e.g., a protease cleavage site) between the encoded TFP and the TCR constant domain. The cleavage site can be a protease cleavage site. The cleavage site can be a self cleaving peptide such as a T2A, P2A, E2A or F2A cleavage site. The cleavage site can comprise a sequence of SEQ ID NO: 23.

[0286] T2A cleavage site: EGRGSLLT C GD VEENPGP (SEQ ID NO: 23).

[0287] The TCR subunit of the TFP and the constant domain can comprise a sequence derived from a same TCR chain or a different TCR chain. In some cases, the TCR subunit of the TFP and the constant domain are derived from different TCR chains. For example, the TCR subunit can comprise (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain, where the TCR extracellular domain, the transmembrane domain and the intracellular domain are derived from a TCR alpha chain, and the constant domain can comprise a constant domain of a TCR beta chain For another example, the TCR subunit can comprise (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain, where the TCR extracellular domain, the transmembrane domain and the intracellular domain are derived from a TCR beta chain, and the constant domain can comprise a constant domain of a TCR alpha chain. For another example, the TCR subunit can comprise (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain, where the TCR extracellular domain, the transmembrane domain and the intracellular domain are derived from a TCR gamma chain, and the constant domain can comprise a constant domain of a TCR delta chain. For yet another example, the TCR subunit can comprise (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain, where the TCR extracellular domain, the transmembrane domain and the intracellular domain are derived from a TCR delta chain, and the constant domain can comprise a constant domain of a TCR gamma chain.

[0288] In some instances, the TCR subunit and the antibody domain, the antigen domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some instances, the linker sequence comprises (G4S)n, wherein n=l to 4.

[0289] In some instances, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR gamma, TCR delta, TCR alpha or TCR beta. In some instances, the intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR gamma, only TCR delta, only TCR alpha or only TCR beta.

[0290] In some instances, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two or all of (i), (ii), and (iii) are from the same TCR subunit.

[0291] In some instances, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0292] In some instances, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD 134, CD 137, CD 154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0293] In some instances, the TCR subunit comprises a TCR intracellular domain of TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, or a fragment thereof. In some instances, the TCR subunit comprises an intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto.

[0294] In some instances, the TCR subunit can comprise (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain of a TCR gamma chain or a TCR delta chain. The TCR extracellular domain can comprise the extracellular portion of a constant domain of a TCR gamma chain or a TCR delta chain, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprising (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a delta constant domain, or a fragment thereof, e.g., a delta constant domain described herein. The delta constant domain can have the sequence of SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, thhe TCR subunit comprising (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a gamma constant domain, e.g., a gamma constant domain described herein. The gamma constant domain can have the sequence of SEQ ID NO:21 or SEQ ID NO: 155, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The extracellular domain of the TFP may not comprise the variable domain of a gamma chain or a delta chain.

[0295] The TCR subunit of the TFP can comprise the extracellular, transmembrane and intracellular domain of CD3 epsilon, CD3 gamma, or CD3 delta. In some embodiments, recombinant nucleic acid comprises a TFP comprising the extracellular, transmembrane and intracellular domain of CD3 epsilon, , CD3 gamma, or CD3 delta and the constant domains of TCR beta and TCR alpha. In some embodiments, recombinant nucleic acid comprises a TFP comprising the extracellular, transmembrane and intracellular domain of CD3 epsilon and the constant domains of TCR gamma and TCR delta. In some embodiments, recombinant nucleic acid comprises a TFP comprising the extracellular, transmembrane and intracellular domain of CD3 epsilon and full length TCF gamma and full length TCR delta. In some embodiments, the TCR subunit of the TFP comprises CD3 epsilon. The TCR subunit of CD3 epsilon can comprise the sequence of SEQ ID NO:258 functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

In some instances, the TCR subunit comprising at least a portion of a murine TCR alpha or murine TCR beta extracellular domain and a murine TCR alpha or murine TCR beta transmembrane domain is or comprises a TCR alpha constant domain or a TCR beta constant domain. The TCR subunit can comprise an intracellular domain of murine TCR alpha or murine TCR beta. The TCR constant domain can be a TCR alpha constant domain, e.g., a TCR alpha constant domain described herein. The TCR alpha constant domain can comprise SEQ ID NO: 17, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, or SEQ ID NO:207, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The sequence encoding the TCR alpha constant domain can further encode a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR alpha constant domain. The second antigen binding domain or ligand binding domain can be the same or different as the antigen binding domain or ligand binding domain of the TFP. The TCR alpha constant domain can comprise a murine TCR alpha constant domain. The murine TCR alpha constant domain can comprise amino acids 2-137 of the murine TCR alpha constant domain. The murine TCR alpha constant domain can comprise amino acids 2-137 of SEQ ID NO: 146. The murine TCR alpha constant domain can comprise a sequence of SEQ ID NO:207. The murine TCR alpha constant domain can comprise amino acids 82-137 of SEQ ID NO: 146. The murine TCR alpha constant domain comprises a sequence of SEQ ID NO: 17. The TCR constant domain can be a TCR beta constant domain, e.g., a TCR beta constant domain described herein. The TCR beta constant domain can comprise SEQ ID NO: 18, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, or SEQ ID NO:209, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The sequence encoding the TCR beta constant domain can further encode a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR beta constant domain. The second antigen binding domain or ligand binding domain can be the same or different as the antigen binding domain or ligand binding domain of the TFP. TCR beta constant domain can comprise a murine TCR beta constant domain. The murine TCR beta constant domain can comprise amino acids 2-173 of the murine TCR beta constant domain. The murine TCR beta constant domain can comprise amino acids 2- 173 of SEQ ID NO: 152. The murine TCR beta constant domain can comprise SEQ ID NO:209. The TCR beta constant domain can comprise amino acids 123-173 of SEQ ID NO: 152. The TCR beta constant domain can comprise SEQ ID NO: 18

[0296] The recombinant nucleic acid can comprise sequence encoding a TCR alpha constant domain and a TCR beta constant domain. The TCR alpha constant domain can comprise SEQ ID NO: 17, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, or SEQ ID NO:207, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The TCR beta constant domain can comprise SEQ ID NO: 18, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, or SEQ ID NO:209, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. The intracellular signaling domain can be CD3 epsilon, CD3 gamma, or CD3 delta The intracellular signaling domain can be CD3 epsilon. [0297] The sequence encoding the TCR constant domain can comprise from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence. The sequence encoding the TCR constant domain can comprise, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence. The sequence encoding the TCR constant domain can comprise, from 5’ to 3’, a first leader sequence, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker, and a TRBC gene sequence. The sequence encoding the TCR constant domain can comprise, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker, and a TRBC gene sequence. The sequence encoding the TCR constant domain can comprise, from 5 ’-3’, a first leader sequence, a TRAC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRBC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence.

[0298] As described herein, the at least one but not more than 20 modifications thereto of a sequence described herein can comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP.

[0299] In some instances, the TCR subunit comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4- IBB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.

[0300] In some instances, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some instances, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2, CD27, CD28, CDS, IC AM- 1 , LFA-1 (CDlla/CD18), ICOS (CD278), and 4-1BB (CD137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto.

[0301] In some instances, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3 a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some instances, the ITAM replaces an ITAM of CD3 gamma, CD3 delta, or CD3 epsilon. In some instances, the ITAM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit.

[0302] In some instances, the TFP, the TCR gamma constant domain, the TCR delta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide. In some instances, (a) the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR delta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (b) the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR gamma, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or (c) the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0303] In some instances, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP.

[0304] The antibody or antigen binding domain can be an antibody fragment. The antibody or antigen binding domain can be murine, human or humanized. In some instances, the human or humanized antibody is an antibody fragment. In some instances, the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain. In some instances, human or humanized antibody comprising an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, anti-B-cell maturation antigen (BCMA) binding domain, anti- mesothelin (MSLN) binding domain, anti-CD22 binding domain, anti -PD- 1 binding domain, anti-BAFF orBAFF receptor binding domain, and anti-ROR-1 binding domain.

[0305] An antigen binding domain described herein can be selected from a group consisting of an anti-CD19 binding domain, an anti-B-cell maturation antigen (BCMA) binding domain, an anti-mesothelin (MSLN) binding domain, an anti-CD20 binding domain, an anti-CD70 binding domain, an anti-79b binding domain, an anti-HER2 binding domain, an anti-PMSA binding domain, an anti-MUC16 binding domain, an anti-CD22 binding domain, an anti-PD-Ll binding domain, an anti BAFF or BAFF receptor binding domain, an anti-Nectin-4 binding domain, an anti-TROP-2 binding domain, an anti-GPC3 binding domain, and anti-ROR-1 binding domain. [0306] In some instances, the nucleic acid is selected from the group consisting of a DNA and an RNA. In some instances, the nucleic acid is an mRNA. In some instances, the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid. In some instances, the nucleic analog is selected from the group consisting of 2’-0-methyl, 2’-0-methoxyethyl (2’-0-MOE), 2’-0- aminopropyl, 2’-deoxy, T-deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2-0- dimethylaminoethyl (2’-0-DMAOE), 2’-0-dimethylaminopropyl (2’-0-DMAP), T-O- dimethylaminoethyloxyethyl (2’-0-DMAEOE), 2’-0-N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2’-fluoroN3-P5’-phosphoramidite.

[0307] In some instances, the recombinant nucleic acid further comprises a leader sequence. In some instances, the recombinant nucleic acid further comprises a promoter sequence. In some instances, the recombinant nucleic acid further comprises a sequence encoding a poly(A) tail. In some instances, the recombinant nucleic acid further comprises a 3’UTR sequence. In some instances, the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid. In some instances, the nucleic acid is an in vitro transcribed nucleic acid.

[0308] In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR beta transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain.

[0309] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP). The TFP can comprise a TCR subunit comprising at least a portion of a TCR extracellular domain. The TCR subunit can further comprise a transmembrane domain. The TCR subunit can further comprise an intracellular domain of TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, or a fragment thereof. In some instances, the TCR subunit comprises an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or comprises an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta. The TFP can further comprise a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof. The recombinant nucleic acid molecule can comprise a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain, a TCR alpha constant domain and a TCR beta constant domain, TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell. In some instances, the binding ligand is capable of binding an Fc domain of the antibody. In some instances, the binding ligand is capable of selectively binding an IgGl antibody. In some instances, the binding ligand is capable of specifically binding an IgGl antibody. In some instances, the antibody or fragment thereof binds to a cell surface antigen. In some instances, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some instances, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some instances, the binding ligand does not comprise an antibody or fragment thereof. In some instances, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some instances, the binding ligand comprises a CD 16-binding polypeptide.

In some instances, the binding ligand is human or humanized. In some instances, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some instances, the antibody or fragment thereof is capable of being secreted from a cell.

[0310] In some instances, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some instances, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules.

[0311] In some instances, the TCR subunit and the antibody domain, the antigen domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some instances, the linker sequence comprises (G4S)n, wherein n=l to 4.

[0312] In some instances, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR gamma, or TCR delta. In some instances, the intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha or only TCR beta.

[0313] In some instances, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit.

[0314] In some instances, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0315] In some instances, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD 134, CD 137, CD 154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0316] In some instances, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto. [0317] In some instances, the TCR subunit comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4- IBB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.

[0318] In some instances, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some instances, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2, CD27, CD28, CDS, IC AM- 1 , LFA-1 (CDlla/CD18), ICOS (CD278), and 4-1BB (CD137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto.

[0319] In some instances, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some instances, the ITAM replaces an ITAM of CD3 gamma, CD3 delta, or CD3 epsilon. In some instances, the ITAM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit.

[0320] In some instances, the TFP, the TCR gamma constant domain, the TCR delta constant domain, the TCR alpha constant domain, the TCR beta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide. In some instances, (a) the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR beta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (b) the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR alpha, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (c) the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (d) the TCR constant domain is a TCR alpha constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR beta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or (e) the TCR constant domain is a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR alpha, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0321] In some instances, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP.

[0322] In some instances, the human or humanized antibody is an antibody fragment. In some instances, the antibody fragment is a scFv, a single domain antibody domain (sdAb), a VH domain or a VL domain. In some instances, human or humanized antibody comprising an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, anti-B-cell maturation antigen (BCMA) binding domain, anti-mesothelin (MSLN) binding domain, anti- CD22 binding domain, anti-PD-1 binding domain, anti PD-L1 binding domain, anti IL13Ra2 binding domain, anti-BAFF or BAFFR binding domain, and anti-ROR-1 binding domain.

[0323] In some instances, the nucleic acid is selected from the group consisting of a DNA and an RNA. In some instances, the nucleic acid is an mRNA. In some instances, the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid. In some instances, the nucleic analog is selected from the group consisting of 2’-0-methyl, 2’-0-methoxyethyl (2’-0-M0E), 2’-0- aminopropyl, 2’-deoxy, T-deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2-0- dimethylaminoethyl (2’-0-DMAOE), 2’-0-dimethylaminopropyl (2’-0-DMAP), T-O- dimethylaminoethyloxyethyl (2’-0-DMAEOE), 2’-0-N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2’-fluoroN3-P5’-phosphoramidite.

[0324] In some instances, the recombinant nucleic acid further comprises a leader sequence. In some instances, the recombinant nucleic acid further comprises a promoter sequence. In some instances, the recombinant nucleic acid further comprises a sequence encoding a poly(A) tail. In some instances, the recombinant nucleic acid further comprises a 3’UTR sequence. In some instances, the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid. In some instances, the nucleic acid is an in vitro transcribed nucleic acid.

[0325] In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR beta transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain. Alternatively, the recombinant nucleic acid comprises a sequence encoding a TCR gamma or TCR delta domain, e.g., a transmembrane domain.

[0326] Disclosed herein, in some embodiments, are recombinant nucleic acids comprising a sequence encoding a T cell receptor (TCR) fusion protein (TFP). The TFP can comprise a TCR subunit. The TCR subunit can comprise at least a portion of a TCR extracellular domain. The TCR subunit can further comprise a transmembrane domain. The TCR subunit can further comprise an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta The TFP can comprise an antigen domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell. The recombinant nucleic acid molecule can comprise a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain, a TCR alpha constant domain and a TCR beta constant domain, TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell. In some instances, the antigen domain comprises a ligand. In some instances, the ligand binds to the receptor of a cell. In some instances, the ligand binds to the polypeptide expressed on a surface of a cell. In some instances, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some instances, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some instances, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some instances, the antigen domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some instances, the antigen domain comprises a monomer or a dimer of the ligand or fragment thereof. In some instances, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some instances, the ligand or fragment thereof is a monomer or a dimer. In some instances, the antigen domain does not comprise an antibody or fragment thereof. In some instances, the antigen domain does not comprise a variable region. In some instances, the antigen domain does not comprise a CDR. In some instances, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof.

[0327] In some instances, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some instances, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules.

[0328] In some instances, the TCR subunit and the antibody domain, the antigen domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some instances, the linker sequence comprises (G4S)n, wherein n=l to 4. [0329] In some instances, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR delta, or TCR gamma. In some instances, the intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha, only TCR beta, only TCR delta, or only TCR gamma.

[0330] In some instances, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit.

[0331] In some instances, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR delta chain, a TCR gamma chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0332] In some instances, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR delta chain, a TCR gamma chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD 16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, CD154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications.

[0333] In some instances, the TCR subunit comprises a TCR intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta. In some instances, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto.

[0334] In some instances, the TCR subunit comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4- IBB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.

[0335] In some instances, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some instances, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2, CD27, CD28, CDS, IC AM- 1 , LFA-1 (CDlla/CD18), ICOS (CD278), and 4-1BB (CD137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto. [0336] In some instances, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some instances, the ITAM replaces an ITAM of CD3 gamma, CD3 delta, or CD3 epsilon. In some instances, the ITAM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit.

[0337] In some instances, the TFP, the TCR gamma constant domain, the TCR delta constant domain, the TCR alpha constant domain, the TCR beta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide. In some instances, (a) the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR beta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (b) the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR gamma, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (c) the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (d) the TCR constant domain is a TCR alpha constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR beta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or (e) the TCR constant domain is a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR alpha, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0338] In some instances, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP. [0339] In some instances, the human or humanized antibody is an antibody fragment. In some instances, the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain. In some instances, human or humanized antibody comprising an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, anti-CD20 binding domain, anti-mesothelin binding domain, anti-PMSA binding domain, anti-CD70 binding domain, anti-CD79b binding domain, anti-MUC16 binding domain, anti-anti -B-cell maturation antigen (BCMA) binding domain, anti-mesothelin (MSLN) binding domain, anti-IL13Ra2 binding domain, anti-CD22 binding domain, anti-BAFF or anti-BAFFR binding domain, anti- PD-1 binding domain, anti-PD-Ll binding domain, and anti-ROR-1 binding domain.

[0340] In some instances, the nucleic acid is selected from the group consisting of a DNA and an RNA. In some instances, the nucleic acid is an mRNA. In some instances, the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid. In some instances, the nucleic analog is selected from the group consisting of 2’-0-methyl, 2’-0-methoxyethyl (2’-0-MOE), 2’-0- aminopropyl, 2’-deoxy, T-deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2-0- dimethylaminoethyl (2’-0-DMAOE), 2’-0-dimethylaminopropyl (2’-0-DMAP), T-O- dimethylaminoethyloxyethyl (2’-0-DMAEOE), 2’-0-N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2^,-fluoroN3-P5^,-phosphoramidite.

[0341] In some instances, the recombinant nucleic acid further comprises a leader sequence. In some instances, the recombinant nucleic acid further comprises a promoter sequence. In some instances, the recombinant nucleic acid further comprises a sequence encoding a poly(A) tail. In some instances, the recombinant nucleic acid further comprises a 3’UTR sequence. In some instances, the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid. In some instances, the nucleic acid is an in vitro transcribed nucleic acid.

[0342] In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR beta transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR gamma transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR delta transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR gamma transmembrane domain and a sequence encoding a TCR delta transmembrane domain.

[0343] Further disclosed herein, in some embodiments, are vectors comprising the recombinant nucleic acid disclosed herein. In some instances, the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, an adeno-associated viral vector (AAV), a Rous sarcoma viral (RSV) vector, or a retrovirus vector. In some instances, the vector is an AAV6 vector. In some instances, the vector further comprises a promoter. In some instances, the vector is an in vitro transcribed vector.

[0344] The nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the gene of interest can be produced synthetically, rather than cloned.

[0345] The present disclosure also provides vectors in which a DNA of the present disclosure is inserted. Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity.

[0346] In another embodiment, the vector comprising the nucleic acid encoding the desired TFP of the present disclosure is an adenoviral vector (A5/35). In another embodiment, the expression of nucleic acids encoding TFPs can be accomplished using of transposons such as sleeping beauty, crisper, CAS9, and zinc finger nucleases. See below lune et al. 2009 Nature Reviews Immunology 9.10: 704-716, is incorporated herein by reference.

[0347] The expression constructs of the present disclosure may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art (see, e.g., U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties). In another embodiment, the present disclosure provides a gene therapy vector.

[0348] The nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. [0349] Further, the expression vector may be provided to a cell in the form of a viral vector.

Viral vector technology is well known in the art and is described, for example, in Sambrook et al., 2012, Molecular Cloning: A Laboratory Manual, volumes 1-4, Cold Spring Harbor Press, NY), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, ( e.g ., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193). [0350] A number of virally based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In one embodiment, lentivirus vectors are used.

[0351] Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription.

[0352] An example of a promoter that is capable of expressing a TFP transgene in a mammalian T cell is the EF la promoter. The native EFla promoter drives expression of the alpha subunit of the elongation factor- 1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. The EFla promoter has been extensively used in mammalian expression plasmids and has been shown to be effective in driving TFP expression from transgenes cloned into a lentiviral vector (see, e.g., Milone et al., Mol. Ther. 17(8): 1453-1464 (2009)). Another example of a promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTY), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the elongation factor- la promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the present disclosure should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the present disclosure. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline-regulated promoter.

[0353] In order to assess the expression of a TFP polypeptide or portions thereof, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic- resistance genes, such as neo and the like.

[0354] Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82) Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5’ flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription.

[0355] Methods of introducing and expressing genes into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means.

[0356] Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al., 2012, Molecular Cloning: A Laboratory Manual, volumes 1-4, Cold Spring Harbor Press, NY). A preferred method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection [0357] Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like (see, e.g., U.S. Pat. Nos. 5,350,674 and 5,585,362.

[0358] Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). Other methods of state-of-the-art targeted delivery of nucleic acids are available, such as delivery of polynucleotides with targeted nanoparticles or other suitable sub-micron sized delivery system.

[0359] In the case where a non-viral delivery system is utilized, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid/DNA or lipid/expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.

[0360] Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, Mo.; dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories (Plainview, N.Y.); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, Ala.). Stock solutions of lipids in chloroform or chloroform/methanol can be stored at about -20 °C. Chloroform is used as the only solvent since it is more readily evaporated than methanol. “Liposome” is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh et al., 1991 Glycobiology 5: 505-10). However, compositions that have different structures in solution than the normal vesicular structure are also encompassed. For example, the lipids may assume a micellar structure or merely exist as nonuniform aggregates of lipid molecules. Also contemplated are lipofectamine- nucleic acid complexes.

[0361] Regardless of the method used to introduce exogenous nucleic acids into a host cell or otherwise expose a cell to the inhibitor of the present disclosure, in order to confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELIS As and western blots) or by assays described herein to identify agents falling within the scope of the present disclosure.

[0362] The present disclosure further provides a vector comprising a TFP encoding nucleic acid molecule. In one aspect, a TFP vector can be directly transduced into a cell, e.g., a T cell In one aspect, the vector is a cloning or expression vector, e.g., a vector including, but not limited to, one or more plasmids (e.g., expression plasmids, cloning vectors, mini circles, minivectors, double minute chromosomes), retroviral and lentiviral vector constructs. In one aspect, the vector is capable of expressing the TFP construct in mammalian T cells. In one aspect, the mammalian T cell is a human T cell.

[0363] In an aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, and (ii) an antibody comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain, or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0364] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain, or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0365] In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding a delta constant domain. In some embodiments, the intracellular domain is an intracellular domain of TCR gamma. In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding a gamma constant domain. In some embodiments, the intracellular domain is an intracellular domain of TCR delta. In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to both a sequence encoding a TCR delta constant domain or fragment thereof and a TCR gamma constant domain or fragment thereof. In some embodiments, the intracellular signaling domain is CD3 epsilon, CD3 gamma, or CD3 delta. In some embodiments, the intracellular signaling domain is CD3 epsilon. In some embodiments, the recombinant nucleic acid further comprises at least one leader sequence and at least one linker. In some embodiments, the recombinant nucleic acid further comprises a portion of a TCR alpha constant domain, a portion of a TCR beta domain, or both. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRGC gene sequence. In some embodiments, the sequence comprises, from 5’ -3’, a first leader sequence, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker sequence, and a TRGC gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, an antigen binding domain sequence, a first linker sequence, a TRDC gene sequence, a cleavable linker, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, and a TRGC gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, a TRDC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRGC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence. In some embodiments, the sequence comprises, from 5 ’-3’, a first leader sequence, a first antigen binding domain sequence, a first linker sequence, a TRDC gene sequence or fragment thereof, a TRAC gene sequence or fragment thereof, a cleavable linker sequence, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, a TRGC gene sequence or fragment thereof, and a TRBC gene sequence or fragment thereof. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:l. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:2. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:3. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:4. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO:5. In some embodiments, the binding ligand is capable of binding an Fc domain of the antibody. In some embodiments, the binding ligand is capable of selectively binding an IgGl antibody. In some embodiments, the binding ligand is capable of specifically binding an IgG4 antibody. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen In some embodiments, the antibody or fragment thereof is murine, human or humanized. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some embodiments, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the binding ligand does not comprise an antibody or fragment thereof. In some embodiments, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some embodiments, the binding ligand comprises a CD 16-binding polypeptide. In some embodiments, the binding ligand is human or humanized. In some embodiments, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some embodiments, the antibody or fragment thereof is capable of being secreted from a cell.

[0366] In another aspect, provided herein is a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, and (ii) an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0367] In some embodiments, the recombinant nucleic acid further comprises at least a partial sequence encoding a TCR alpha constant domain, a TCR beta constant domain, or a partial sequence of both a TCR alpha constant domain and a TCR beta constant domain. In some embodiments, the antigen binding domain comprises a ligand. In some embodiments, the ligand binds to the receptor of a cell. In some embodiments, the ligand binds to the polypeptide expressed on a surface of a cell. In some embodiments, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some embodiments, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some embodiments, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some embodiments, the antigen binding domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof. In some embodiments, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the ligand or fragment thereof is a monomer or a dimer. In some embodiments, the antigen binding domain does not comprise an antibody or fragment thereof. In some embodiments, the antigen binding domain does not comprise a variable region. In some embodiments, the antigen binding domain does not comprise a CDR. In some embodiments, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof. In some embodiments, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some embodiments, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules. In some embodiments, the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some embodiments, the linker sequence comprises (G4S)n, wherein n=l to 4. In some embodiments, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR delta, or TCR gamma. In some embodiments, the encoded intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha, TCR beta, TCR gamma, or TCR delta In some embodiments, the encoded TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit. In some embodiments, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR extracellular domain comprises a constant domain or a portion thereof of a TCR gamma chain or a TCR delta chain. In some embodiments, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137,

CD 154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto. In some embodiments, the TCR subunit further comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.

[0368] In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some embodiments, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), and 4-1BB (CD137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some embodiments, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP 12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some embodiments, the IT AM replaces an IT AM of CD3 gamma, CD3 delta, or CD3 epsilon. In some embodiments, the IT AM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit. In some embodiments, the TFP, the TCR gamma constant domain, the TCR delta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide.

[0369] In some embodiments, the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR delta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR gamma, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0370] In some embodiments, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP. In some embodiments, the antibody is an antibody fragment. In some embodiments the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain. In some embodiments, an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, an anti-B-cell maturation antigen (BCMA) binding domain, an anti-mesothelin (MSLN) binding domain, an anti-CD20 binding domain, an anti-CD70 binding domain, an anti- 79b binding domain, an anti-HER2 binding domain, an anti-PMSA binding domain, an anti- MUC16 binding domain, an anti-CD22 binding domain, an anti-PD-Ll binding domain, an anti BAFF or BAFF receptor binding domain, and anti-ROR-1 binding domain. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR beta transmembrane domain. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain.

[0371] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, and (ii) an antibody or fragment thereof comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain or a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0372] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain or a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0373] In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding an alpha constant domain. In some embodiments, the intracellular domain is an intracellular domain of TCR beta. In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding a beta constant domain. In some embodiments, the intracellular domain is an intracellular domain of TCR alpha. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO: 10. In some embodiments, the recombinant nucleic acid further comprises at least one leader sequence and at least one linker. In some embodiments, the binding ligand is capable of binding an Fc domain of the antibody. In some embodiments, the binding ligand is capable of selectively binding an IgGl antibody. In some embodiments, the binding ligand is capable of specifically binding an IgG4 antibody. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen. In some embodiments, the antibody or fragment thereof is murine, human or humanized. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some embodiments, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the binding ligand does not comprise an antibody or fragment thereof. In some embodiments, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some embodiments, the binding ligand comprises a CD 16-binding polypeptide. In some embodiments, the binding ligand is human or humanized.

In some embodiments, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some embodiments, the antibody or fragment thereof is capable of being secreted from a cell. [0374] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta, and (ii) an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain or a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0375] In some embodiments, the TCR constant domain is a murine TCR constant domain, e.g., a murine TCR alpha constant domain or a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain. In some embodiments, the extracellular domain comprises at least a portion of a TCR alpha extracellular domain or TCR beta extracellular domain. In some embodiments, the TCR alpha extracellular domain or TCR beta extracellular domain is a murine TCR alpha extracellular domain or a murine TCR beta extracellular domain. In some embodiments, the extracellular domain comprises at least a portion of a TCR alpha constant domain or TCR beta constant domain. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain. In some embodiments, the recombinant nucleic acid further comprises at least a partial sequence encoding a TCR gamma constant domain, a TCR delta constant domain, or a partial sequence of both a TCR gamma constant domain and a TCR delta constant domain. In some embodiments, the antigen binding domain comprises a ligand. In some embodiments, the ligand binds to the receptor of a cell. In some embodiments, the ligand binds to the polypeptide expressed on a surface of a cell. In some embodiments, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some embodiments, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some embodiments, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some embodiments, the antigen binding domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof.

[0376] In some embodiments, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the ligand or fragment thereof is a monomer or a dimer. In some embodiments, the antigen binding domain does not comprise an antibody or fragment thereof. In some embodiments, the antigen binding domain does not comprise a variable region. In some embodiments, the antigen binding domain does not comprise a CDR. In some embodiments, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof.

In some embodiments, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some embodiments, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules. In some embodiments, the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some embodiments, the linker sequence comprises (G4S)n, wherein n=l to 4. In some embodiments, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR delta, or TCR gamma. In some embodiments, the encoded intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha, TCR beta, TCR gamma, or TCR delta In some embodiments, the encoded TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit. In some embodiments, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a TCR zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, CD154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto. In some embodiments, the TCR subunit further comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.

[0377] In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some embodiments, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2,

CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), and 4-1BB (CD137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some embodiments, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP 12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some embodiments, the IT AM replaces an IT AM of CD3 gamma, CD3 delta, or CD3 epsilon. In some embodiments, the IT AM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit. In some embodiments, the TFP, the TCR alpha constant domain, the TCR beta domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide.

[0378] In some embodiments, the TCR constant domain is a TCR alpha constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; the TCR constant domain is a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or the TCR constant domain is a TCR alpha constant domain and a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0379] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, (2) a murine TCR alpha or murine TCR beta transmembrane domain, and (3) an intracellular domain of murine TCR alpha or murine TCR beta, and (ii) an antibody or fragment thereof comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0380] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, (2) a murine TCR alpha or murine TCR beta transmembrane domain, and (3) an intracellular domain of murine TCR alpha or murine TCR beta, and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0381] In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding an alpha constant domain. In some embodiments, the intracellular domain is an intracellular domain of TCR beta. In some embodiments, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding a beta constant domain. In some embodiments, the intracellular domain is an intracellular domain of TCR alpha. In some embodiments, the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence. In some embodiments, the sequence encodes the polypeptide as set forth in SEQ ID NO: 10. In some embodiments, the recombinant nucleic acid further comprises at least one leader sequence and at least one linker. In some embodiments, the binding ligand is capable of binding an Fc domain of the antibody. In some embodiments, the binding ligand is capable of selectively binding an IgGl antibody. In some embodiments, the binding ligand is capable of specifically binding an IgG4 antibody. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen. In some embodiments, the antibody or fragment thereof is murine, human or humanized. In some embodiments, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some embodiments, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the binding ligand does not comprise an antibody or fragment thereof. In some embodiments, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some embodiments, the binding ligand comprises a CD 16-binding polypeptide. In some embodiments, the binding ligand is human or humanized.

In some embodiments, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some embodiments, the antibody or fragment thereof is capable of being secreted from a cell.

[0382] In another aspect, the present disclosure provides a recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, (2) a murine TCR alpha or murine TCR beta transmembrane domain, and (3) an intracellular domain of murine TCR alpha or murine TCR beta, and (ii) an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

[0383] In some embodiments, the extracellular domain comprises at least a portion of a TCR alpha constant domain or TCR beta constant domain. In some embodiments, the recombinant nucleic acid further comprises at least a partial sequence encoding a TCR gamma constant domain, a TCR delta constant domain, or a partial sequence of both a TCR gamma constant domain and a TCR delta constant domain. In some embodiments, the antigen binding domain comprises a ligand. In some embodiments, the ligand binds to the receptor of a cell. In some embodiments, the ligand binds to the polypeptide expressed on a surface of a cell. In some embodiments, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some embodiments, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some embodiments, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some embodiments, the antigen binding domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof. In some embodiments, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some embodiments, the ligand or fragment thereof is a monomer or a dimer. In some embodiments, the antigen binding domain does not comprise an antibody or fragment thereof. In some embodiments, the antigen binding domain does not comprise a variable region. In some embodiments, the antigen binding domain does not comprise a CDR. In some embodiments, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof. In some embodiments, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some embodiments, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some embodiments, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules. In some embodiments, the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some embodiments, the linker sequence comprises (G4S)n, wherein n=l to 4. In some embodiments, the transmembrane domain is a TCR transmembrane domain from TCR alpha or TCR beta, e.g., murine TCR alpha or TCR beta.

[0384] In some embodiments, the encoded TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit.

[0385] In some embodiments, the TCR extracellular domain comprises an extracellular domain or portion thereof of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some embodiments, the TCR subunit comprises a TCR intracellular domain of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, or an amino acid sequence having at least one modification thereto. In some embodiments, the TCR subunit further comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto.

[0386] In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some embodiments, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2,

CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), and 4-1BB (CD137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some embodiments, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP 12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some embodiments, the IT AM replaces an IT AM of CD3 gamma, CD3 delta, or CD3 epsilon. In some embodiments, the IT AM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit. In some embodiments, the TFP, the TCR alpha constant domain, the TCR beta domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide. In some embodiments, the TCR constant domain is a TCR alpha constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; the TCR constant domain is a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or the TCR constant domain is a TCR alpha constant domain and a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

[0387] In some embodiments, the nucleic acid is selected from the group consisting of a DNA and an RNA. In some embodiments, the nucleic acid is an mRNA. In some embodiments, the nucleic acid is a circRNA. In some embodiments, the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid. In some embodiments, the nucleic analog is selected from the group consisting of 2 ’-O-methyl, 2 ’-O-m ethoxy ethyl (2’-0-M0E), 2’-0-aminopropyl, 2’-deoxy, T- deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2'-0-dimethylaminoethyl (2’-0-DMA0E), 2’-0- dimethylaminopropyl (2’-0-DMAP), T-O-dimethylaminoethyloxyethyl (2’-0-DMAE0E), 2’-0- N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2’-fluoro N3- P5’-phosphoramidite. In some embodiments, the recombinant nucleic acid further comprises a leader sequence. In some embodiments, the recombinant nucleic acid further comprises a promoter sequence. In some embodiments, the recombinant nucleic acid further comprises a sequence encoding a poly(A) tail. In some embodiments, the recombinant nucleic acid further comprises a 3’UTR sequence. In some embodiments, the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid. In some embodiments, the nucleic acid is an in vitro transcribed nucleic acid.

[0388] In another aspect, the present disclosure provides a vector comprising the recombinant nucleic acid described herein.

[0389] In some embodiments, the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, an adeno-associated viral vector (AAV), a Rous sarcoma viral (RSV) vector, or a retrovirus vector. In some embodiments, the vector is an AAV6 vector. In some embodiments, the vector further comprises a promoter. In some embodiments, the vector is an in vitro transcribed vector.

[0390] In another aspect, the present disclosure provides a modified T cell comprising the recombinant nucleic acid described herein, or the vector described herein, and the modified T cell comprises a functional disruption of an endogenous TCR. [0391] In another aspect, the present disclosure provides modified T cell comprising the sequence encoding the TFP of the nucleic acid described herein or a TFP encoded by the sequence of the nucleic acid described herein encoding the TFP, and the modified T cell comprises a functional disruption of an endogenous TCR.

[0392] In another aspect, the present disclosure provides a modified allogenic T cell comprising the sequence encoding the TFP described herein or a TFP encoded by the sequence of the nucleic acid described herein encoding the TFP.

[0393] In some embodiments, the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain. In some embodiments, the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain. In some embodiments, the TCR constant domain, e g., the TCR alpha constant domain, the TCR beta constant domain or the TCR alpha constant domain and the TCR beta constant domain, is a murine TCR constant domain, e.g., a murine TCR alpha constant domain, a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain. In some embodiments, the endogenous TCR that is functionally disrupted is an endogenous TCR alpha chain, an endogenous TCR beta chain, or an endogenous TCR alpha chain and an endogenous TCR beta chain. In some embodiments, the endogenous TCR that is functionally disrupted has reduced binding to MHC -peptide complex compared to that of an unmodified control T cell. In some embodiments, the functional disruption is a disruption of a gene encoding the endogenous TCR. In some embodiments, the disruption of a gene encoding the endogenous TCR is a removal of a sequence of the gene encoding the endogenous TCR from the genome of a T cell. In some embodiments, the T cell is a human T cell selected from CD4 cells, CD8 cells, naive T-cells, memory stem T-cells, central memory T- cells, double negative T-cells, effector memory T-cells, effector T-cells, ThO cells, TcO cells, Thl cells, Tel cells, Th2 cells, Tc2 cells, Thl7 cells, Th22 cells, alpha/beta T cells, gamma/delta T cells, natural killer (NK) cells, natural killer T ( KT) cells, hematopoietic stem cells and pluripotent stem cells. In some embodiments, the T cell is a CD8+ or CD4+ T cell In some embodiments, the T cell is an allogenic T cell. In some embodiments, the modified T cell comprises a nucleic acid encoding an inhibitory molecule that comprises a first polypeptide comprising at least a portion of an inhibitory molecule, associated with a second polypeptide comprising a positive signal from an intracellular signaling domain. In some embodiments, the inhibitory molecule comprises the first polypeptide comprising at least a portion of PD1 and the second polypeptide comprising a costimulatory domain and primary signaling domain.

[0394] In another aspect, the present disclosure provides a pharmaceutical composition comprising: the modified T cells described herein; and a pharmaceutically acceptable carrier. [0395] In another aspect, the present disclosure provides a method of producing the modified T cell described herein, the method comprising disrupting an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain; thereby producing a T cell containing a functional disruption of an endogenous TCR gene; and transducing the T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid described herein, or the vector described herein.

[0396] In some embodiments, disrupting comprises transducing the T cell with a nuclease protein or a nucleic acid sequence encoding a nuclease protein that targets the endogenous gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain. [0397] In another aspect, the present disclosure provides a method of producing the modified T cell described herein, the method comprising transducing a T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid described herein, or the vector described herein.

[0398] In some embodiments, the T cell containing a functional disruption of an endogenous TCR gene is a T cell containing a functional disruption of an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain. In some embodiments, the T cell is a human T cell. In some embodiments, the T cell containing a functional disruption of an endogenous TCR gene has reduced binding to MHC-peptide complex compared to that of an unmodified control T cell. In some embodiments, the nuclease is a meganuclease, a zinc-finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a CRISPR/Cas nuclease, or a megaTAL nuclease. In some embodiments, the sequence comprised by the recombinant nucleic acid or the vector is inserted into the endogenous TCR subunit gene at the cleavage site, and wherein the insertion of the sequence into the endogenous TCR subunit gene functionally disrupts the endogenous TCR subunit. In some embodiments, the nuclease is a meganuclease. In some embodiments, the meganuclease comprises a first subunit and a second subunit, wherein the first subunit binds to a first recognition half-site of the recognition sequence, and wherein the second subunit binds to a second recognition half-site of the recognition sequence. In some embodiments, the meganuclease is a single-chain meganuclease comprising a linker, wherein the linker covalently joins the first subunit and the second subunit. [0399] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein.

[0400] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the method described herein; and (b) a pharmaceutically acceptable carrier.

[0401] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the method described herein; and (b) a pharmaceutically acceptable carrier.

[0402] In some embodiments, the modified T cell is an allogeneic T cell. In some embodiments, less cytokines are released in the subject compared a subject administered an effective amount of an unmodified control T cell. In some embodiments, less cytokines are released in the subject compared a subject administered an effective amount of a modified T cell comprising the recombinant nucleic acid described herein, or the vector described herein. In some embodiments, the method comprises administering the pharmaceutical composition in combination with an agent that increases the efficacy of the pharmaceutical composition. In some embodiments, the method comprises administering the pharmaceutical composition in combination with an agent that ameliorates one or more side effects associated with the pharmaceutical composition. In some embodiments, the cancer is a solid cancer, a lymphoma or a leukemia. In some embodiments, the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, cervical cancer, brain cancer, liver cancer, pancreatic cancer, kidney and stomach cancer. In some embodiments, less cytokines are released in the subject compared to a subject administered an effective amount of an autologous T cell expressing the TFP described herein. In some embodiments, the method does not induce graft versus host disease. In some embodiments, the subject has a reduced risk of developing graft versus host disease compared to a subject administered an effective amount of an autologous T cell expressing the TFP described herein.

[0403] In another aspect, the present disclosure provides the recombinant nucleic acid described herein, the vector described herein, the modified T cell described herein, or the pharmaceutical composition described herein, for use as a medicament or in the preparation of a medicament. [0404] Disclosed herein, in some embodiments, are recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, TCR gamma, TCR delta, TCR alpha or TCR beta, and (ii) a human or humanized antibody comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain, or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell. [0405] Disclosed herein, in some embodiments, are recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR gamma or TCR delta and (ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain, or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell comprising a functional disruption of an endogenous TCR.

[0406] In one embodiment, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to a sequence encoding a delta constant domain. In another embodiment, a sequence encoding the antigen binding domain or ligand binding domain is operatively linked to both a sequence encoding a TCR delta constant domain or fragment thereof and a TCR gamma constant domain or fragment thereof. In another embodiment, the intracellular signaling domain is CD3s. In another embodiment, the intracellular signaling domain is CD3y.

In another embodiment, the recombinant nucleic acid further comprises at least one leader sequence and at least one linker. In another embodiment, the recombinant nucleic acid further comprises a portion of a TCR alpha constant domain, a portion of a TCR beta domain, or both. [0407] In another embodiment, the recombinant nucleic acid sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRGC gene sequence. [0408] In another embodiment, the recombinant nucleic acid sequence comprises, from 5’-3’, a first leader sequence, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker sequence, and a TRGC gene sequence. [0409] In another embodiment, the recombinant nucleic acid sequence comprises, from 5’-3’, a first leader sequence, an antigen binding domain sequence, a first linker sequence, a TRDC gene sequence, a cleavable linker, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, and a TRGC gene sequence.

[0410] In another embodiment, the recombinant nucleic acid sequence comprises, from 5’-3’, a first leader sequence, a TRDC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRGC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence.

[0411] In another embodiment, the recombinant nucleic acid sequence comprises, from 5’-3’, a first leader sequence, a first antigen binding domain sequence, a first linker sequence, a TRDC gene sequence or fragment thereof, a TRAC gene sequence or fragment thereof, a cleavable linker sequence, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, a TRGC gene sequence or fragment thereof, and a TRBC gene sequence or fragment thereof.

[0412] In one embodiment, the sequence encodes the polypeptide as set forth in SEQ ID NO: 1.

In another embodiment, sequence encodes the polypeptide as set forth in SEQ ID NO:2. In another embodiment, the sequence encodes the polypeptide as set forth in SEQ ID NO:3. In another embodiment, the sequence encodes the polypeptide as set forth in SEQ ID NO:4. In another embodiment, the sequence encodes the polypeptide as set forth in SEQ ID NO: 5. In one embodiment, the recombinant nucleic acid sequence further comprises at least a partial sequence encoding a TCR alpha constant domain, a TCR beta constant domain, or a partial sequence of both a TCR alpha constant domain and a TCR beta constant domain.

[0413] In some instances, the binding ligand is capable of binding an Fc domain of the antibody. In some instances, the binding ligand is capable of selectively binding an IgGl antibody. In some instances, the binding ligand is capable of specifically binding an IgGl antibody. In some instances, the antibody or fragment thereof binds to a cell surface antigen. In some instances, the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell. In some instances, the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some instances, the binding ligand does not comprise an antibody or fragment thereof. In some instances, the binding ligand comprises a CD 16 polypeptide or fragment thereof. In some instances, the binding ligand comprises a CD16-binding polypeptide. In some instances, the binding ligand is human or humanized. In some instances, the recombinant nucleic acid further comprises a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand. In some instances, the antibody or fragment thereof is capable of being secreted from a cell.

[0414] Disclosed herein, in some embodiments, are recombinant nucleic acid comprising (a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a TCR extracellular domain, (2) a transmembrane domain, and (3) an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR gamma or TCR delta and (ii) an antigen domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and (b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a T cell comprising a functional disruption of an endogenous TCR. In some instances, the antigen domain comprises a ligand. In some instances, the ligand binds to the receptor of a cell. In some instances, the ligand binds to the polypeptide expressed on a surface of a cell. In some instances, the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide. In some instances, the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein. In some instances, the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof. In some instances, the antigen domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some instances, the antigen domain comprises a monomer or a dimer of the ligand or fragment thereof. In some instances, the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer. In some instances, the ligand or fragment thereof is a monomer or a dimer. In some instances, the antigen domain does not comprise an antibody or fragment thereof In some instances, the antigen domain does not comprise a variable region. In some instances, the antigen domain does not comprise a CDR. In some instances, the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof. [0415] In some embodiments, for the recombinant nucleic acids disclosed above, the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell. In some instances, the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within a same nucleic acid molecule. In some instances, the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules. In some instances, the TCR subunit and the antibody domain, the antigen domain or the binding ligand or fragment thereof are operatively linked by a linker sequence. In some instances, the linker sequence comprises (G4S)_n, wherein n=l to 4. In some instances, the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR gamma or TCR delta In some instances, the intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha, only TCR beta, only TCR gamma or only TCR delta. In some instances, the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit. In some instances, the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some instances, the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, a CD3 zeta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, CD45, CD4, CD5, CD8, CD9, CD 16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, CD154, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications. In some instances, the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto. In some instances, the TCR subunit comprises an intracellular domain comprising a stimulatory domain of a protein selected from a functional signaling domain of 4- 1BB and/or a functional signaling domain of CD3 zeta, or an amino acid sequence having at least one modification thereto. In some instances, the recombinant nucleic acid further comprises a sequence encoding a costimulatory domain. In some instances, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of 0X40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), and 4-lBB (CD 137), and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some instances, the TCR subunit comprises an immunoreceptor tyrosine-based activation motif (IT AM) of a TCR subunit that comprises an IT AM or portion thereof of a protein selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain, Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b 1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and amino acid sequences thereof having at least one but not more than 20 modifications thereto. In some instances, the ITAM replaces an ITAM of CD3 gamma, CD3 delta, or CD3 epsilon. In some instances, the ITAM is selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit and replaces a different ITAM selected from the group consisting of CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, and CD3 delta TCR subunit. In some instances, the TFP, the TCR gamma constant domain, the TCR delta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide. In some instances, (a) the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR delta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; (b) the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR gamma, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or (c) the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof. In some instances, the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP. In some instances, the antibody is an antibody fragment. In some instances, the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain. In some instances, human or humanized antibody comprising an antigen binding domain is selected from a group comprising an anti-CD 19 binding domain, anti-B-cell maturation antigen (BCMA) binding domain, anti-mesothelin (MSLN) binding domain, anti-MUC16 binding domain, anti-IL13Ra2 binding domain, anti-CD22 binding domain, anti-PD-1 binding domain, anti-PD-Ll binding domain, anti-BAFF or BAFF receptor binding domain, and anti-ROR-1 binding domain. In some instances, the nucleic acid is selected from the group consisting of a DNA and an RNA. In some instances, the nucleic acid is an mRNA. In some instances, the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid. In some instances, the nucleic analog is selected from the group consisting of 2 ’-O-methyl, 2 ’-O-m ethoxy ethyl (2’-0-M0E), 2’-0-aminopropyl, 2’-deoxy, T- deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2'-0-dimethylaminoethyl (2’-0-DMA0E), 2’-0- dimethylaminopropyl (2’-0-DMAP), T-O-dimethylaminoethyloxyethyl (2’-0-DMAE0E), 2’-0- N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2’-fluoro N3- P5’-phosphoramidite. In some instances, the recombinant nucleic acid further comprises a leader sequence. In some instances, the recombinant nucleic acid further comprises a promoter sequence. In some instances, the recombinant nucleic acid further comprises a sequence encoding a poly(A) tail. In some instances, the recombinant nucleic acid further comprises a 3’UTR sequence. In some instances, the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid. In some instances, the nucleic acid is an in vitro transcribed nucleic acid. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR beta transmembrane domain. In some instances, the recombinant nucleic acid further comprises a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain.

[0416] Disclosed herein, in some embodiments, are vectors comprising the recombinant nucleic acid disclosed herein. In some instances, the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, an adeno-associated viral vector (AAV), a Rous sarcoma viral (RSV) vector, or a retrovirus vector. In some instances, the vector is an AAV6 vector. In some instances, the vector further comprises a promoter. In some instances, the vector is an in vitro transcribed vector.

[0417] Disclosed herein, in some embodiments, are modified T cell comprising the recombinant nucleic acid disclosed above, or the vector disclosed above; wherein the modified T cell comprises a functional disruption of an endogenous TCR. Further disclosed herein, in some embodiments, are modified T cells comprising the sequence encoding the TFP of the nucleic acid disclosed above or a TFP encoded by the sequence of the nucleic acid disclosed above encoding the TFP, wherein the modified T cell comprises a functional disruption of an endogenous TCR. Also disclosed herein, are modified allogenic T cell comprising the sequence encoding the TFP disclosed above or a TFP encoded by the sequence of the nucleic acid disclosed above encoding the TFP. In some instances, the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain. In some instances, the endogenous TCR that is functionally disrupted is an endogenous TCR alpha chain, an endogenous TCR beta chain, or an endogenous TCR alpha chain and an endogenous TCR beta chain. In some instances, the endogenous TCR that is functionally disrupted has reduced binding to MHC-peptide complex compared to that of an unmodified control T cell. In some instances, the functional disruption is a disruption of a gene encoding the endogenous TCR. In some instances, the disruption of a gene encoding the endogenous TCR is a removal of a sequence of the gene encoding the endogenous TCR from the genome of a T cell. In some instances, the T cell is a human T cell. In some instances, the T cell is a CD8+ T cell, a CD4+ T cell, a naive T cell, a memory stem T cell, a central memory T cell, a double negative T cell, an effector memory T cell, an effector T cell, a ThO cell, a TcO cell, a Thl cell, a Tel cell, a Th2 cell, a Tc2 cell, a Thl 7 cell, a Th22 cell, a gamma delta T cell, a natural killer (NK) cell, a natural killer T (NKT) cell, a hematopoietic stem cell, or a pluripotent stem cell. In some instances, the T cell is a CD8+ or CD4+ T cell. In some embodiments, the T cell is a CD4+CD8+ T cell. In some instances, the T cell is an allogenic T cell. In some instances, the modified T cells further comprise a nucleic acid encoding an inhibitory molecule that comprises a first polypeptide comprising at least a portion of an inhibitory molecule, associated with a second polypeptide comprising a positive signal from an intracellular signaling domain. In some instances, the inhibitory molecule comprises the first polypeptide comprising at least a portion of PD1 and the second polypeptide comprising a costimulatory domain and primary signaling domain.

[0418] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising: (a) the modified T cells of the disclosure; and (b) a pharmaceutically acceptable carrier.

[0419] Disclosed herein, in some embodiments, are method of producing the modified T cell of the disclosure, the method comprising (a) disrupting an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain; thereby producing a T cell containing a functional disruption of an endogenous TCR gene; and (b) transducing the T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid, or the vector disclosed herein. In some instances, disrupting comprises transducing the T cell with a nuclease protein or a nucleic acid sequence encoding a nuclease protein that targets the endogenous gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain. Further disclosed herein, in some embodiments, are method of producing the modified T cell of the disclosure, the method comprising transducing a T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid, or the vector disclosed herein. In some instances, the T cell containing a functional disruption of an endogenous TCR gene is a T cell containing a functional disruption of an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain. In some instances, the T cell is a human T cell. In some instances, the T cell containing a functional disruption of an endogenous TCR gene has reduced binding to MHC -peptide complex compared to that of an unmodified control T cell. In some instances, the nuclease is a meganuclease, a zinc- finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a CRISPR/Cas nuclease, or a megaTAL nuclease. In some instances, the sequence comprised by the recombinant nucleic acid or the vector is inserted into the endogenous TCR subunit gene at the cleavage site, and wherein the insertion of the sequence into the endogenous TCR subunit gene functionally disrupts the endogenous TCR subunit. In some instances, the nuclease is a meganuclease. In some instances, the meganuclease comprises a first subunit and a second subunit, wherein the first subunit binds to a first recognition half-site of the recognition sequence, and wherein the second subunit binds to a second recognition half-site of the recognition sequence. In some instances, the meganuclease is a single-chain meganuclease comprising a linker, wherein the linker covalently joins the first subunit and the second subunit.

[0420] Disclosed herein, in some embodiments, are method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein. Also disclosed herein, in some embodiments, are method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the methods disclosed herein; and (b) a pharmaceutically acceptable carrier. In some instances, the modified T cell is an allogeneic T cell. In some instances, less cytokines are released in the subject compared a subject administered an effective amount of an unmodified control T cell. In some instances, less cytokines are released in the subject compared a subject administered an effective amount of a modified T cell comprising the recombinant nucleic acid disclosed herein, or the vector disclosed herein. In some instances, the method comprises administering the pharmaceutical composition in combination with an agent that increases the efficacy of the pharmaceutical composition. In some instances, the method comprises administering the pharmaceutical composition in combination with an agent that ameliorates one or more side effects associated with the pharmaceutical composition. In some instances, the cancer is a solid cancer, a lymphoma or a leukemia. In some instances, the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, cervical cancer, brain cancer, liver cancer, pancreatic cancer, kidney and stomach cancer.

[0421] Disclosed herein, in some embodiments, are recombinant nucleic acid, the vector, the modified T cell, or the pharmaceutical composition disclosed herein, for use as a medicament or in the preparation of a medicament.

Modified T cells

[0422] Disclosed herein, in some embodiments, are modified T cells comprising the recombinant nucleic acid disclosed herein, or the vectors disclosed herein; wherein the modified T cell comprises a functional disruption of an endogenous TCR. Also disclosed herein, in some embodiments, are modified T cells comprising the sequence encoding the TFP of the nucleic acid disclosed herein or a TFP encoded by the sequence of the nucleic acid disclosed herein, wherein the modified T cell comprises a functional disruption of an endogenous TCR. Further disclosed herein, in some embodiments, are modified allogenic T cells comprising the sequence encoding the TFP disclosed herein or a TFP encoded by the sequence of the nucleic acid disclosed herein. [0423] In some instances, the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain, a TCR alpha constant domain and a TCR beta constant domain, a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain. In some instances, the endogenous TCR that is functionally disrupted is an endogenous TCR alpha chain, an endogenous TCR beta constant domain, an endogenous TCR alpha constant domain and an endogenous TCR beta constant domain, an endogenous TCR gamma chain, an endogenous TCR delta chain, or an endogenous TCR gamma chain and an endogenous TCR delta chain. In some instances, the endogenous TCR that is functionally disrupted has reduced binding to MHC-peptide complex compared to that of an unmodified control T cell. In some instances, the functional disruption is a disruption of a gene encoding the endogenous TCR. In some instances, the disruption of a gene encoding the endogenous TCR is a removal of a sequence of the gene encoding the endogenous TCR from the genome of a T cell. In some instances, the T cell is a human T cell. In some instances, the T cell is a CD8+ or CD4+ T cell. In some instances, the T cell is an allogenic T cell. In some instances, the modified T cells further comprise a nucleic acid encoding an inhibitory molecule that comprises a first polypeptide comprising at least a portion of an inhibitory molecule, associated with a second polypeptide comprising a positive signal from an intracellular signaling domain. In some instances, the inhibitory molecule comprises the first polypeptide comprising at least a portion of PD1 and the second polypeptide comprising a costimulatory domain and primary signaling domain.

Sources of T cells

[0424] Prior to expansion and genetic modification, a source of T cells is obtained from a subject. The term “subject” is intended to include living organisms in which an immune response can be elicited ( e.g ., mammals). Examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain aspects of the present disclosure, any number of T cell lines available in the art, may be used. In certain aspects of the present disclosure, T cells can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll™ separation. In one preferred aspect, cells from the circulating blood of an individual are obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In one aspect, the cells collected by apheresis may be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps. In one aspect of the present disclosure, the cells are washed with phosphate buffered saline (PBS). In an alternative aspect, the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. Initial activation steps in the absence of calcium can lead to magnified activation. As those of ordinary skill in the art would readily appreciate a washing step may be accomplished by methods known to those in the art, such as by using a semi-automated “flow- through” centrifuge (for example, the Cobe® 2991 cell processor, the Baxter Oncology CytoMate™, or the Haemonetics® Cell Saver® 5) according to the manufacturer’s instructions. After washing, the cells may be resuspended in a variety of biocompatible buffers, such as, for example, Ca-free, Mg-free PBS, PlasmaLyte A, or other saline solution with or without buffer. Alternatively, the undesirable components of the apheresis sample may be removed, and the cells directly resuspended in culture media. [0425] In one aspect, T cells are isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL^®gradient or by counterflow centrifugal elutriation. A specific subpopulation of T cells, such as CD3+, CD28+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells, can be further isolated by positive or negative selection techniques. For example, in one aspect, T cells are isolated by incubation with anti-CD3/anti-CD28 (e.g., 3x28)-conjugated beads, such as DYNABEADS^® M-450 CD3/CD28 T, for a time period sufficient for positive selection of the desired T cells. In one aspect, the time period is about 30 minutes. In a further aspect, the time period ranges from 30 minutes to 36 hours or longer and all integer values there between. In a further aspect, the time period is at least 1, 2, 3, 4, 5, or 6 hours. In yet another preferred aspect, the time period is 10 to 24 hours. In one aspect, the incubation time period is 24 hours. Longer incubation times may be used to isolate T cells in any situation where there are few T cells as compared to other cell types, such in isolating tumor infiltrating lymphocytes (TIL) from tumor tissue or from immunocompromised individuals. Further, use of longer incubation times can increase the efficiency of capture of CD8+ T cells. Thus, by simply shortening or lengthening the time T cells are allowed to bind to the CD3/CD28 beads and/or by increasing or decreasing the ratio of beads to T cells (as described further herein), subpopulations of T cells can be preferentially selected for or against at culture initiation or at other time points during the process. Additionally, by increasing or decreasing the ratio of anti-CD3 and/or anti-CD28 antibodies on the beads or other surface, subpopulations of T cells can be preferentially selected for or against at culture initiation or at other desired time points. The skilled artisan would recognize that multiple rounds of selection can also be used in the context of this present disclosure. In certain aspects, it may be desirable to perform the selection procedure and use the “unselected” cells in the activation and expansion process. “Unselected” cells can also be subjected to further rounds of selection.

[0426] Enrichment of a T cell population by negative selection can be accomplished with a combination of antibodies directed to surface markers unique to the negatively selected cells.

One method is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected. For example, to enrich for CD4+ cells by negative selection, a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD1 lb, CD16, HLA-DR, and CD8. In certain aspects, it may be desirable to enrich for or positively select for regulatory T cells which typically express CD4+, CD25+, CD62Lhi, GITR+, and FoxP3+. Altematively, in certain aspects, T regulatory cells are depleted by anti-C25 conjugated beads or other similar method of selection.

[0427] In one embodiment, a T cell population can be selected that expresses one or more of IFN-g TNF-alpha, IL-17A, IL-2, IL-3, IL-4, GM-CSF, IL-10, IL-13, granzyme B, and perforin, or other appropriate molecules, e.g., other cytokines. Methods for screening for cell expression can be determined, e.g., by the methods described in PCT Publication No.: WO 2013/126712. [0428] For isolation of a desired population of cells by positive or negative selection, the concentration of cells and surface (e.g., particles such as beads) can be varied. In certain aspects, it may be desirable to significantly decrease the volume in which beads and cells are mixed together (e.g, increase the concentration of cells), to ensure maximum contact of cells and beads. For example, in one aspect, a concentration of 2 billion cells/mL is used. In one aspect, a concentration of 1 billion cells/mL is used. In a further aspect, greater than 100 million cells/mL is used. In a further aspect, a concentration of cells of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells/mL is used. In yet one aspect, a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/mL is used. In further aspects, concentrations of 125 or 150 million cells/mL can be used. Using high concentrations can result in increased cell yield, cell activation, and cell expansion. Further, use of high cell concentrations allows more efficient capture of cells that may weakly express target antigens of interest, such as CD28-negative T cells, or from samples where there are many tumor cells present (e.g., leukemic blood, tumor tissue, etc.). Such populations of cells may have therapeutic value and would be desirable to obtain. For example, using high concentration of cells allows more efficient selection of CD8+ T cells that normally have weaker CD28 expression.

[0429] In a related aspect, it may be desirable to use lower concentrations of cells. By significantly diluting the mixture of T cells and surface (e.g., particles such as beads), interactions between the particles and cells is minimized. This selects for cells that express high amounts of desired antigens to be bound to the particles. For example, CD4+ T cells express higher levels of CD28 and are more efficiently captured than CD8+ T cells in dilute concentrations. In one aspect, the concentration of cells used is 5xl0⁶/mL. In other aspects, the concentration used can be from about lxl0⁵/mL to lxlOVmL, and any integer value in between. In other aspects, the cells may be incubated on a rotator for varying lengths of time at varying speeds at either 2-10 °C or at room temperature.

[0430] T cells for stimulation can also be frozen after a washing step. Wishing not to be bound by theory, the freeze and subsequent thaw step provides a more uniform product by removing granulocytes and to some extent monocytes in the cell population. After the washing step that removes plasma and platelets, the cells may be suspended in a freezing solution. While many freezing solutions and parameters are known in the art and will be useful in this context, one method involves using PBS containing 20% DMSO and 8% human serum albumin, or culture media containing 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin and 7.5% DMSO, or 31.25% Plasmalyte-A, 31.25% Dextrose 5%, 0.45% NaCl, 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin, and 7.5% DMSO or other suitable cell freezing media containing for example, Hespan and PlasmaLyte A, the cells then are frozen to -80 °C at a rate of 1 per minute and stored in the vapor phase of a liquid nitrogen storage tank. Other methods of controlled freezing may be used as well as uncontrolled freezing immediately at -20 °C or in liquid nitrogen. In certain aspects, cryopreserved cells are thawed and washed as described herein and allowed to rest for one hour at room temperature prior to activation using the methods of the present disclosure.

[0431] Also contemplated in the context of the present disclosure is the collection of blood samples or apheresis product from a subject at a time period prior to when the expanded cells as described herein might be needed. As such, the source of the cells to be expanded can be collected at any time point necessary, and desired cells, such as T cells, isolated and frozen for later use in T cell therapy for any number of diseases or conditions that would benefit from T cell therapy, such as those described herein. In one aspect a blood sample or an apheresis is taken from a generally healthy subject. In certain aspects, a blood sample or an apheresis is taken from a generally healthy subject who is at risk of developing a disease, but who has not yet developed a disease, and the cells of interest are isolated and frozen for later use. In certain aspects, the T cells may be expanded, frozen, and used at a later time. In certain aspects, samples are collected from a patient shortly after diagnosis of a particular disease as described herein but prior to any treatments. In a further aspect, the cells are isolated from a blood sample or an apheresis from a subject prior to any number of relevant treatment modalities, including but not limited to treatment with agents such as natalizumab, efalizumab, antiviral agents, chemotherapy, radiation, immunosuppressive agents such as cyclosporin, azathioprine, methotrexate, and mycophenolate, antibodies, or other immunoablative agents such as alemtuzumab, anti-CD3 antibodies, cytoxan, fludarabine, cyclosporin, tacrolimus, rapamycin, mycophenolic acid, steroids, romidepsin, and irradiation.

[0432] In a further aspect of the present disclosure, T cells are obtained from a patient directly following treatment that leaves the subject with functional T cells. In this regard, it has been observed that following certain cancer treatments, in particular treatments with drugs that damage the immune system, shortly after treatment during the period when patients would normally be recovering from the treatment, the quality of T cells obtained may be optimal or improved for their ability to expand ex vivo. Likewise, following ex vivo manipulation using the methods described herein, these cells may be in a preferred state for enhanced engraftment and in vivo expansion. Thus, it is contemplated within the context of the present disclosure to collect blood cells, including T cells, dendritic cells, or other cells of the hematopoietic lineage, during this recovery phase. Further, in certain aspects, mobilization (for example, mobilization with GM-CSF) and conditioning regimens can be used to create a condition in a subject wherein repopulation, recirculation, regeneration, and/or expansion of particular cell types is favored, especially during a defined window of time following therapy. Illustrative cell types include T cells, B cells, dendritic cells, and other cells of the immune system.

Activation and Expansion of T Cells

[0433] T cells may be activated and expanded generally using methods as described, for example, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and 7,572,631.

[0434] Generally, the T cells of the present disclosure may be expanded by contact with a surface having attached thereto an agent that stimulates a CD3/TCR complex associated signal and a ligand that stimulates a costimulatory molecule on the surface of the T cells. In particular, T cell populations may be stimulated as described herein, such as by contact with an anti-CD3 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore. For co-stimulation of an accessory molecule on the surface of the T cells, a ligand that binds the accessory molecule is used. For example, a population of T cells can be contacted with an anti-CD3 antibody and an anti-CD28 antibody, under conditions appropriate for stimulating proliferation of the T cells. To stimulate proliferation of either CD4+ T cells or CD8+ T cells, an anti-CD3 antibody and an anti-CD28 antibody. Examples of an anti-CD28 antibody include 9.3, B-T3, XR-CD28 (Diaclone, Besancon, France) can be used as can other methods commonly known in the art (Berg et al., Transplant Proc. 30(8):3975-3977, 1998; Haanen et al., J. Exp. Med. 190(9): 13191328, 1999; Garland et al., J. Immunol. Meth. 227(1- 2): 53 -63, 1999). T cells may additionally be activated and expanded in the presence of a cytokine with or without an anti-CD3 and/or CD28 antibody. Exemplary cytokines include IL-2, IL-7, IL-15, and IL-21. [0435] T cells that have been exposed to varied stimulation times may exhibit different characteristics. For example, typical blood or apheresed peripheral blood mononuclear cell products have a helper T cell population (TH, CD4+) that is greater than the cytotoxic or suppressor T cell population (TC, CD8+). Ex vivo expansion of T cells by stimulating CD3 and CD28 receptors produces a population of T cells that prior to about days 8-9 consists predominately of TH cells, while after about days 8-9, the population of T cells comprises an increasingly greater population of TC cells. Accordingly, depending on the purpose of treatment, infusing a subject with a T cell population comprising predominately of TH cells may be advantageous. Similarly, if an antigen-specific subset of TC cells has been isolated it may be beneficial to expand this subset to a greater degree.

[0436] Further, in addition to CD4 and CD8 markers, other phenotypic markers vary significantly, but in large part, reproducibly during the course of the cell expansion process.

Thus, such reproducibility enables the ability to tailor an activated T cell product for specific purposes.

[0437] Once an anti-CD 19 anti-BCMA, anti-CD22, anti-RORl, anti-PD-1, or anti-BAFF, anti- MUC16, anti-mesothelin, anti-HER2, anti-PMSA, anti-CD20, anti-CD70, anti-GPC3, anti- Nectin-4, anti-Trop2, or antiCD79b TFP is constructed, various assays can be used to evaluate the activity of the molecule, such as but not limited to, the ability to expand T cells following antigen stimulation, sustain T cell expansion in the absence of re-stimulation, and anti-cancer activities in appropriate in vitro and animal models. Assays to evaluate the effects of an anti- CD^ anti-BCMA, anti-GPC3, anti-Nectin-4, anti-Trop2, anti-CD22, anti-MSLN, anti-CD79B, anti-RORl, anti-PD-1, anti-IL13Ra2, anti-PD-Ll, anti-CD20, anti-CD70, or anti-BAFF or BAFFR TFP are described in further detail below.

[0438] Western blot analysis of TFP expression in primary T cells can be used to detect the presence of monomers and dimers (see, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009)). Very briefly, T cells (1:1 mixture of CD4⁺ and CD8⁺ T cells) expressing the TFPs are expanded in vitro for more than 10 days followed by lysis and SDS-PAGE under reducing conditions. TFPs are detected by western blotting using an antibody to a TCR chain. The same T cell subsets are used for SDS-PAGE analysis under non-reducing conditions to permit evaluation of covalent dimer formation.

[0439] In vitro expansion of TFP⁺ T cells following antigen stimulation can be measured by flow cytometry. For example, a mixture of CD4⁺ and CD8⁺ T cells are stimulated with alphaCD3/alphaCD28 and APCs followed by transduction with lentiviral vectors expressing GFP under the control of the promoters to be analyzed. Exemplary promoters include the CMV IE gene, EF-lalpha, ubiquitin C, or phosphoglycerokinase (PGK) promoters. GFP fluorescence is evaluated on day 6 of culture in the CD4+ and/or CD8+ T cell subsets by flow cytometry (see, e.g ., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009)). Alternatively, a mixture of CD4+ and CD8+ T cells are stimulated with alphaCD3/alphaCD28 coated magnetic beads on day 0, and transduced with TFP on day 1 using a bicistronic lentiviral vector expressing TFP along with eGFP using a 2A ribosomal skipping sequence. Cultures are re-stimulated with either TAA+ K562 cells (K562-TAA), wild-type K562 cells (K562 wild type) or K562 cells expressing hCD32 and 4-1BBL in the presence of anti-CD3 and anti-CD28 antibody (K562-BBL-3/28) following washing. Exogenous IL-2 is added to the cultures every other day at 100 IU/mL. GFP+ T cells are enumerated by flow cytometry using bead-based counting (see, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009)).

[0440] Sustained TFP+ T cell expansion in the absence of re-stimulation can also be measured (see, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009)). Briefly, mean T cell volume (fl) is measured on day 8 of culture using a Coulter Multisizer III particle counter following stimulation with alphaCD3/alphaCD28 coated magnetic beads on day 0, and transduction with the indicated TFP on day 1.

[0441] Animal models can also be used to measure a TFP-T activity. For example, xenograft model using, e.g., human CD 19-specific TFP+ T cells to treat a primary human pre-B ALL in immunodeficient mice can be used (see, e.g., Milone et al, Molecular Therapy 17(8): 1453-1464 (2009)). After establishment of ALL, mice are randomized as to treatment groups. Different numbers of engineered T cells are coinjected at a 1:1 ratio into NOD/SC I D/y-/- mice bearing B- ALL. The number of copies of each vector in spleen DNA from mice is evaluated at various times following T cell injection. Animals are assessed for leukemia at weekly intervals.

Peripheral blood CD 19+ B-ALL blast cell counts are measured in mice that are injected with alphaCD19-zeta TFP+ T cells or mock-transduced T cells. Survival curves for the groups are compared using the log-rank test. In addition, absolute peripheral blood CD4+ and CD8+ T cell counts 4 weeks following T cell injection in NOD/SCID/y-/- mice can also be analyzed. Mice are injected with leukemic cells and 3 weeks later are injected with T cells engineered to express TFP by a bicistronic lentiviral vector that encodes the TFP linked to eGFP. T cells are normalized to 45-50% input GFP+ T cells by mixing with mock-transduced cells prior to injection, and confirmed by flow cytometry. Animals are assessed for leukemia at 1-week intervals. Survival curves for the TFP+ T cell groups are compared using the log-rank test.

[0442] Dose dependent TFP treatment response can be evaluated (see, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009)). For example, peripheral blood is obtained 35-70 days after establishing leukemia in mice injected on day 21 with TFP T cells, an equivalent number of mock-transduced T cells, or no T cells. Mice from each group are randomly bled for determination of peripheral blood CD 19+ ALL blast counts and then killed on days 35 and 49. The remaining animals are evaluated on days 57 and 70.

[0443] Assessment of cell proliferation and cytokine production has been previously described, e.g ., atMilone et al., Molecular Therapy 17(8): 1453-1464 (2009). Briefly, assessment of TFP- mediated proliferation is performed in microtiter plates by mixing washed T cells with K562 cells expressing the tumor associated antigen (TAA, e.g., CD19) CD19 (K19) or CD32 and CD137 (KT32-BBL) for a final T cell:K562 ratio of 2: 1. K562 cells are irradiated with gamma- radiation prior to use. Anti-CD3 (clone OKT3) and anti-CD28 (clone 9.3) monoclonal antibodies are added to cultures with KT32-BBL cells to serve as a positive control for stimulating T cell proliferation since these signals support long-term CD8+ T cell expansion ex vivo. T cells are enumerated in cultures using CountBright™ fluorescent beads (Invitrogen) and flow cytometry as described by the manufacturer. TFP+ T cells are identified by GFP expression using T cells that are engineered with eGFP-2A linked TFP-expressing lentiviral vectors. For TFP+ T cells not expressing GFP, the TFP+ T cells are detected with biotinylated recombinant CD 19 protein and a secondary avidin-PE conjugate. CD4+ and CD8+ expression on T cells are also simultaneously detected with specific monoclonal antibodies (BD Biosciences). Cytokine measurements are performed on supernatants collected 24 hours following re-stimulation using the human TH1/TH2 cytokine cytometric bead array kit (BD Biosciences) according the manufacturer’s instructions. Fluorescence is assessed using a FACScalibur™ flow cytometer (BD Biosciences), and data are analyzed according to the manufacturer’s instructions.

[0444] Cytotoxicity can be assessed by a standard ⁵¹Cr-release assay (see, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009)). Target cells (K562 lines and primary pro-B-ALL cells) are loaded with ⁵¹Cr (as NaCrCU, New England Nuclear) at 37 °C for 2 hours with frequent agitation, washed twice in complete RPMI and plated into microtiter plates. Effector T cells are mixed with target cells in the wells in complete RPMI at varying ratios of effector cell Target cell (E:T). Additional wells containing media only (spontaneous release, SR) or a 1% solution of Triton-X 100 detergent (total release, TR) are also prepared. After 4 hours of incubation at 37 °C, supernatant from each well is harvested Released ⁵¹Cr is then measured using a gamma particle counter (Packard Instrument Co., Waltham, Mass.). Each condition is performed in at least triplicate, and the percentage of lysis is calculated using the formula: % Lysis=(ER-SR)/(TR-SR), where ER represents the average ⁵¹Cr released for each experimental condition. [0445] Imaging technologies can be used to evaluate specific trafficking and proliferation of TFPs in tumor-bearing animal models. Such assays have been described, e.g., in Barrett et al., Human Gene Therapy 22:1575-1586 (2011). NOD/SCID/yc-/- (NSG) mice are injected IV with Nalm-6 cells (ATCC® CRL-3273™) followed 7 days later with T cells 4 hour after electroporation with the TFP constructs. The T cells are stably transfected with a lentiviral construct to express firefly luciferase, and mice are imaged for bioluminescence. Alternatively, therapeutic efficacy and specificity of a single injection of TFP+ T cells in Nalm-6 xenograft model can be measured as the following: NSG mice are injected with Nalm-6 transduced to stably express firefly luciferase, followed by a single tail-vein injection of T cells electroporated with a TAA-TFP 7 days later. Animals are imaged at various time points post injection. For example, photon-density heat maps of firefly luciferase positive leukemia in representative mice at day 5 (2 days before treatment) and day 8 (24 hours post TFP+ PBLs) can be generated.

[0446] Other assays, including those described in the Example section herein as well as those that are known in the art can also be used to evaluate the anti-CD 19, anti-BCMA, , anti-CD22, anti-MSLN, anti-CD79B, anti-GPC3, anti-Nectin-4, anti-Trop2, anti-IL13Ra2, anti-PD-1, anti- ROR1, anti-PD-Ll, or anti-BAFF or BAFFR TFP constructs disclosed herein.

Pharmaceutical Compositions

[0447] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising: (a) the modified T cells of the disclosure; and (b) a pharmaceutically acceptable carrier. Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives. Compositions of the present disclosure are in one aspect formulated for intravenous administration.

[0448] Pharmaceutical compositions of the present disclosure may be administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient’s disease, although appropriate dosages may be determined by clinical trials.

[0449] In one embodiment, the pharmaceutical composition is substantially free of, e.g., there are no detectable levels of a contaminant, e.g., selected from the group consisting of endotoxin, mycoplasma, replication competent lentivirus (RCL), p24, VSV-G nucleic acid, HIV gag, residual anti-CD3/anti-CD28 coated beads, mouse antibodies, pooled human serum, bovine serum albumin, bovine serum, culture media components, vector packaging cell or plasmid components, a bacterium and a fungus. In one embodiment, the bacterium is at least one selected from the group consisting of Alcaligenes faecalis, Candida albicans, Escherichia coli, Haemophilus influenza, Neisseria meningitides, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumonia, and Streptococcus pyogenes group A.

[0450] When “an immunologically effective amount,” “an anti-tumor effective amount,” “a tumor-inhibiting effective amount,” or “therapeutic amount” is indicated, the precise amount of the compositions of the present disclosure to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). It can generally be stated that a pharmaceutical composition comprising the T cells described herein may be administered at a dosage of 10⁴ to 10⁹ cells/kg body weight, in some instances 10⁵ to 10⁶ cells/kg body weight, including all integer values within those ranges. T cell compositions may also be administered multiple times at these dosages. The cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, e.g ., Rosenberg et al., New Eng. J. Med. 319:1676, 1988).

[0451] In certain aspects, it may be desired to administer activated T cells to a subject and then subsequently redraw blood (or have an apheresis performed), activate T cells therefrom according to the present disclosure, and reinfuse the patient with these activated and expanded T cells. This process can be carried out multiple times every few weeks. In certain aspects, T cells can be activated from blood draws of from 10 cc to 400 cc. In certain aspects, T cells are activated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc, 80 cc, 90 cc, or 100 cc. [0452] The administration of the subject compositions may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The compositions described herein may be administered to a patient trans arterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally. In one aspect, the T cell compositions of the present disclosure are administered to a patient by intradermal or subcutaneous injection. In one aspect, the T cell compositions of the present disclosure are administered by i.v. injection. The compositions of T cells may be injected directly into a tumor, lymph node, or site of infection.

[0453] In a particular exemplary aspect, subjects may undergo leukapheresis, wherein leukocytes are collected, enriched, or depleted ex vivo to select and/or isolate the cells of interest, e.g., T cells. These T cell isolates may be expanded by methods known in the art and treated such that one or more TFP constructs of the present disclosure may be introduced, thereby creating a modified T-T cell of the present disclosure. Subjects in need thereof may subsequently undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain aspects, following or concurrent with the transplant, subjects receive an infusion of the expanded modified T cells of the present disclosure. In an additional aspect, expanded cells are administered before or following surgery.

[0454] The dosage of the above treatments to be administered to a patient will vary with the precise nature of the condition being treated and the recipient of the treatment. The scaling of dosages for human administration can be performed according to art-accepted practices. The dose for alemtuzumab, for example, will generally be in the range 1 to about 100 mg for an adult patient, usually administered daily for a period between 1 and 30 days. The preferred daily dose is 1 to 10 mg per day although in some instances larger doses of up to 40 mg per day may be used (described in U.S. Pat. No. 6,120,766).

[0455] In one embodiment, the TFP is introduced into T cells, e.g ., using in vitro transcription, and the subject {e.g., human) receives an initial administration of TFP T cells of the present disclosure, and one or more subsequent administrations of the TFP T cells of the present disclosure, wherein the one or more subsequent administrations are administered less than 15 days, e.g., 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 days after the previous administration. In one embodiment, more than one administration of the TFP T cells of the present disclosure are administered to the subject (e.g., human) per week, e.g., 2, 3, or 4 administrations of the TFP T cells of the present disclosure are administered per week. In one embodiment, the subject (e.g., human subject) receives more than one administration of the TFP T cells per week (e.g, 2, 3 or 4 administrations per week) (also referred to herein as a cycle), followed by a week of no TFP T cells administrations, and then one or more additional administration of the TFP T cells (e.g, more than one administration of the TFP T cells per week) is administered to the subject. In another embodiment, the subject (e.g, human subject) receives more than one cycle of TFP T cells, and the time between each cycle is less than 10, 9, 8, 7, 6, 5, 4, or 3 days. In one embodiment, the TFP T cells are administered every other day for 3 administrations per week In one embodiment, the TFP T cells of the present disclosure are administered for at least two, three, four, five, six, seven, eight or more weeks.

[0456] In one aspect, CD 19 TFP T cells are generated using lentiviral viral vectors, such as lentivirus. TFP-T cells generated that way will have stable TFP expression.

[0457] In one aspect, TFP T cells transiently express TFP vectors for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days after transduction. Transient expression of TFPs can be affected by RNA TFP vector delivery. In one aspect, the TFP RNA is transduced into the T cell by electroporation. [0458] A potential issue that can arise in patients being treated using transiently expressing TFP T cells (particularly with murine scFv bearing TFP T cells) is anaphylaxis after multiple treatments.

[0459] Without being bound by this theory, it is believed that such an anaphylactic response might be caused by a patient developing humoral anti-TFP response, i.e., anti-TFP antibodies having an anti-IgE isotype. It is thought that a patient’s antibody producing cells undergo a class switch from IgG isotype (that does not cause anaphylaxis) to IgE isotype when there is a ten to fourteen day break in exposure to antigen.

[0460] If a patient is at high risk of generating an anti-TFP antibody response during the course of transient TFP therapy (such as those generated by RNA transductions), TFP T cell infusion breaks should not last more than ten to fourteen days.

Methods of Producing Modified T cells

[0461] Disclosed herein, in some embodiments, are methods of producing the modified T cell of the disclosure, the method comprising (a) disrupting an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, or any combination thereof; thereby producing a T cell containing a functional disruption of an endogenous TCR gene; and (b) transducing the T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid of the disclosure, or the vectors disclosed herein. In some instances, disrupting comprises transducing the T cell with a nuclease protein or a nucleic acid sequence encoding a nuclease protein that targets the endogenous gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain.

[0462] Further disclosed herein, in some embodiments, are methods of producing the modified T cell of the disclosure, the method comprising transducing a T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid disclosed herein, or the vectors disclosed herein. In some instances, the T cell containing a functional disruption of an endogenous TCR gene is a T cell containing a functional disruption of an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain. [0463] In some instances, the T cell is a human T cell. In some instances, the T cell containing a functional disruption of an endogenous TCR gene has reduced binding to MHC-peptide complex compared to that of an unmodified control T cell.

[0464] In some instances, the nuclease is a meganuclease, a zinc-finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a CRISPR/Cas nuclease, CRISPR/Cas nickase, or a megaTAL nuclease. In some instances, the sequence comprised by the recombinant nucleic acid or the vector is inserted into the endogenous TCR subunit gene at the cleavage site, and wherein the insertion of the sequence into the endogenous TCR subunit gene functionally disrupts the endogenous TCR subunit. In some instances, the nuclease is a meganuclease. In some instances, the meganuclease comprises a first subunit and a second subunit, wherein the first subunit binds to a first recognition half-site of the recognition sequence, and wherein the second subunit binds to a second recognition half-site of the recognition sequence. In some instances, the meganuclease is a single-chain meganuclease comprising a linker, wherein the linker covalently joins the first subunit and the second subunit.

Gene Editins Technologies

[0465] In some embodiments, the modified T cells disclosed herein are engineered using a gene editing technique such as clustered regularly interspaced short palindromic repeats (CRISPR®, see, e.g., US Patent No. 8,697,359), transcription activator-like effector (TALE) nucleases (TALENs, see, e.g., U.S. Patent No. 9,393,257), meganucleases (endodeoxyribonucl eases having large recognition sites comprising double-stranded DNA sequences of 12 to 40 base pairs), zinc finger nuclease (ZFN, see, e.g., Urnov et ah, Nat. Rev. Genetics (2010) vl 1, 636-646), or megaTAL nucleases (a fusion protein of a meganuclease to TAL repeats) methods. In this way, a chimeric construct may be engineered to combine desirable characteristics of each subunit, such as conformation or signaling capabilities. See also Sander & Joung, Nat. Biotech. (2014) v32, 347-55; and June et ah, 2009 Nature Reviews Immunol. 9.10: 704-716, each incorporated herein by reference. In some embodiments, one or more of the extracellular domain, the transmembrane domain, or the cytoplasmic domain of a TFP subunit are engineered to have aspects of more than one natural TCR subunit domain (i.e., are chimeric).

[0466] Recent developments of technologies to permanently alter the human genome and to introduce site-specific genome modifications in disease relevant genes lay the foundation for therapeutic applications. These technologies are now commonly known as “genome editing. [0467] The endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain can be inactivated in the modified cell (e.g., modified T cell) described herein. The inactivation can include disruption of genomic gene locus, gene silencing, inhibition or reduction of transcription, or inhibition or reduction of translation. The endogenous TCR gene can be silenced, for example, by inhibitory nucleic acids such as siRNA and shRNA. The translation of the endogenous TCR gene can be inhibited by inhibitory nucleic acids such as microRNA. In some embodiments, gene editing techniques are employed to disrupt an endogenous TCR gene. In some embodiments, mentioned endogenous TCR gene encodes a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain. In some embodiments, gene editing techniques pave the way for multiplex genomic editing, which allows simultaneous disruption of multiple genomic loci in endogenous TCR gene. In some embodiments, multiplex genomic editing techniques are applied to generate gene-disrupted T cells that are deficient in the expression of endogenous TCR, and/or human leukocyte antigens (HLAs), and/or programmed cell death protein 1 (PD1), and/or other genes.

[0468] Current gene editing technologies comprise meganucleases, zinc-finger nucleases (ZFN), TAL effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPRyCRISPR-associated (Cas) system. These four major classes of gene-editing techniques share a common mode of action in binding a user-defined sequence of DNA and mediating a double-stranded DNA break (DSB). DSB may then be repaired by either non-homologous end joining (NHEJ) or -when donor DNA is present- homologous recombination (HR), an event that introduces the homologous sequence from a donor DNA fragment. Additionally, nickase nucleases generate single-stranded DNA breaks (SSB). DSBs may be repaired by single strand DNA incorporation (ssDI) or single strand template repair (ssTR), an event that introduces the homologous sequence from a donor DNA.

[0469] Genetic modification of genomic DNA can be performed using site-specific, rare-cutting endonucleases that are engineered to recognize DNA sequences in the locus of interest. Methods for producing engineered, site-specific endonucleases are known in the art. For example, zinc- finger nucleases (ZFNs) can be engineered to recognize and cut predetermined sites in a genome. ZFNs are chimeric proteins comprising a zinc finger DNA-binding domain fused to the nuclease domain of the Fokl restriction enzyme. The zinc finger domain can be redesigned through rational or experimental means to produce a protein that binds to a pre-determined DNA sequence -18 basepairs in length. By fusing this engineered protein domain to the Fokl nuclease, it is possible to target DNA breaks with genome-level specificity. ZFNs have been used extensively to target gene addition, removal, and substitution in a wide range of eukaryotic organisms (reviewed in Durai et al. (2005), Nucleic Acids Res 33, 5978) Likewise, TAL-effector nucleases (TALENs) can be generated to cleave specific sites in genomic DNA. Like a ZFN, a TALEN comprises an engineered, site-specific DNA-binding domain fused to the Fokl nuclease domain (reviewed in Mak et al. (2013), Curr Opin Struct Biol 23:93-9). In this case, however, the DNA binding domain comprises a tandem array of TAL-effector domains, each of which specifically recognizes a single DNA basepair. Compact TALENs have an alternative endonuclease architecture that avoids the need for dimerization (Beurdeley et al. (2013), Nat Commun. 4: 1762). A Compact TALEN comprises an engineered, site-specific TAL-effector DNA-binding domain fused to the nuclease domain from the I-Tevl homing endonuclease.

Unlike Fokl, I-Tevl does not need to dimerize to produce a double-strand DNA break so a Compact TALEN is functional as a monomer.

[0470] Engineered endonucleases based on the CRISPR/Cas9 system are also known in the art (Ran et al. (2013), Nat Protoc. 8:2281-2308; Mali et al. (2013), Nat Methods 10:957-63). The CRISPR gene-editing technology is composed of an endonuclease protein whose DNA-targeting specificity and cutting activity can be programmed by a short guide RNA or a duplex crRNA/TracrRNA. A CRISPR endonuclease comprises two components: (1) a caspase effector nuclease, typically microbial Cas9; and (2) a short “guide RNA” or a RNA duplex comprising a 18 to 20 nucleotide targeting sequence that directs the nuclease to a location of interest in the genome. By expressing multiple guide RNAs in the same cell, each having a different targeting sequence, it is possible to target DNA breaks simultaneously to multiple sites in the genome (multiplex genomic editing).

[0471] There are two classes of CRISPR systems known in the art (Adli (2018) Nat. Commun. 9:1911), each containing multiple CRISPR types. Class 1 contains type I and type III CRISPR systems that are commonly found in Archaea. And, Class P contains type II, IV, V, and VI CRISPR systems. Although the most widely used CRISPR/Cas system is the type II CRISPR- Cas9 system, CRISPR/Cas systems have been repurposed by researchers for genome editing. More than 10 different CRISPR/Cas proteins have been remodeled within last few years (Adli (2018) Nat. Commun. 9: 1911). Among these, such as Casl2a (Cpfl) proteins from Acid- aminococcus sp (AsCpfl) and Lachnospiraceae bacterium (LbCpfl), are particularly interesting. [0472] Homing endonucleases are a group of naturally-occurring nucleases that recognize 15-40 base-pair cleavage sites commonly found in the genomes of plants and fungi. They are frequently associated with parasitic DNA elements, such as group 1 self-splicing introns and inteins. They naturally promote homologous recombination or gene insertion at specific locations in the host genome by producing a double -stranded break in the chromosome, which recruits the cellular DNA-repair machinery (Stoddard (2006), Q. Rev. Biophys. 38: 49-95) Specific amino acid substations could reprogram DNA cleavage specificity of homing nucleases (Niyonzima (2017), Protein Eng Des Sel. 30(7): 503-522). Meganucleases (MN) are monomeric proteins with innate nuclease activity that are derived from bacterial homing endonucleases and engineered for a unique target site (Gersbach (2016), Molecular Therapy. 24: 430-446). In some embodiments, meganuclease is engineered I-Crel homing endonuclease. In other embodiments, meganuclease is engineered I-Scel homing endonuclease. [0473] In addition to mentioned four major gene editing technologies, chimeric proteins comprising fusions of meganucleases, ZFNs, and TALENs have been engineered to generate novel monomeric enzymes that take advantage of the binding affinity of ZFNs and TALENs and the cleavage specificity of meganucleases (Gersbach (2016), Molecular Therapy 24: 430-446). For example, A megaTAL is a single chimeric protein, which is the combination of the easy-to- tailor DNA binding domains from TALENs with the high cleavage efficiency of meganucleases. [0474] In order to perform the gene editing technique, the nucleases, and in the case of the CRISPR/ Cas9 system, a gRNA, may need to be efficiently delivered to the cells of interest. Delivery methods such as physical, chemical, and viral methods are also know in the art (Mali (2013). Indian J. Hum. Genet. 19: 3-8.). In some instances, physical delivery methods can be selected from the methods but not limited to electroporation, microinjection, or use of ballistic particles. On the other hand, chemical delivery methods require use of complex molecules such calcium phosphate, lipid, or protein. In some embodiments, viral delivery methods are applied for gene editing techniques using viruses such as but not limited to adenovirus, lentivirus, and retrovirus.

[0475] As an example, the endogenous TCR gene (e.g., a TRAC locus or a TRBC locus) encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain can be inactivated by CRISPR/Cas9 system. The gRNA used to inactivate (e.g., disrupt) the TRAC locus can comprise a sequence of SEQ ID: 196. The gRNA used to disrupt the TRBC locus can comprise a sequence of SEQ ID: 197.

[0476] CTCGACCAGCTTGACATCAC (SEQ ID NO: 196).

[0477] ACACTGGTGTGCCTGGCCAC (SEQ ID NO: 197).

Methods of Treatment

[0478] Disclosed herein, in some embodiments, are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical compositions disclosed herein. Further disclosed herein, in some embodiments, are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the methods disclosed herein; and (b) a pharmaceutically acceptable carrier.

[0479] In some instances, the modified T cell is an allogeneic T cell. In some instances, less cytokines are released in the subject compared a subject administered an effective amount of an unmodified control T cell. In some instances, less cytokines are released in the subject compared a subject administered an effective amount of a modified T cell comprising the recombinant nucleic acid disclosed herein, or the vector disclosed herein.

[0480] In some instances, the method comprises administering the pharmaceutical composition in combination with an agent that increases the efficacy of the pharmaceutical composition. In some instances, the method comprises administering the pharmaceutical composition in combination with an agent that ameliorates one or more side effects associated with the pharmaceutical composition.

[0481] In some instances, the cancer is a solid cancer, a lymphoma or a leukemia. In some instances, the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, cervical cancer, brain cancer, liver cancer, pancreatic cancer, kidney and stomach cancer.

[0482] The present disclosure includes a type of cellular therapy where T cells are genetically modified to express a TFP and a TCR gamma and/or delta constant domain and the modified T cell is infused to a recipient in need thereof. The infused cell is able to kill tumor cells in the recipient. Unlike antibody therapies, modified T cells are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control. In various aspects, the T cells administered to the patient, or their progeny, persist in the patient for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen month, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty-one months, twenty-two months, twenty-three months, two years, three years, four years, or five years after administration of the T cell to the patient.

[0483] The present disclosure also includes a type of cellular therapy where T cells are modified, e.g ., by in vitro transcribed RNA, to transiently express a TFP and a TCR gamma and/or delta constant domain and the modified T cell is infused to a recipient in need thereof. The infused cell is able to kill tumor cells in the recipient. Thus, in various aspects, the T cells administered to the patient, is present for less than one month, e.g., three weeks, two weeks, or one week, after administration of the T cell to the patient.

[0484] Without wishing to be bound by any particular theory, the anti-tumor immunity response elicited by the modified T cells may be an active or a passive immune response, or alternatively may be due to a direct vs indirect immune response.

[0485] In one aspect, the human modified T cells of the disclosure may be a type of vaccine for ex vivo immunization and/or in vivo therapy in a mammal In one aspect, the mammal is a human. [0486] With respect to ex vivo immunization, at least one of the following occurs in vitro prior to administering the cell into a mammal: i) expansion of the cells, ii) introducing a nucleic acid encoding a TFP and a TCR gamma and/or delta constant domain to the cells or iii) cryopreservation of the cells.

[0487] Ex vivo procedures are well known in the art and are discussed more fully below. Briefly, cells are isolated from a mammal ( e.g ., a human) and genetically modified (i.e., transduced or transfected in vitro ) with a vector disclosed herein. The modified T cell can be administered to a mammalian recipient to provide a therapeutic benefit. The mammalian recipient may be a human and the modified cell can be autologous with respect to the recipient. Alternatively, the cells can be allogeneic, syngeneic or xenogeneic with respect to the recipient.

[0488] The procedure for ex vivo expansion of hematopoietic stem and progenitor cells is described in U.S. Pat. No. 5,199,942, incorporated herein by reference, can be applied to the cells of the present disclosure. Other suitable methods are known in the art, therefore the present disclosure is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of T cells comprises: (1) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo. In addition to the cellular growth factors described in U.S. Pat. No. 5,199,942, other factors such as flt3-L, IL-1, IL-3 and c-kit ligand, can be used for culturing and expansion of the cells.

[0489] In addition to using a cell-based vaccine in terms of ex vivo immunization, the present disclosure also provides compositions and methods for in vivo immunization to elicit an immune response directed against an antigen in a patient.

[0490] Generally, the cells activated and expanded as described herein may be utilized in the treatment and prevention of diseases that arise in individuals who are immunocompromised. [0491] The modified T cells of the present disclosure may be administered either alone, or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2 or other cytokines or cell populations.

Combination Therapies

[0492] A modified T cell described herein may be used in combination with other known agents and therapies. Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. [0493] In some embodiments, the “at least one additional therapeutic agent” includes a modified T cell. Also provided are T cells that express multiple TFPs, which bind to the same or different target antigens, or same or different epitopes on the same target antigen. Also provided are populations of T cells in which a first subset of T cells express a first TFP and a TCR gamma and/or delta constant domain and a second subset of T cells express a second TFP and a TCR gamma and/or delta constant domain.

[0494] A modified T cell described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the modified T cell described herein can be administered first, and the additional agent can be administered second, or the order of administration can be reversed. [0495] In further aspects, a modified T cell described herein may be used in a treatment regimen in combination with surgery, chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and tacrolimus, antibodies, or other immunoablative agents such as alemtuzumab, anti-CD3 antibodies or other antibody therapies, cytoxin, fludarabine, cyclosporin, tacrolimus, rapamycin, mycophenolic acid, steroids, romidepsin, cytokines, and irradiation peptide vaccine, such as that described in Izumoto et al., 2008 J. Neurosurg. 108:963-971.

[0496] In one embodiment, the subject can be administered an agent which reduces or ameliorates a side effect associated with the administration of a modified T cell. Side effects associated with the administration of a modified T cell include but are not limited to cytokine release syndrome (CRS), and hemophagocytic lymphohistiocytosis (HLH), also termed Macrophage Activation Syndrome (MAS). Symptoms of CRS include high fevers, nausea, transient hypotension, hypoxia, and the like. Accordingly, the methods disclosed herein can comprise administering a modified T cell described herein to a subject and further administering an agent to manage elevated levels of a soluble factor resulting from treatment with a modified T cell. In one embodiment, the soluble factor elevated in the subject is one or more of PTM-g,

TNFa, IL-2 and IL-6. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. Such agents include, but are not limited to a steroid, an inhibitor of TNFa, and an inhibitor of IL-6. An example of a TNFa inhibitor is entanercept. An example of an IL-6 inhibitor is tocilizumab (toe).

[0497] In one embodiment, the subject can be administered an agent which enhances the activity of a modified T cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., Programmed Death 1 (PD1), can, in some embodiments, decrease the ability of a modified T cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and TGFR beta. Inhibition of an inhibitory molecule, e.g., by inhibition at the DNA, RNA or protein level, can optimize a modified T cell performance. In embodiments, an inhibitory nucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., an siRNA or shRNA, can be used to inhibit expression of an inhibitory molecule in the TFP- expressing cell. In an embodiment the inhibitor is a shRNA. In an embodiment, the inhibitory molecule is inhibited within a modified T cell. In these embodiments, a dsRNA molecule that inhibits expression of the inhibitory molecule is linked to the nucleic acid that encodes a component, e.g., all of the components, of the TFP. In one embodiment, the inhibitor of an inhibitory signal can be, e.g., an antibody or antibody fragment that binds to an inhibitory molecule. For example, the agent can be an antibody or antibody fragment that binds to PD1, PD-L1, PD-L2 or CTLA4 (e.g., ipilimumab (also referred to as MDX-010 and MDX-101, and marketed as Yervoy^®; Bristol-Myers Squibb; tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206)). In an embodiment, the agent is an antibody or antibody fragment that binds to TIM3. In an embodiment, the agent is an antibody or antibody fragment that binds to LAG3.

[0498] In some embodiments, the agent which enhances the activity of a modified T cell can be, e.g., a fusion protein comprising a first domain and a second domain, wherein the first domain is an inhibitory molecule, or fragment thereof, and the second domain is a polypeptide that is associated with a positive signal, e.g., a polypeptide comprising an intracellular signaling domain as described herein. In some embodiments, the polypeptide that is associated with a positive signal can include a costimulatory domain of CD28, CD27, ICOS, e.g., an intracellular signaling domain of CD28, CD27 and/or ICOS, and/or a primary signaling domain, e.g., of CD3 zeta, e.g., described herein. In one embodiment, the fusion protein is expressed by the same cell that expressed the TFP. In another embodiment, the fusion protein is expressed by a cell, e.g., a T cell that does not express an anti-TAA TFP.

EXAMPLES

[0499] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples specifically point out various aspects of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

Background for Examples

[0500] T-Cell Receptor (TCR) is formed by a complex of dimers TCRoc/b, CD3y/s, CD36/s and the homodimer ϋϋ3z/z. In some particular T cells, TCRy/d are expressed instead of TCRa/b to form a functional TCR. TCRa/b/g/d have a constant domain common to all T-cells and a variable domain specific to an antigen. TRAC, TRBC, TRGC and TRDC genes encode for the constant C-terminal region of TCRa, TCRb, TCRy and TCRb respectively. Despite high structural homology between those molecules, TCRa only pairs with TCRb and TCRy only pairs with TCRb. Hence, a TCR complex is formed with TCRa/b in a/b T cells or with TCRy/d in g/d T cells.

[0501] Disruption of the TCRa/b/g/d constant region(s) blocks the translocation of TCR protein(s) to the cell surface. Thus, inhibiting assembly of the TCR receptor complex. Impairing the translocation of a TCRa or TCRb is enough to inhibit the assembling of entire TCR receptor in TCRa/b T cells. Similarly, impairing the translocation of a TCRy or TCRb is enough to inhibit assembly of the entire TCR receptor in TCRy/d T cells. Inactivation of the TCR complex may therefore be done by targeting the TRAC or TRBC genes with a gene editing method using clustered regularly interspaced short palindromic repeat (CRISPR) method, transcription activator-like effector nucleases (TALENs), zinc finger nucleases or meganucleases. However, TFP T cells based on CD3s or CD3y or CD35 fusion proteins require surface expression of TCRot/b or TCRy/d to incorporate into a functional TCR complex.

[0502] Activation of the TCR complex on the surface of alloreactive donor T cells by mismatched HLA molecules or cognate antigens (i.e., recognition of antigens presented by the major histocompatibility complex (MHC) on antigen presenting cells) can trigger unwanted effects such as graft-versus-host disease (GvHD) and cytokine release syndrome (CRS). Thus, the following Examples describe methods of introducing a transgene in TCRa or TCR knock out cells encoding for a truncated version of TCRa (murine) and TCRP (murine) having a binder on one or both, or on a CD3 TFP, or a truncated or full length TCRy or TCR5, having a binder on one or both truncated TCRs, or on a CD3 TFP with the fusion protein itself separated by a self cleavage signal (e.g., T2A). In one embodiment, the truncated version of TCRy or TCR5 includes the transmembrane domain and the connecting peptide domain (CP), and the constant domain of TCRy or TCR6. In another embodiment, the truncated version of TCRy or TCR5 includes the transmembrane domain and the connecting peptide domain (CP), and the constant domain of TCRa or TCR . In another embodiment, the TFP’s antigen binding domain is fused at the N- terminal end of either or both the truncated TCRy and/or TCR5.

Example 1. crRNA (CRISPR RNA) design

[0503] crRNAs to inactivate TRA were designed with “Dunne 2017” algorithm accessible on DeskGen™ CRISPR library website (www.deskgen.com). Any crRNAs binding the TRA locus are able to efficiently generate double strand breaks in the TRA gene. To minimize off-target activity of the CRISPR endonuclease, the crRNAs used have an off-target score of >90%, comprising at least 3 mismatches with the closest homolog sequence in the Genome Reference Consortium Human genome build 38 (GRCh38/hg38) genome. In a preferred embodiment, one mismatch is located in the 8 bp upstream to the protospacer adjacent motif (PAM). Tables 1-2 show exemplary crRNA sequences selected to inactivate the TRA gene (Table 1) and predicted off target activity (Table 2).

Table 1: crRNAs selected to inactivate TRA gene:

Table 2: Predicted off-target sites; mismatches between on and off-target are indicated in bold

[0504] crRNAs to inactivate the TRBC genes were designed with Dunne 2017 algorithm as described above. As the constant region of TCRJ3 is encoded by two genes, TRBC1 and TRBC2, crRNAs are directed against sequences identical in both TRBC1 and TRBC2. Consequently, the off-target score generated by DeskGen™ is lower than 94%. However, aside from targeting TRBC1 and TRBC2, other homolog sequences between crRNAs and the GRCh38/hg38 genome carry at least 3 mismatches. In a preferred embodiment, one of those mismatches is localized in the 8 bp upstream to the Protospacer adjacent motif (PAM). Tables 3-4 show exemplary crRNA sequences selected to inactivate the TRB gene (Table 3) and predicted off target activity (Table

4)·

Table 3: crRNAs selected to inactivate TRB gene

Table 4: Predicted off-targets, mismatches between on and off-target are indicted in bold

Example 2: Editing of endogenous TCRa or b in Jurkat cells

[0505] Inactivation of the TRAC or TRBC genes in Jurkat cells was done by electroporation of SpCas9 ribonucleoproteins (RNPs) directed against TRAC or TRBC genes. Cells were maintained at 0.2xl0⁶ cells per mL in RPMI 1640 medium supplemented with 10% Fetal Bovine Serum (FBS) and 300mg/L L-Glutamine until electroporation. SpCas9 ribonucleoproteins targeting TRA or TRB genes were prepared by annealing crRNA targeting either TRAC (TRAC2-4598) or TRBC (TRBC-44345) with tracrRNA at a molecular ratio of 1 : 1. Annealed duplexes were mixed with SpCas9 protein at a molecular ratio of 1.5:1. 0.61 mM of RNPs were mixed with 2.5xl0⁶ T cells and electroporated according to the manufacturer’s protocol for the Neon Transfection System (Thermo Fisher Scientific). Electroporation was set at 1600V, 10ms, 3 pulses. After pulse the cells were immediately transferred to warm medium and incubated at 37°C for three days.

[0506] Editing efficacy was assessed by observing loss of surface expression of TCRocP and CD3s via flow cytometry. Results are shown in Figure 1 for TRA edited cells (left panel) and TRB edited cells (right panel). Edited Jurkat cells were purified via Magnetic- Activated Cell Sorting (MACS, Miltenyi Biotec) cell separation system. Edited Jurkat cells were negatively selected against anti-TCRocP (clone: IP27) (eBioscience #17-9986-42) antibody and anti-CD3s (clone: SK7) antibody (eBioscience #25-0036-42). Cells expressing TCRocP or CD3s at their surface were immobilized to MACS MS (Cat. #130-041-301) or LS (Cat. #130-041-306) columns, while edited Jurkat cells, negative for both TCRocP and CD3s, were collected in the column flow through and maintained in culture at 0.4xl0⁶ cells/mL in the medium specified above. TCRa and TCRp knock out cells are herein called TRA-/- or TRB-/- Jurkat cells.

Example 3: Generation of allogeneic T cell receptor fusion protein T cells

Transduction of Jurkat cells

[0507] TFP transgenes were introduced in Jurkat cells using lentiviruses as described, e.g., in co pending U.S. Patent Publication No. 2017-0166622. Jurkat cells were incubated with virus at a multiplicity of infection (MO I) of five. Medium was replaced twenty-four-hours post incubation. Transduction efficacy and TFP expression was assessed with flow cytometry using a ligand specific to the TFP binder of interest and/or surface expression of TCRaJ3 and CD3s. TRAC-/- and TRBC-/- Jurkat cells were transduced with TCR/d TFPs and restoration of surface TCR was indicated by highly positive CD3e staining (Figure 2). TRBC-/- Jurkat cells were also transduced with anti-CD 19 TCRfi TFP or anti-CD 19 TCRfl TFP having only the constant domain of TCRP (Figure 12B). The results show that, while the TFP having the entire human TCRP is expressed on the cell surface, the TFP having only the constant domain of human TCRP is not expressed on the cell surface (Figure 13). This is because the constant domain of TCRP is not able to localize to the cell surface, whereas it is known that the constant domain of murine TCRP and murine human chimeras of the TCRP are able to localize to the cell surface. Transduction of T cells

[0508] TFP transgenes were introduced into T cells using lentiviruses as described, e.g., in copending U.S. Patent Publication No. 2017-0166622. T cells were mixed together with viruses at a multiplicity of infection (MOI) of five plus lOOng/mL of LentiBOOST™ (Sirion Biotech). Transduction efficacy and TFP expression was assessed with flow cytometry using a ligand specific to the TFP binder of interest and/or surface expression of TCRaP and CD3e.

Description of Transgenes

[0509] In a/b T cells inactivation of TRAC or TRBC blocks the translocation to the cell surface of all TCR subunits. TCRa or TCRP cannot pair with TCRy or TCR5. Consequently, an exogenous TRGC and TRDC transgenes or TRAC and TRBC transgenes are expressed in TRAC⁷ or TRBC⁷ cells to restore a functional TFP T cell.

Expression of human TCRy/d TFP

[0510] TCRa negative cells still express TCRP and, reciprocally, TCRa is expressed in TCRP negative cells; However, TCRa or TCRp cannot pair with TCRv or TCR6. Therefore, TCRy TFP and TCR5 TFPs were expressed together in TRAC⁷ cells or in TRB⁷ cells. Multiple formats of TCRy/d TFPs were tested in TCR negative cells to determine the optimal construction to restore translocation of the entire TCR complex (see Figure 3 schematic). In one embodiment, TCRy/d TFPs were generated by assembling the constant domains of TCRy or/and TCR5 with an antigen binder (e.g., scFv or sdAb). In another embodiment, TCRv/d constant domains are expressed together with a CD3c TFP (Figure 4) TRGC1 and TRDC residues are numerated according to the the sequences provided herein and according to international ImMunoGeneTics information system (IMGT).

Source of TCR Subunits

[0511] A TCR complex contains the CD3-epsilon polypeptide, the CD3-gamma poly peptide, the CD3-delta polypeptide, and the TCR alpha chain polypeptide and the TCR beta chain polypeptide or the TCR delta chain polypeptide and the TCR gamma chain polypeptide. TCR alpha, TCR beta, TCR gamma, and TCR delta recruit the CD3 zeta polypeptide. The human CD3-epsilon polypeptide canonical sequence is Uniprot Accession No. P07766. The human CD3-gamma polypeptide canonical sequence is Uniprot Accession No. P09693. The human CD3-delta polypeptide canonical sequence is Uniprot Accession No. P043234. The human CD3- zeta polypeptide canonical sequence is Uniprot Accession No. P20963. The human TCR alpha chain canonical sequence is Uniprot Accession No. Q6ISU1. The murine TCR alpha chain canonical sequence is Uniprot Accession No. A0A075B662. The human TCR beta chain constant region canonical sequence is Uniprot Accession No. P01850. The murine TCR beta chain constant region canonical sequence is Uniprot Accession No. P01852.

[0512] The human CD3-epsilon polypeptide canonical sequence is:

MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILW QUNDKNIGGDEDDKNIGSDEDHLSLKEF SELEQ SGYYV CYPRGSKPED ANF YLYLRARV CENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQ NKERPPPVPNPD YEPIRKGQRDLY SGLNQRRI (SEQ ID NO: 124).

[0513] The mature human CD3-epsilon polypeptide sequence is:

DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHL SLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITG GLLLLVYYW SKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPD YEPIRKGQRDLY S GLNQRRI (SEQ ID NO:258).

[0514] The signal peptide of human CD3e is:

MQSGTHWRVLGLCLLSVGVWGQ (SEQ ID NO: 125)

[0515] The extracellular domain of human CD3e is:

DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHL SLKEF SELEQ S GYYVCYPRGSKPED ANF YLYLRARV CENCMEMD (SEQ ID NO: 126). [0516] The transmembrane domain of human CD3c is:

VMS VATIVIVDICIT GGLLLLVYYW S (SEQ ID NO: 127).

[0517] The intracellular domain of human CD3 is:

KNRR AK AKP VTRGAGAGGRQRGQNKERPPP VPNPD YEPIRKGQRDL Y S GLN QRRI (SEQ ID NO: 128).

[0518] The human CD3-gamma polypeptide canonical sequence is:

MEOGKGT A VT II A Til J OGTT AOSTKGNHT VK VYDY OEDGSVT J TCP AE AKNTTWTKDG KMIGFLTEDKKKWNLGSNAKDPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATISG FLFAEIVSIFVLAVGVYFIAGQDGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQG NQLRRN (SEQ ID NO: 129).

[0519] The mature human CD3-gamma polypeptide sequence is:

QSD GNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGKMIGFLTEDKKKWNLGSNAK DPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATISGFLFAEIVSIFVLAVGVYFIAGQ DGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLRRN (SEQ ID NO: 130). [0520] The signal peptide of human CD3y is:

MEOGKGT A VT II A ill J QGTI A (SEQ ID NO: 131).

[0521] The extracellular domain of human CD3y is:

QSD GNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGKMIGFLTEDKKKWNLGSNAK DPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATIS (SEQ ID NO: 132).

[0522] The transmembrane domain of human CD3 g is:

GFLFAEIV SIF VLAVGVYFIA (SEQ ID NO: 133).

[0523] The intracellular domain of human CD3y is:

GQDGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLRRN (SEQ ID NO: 134). [0524] The human CD3-delta polypeptide canonical sequence is:

MEHSTFLSGLVLATLLSQVSPFKIPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDLG KRILDPRGIYRCNGTDIYKDKESTVQVHYRMCQSCVELDPATVAGIIVTDVIATLLLALG VFCFAGHETGRLSGAADTQALLRNDQVYQPLRDRDDAQYSHLGGNWARNKS (SEQ ID NO: 135).

[0525] The mature human CD3 -delta polypeptide sequence is:

FKIPIEELEDRVF VN CNT SIT W VEGT V GTLL SDITRLDLGKRILDPRGIYRCN GTDIYKDKE S T VQ VHYRMC Q S C VELDP AT VAGIIVTD VIATLLL ALGVF CF AGHET GRLS GAADT Q AL LRNDQVYQPLRDRDDAQYSHLGGNWARNKS (SEQ ID NO: 136).

[0526] The signal peptide of human CD35 is:

MEHSTFLSGLVLATLLSQVSP (SEQ ID NO: 137). [0527] The extracellular domain of human CD35 is:

FKIPIEELEDRVF VN CNT SIT W VEGT V GTLL SDITRLDLGKRILDPRGFYRCN GTDFYKDKE STVQVHYRMCQSCVELDPATVA (SEQ ID NO: 138).

[0528] The transmembrane domain of human CD36 is:

GIIVTD VIATLLL ALGVF CF A (SEQ ID NO: 139).

[0529] The intracellular domain of human CD35 is:

GHETGRLSGAADTQALLRNDQVYQPLRDRDDAQYSHLGGNWARNK (SEQ ID NO: 140) [0530] The human CD3-zeta polypeptide canonical sequence is:

MKWKALFTAAILQ AQLPITEAQ SF GLLDPKLCYLLDGILFIY GVILT ALFLRVKF SRS AD A P A YOOGONOT YNF.I NT GRRFFYDVi DK R R GR DPFViGGK POR R K NPOFGT YNF.I OKDK MAEAY SEIGMKGERRRGKGHDGLY QGLSTATKDTYD ALHMQALPPR (SEQ ID NO: 141).

[0531] The human TCR alpha chain constant region canonical sequence is:

IQNPDP A VY QLRD SK S SDKS VCLFTDFD SQTNVSQ SKD SDVYITDKTVLDMRSMDFKSN SAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRI LLLKVAGFNLLMTLRLW S S (SEQ ID NO: 142).

[0532] The human TCR alpha chain human IgC sequence is:

IQNPDP A VYQLRD SK S SDKS VCLFTDFD SQTNVSQ SKD SDVYITDKTVLDMRSMDFKSN SAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLS (SEQ ID NO: 143)

[0533] The transmembrane domain of the human TCR alpha chain is:

VIGFRILLLK V AGFNLLMTLRLW (SEQ ID NO: 144).

[0534] The intracellular domain of the human TCR alpha chain is: SS (SEQ ID NO: 145)

[0535] The murine TCR alpha chain constant (mTRAC) region canonical sequence is: XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSN GAIAWSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILL LKV AGFNLLMTLRLW S S (SEQ ID NO: 146)

[0536] The transmembrane domain of the murine TCR alpha chain is:

MGLRILLLKV AGFNLLMTLRLW (SEQ ID NO: 147).

[0537] The intracellular domain of the murine TCR alpha chain is: SS

[0538] The human TCR beta chain constant region (mTRBC) canonical sequence is:

EDLNK VFPPEVA VFEP SEAEISHT QK ATLV CLAT GFFPDHVEL S W W VN GKEVHS GV S TD PQPLKEQP ALND SRYCLS SRLRVS ATFWQNPRNHFRCQ VQF YGLSENDEWTQDRAKP V TQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRK DF (SEQ ID NO: 148).

[0539] The human TCR beta chain human IgC sequence is:

EDLNK VFPPEV A VFEP SEAEISHT QK ATLV CLAT GFFPDHVEL S W W VN GKE VHS GV S TD PQPLKEQP ALND SRYCLS SRLRVS ATFWQNPR HFRCQ VQF YGLSENDEWTQDRAKP V TQIVSAEAWGRADCGFTSVSYQQGVLSATILYE (SEQ ID NO: 149)

[0540] The transmembrane domain of the human TCR beta chain is:

ILLGKATLY AVLV S ALVLMAM (SEQ ID NO: 150).

[0541] The intracellular domain of the human TCR beta chain is:

VKRKDF (SEQ ID NO: 151)

[0542] The murine TCR beta chain constant region canonical sequence is:

EDLRNVTPPK V SLFEP SK AEIANKQK ATL V CL ARGFFPDHVEL S W W VNGKEVHS GV S TD PQAYKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNIS AEAW GRADCGITS ASY QQGVLS ATILYEILLGKATLYAVLVSTLVVMAMVKRKN S (SEQ ID NO: 152).

[0543] The transmembrane domain of the murine TCR beta chain is:

IL YEILLGK ATLY AVLV S TLVVMAMVK (SEQ ID NO: 153).

[0544] The intracellular domain of the murine TCR beta chain is:

KRKNS (SEQ ID NO: 154)

[0545] The human TCR gamma chain constant region canonical sequence is: DKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGN TMKTNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDN C SKD ANDTLLLQLTNT S A YYM YLLLLLK S V VYF AIITC CLLRRT AF CCN GEK S (SEQ ID NO:21).

[0546] The human TCR gamma human IgC sequence is:

DKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGN TMKTNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDN C SKD ANDTLLLQLTNT S A (SEQ ID NO: 155)

[0547] The transmembrane domain of the human TCR gamma chain is:

YYMYLLLLLK S VV YF AIIT CCLL (SEQ ID NO 156)

[0548] The intracellular domain of the human TCR gamma chain is:

RRTAFCCNGEKS (SEQ ID NO: 157)

[0549] The human TCR delta chain C region canonical sequence is: SQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLG K YEDSNS VT C S VQHDNKT VHS TDFEVKTD S TDHVKPKETENTKQP SKS CHKPK AIVHTE KVNMMSLTVLGLRMLFAKTVAVNFLLTAKLFFL (SEQ ID NO:243).

[0550] The human TCR delta human IgC sequence is:

SQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLG KYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHTE KVNMMSLTV (SEQ ID NO: 265)

[0551] The transmembrane domain of the human TCR delta chain is:

LGLRMLF AKT V A VNFLLTAKLFF (SEQ ID NO: 158).

[0552] The intracellular domain of the human TCR delta chain is: L

TCRy/d FMC63 TFP expressed in TRA or J RB cells

Nt-FMC63-TRDC(1-153)-T2A-TRGC1(1-173)-Ct including signal peptide (Nt-FMC63- TRDC(-6, 189)-2A-TRGC1(1.8, 189)-Ct according to IMGT numbering):

MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPD

GTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKL

EITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPP

RKGLEWLGYIW GSETT YYNS ALK SRLTIDCDN SK S Q VFLKMN SLQTDDT AIY Y C AKHYY Y

GGS Y AMD YW GQGT S VT V S S AAAGGGGSGGGGS GGGGSLE S QPHTKP S VF VMKN GTNV A

CLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHS

TDFEVKTD S TDHVKPKETENTKQP SK SCHKPK AIVHTEK V MM SLT VLGLRMLF AKT VA V

NFLLTAKLFFLGSGEGRGSLLTCGDVEENPGPMLLLVTSLLLCELPHPAFLLIPDKQLDADV

SPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGNTMKTNDTYM

KFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQ

LTNTSAYYMYLLLLLKSVVYFAIITCCLLRRTAFCCNGEKS (SEQ ED NO: l)

Nt-FMC63-TRDC(1-153)-T2A-FMC63-TRGC1(1-173)-Ct (Nt-FMC63-TRDC(-6,1 89)-2A- FMC63-TRGC1(1.8, 189)-Ct according to IMGT numbering):

MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPD GTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKL EITGSTSGSGKPGSGEGSTKGEVKLQESGPGLYAPSQSLSVTCTYSGYSLPDYGVSWIRQPP RKGLEWLGVIW GSETT YYNS ALK SRLTIIKDN SK S Q VFLKMN SLQTDDT AIY Y C AKFIYY Y GGS Y AMD YW GQGT S VT V S S AAAGGGGSGGGGS GGGGSLE S QPHTKP S VF VMKN GTNVA CLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHS TDFEVKTD S TDHVKPKETENTKQP SK SCHKPK AIVHTEK VNMM SLT VLGLRMLF AKT VA V NFLLTAKLFFLGSGEGRGSLLTCGDVEENPGPMLLLVTSLLLCELPHPAFLLIPDIQMTQTTS SLSASLGDRVTISCRASQDISKYL WYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDY SLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGP GLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIK DN SKSQ VFLKMN SLQTDDTAIYYC AKHYYY GGS YAMD YW GQGTS VTV S S AAAGGGGSG GGGS GGGGSLEDKQLD AD V SPKPTIFLP S IAETKLQK AGT YLCLLEKFFPD VD IHW QEKK S NTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVI TMDPKDN C SKD AND TLLLQLTNT S A Y YM YLLLLLK S V V YF AIIT C CLLRRT AF C CN GEK S (SEQ ID NO: 2)

Nt-TRDC(l-153)-T2A-TRGCl(l-173)-T2A-FMC63-CD3s(l-185)-Ct (Nt-TRDC(-6, 189)-2A- TRGC1(1.8, 189)-2A-FMC63-CD3s(l, 186)-Ct according to IMGT numbering):

MLLLVTSLLLCELPHPAFLLIPSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKIT

EFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETEN

TKQP SK S CHKPK AILΉTEK VNMMSLT VLGLRMLF AKT V A VNFLLT AKLFFLGS GEGRGSLL

TCGDVEENPGPMLLLVTSLLLCELPHPAFLLIPDKQLDADVSPKPTIFLPSIAETKLQKAGTY

LCLLEKFFPDVIKIHWQEKKSNTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDKEHRCIVR

HENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQLTNTSAYYMYLLLLLKSVYY

FAIITCCLLRRTAFCCNGEKSGSGEGRGSLLTCGDVEENPGPMLLLVTSLLLCELPHPAFLLIP

DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRF

SGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKG

EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNS

ALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSA

AAGGGGSGGGGSGGGGSLEDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDK

NIGGDEDDKNIGSDEDHLSLKEF SELEQ S GYYV C YPRGSKPED ANF YLYLR ARV CEN CME

MDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVP

NPDYEPIRKGQRDLY SGLNQRRI (SEQ ID NO:3)

Nt- TRDC(1-153)-T2A-FMC63-TRGC 1 (1 -173)-Ct-( Nt-TRDC(-6,189)-2A-FMC63- TRGC1(1.8, 189)-Ct according to IMGT numbering) (with signal peptide):

MLLLVTSLLLCELPHPAFLLIPSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKIT

EFDP AIVISP SGKYNA VKLGKYED SN S VTCS VQHDNKT VHSTDFEVKTD STDHVKPKETEN

TKQP SK S CHKPK AIVHTEK VNMMSLT VLGLRMLF AKT V A VNFLLT AKLFFLGS GEGRGSLL

TCGDVEENPGPMLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISK

YLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNT

LPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLP

DYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTA

IYY C AKHYYY GGS Y AMD YW GQGTS VT V S S AAAGGGGSGGGGSGGGGSLEDKQLD AD V S

PKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGNTMKTNDTYMK

FSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQL

TNTS AYYMYLLLLLKS VVYF AIIT CCLLRRT AFCCNGEKS (SEQ ID NO:4)

Nt- FMC63-TRDC(1-129)-TRAC(116-140)-T2A-FMC63-TRGC1(1-106)-TRBC1(145-177)-Ct (Nt- FMC63-TRDC(-6, 165)-TRAC(150, 174)-2A-FMC63-TRGC1(1.8, 189)-TRBC1(142, 173)- Ct according to IMGT numbering) :

MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPD GTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKL EITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPP RKGLEWLGVIW GSETT YYNS ALK SRLTIDCDN SK S Q VFLKMN SLQTDDT AIY Y C AKHYYY GGS Y AMD YW GQGT S VT V S S AAAGGGGSGGGGS GGGGSLE S QPHTKP S VF VMKN GTNV A CLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHS TDFEVKTD S TDHVKPKETENTKQP SK SCHKPK AIVHTEK VNMM SLT VYIGFRILLLK V AGF NLLMTLRLWSSGSGEGRGSLLTCGDVEENPGPMLLLVTSLLLCELPHPAFLLIPDIQMTQTT SSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTD YSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESG PGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTII KDN SKSQ VFLKMN SLQTDDTAIYYC AKHYYY GGS YAMD YW GQGT S VTV S S AAAGGGGS GGGGS GGGGSLEDKQLD AD V SPKPTIFLP S I AETKLQK AGT YLCLLEKFFPD VIKIHW QEKK SNTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPTILYEI LLGKATLYAVLV S ALVLMAMVKRKDF (SEQ ID NO: 5)

Nt-FMC63-TRDC(1-153)-T2A-TRGC1(1-173)-Ct without signal peptide (amino acid sequence) (Nt-FMC63-TRDC(-6, 189)-2A-TRGC1(1.8, 189)-Ct according to IMGT numbering):

DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRF

SGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKG

EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNS

ALKSRLTUKDN SKSQ VFLKMN SLQTDDT AIYY C AKHYYY GGS YAMD YW GQGT S VTV S S A

AAGGGGSGGGGSGGGGSLESQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITE

FDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENT

KQP SK S CF1KPK AIVHTEK VNMM SLT VLGLRMLF AKT VAVNELLT AKLFFLGS GEGRGSLLT

CGDVEENPGPMLLLVTSLLLCELPHPAFLLIPDKQLDADVSPKPTIFLPSIAETKLQKAGTYL

CLLEKFFPDVDCIHWQEKKSNTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDKEHRCIVRH

ENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQLTNTSAYYMYLLLLLKSVVYF

AIITCCLLRRTAFCCNGEKS (SEQ ID NO:6)

Nt-FMC63-TRDC(1-153)-T2A-TRGC1(1-173)-Ct without signal peptide (nucleic acid sequence) (Nt-FMC63-TRDC(-6, 189)-2A-TRGC1(1.8, 189)-Ct according to IMGT numbering):

GACATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCAC

CATCAGTTGCAGGGCAAGTCAGGACATTAGTAAATATTTAAATTGGTATCAGCAGAAA

CCAGATGGAACTGTTAAACTCCTGATCTACCATACATCAAGATTACACTCAGGAGTCCC

ATCAAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGG

AGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTC

GGAGGGGGGACTAAGTTGGAAATAACAGGCTCCACCTCTGGATCCGGCAAGCCCGGAT

CTGGCGAGGGATCCACCAAGGGCGAGGTGAAACTGCAGGAGTCAGGACCTGGCCTGGT

GGCGCCCTCACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCATTACCCGACT

ATGGTGTAAGCTGGATTCGCCAGCCTCCACGAAAGGGTCTGGAGTGGCTGGGAGTAAT

ATGGGGTAGTGAAACCACATACTATAATTCAGCTCTCAAATCCAGACTGACCATCATCA

AGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACAC

AGCCATTTACTACTGTGCCAAACATTATTACTACGGTGGTAGCTATGCTATGGACTACT

GGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCGGCCGCAGGTGGAGGAGGTTCTGG

AGGTGGTGGATCAGGTGGTGGAGGATCTTTAGAAAGTCAGCCTCATACCAAACCATCC

GTTTTTGTCATGAAAAATGGAACAAATGTCGCTTGTCTGGTGAAGGAATTCTACCCCAA

GGATATAAGAATAAATCTCGTGTCATCCAAGAAGATAACAGAGTTTGATCCTGCTATTG

TCATCTCTCCCAGTGGGAAGTACAATGCTGTCAAGCTTGGTAAATATGAAGATTCAAAT TCAGTGACATGTTCAGTTCAACACGACAATAAAACTGTGCACTCCACTGACTTTGAAGT

GAAGACAGATTCTACAGATCACGTAAAACCAAAGGAAACTGAAAACACAAAGCAACC

TTCAAAGAGCTGCCATAAACCCAAAGCCATAGTTCATACCGAGAAGGTGAACATGATG

TCCCTCACAGTGCTTGGGCTACGAATGCTGTTTGCAAAGACTGTTGCCGTCAATTTTCTC

TTGACTGCCAAGTTATTTTTCTTGGGGTCAGGCGAGGGCAGAGGAAGTCTGCTAACATG

CGGTGACGTCGAGGAGAATCCTGGACCTATGCTACTACTTGTGACCTCACTATTGTTAT

GCGAACTCCCTCATCCCGCATTCTTGCTGATTCCAGATAAACAACTTGATGCAGATGTT

TCCCCCAAGCCCACTATTTTTCTTCCTTCAATTGCTGAAACAAAGCTCCAGAAGGCTGG

AACATACCTTTGTCTTCTTGAGAAATTTTTCCCTGATGTTATTAAGATACATTGGCAAGA

AAAGAAGAGC AAC ACGATTCTGGGAT CC C AGGAGGGGAAC AC C AT GAAGAC T A ACGA

C AC AT AC AT GAAATTT AGC TGGTT AAC GGT GC C AGAAAAGT C AC T GGAC AAAGAAC AC

AGATGTATCGTCAGACATGAGAATAATAAAAACGGAGTTGATCAAGAAATTATCTTTC

CTCCAATAAAGACAGATGTCATCACAATGGATCCCAAAGACAATTGTTCAAAAGATGC

AAATGATACACTACTGCTGCAGCTCACAAACACCTCTGCATATTACATGTACCTCCTCC

TGCTCCTCAAGAGTGTGGTCTATTTTGCCATCATCACCTGCTGTCTGCTTAGAAGAACG

GCTTTCTGCTGC AATGGAGAGAAAT C A (SEQ ID NO: 7)

Nt-TRDC(1-153)-T2A-FMC63-TRGC1(1-173)-Ct (without signal peptide; amino acid sequence) (Nt-TRDC(-6,189)-2A-FMC63-TRGC1(1.8, 189)-Ct according to IMGT numbering) :

SQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGK

YEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHTEKVN

MMSLTVLGLRMLFAKTVAVNFLLTAKLFFLGSGEGRGSLLTCGDVEENPGPMLLLVTSLLL

CELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHT

SRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSG

KPGSGEGSTKGEVKLQESGPGLYAPSQSLSVTCTYSGYSLPDYGVSWIRQPPRKGLEWLGV

IWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYW

GQGTSVTVSSAAAGGGGSGGGGSGGGGSLEDKQLDADVSPKPTIFLPSIAETKLQKAGTYL

CLLEKFFPDVDCIHWQEKKSNTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDKEHRCIVRH

ENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQLTNTSAYYMYLLLLLKSVVYF

AIITCCLLRRTAFCCNGEKS (SEQ ID NO: 8)

Nt-TRDC(1-153)-T2A-FMC63-TRGC1(1-173)-Ct (with signal peptide; nucleic acid sequence) (Nt-TRDC(-6,189)-2A-FMC63-TRGC1(1.8, 189)-Ct according to IMGT numbering):

AGTCAGCCTCATACCAAACCATCCGTTTTTGTCATGAAAAATGGAACAAATGTCGCTTG

TCTGGTGAAGGAATTCTACCCCAAGGATATAAGAATAAATCTCGTGTCATCCAAGAAG

ATAACAGAGTTTGATCCTGCTATTGTCATCTCTCCCAGTGGGAAGTACAATGCTGTCAA

GCTTGGTAAATATGAAGATTCAAATTCAGTGACATGTTCAGTTCAACACGACAATAAA

ACTGTGCACTCCACTGACTTTGAAGTGAAGACAGATTCTACAGATCACGTAAAACCAA

AGGAAACTGAAAACACAAAGCAACCTTCAAAGAGCTGCCATAAACCCAAAGCCATAGT

TCATACCGAGAAGGTGAACATGATGTCCCTCACAGTGCTTGGGCTACGAATGCTGTTTG

CAAAGACTGTTGCCGTCAATTTTCTCTTGACTGCCAAGTTATTTTTCTTGGGGTCAGGCG

AGGGCAGAGGAAGTCTGCTAACATGCGGTGACGTCGAGGAGAATCCTGGACCTATGCT

ACTACTTGTGACCTCACTATTGTTATGCGAACTCCCTCATCCCGCATTCTTGCTGATTCC

AGACATTCAGATGACTCAAACAACTTCCAGCCTCTCCGCCTCACTCGGCGACCGCGTAA CAATAAGCTGTCGGGCCTCGCAAGATATTAGTAAGTACCTGAATTGGTATCAGCAAAA

ACCCGATGGTACAGTCAAGCTTCTGATCTACCATACCAGTCGTCTGCACAGCGGTGTCC

CCAGCAGGTTCAGCGGCTCAGGATCTGGTACCGATTATTCACTGACGATTTCCAACCTT

GAGCAGGAGGACATCGCCACCTACTTCTGCCAGCAGGGTAATACTCTGCCGTACACATT

CGGGGGCGGTACCAAGCTCGAGATCACGGGTTCAACAAGCGGTTCTGGCAAGCCAGGC

AGCGGCGAGGGGAGTACAAAGGGGGAGGTGAAGTTGCAGGAAAGTGGCCCTGGATTG

GTGGCCCCGAGCCAGAGTCTGTCTGTCACCTGCACAGTTTCCGGAGTAAGTCTGCCTGA

TTACGGAGTGTCCTGGATCAGACAGCCACCTCGAAAGGGCTTGGAGTGGCTTGGGGTC

ATTTGGGGCAGTGAAACCACATACTACAACAGCGCTCTTAAGTCCAGGCTCACTATCAT

CAAGGACAATTCAAAGAGCCAAGTATTCTTGAAAATGAATTCCCTGCAGACTGATGAC

ACCGCTATTTATTATTGCGCTAAACATTATTACTATGGAGGTTCTTATGCCATGGACTAC

TGGGGGCAGGGTACCTCTGTGACAGTGAGTTCAGCTGCAGCTGGAGGTGGAGGTAGCG

GAGGCGGT GGT AGT GGAGGGGGT GGTT C TC T GGAAGAT AAAC AACTT GAT GC AGAT GT

TTCCCCCAAGCCCACTATTTTTCTTCCTTCAATTGCTGAAACAAAGCTCCAGAAGGCTG

GAACATACCTTTGTCTTCTTGAGAAATTTTTCCCTGATGTTATTAAGATACATTGGCAAG

AAAAGAAGAGCAACACGATTCTGGGATCCCAGGAGGGGAACACCATGAAGACTAACG

ACACATACATGAAATTTAGCTGGTTAACGGTGCCAGAAAAGTCACTGGACAAAGAACA

C AGAT GTAT CGT CAGACAT GAGAATAATAAAAACGGAGTTGAT C AAGAAATTATCTTT

CCTCCAATAAAGACAGATGTCATCACAATGGATCCCAAAGACAATTGTTCAAAAGATG

CAAATGATACACTACTGCTGCAGCTCACAAACACCTCTGCATATTACATGTACCTCCTC

CTGCTCCTCAAGAGTGTGGTCTATTTTGCCATCATCACCTGCTGTCTGCTTAGAAGAAC

GGCTTTCTGCTGCAATGGAGAGAAATCA (SEQ ID NO: 9)

Expression of murine KΊ Li TFP

[0553] TCRa negative cells still express TCRJ3 and, reciprocally, TCRa is expressed in TCR negative cells; However, TCRa or TCRp TFPs generated by assembling the constant domains of TCRa and/or TCR with an antigen binder (e.g., scFv or sdAb) can pair with the constant domain of TCRa or TCRp. However, the constant domain of human TCRa and TCRP is not able to migrate to the cell surface. Murine or human murine chimera TCRa and TCRP constant domains can be used. Figure 12A is a schematic diagram showing which TFPs can and cannot reconsititute at the cell surface. Murine anti-CD 19 TCRa TFP including the murine TCRa constant, intracellular, and transmembrane domains and a protein comprising the TCR constant, intracellular, and transmembrane domains were expressed together in TRA cells or in TRB cells. In one embodiment, TCRa TFPs were generated by assembling the constant domain of TCRa with an antigen binder (e.g., scFv or sdAb).

TCRyld FMC63 TFP expressed in TRA or TRB^~ cells Nt-pLRPO FMC63-mTRAC(82-137) T2A mTRBC(123-173)-Ct (Nt-pLRPO FMC63- mTRAC(197-252) T2A mTRBC(233-283)-Ct according to IMGT numbering) (amino acid sequence):

DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRF S GS GS GTD YSLTISNLEQEDIAT YF C QQGNTLP YTF GGGTKLEIT GGGGS GGGGS GGGGSEV KLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSAL KSRLTID DNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSGAT YPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRLWSSGSGEGRG SLLTCGDVEENPGPGRADCGITS ASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVK RKNS (SEQ ID NO: 10)

Nt-pLRPO FMC63-mTRAC(82-137) T2A mTRBC(123-173)-Ct (Nt-pLRPO FMC63- mTRAC(197-252) T2A mTRBC(233-283)-Ct according to IMGT numbering) (nucleic acid sequence):

GACATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCAC

CATCAGTTGCAGGGCAAGTCAGGACATTAGTAAATATTTAAATTGGTATCAGCAGAAA

CCAGATGGAACTGTTAAACTCCTGATCTACCATACATCAAGATTACACTCAGGAGTCCC

ATCAAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGG

AGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTC

GGAGGGGGGACTAAGTTGGAAATAACAGGAGGTGGAGGTTCTGGTGGAGGAGGTTCA

GGAGGTGGTGGAAGTGAGGTGAAACTGCAGGAGTCAGGACCTGGCCTGGTGGCGCCCT

CACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCATTACCCGACTATGGTGTA

AGC T GGATT CGC C AGC C TC C AC GA A AGGGT C T GGAGT GGC T GGGAGT A AT AT GGGGT A

GTGAAACCACATACTATAATTCAGCTCTCAAATCCAGACTGACCATCATCAAGGACAA

CTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATTT

ACTACTGTGCCAAACATTATTACTACGGTGGTAGCTATGCTATGGACTACTGGGGTCAA

GGAACCTCAGTCACCGTCTCCTCAGGAGCCACCTACCCCAGTTCAGACGTTCCCTGTGA

TGCCACGTTGACTGAGAAAAGCTTTGAAACAGATATGAACCTAAACTTTCAAAACCTGT

CAGTTATGGGACTCCGAATCCTCCTGCTGAAAGTAGCCGGATTTAACCTGCTCATGACG

CTGAGGCTGTGGTCCAGTGGCAGCGGCGAGGGCAGAGGAAGTCTGCTAACATGCGGTG

ACGTCGAGGAGAATCCTGGACCTGGTCGAGCAGACTGTGGTATTACCTCAGCATCCTAT

CAACAAGGAGTCTTGTCTGCCACCATCCTCTATGAGATCCTGCTAGGGAAAGCCACCCT

GTATGCTGTGCTTGTCAGTACACTGGTGGTGATGGCTATGGTCAAAAGAAAGAATTCA

(SEQ ID NO: 11) pLRPO FMC63-TCRbetal (amino acid sequence)

DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRF

SGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKG

EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNS

ALKSRLTIIKDN SKSQ VFLKMN SLQTDDT AIYY C AKHYYY GGS YAMD YW GQGT S VTV S S A

AAGGGGSGGGGSGGGGSLELGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVSWY

QQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSPRT

GLNTEAFFGQGTRLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSW

WVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSE NDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAYLVSA LVLMAMVKRKDF (SEQ ID NO: 12) pLRPO FMC63-TCRbetal (nucleic acid sequence)

GACATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCAC

CATCAGTTGCAGGGCAAGTCAGGACATTAGTAAATATTTAAATTGGTATCAGCAGAAA

CCAGATGGAACTGTTAAACTCCTGATCTACCATACATCAAGATTACACTCAGGAGTCCC

ATCAAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGG

AGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTC

GGAGGGGGGACTAAGTTGGAAATAACAGGCTCCACCTCTGGATCCGGCAAGCCCGGAT

CTGGCGAGGGATCCACCAAGGGCGAGGTGAAACTGCAGGAGTCAGGACCTGGCCTGGT

GGCGCCCTCACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCATTACCCGACT

ATGGTGTAAGCTGGATTCGCCAGCCTCCACGAAAGGGTCTGGAGTGGCTGGGAGTAAT

ATGGGGTAGTGAAACCACATACTATAATTCAGCTCTCAAATCCAGACTGACCATCATCA

AGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACAC

AGCCATTTACTACTGTGCCAAACATTATTACTACGGTGGTAGCTATGCTATGGACTACT

GGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCGGCCGCAGGTGGAGGAGGTTCTGG

AGGTGGAGGTTCAGGTGGAGGTGGTTCACTCGAGCTGGGAGCAGGCCCAGTGGATTCT

GGAGTCACACAAACCCCAAAGCACCTGATCACAGCAACTGGACAGCGAGTGACGCTGA

GATGCTCCCCTAGGTCTGGAGACCTCTCTGTGTCATGGTACCAACAGAGCCTGGACCAG

GGCCTC C AGTT C CTC ATT C AGT ATT AT AAT GGAGAAGAGAGAGC AAAAGGAAAC ATT C

TTGAACGATTCTCCGCACAACAGTTCCCTGACTTGCACTCTGAACTAAACCTGAGCTCT

CTGGAGCTGGGGGACTCAGCTTTGTATTTCTGTGCCAGCAGCCCCCGGACAGGCCTGAA

CACTGAAGCTTTCTTTGGACAAGGCACCAGACTCACAGTTGTAGAGGACCTGAACAAG

GTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCA

AAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTTCCCCGACCACGTGGAGCTGAGCT

GGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACGGACCCGCAGCCCCTCA

AGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTC

GGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGC

TCTCGGAGAATGACGAGTGGACCCAGGATAGGGCCAAACCCGTCACCCAGATCGTCAG

CGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTTACCTCGGTGTCCTACCAGCAAGGG

GTCCTGTCTGCCACCATCCTCTATGAGATCCTGCTAGGGAAGGCCACCCTGTATGCTGT

GCTGGTCAGCGCCCTTGTGTTGATGGCCATGGTCAAGAGAAAGGATTTC (SEQ ID

N0 13) pLRPO FMC63 endoL TRBC1 (126-177) (pLRPO FMC63 endoL TRBC1 (132-309) according to IMGT numbering) (amino acid sequence)

DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRF SGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKG EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNS ALK SRLTIIKDN SK SQ VFLKMN SLQTDDT AI YY C AKHYYY GGS YAMD YW GQGT S VTV S S G VEDLNK VFPPEV A VFEP SE AEISHT QKATL V CLAT GFFPDHVEL S WW VN GKEVHS GV S TDP QPLKEQP ALND SRY CL S SRLRV S ATF W QNPRNHFRCQ V QF Y GL SENDEWTQDR AKP VTQI VSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 14) pLRPO FMC63 endoL TRBC1 (126-177) (pLRPO FMC63 endoL TRBC1 (132-309) according to IMGT numbering) (nucleic acid sequence)

GACATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCAC

CATCAGTTGCAGGGCAAGTCAGGACATTAGTAAATATTTAAATTGGTATCAGCAGAAA

CCAGATGGAACTGTTAAACTCCTGATCTACCATACATCAAGATTACACTCAGGAGTCCC

ATCAAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGG

AGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTC

GGAGGGGGGACTAAGTTGGAAATAACAGGCTCCACCTCTGGATCCGGCAAGCCCGGAT

CTGGCGAGGGATCCACCAAGGGCGAGGTGAAACTGCAGGAGTCAGGACCTGGCCTGGT

GGCGCCCTCACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCATTACCCGACT

ATGGTGTAAGCTGGATTCGCCAGCCTCCACGAAAGGGTCTGGAGTGGCTGGGAGTAAT

ATGGGGTAGTGAAACCACATACTATAATTCAGCTCTCAAATCCAGACTGACCATCATCA

AGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACAC

AGCCATTTACTACTGTGCCAAACATTATTACTACGGTGGTAGCTATGCTATGGACTACT

GGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGGAGTAGAGGACCTGAACAAGGTGTT

CCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAG

GCCACTCTAGTATGTCTAGCTACAGGCTTCTTCCCTGACCACGTGGAGCTGAGCTGGTG

GGT GAAT GGGAAGGAGGT GC AC AGT GGGGT C AGC ACGGACCC GC AGC C AC TT AAAGA

ACAGCCAGCTCTCAATGACTCCAGATACTGTCTAAGCAGTCGACTTAGAGTCTCGGCTA

CATTTTGGCAAAATCCTCGAAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCG

GAGAATGACGAGTGGACCCAGGATAGGGCCAAACCCGTCACCCAGATCGTCAGCGCCG

AGGCC T GGGGT AGAGC AGACTGT GGCTTT AC CT CGGT GTC CT ACC AGC AAGGGGT CC T

GTCTGCCACCATCCTCTATGAGATCCTGCTAGGGAAGGCCACCCTGTATGCTGTGCTGG

TCAGCGCCCTTGTGTTGATGGCCATGGTCAAGAGAAAGGATTTC (SEQ ID NO: 15)

Editing primary human T cells

[0554] TRA or TRB genes are then inactivated in primary T cells from a human donor. Four days prior to electroporation, T cells were activated with TransAct® (Milltenyi) supplemented with IL7/IL15 in TexMac media containing 3% human serum. SpCas9 ribonucleoproteins (RNPs) targeting TRA or TRB genes were prepared by annealed crRNA targeting either TRAC (TRAC2-4598) or TRBC (TRBC-44345) with tracrRNA at a molecular ratio of 1 : 1. Annealed duplexes were mixed with SpCas9 protein at a molecular ratio of 1.5: 1. 0.61 mM of RNPs were mixed with 2.5x10^s T cells and electroporated following the manufacturer’s protocol for the Neon Transfection System, electroporation was set at 1600Y, 10ms, 3 pulses. Cells were immediately transferred to warm medium and incubated at 37°C to allow expansion of edited T cells with an approximate doubling time of 3 to 5 days. Editing efficacy was assessed by measuring loss of surface expression of TCRa and CD3s via flow cytometry. Edited T cells were purified ten days post activation using Magnetic- Activated Cell Sorting (MACS®, Miltenyi Biotec) according to the manufacturer cell separation system and were negatively selected against anti-TCRa.p (clone: IP27) antibody (eBioscience #14-9986-82) and anti-CD3s (Clone: SK7) antibodies (eBioscience #16-0036-81). Cells expressing TCRaP or CD3s at their surface were immobilized on MACS MS (Cat. #130-041-301) or LS (Cat# 130-041-306) columns, while edited T cells, both negative for TCRaP and CD3s, were collected in the column flow-through and maintained in culture at 10⁶ cells/mL in the medium specified above.

Phenotypic characterization of Allogeneic-TFP T cells

[0555] Allogenic-TFP T cells were examined for their expression of human T C Rap (with anti human TCR, Miltenyi Bio, clone BW242/412), human CD3s (with anti-human CD3s BioLegend, clone UCHT1), human CD4 (with anti-human CD4, BioLegend, clone RPA-T4), human CD8 (with anti-human CD8, BioLegend, clone SK-1), human CD45RA and human CCR7 and TFPs (with detection of the CD 19 binder FMC63 by biotinylated CD 19 (Cat.# CD9- H8259, AcroBio). Wild-type T cells and transduced TFPs with control TCRP Full Length (FL) constructs (not edited) from the same donor were examined with the same panel as a comparison. [0556] Results are shown in Figures 5-9. Post TFP transduction and TRAC editing, T cells remain double positive for surface expression of human TCRaP and CD3s (upper right-hand panel). T cells that are edited to delete the TRAC gene, in contrast, show two populations of cells (bottom right hand panel). The majority of the cells have lost surface expression of TCRaP and CD3 . TCRyb TFP transduced T cells (cells transduced with a vector expressing SEQ ID NO, 1, 2, or 4), in contrast, show three distinct populations (left hand panels). While the majority of the cells have lost TCRaP surface expression, there is a new subset of cells that now express CD3s without the expression of TCRaP, suggesting successful re-assembly of the full TCR complex. This population corresponds to cells that are edited to remove TCRap and are transduced to express TCRyb. Figure 6 shows cells after MACS purification to remove residual cells that were expressing TCRap. T cells transduced with TCRyb TFPs now have two populations of cells. Both are negative for TCRap, and one population expresses high levels of CD3e. Figure 7 shows TFP expression of TCRyb transduced TFPs compared to TCR Peta Full Length (FL) control TFPs as well as non-transduced control T cells. Expression of human CD4 and CD8 are not significantly different between TCR Peta FL TFP control and TCRyb TFP T cells; there are also no differences in memory status defined by CD45RA and CCR7 expression (Figures 8 and 9, respectively).

[0557] Figure 14 shows primary T cells transduced 24 hours after activation with a lenti virus containing a-CD19 scFv TFP construct: aCD19-CD3e, aCD19-TCRy(constant)-2A-TCR5 (constant) (FMC63-TRDC(1-153)-T2A-TRGC1(1-173) or FMC63-TRDC(-6, 189)-2A- TRGC1(1.8, 189) according to IMGT numbering), T C Ry( con stant)-2A-aC D 19-TC R6 (constant) (TRDC(1-153)-T2A-FMC63-TRGC1(1-173) or TRDC(-6,189)-2A-FMC63-TRGC1(L8, 189) according to IMGT numbering), or aCD19-TCRa(murine constant)-2A-murineTCRp (constant)(pLRPC FMC63mTRAC_T2A_mTRBC). In all TFP expressing cells except the aCD19-CD3e-expressing cells, the endogenous TCR was inactivated with CRISPR/Cas9 72 hours post activation by targeting the TCRa constant region locus. T cells were purified to remove left over T cells that still expressed the endogenous TCR by negative selection. The flow cytometry panel shown was performed at Day 9 and 10 to assess transduction, editing efficiency and T-cell phenotype. The results demonstrate that allogeneic TFP-expressing cells were successfully engineered by replacing the endogenous T cell receptors a and b subunits with TCR transgenes containing the constant regions of murine TCRa and TCR or human TCRy and TCR5.

MLR of Human TCR-negative T cells expressing TFPs

[0558] Human TCR-negative T cells expressing TFPs are assessed for allogenicity by using a mixed lymphocyte reaction (MLR) assay. Mismatched PBMC donor cells are first depleted of B cells by Magnetic- Activated Cell Sorting of CD-19 negative cells. Irradiated PBMCs (Astarte Biologies) are labelled with the cellular labelling dye CellTrace™ (Thermo Fisher Scientific). Simultaneously, a different colored CellTrace dye is incorporated into target T cells. Human TCR-negative T cells expressing TFPs and wild-type T cells of the same donor are subsequently co-cultured at either a 1 : 1 ratio (PBMCs to T cells) or just T cells alone. The proliferation of donor T cells is monitored by tracking the labelling dye over a six to twelve-day time point. Dye dilutes by half upon cellular division and thus the amount of proliferation that occurred in the T cells is assessed and compared wildtype controls.

Example 4: Cytotoxicity and cytokine production of allogeneic TCR T cells expressing TFPs

[0559] The luciferase-based cytotoxicity assay (“Luc-Cyto” assay) assesses the cytotoxicity of TFP T cells by indirectly measuring the luciferase enzymatic activity in the residual live target cells after co-culture.

Generation of firefly luciferase (Luc) expressing tumor cells

[0560] The target cells used in the Luc-Cyto assay were Nalm6-Luc (CD 19 positive) and K562- Luc (CD19 negative were generated by stably transducing Nalm6 (DSMZ Cat. # ACC 128) and K562 (ATCC® Cat. #CCL-243™)) cells to express firefly luciferase. The DNA encoding firefly luciferase was synthesized by GeneArt® (Thermo Fisher Scientific) and inserted into the multiple cloning site of single-promoter lentiviral vector pCDH527A-l (System Biosciences). The lentiviruses were packaged according to manufacturer’s instruction. Tumor cells were then transduced with the lentivirus for 24 hours and then selected with puromycin (5 pg/niL). The successful generation of Nalm6-Luc and K562-Luc cells was confirmed by measuring the luciferase enzymatic activity in the cells with Bright-Glo™ Luciferase Assay System (Promega). Luc-Cyto assay assessing the cytotoxicity and cytokine production of Allogeneic T cells [0561] The Luc-Cyto assay was set up by mixing T cells with tumor cells at different effector (T cell) to target (tumor cell) (E-to-T) ratios. The target cells (Nalm6-Luc or K562-Luc) were plated at 10,000 cells per well in 96-well plates with RPMI-1640 medium supplemented with 10% heat- inactivated (HI) FBS. Allogeneic TFP T cells were added to the tumor cells at 30000, 10000,

3333 or 1111 cells per well to reach E-to-T ratios of 3-to-l, 1-to-l, or l-to-3 or l-to-9. The mixtures of cells were incubated for 24 hours at 37°C with 5 % CO2. Luciferase enzymatic activity was measured using the Bright-Glo™ Luciferase Assay System (Promega), which measures activity from the residual live target cells in the T cell and tumor cell co-culture.

[0562] Results are shown in Figure 10. The allogeneic TCRyb TFP T cells, showed robust and specific lysis against CD19 positive tumor cells Nalm6-Luc, but not the CD19 negative tumor cells K562-Luc.

[0563] Supernatants were taken from the same co-culture assays after 24 hours to assess allogeneic T cell production of the following cytokines: GM-CSF, PTNGg, IL2, and TNFa. Cytokine production was analyzed using Meso Scale Discovery Technology (MesoScale Diagnostics, LLC), with U-PLEX Biomarker Group I (hu) Assays (Catalog number: K15067L- 4). Robust cytokine secretion was observed from all constructs in a dose-dependent manner (Figure 11).

[0564] Results from additional experiments are shown in Figures 15 and 16 with the same constructs as in Figure 14. The allogeneic TCRyd TFP T cells and murine TCRc/.b T cells showed robust and specific lysis against CD 19 positive tumor cells Nalm6-Luc, but not the CD 19 negative tumor cells K562-Luc (Figure 15). Robust cytokine secretion was observed from all constructs in a dose-dependent manner (Figure 16). The percentage of TFP+ population is displayed on graph to account for differences in TFP transduction efficiency among constructs. Allogeneic TFP cells with aCD19 scFv lysed CD 19+ tumor cells efficiently in vitro and produced cytokines at similar levels as non-edited aCD19 TFP cells.

[0565] Results from additional experiments are shown in Figures 20-23. Allogeneic murine TCRa (FMC63 mTRAC_P2 A mTRB C U5; FMC63 SLmTRAC_P2A_mTRBC U5; FMC63mTRAC_T2A_mTRBC; FMC63mTRAC_T2A_mTRBC U5) and TCRap (FMC63SLmTRAC_P2A_FMC63SLmTRBC U5) TFP T cells showed robust and specific lysis against CD19 positive tumor cells Nalm6-Luc, but not the CD19 negative tumor cells K562-Luc (Figure 20). The percentage of TFP+ population is displayed on graph to account for differences in TFP transduction efficiency among constructs. Robust cytokine secretion was observed from all constructs in a dose-dependent manner (Figure 21). Allogeneic TCR5 (FMC63TRDC T2A TRGC1), TCRyd (FMC63TRDC_T2A_FM63opTRGCl), and TCRe FMC63TCR y9G115 T2A 52cl5 P2A FMC63e) TFP T cells showed robust and specific lysis against CD19 positive tumor cells Nalm6-Luc, but not the CD19 negative tumor cells K562-Luc (Figure 22). The percentage of TFP+ population is displayed on graph to account for differences in TFP transduction efficiency among constructs. Robust cytokine secretion was observed from all constructs in a dose-dependent manner (Figure 23). In Figures 22 and 23, TFP T cells were added to target cells at a 3:1, 1:1, and 0.1:1 ratio. In Figures 21 and 23, cytokine production is shown normalized to cytokine production in non-edited T-cells having an anti-CD 19-CD3 TFP TFP MLR of Human TCR-negative T cells expressing TFPs for Cytokine Expression

[0566] Human TCR-negative or TCR-positive T cells expressing TFPs were assessed for allogenicity by using a mixed lymphocyte reaction (MLR) assay. HLA-mismatched, in vitro- derived dendritic cells were co-cultured with TCR-negative or TCR-positive TFP expressing cells at a 1 :3 (T:DC) ratio for 72 hours. Secreted cytokines were measured in supernatants by MSD assay, as described above. TCR-negative TFP-expressing T cells secreted significantly less cytokine compared with non-edited TFP-expressing T cells and were not alloreactive in a mixed leukocyte reaction with HLA-mismatched dendritic cells. (Figure 17).

Example 5: In vivo efficacy of allogeneic TCR T cells expressing TFPs [0567] A Nalm6-luc tumor mouse model was used to assess the in vivo efficacy of allogeneic TCR T cells expressing TFPs. Tumor cells were injected into NSG mice at Day -10. After establishment of the tumors, mice received one injection of 2.2x10⁶ non-edited or allogeneic TFP cells on Day 0. Mice were imaged every 3 days post TFP cell injection to assess tumor load. In vivo, non-edited TFP-expressing cells exhibited complete antitumor activity, whereas allogeneic TFP-expressing cells showed tumor regression (Figure 18)

[0568] At day 50 post TFP-expressing T cell injection, livers were harvested from non-tumor bearing mice and assessed for Graft-Versus Host Disease (GvHD) via tissue infiltration of human cells. Flow cytometry analysis of human CD7+ cells in mouse liver revealed infiltration of human cells in animals treated with non-edited T cells expressing a aCD19-CD3s (left panels). Infiltration was not observed in TFP-expressing allogeneic cells and mice treated with the allogeneic cells showed no signs of GvHD Infiltration analysis was confirmed with IHC analysis for CD7+ cell staining (n=2; right panels). [0569] Table 5. Antigen binding domain sequences.

[0570] Table 6. Construct sequences.

Vector sequences: pLRPO V5-mTRAC₍₈₂-i₃₇₎ T2A mTRBC, _{l2 ;}-r , (SEQ ID NO: 159)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TTATCAATAC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG AT CCT GGT AT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTT AT GCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GAT AAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACTATGGTTG CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGT A A GGAGAAAAT A CCGCATCAGG CGCCATTCGC C ATT C AGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGT AAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACT AGTT ATT A AT AGT A AT C AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA 1861 T AGGGACTTT CCATT GACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 T AC AT C A AGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCT GGC A TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG C AGT AC AT CT 2041 ACGTATTAGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTTAGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CG A A AGT AAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GG AGGCT AG A AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC TAGAACGATT CGCAGTTAAT 2761 CCTGGCCTTT T AG AG AC AT C AGAAGGCTGT AG AC A A AT AC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TTATATAATA CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG GACAATTGGA GAAGTGAATT AT AT AA AT AT AAAGTAGTAA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GGAAGCACTA TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGCAGCAGAA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GGAAAGATAC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT AAATCTCTGG AACAGATTTG G A AT A AC AT G ACCTGGATGG AGTGGGACAG 3481 AG A A ATT A AC A ATT AC AC A A GCTTAATACA CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT T ATT GG A ATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 TAACATAACA AATTGGCTGT GGTATATAAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT 3781 ATTCATCCAC AATTTTAAAA GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGT AG AC AT A ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TT AC A A A A AT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG GAGAACCGTA TATAAGTGCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACTGGTATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT T GGGGGG AGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAggtaag cctatcccta accctctcct cggtctcgat tctacgGGAG

5281 CCACCTACCC CAGTTCAGAC GTTCCCTGTG ATGCCACGTT GACTGAGAAA AGCTTTGAAA 5341 C AG AT AT G A A CCTAAACTTT CAAAACCTGT CAGTTATGGG ACTCCGAATC CTCCTGCTGA 5401 AAGTAGCCGG ATTTAACCTG CTCATGACGC TGAGGCTGTG GTCCAGTGGC AGCGGCGAGG 5461 GCAGAGGAAG TCTGCTAACA TGCGGTGACG TCGAGGAGAA TCCTGGACCT GGTCGAGCAG 5521 ACT GT GGT AT TACCTCAGCA TCCTATCAAC AAGGAGTCTT GTCTGCCACC ATCCTCTATG 5581 AGATCCTGCT AGGGAAAGCC ACCCTGTATG CTGTGCTTGT CAGTACACTG GTGGTGATGG 5641 CTATGGTCAA AAGAAAGAAT T CAT GAG AT A TCGAGCATCT TACCGCCATT TATACCCATA 5701 TTTGTTCTGT TTTTCTTGAT TTGGGTATAC ATTTAAATGT T A AT A A A AC A AAATGGTGGG

5821 AACATGTTAA GAAACTTTCC CGTTATTTAC GCTCTGTTCC TGTTAATCAA CCTCTGGATT 5881 ACAAAATTTG TGAAAGATTG ACTGATATTC TTAACTATGT TGCTCCTTTT ACGCTGTGTG 5941 GATATGCTGC TTTATAGCCT CTGTATCTAG CTATTGCTTC CCGTACGGCT TTCGTTTTCT 6001 CCTCCTTGTA TAAATCCTGG TTGCTGTCTC TTTTAGAGGA GTTGTGGCCC GTTGTCCGTC 6061 AACGTGGCGT GGTGTGCTCT GTGTTTGCTG ACGCAACCCC CACTGGCTGG GGCATTGCCA 6121 CCACCTGTCA ACTCCTTTCT GGGACTTTCG CTTTCCCCCT CCCGATCGCC ACGGCAGAAC 6181 T CAT CGCCGC CTGCCTTGCC CGCTGCTGGA CAGGGGCTAG GTTGCTGGGC ACTGATAATT 6241 CCGTGGTGTT GTCAGTACTG GTACCTTTAA GACCAATGAC TTACAAGGCA GCTGTAGATC 6301 TTAGCCACTT TTT A A A AG A A AAGGGGGGAC TGGAAGGGCT A ATT C ACT CC CAAAGAAGAC 6361 AAGATCTGCT TTTTGCCTGT ACTGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC 6421 TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTTC 6481 AATGATCATA ATCAAGCCAT ATCACATCTG T AG AGGTTT A CTTGCTTTAA AAAACCTCCA 6541 CACCTCCCCC TGAACCTGAA AC AT A A A AT G AATGCAATTG TTGTTGTTAA CTTGTTTATT 6601 GC AGCTT AT A ATGGTTACAA ATAAAGCAAT AGCATCACAA ATTTCACAAA TAAAGCATTT 6661 TTTTCACTGC ATTCTAGTTG TGGTTTGTCC AAACTCATCA ATGTATCTTA TCATGTCTGG 6721 ATCTGCGTCG ACACGAAGAG ACGACTGACT GACTGACTGG AAAGAGGAAG GGCTGGAAGA 6781 GGAAGGAGCT T GAT CC AG AT CCCGATCTCG ATCCAGATCC GGATCGCAGC TTGGCGTAAT 6841 CATGGTCATA GCTGTTTCCT GTGTGAAATT GTTATCCGCT CACAATTCCA CACAACATAC 6901 GAGCCGGAAG CATAAAGTGT AAAGCCTGGG GTGCCTAATG AGTGAGCTAA CTCACATTAA 6961 TTGCGTTGCG CTCACTGCCC GCTTTCCAGT CGGGAAACCT GTCGTGCCAG CTGCATTAAT 7021 GAATCGGCCA ACGCGCGGGG AGAGGCGGTT TGCGTATTGG GCGCTCTTCC GCTTCCTCGC 7081 TCACTGACTC GCTGCGCTCG GTCGTTCGGC TGCGGCGAGC GGTATCAGCT CACTCAAAGG 7141 CGGTAATACG GTTATCCACA GAATCAGGGG ATAACGCAGG AAAGAACATG TGAGCAAAAG 7201 GCCAGCAAAA GGCCAGGAAC CGT A A A A AGG CCGCGTTGCT GGCGTTTTTC CATAGGCTCC 7261 GCCCCCCTGA CGAGCATCAC AAAAATCGAC GCTCAAGTCA GAGGTGGCGA AACCCGACAG 7321 GACTATAAAG ATACCAGGCG TTTCCCCCTG GAAGCTCCCT CGTGCGCTCT CCTGTTCCGA 7381 CCCTGCCGCT TACCGGATAC CTGTCCGCCT TTCTCCCTTC GGGAAGCGTG GCGCTTTCTC 7441 ATAGCTCACG CTGTAGGTAT CTCAGTTCGG TGTAGGTCGT TCGCTCCAAG CTGGGCTGTG 7501 TGCACGAACC CCCCGTTCAG CCCGACCGCT GCGCCTTATC CGGTAACTAT CGTCTTGAGT 7561 CCAACCCGGT AAGACACGAC TTATCGCCAC TGGCAGCAGC CACTGGTAAC AGGATTAGCA 7621 GAGCGAGGTA TGTAGGCGGT GCTACAGAGT TCTTGAAGTG GTGGCCTAAC TACGGCTACA 7681 CTAGAAGAAC AGT ATTTGGT ATCTGCGCTC TGCTGAAGCC AGTTACCTTC GGAAAAAGAG 7741 TTGGTAGCTC TTGATCCGGC AAACAAACCA CCGCTGGTAG CGGTGGTTTT TTTGTTTGCA 7801 AGCAGCAGAT TACGCGCAGA AAAAAAGGAT CT C A AG A AG A TCCTTTGATC TTTTCTACGG 7861 GGTCTGACGC TCAGTGGAAC GAAAACTCAC GTTAAGGGAT TTTGGTCATG AGATTATCAA 7921 AAAGGATCTT CACCTAGATC CTTTTAAATT AAAAATGAAG TTTTAAATCA AT CT A A AGT A 7981 T AT AT G AGT A AACTTGGTCT GACAGTTACC A AT GCTT A AT CAGTGAGGCA CCTATCTCAG 8041 CGATCTGTCT ATTTCGTTCA TCCATAGTTG CCTGACTCCC CGTCGTGTAG ATAACTACGA 8101 TACGGGAGGG CTTACCATCT GGCCCCAGTG CTGCAATGAT ACCGCAGCTT GGGAAACCAT 8161 AAGAGCTGAA GCCAGTTACC TT CGG A A A A A GAGTTGGTAG CTCTTGATCC GGCAAACAAA

8281 GATCTCAAGA AGATCCTTTG ATCTTTTCTA CGGGGTCTGA CGCTCAGTGG AACGAAAACT 8341 CACGTTAAGG GATTTTGGTC ATGAGCTTGC GCCGTCCCGT CAAGTCAGCG TAATGCTCTG 8401 CCAGTGTTAC AA pLRPO FMC63-mTRAC₍₈₂-i₃₇₎ T2A niTRBC₍n;-ni, (SEQ ID NO: 160)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TT AT CA AT AC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA AT AAGGTT AT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTTATGCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA T C AGG AT ATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GATAAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACTATGGTTG CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGT A A GGAGAAAAT A CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT A AT AGT A AT C AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTT ACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA 1861 T AGGGACTTT CCATT GACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 T AC AT C A AGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGT ATT AGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTTAGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA A A A ATT CGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC TAGAACGATT CGCAGTTAAT 2761 CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT AAT A CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GT A AG AAA AA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG GACAATTGGA GAAGTGAATT AT AT AA AT AT AAAGTAGTAA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GG A AGC ACT A TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGC AGC AG AA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GGAAAGATAC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT A AAT CTCTGG AACAGATTTG G A AT A AC AT G ACCTGGATGG AGT GGG AC AG 3481 AG A A ATT A AC A ATT AC AC A A GCTTAATACA CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT T ATT GG A ATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 TAACATAACA AATTGGCTGT GGTATATAAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC T AT AGT G A AT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC A A AT GGC AGT 3781 ATTCATCCAC AATTTTAAAA GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGT AG AC AT A ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG GAGAACCGTA TATAAGTGCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GT GGG AG AGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACT GGT ATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 5281 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT T AGT A A AT AT TT A A ATT GGT 5341 ATCAGCAGAA ACCAGATGGA ACTGTTAAAC TCCTGATCTA CCATACATCA AGATTACACT 5401 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AG ATT ATTCT CT C ACC ATT A 5461 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 5521 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGAGG TGGAGGTTCT GGTGGAGGAG 5581 GTTCAGGAGG TGGTGGAAGT GAGGTGAAAC TGCAGGAGTC AGGACCTGGC CTGGTGGCGC 5641 CCTCACAGAG CCTGTCCGTC ACATGCACTG TCTCAGGGGT CTCATTACCC GACTATGGTG 5701 TAAGCTGGAT TCGCCAGCCT CCACGAAAGG GTCTGGAGTG GCTGGGAGTA ATATGGGGTA 5761 GTGAAACCAC AT ACT AT A AT TCAGCTCTCA AATCCAGACT GACCATCATC AAGGACAACT 5821 CCAAGAGCCA AGTTTTCTTA AAAATGAACA GTCTGCAAAC TGATGACACA GCCATTTACT 5881 ACTGTGCCAA ACATTATTAC TACGGTGGTA GCTATGCTAT GGACTACTGG GGTCAAGGAA 5941 CCTCAGTCAC CGTCTCCTCA GGAGCCACCT ACCCCAGTTC AGACGTTCCC TGTGATGCCA 6001 CGTTGACTGA GAAAAGCTTT G AA AC AG AT A TGAACCTAAA CTTTCAAAAC CTGTC AGTT A 6061 TGGGACTCCG AATCCTCCTG CTGAAAGTAG CCGGATTTAA CCTGCTCATG ACGCTGAGGC 6121 TGTGGTCCAG TGGCAGCGGC GAGGGCAGAG GAAGTCTGCT AACATGCGGT GACGTCGAGG 6181 AGAATCCTGG ACCTGGTCGA GCAGACTGTG GTATTACCTC AGCATCCTAT CAACAAGGAG 6241 TCTTGTCTGC CACCATCCTC TATGAGATCC TGCTAGGGAA AGCCACCCTG TATGCTGTGC 6301 TTGTCAGTAC ACTGGTGGTG ATGGCTATGG T C A A A AG AAA GAATTCATGA GATATCGAGC 6361 ATCTTACCGC C ATTT AT ACC CATATTTGTT CTGTTTTTCT TGATTTGGGT ATACATTTAA 6421 ATGTTAATAA AACAAAATGG TGGGGCAATC ATTT AC ATTT TTAGGGATAT GTAATTACTA 6481 GTTCAGGTGT ATTGCCACAA G AC A A AC AT G TT A AG A A ACT TTCCCGTTAT TTACGCTCTG 6541 TTCCTGTTAA TCAACCTCTG GATT AC A A A A TTTGTGAAAG ATTGACTGAT ATTCTTAACT 6601 ATGTTGCTCC TTTTACGCTG TGTGGATATG CTGCTTTATA GCCTCTGTAT CTAGCTATTG 6661 CTTCCCGTAC GGCTTTCGTT TTCTCCTCCT TGTATAAATC CTGGTTGCTG TCTCTTTTAG 6721 AGGAGTTGTG GCCCGTTGTC CGTCAACGTG GCGTGGTGTG CTCTGTGTTT GCTGACGCAA 6781 CCCCCACTGG CTGGGGCATT GCCACCACCT GTCAACTCCT TTCTGGGACT TTCGCTTTCC 6841 CCCTCCCGAT CGCCACGGCA GAACTCATCG CCGCCTGCCT TGCCCGCTGC TGGACAGGGG 6901 CTAGGTTGCT GGGCACTGAT AATTCCGTGG TGTTGTCAGT ACTGGTACCT TTAAGACCAA 6961 TGACTTACAA GGCAGCTGTA GATCTTAGCC ACTTTTT AAA AGAAAAGGGG GGACTGGAAG 7021 GGCTAATTCA CTCCCAAAGA AGACAAGATC TGCTTTTTGC CTGTACTGGG TCTCTCTGGT 7081 TAGACCAGAT CTGAGCCTGG GAGCTCTCTG GCTAACTAGG GAACCCACTG CTTAAGCCTC 7141 AATAAAGCTT GCCTTGAGTG CTTCAATGAT CATAATCAAG CCATATCACA TCTGTAGAGG 7201 TTTACTTGCT TTAAAAAACC TCCACACCTC CCCCTGAACC T G A A AC AT A A AATGAATGCA 7261 ATTGTTGTTG TTAACTTGTT TATTGCAGCT TATAATGGTT AC A A AT A A AG C A AT AGC AT C

7381 ATCAATGTAT CTTATCATGT CTGGATCTGC GTCGACACGA AGAGACGACT GACTGACTGA 7441 CTGGAAAGAG GAAGGGCTGG AAGAGGAAGG AGCTTGATCC AGATCCCGAT CTCGATCCAG 7501 ATCCGGATCG CAGCTTGGCG TAATCATGGT CATAGCTGTT TCCTGTGTGA AATTGTTATC 7561 CGCT C AC A AT TCCACACAAC ATACGAGCCG G A AGC AT AAA GTGTAAAGCC TGGGGTGCCT 7621 AATGAGTGAG CTAACTCACA TTAATTGCGT TGCGCTCACT GCCCGCTTTC CAGTCGGGAA 7681 ACCTGTCGTG CCAGCTGCAT TAATGAATCG GCCAACGCGC GGGGAGAGGC GGTTTGCGTA 7741 TTGGGCGCTC TTCCGCTTCC TCGCTCACTG ACTCGCTGCG CTCGGTCGTT CGGCTGCGGC 7801 GAGCGGTATC AGCTCACTCA AAGGCGGTAA TACGGTTATC CACAGAATCA GGGGATAACG 7861 CAGGAAAGAA CATGTGAGCA AAAGGCCAGC AAAAGGCCAG GAACCGTAAA AAGGCCGCGT 7921 TGCTGGCGTT TTTCCATAGG CTCCGCCCCC CTGACGAGCA TCACAAAAAT CGACGCTCAA 7981 GTCAGAGGTG GCGAAACCCG ACAGGACTAT AAAGATACCA GGCGTTTCCC CCTGGAAGCT 8041 CCCTCGTGCG CTCTCCTGTT CCGACCCTGC CGCTTACCGG ATACCTGTCC GCCTTTCTCC 8101 CTTCGGGAAG CGTGGCGCTT TCTCATAGCT CACGCTGTAG GTATCTCAGT TCGGTGTAGG 8161 TCGTTCGCTC CAAGCTGGGC TGTGTGCACG AACCCCCCGT TCAGCCCGAC CGCTGCGCCT 8221 TATCCGGTAA CTATCGTCTT GAGTCCAACC CGGTAAGACA CGACTTATCG CCACTGGCAG 8281 CAGCCACTGG TAACAGGATT AGCAGAGCGA GGTATGTAGG CGGTGCTACA GAGTTCTTGA 8341 AGTGGTGGCC TAACTACGGC T AC ACT AG A A G A AC AGT ATT TGGTATCTGC GCTCTGCTGA 8401 AGCCAGTTAC CTTCGGAAAA AGAGTTGGTA GCTCTTGATC CGGCAAACAA ACCACCGCTG

8941 AGC AG ATT AC GCGCAGAAAA AAAGGATCTC AAGAAGATCC TTTGATCTTT TCTACGGGGT 9001 CTGACGCTCA GTGGAACGAA AACTCACGTT AAGGGATTTT GGTCATGAGC TTGCGCCGTC 9061 CCGTCAAGTC AGCGTAATGC TCTGCCAGTG TTACAA pLRPO FMC63mTRAC_P2A_Mtrbc (SEQ ID NO: 161)

1 TG AT CAT AAT C AAGCCAT AT C AC AT CT GT A GAGGTTT ACT T GCTTT AAA A AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT TTCACAAATA AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC AT GT CT GG AT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGCAGCTT GGCGTAATCA 361 TGGTCATAGC TGTTTCCTGT GTGAAATTGT TATCCGCTCA CAATTCCACA CAACATACGA 421 GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG TGAGCTAACT CACATTAATT 481 GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT GC ATT AATGA 541 ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC GCTCTTCCGC TTCCTCGCTC 601 ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA CTCAAAGGCG 661 GTAATACGGT T AT CC AC AG A ATCAGGGGAT AACGCAGGAA AGAACATGTG AGCAAAAGGC 721 CAGCAAAAGG CCAGGAACCG TAAAAAGGCC GCGTTGCTGG CGTTTTTCCA TAGGCTCCGC 781 CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA CCCGACAGGA 841 CT AT A A AG AT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC TGTTCCGACC 901 CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC GCTTTCTCAT 961 AGCTCACGCT GT AGGT AT CT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT GGGCTGTGTG 1021 CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG TCTTGAGTCC 1081 AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATTAGCAGA 1141 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 1201 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT

1321 CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT TTCTACGGGG 1381 TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG ATTATCAAAA 1441 AGGATCTTCA CCTAGATCCT TTTAAATTAA AAATGAAGTT TTAAATCAAT CTAAAGTATA 1501 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 1561 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTGT AGAT A ACT ACG AT A 1621 CGGGAGGGCT TACCATCTGG CCCCAGTGCT GCAATGATAC CGCAGCTTGG GAAACCATAA 1681 GAGCT GAAGC CAGTTACCTT CGGAAAAAGA GTTGGTAGCT CTTGATCCGG CAAACAAACC 1741 ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC AAGCAGCAGA TTACGCGCAG AAAAAAAGGA 1801 TCTCAAGAAG ATCCTTTGAT CTTTTCTACG GGGTCTGACG CTCAGTGGAA CGAAAACTCA 1861 CGTTAAGGGA TTTTGGTCAT GAGCTTGCGC CGTCCCGTCA AGTCAGCGTA ATGCTCTGCC 1921 AGTGTTACAA CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT

2041 AAGGAGAAAA CTCACCGAGG CAGTTCCATA GGATGGCAAG ATCCTGGTAT CGGTCTGCGA 2101 TTCCGACTCG TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT 2161 C A AGT GAG A A ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTTATGCA 2221 TTTCTTTCCA GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT 2281 CAACCAAACC GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT 2341 TAAAAGGACA ATT AC A A AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT 2401 CAACAATATT TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG 2461 GGATCGCAGT GGTGAGTAAC CATGCATCAT CAGGAGTACG GAT A A A AT GC TTGATGGTCG 2521 GAAGAGGCAT AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG 2581 CAACGCTACC TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC 2641 GAT AG ATT GT CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT 2701 CAGCATCCAT GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA 2761 CACCCCTTGT ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT 2821 TATCTTGTGC A AT GT A AC AT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC 2881 CATGACATTA ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC 2941 GAGAT AGAGT TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC 3001 TCCAACGTCA AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA 3061 CCCAAATCAA GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG 3121 AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAG 3181 AAAGCGAAAG GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC 3241 ACCACACCCG CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT ATGGTTG CTTTGACGTA 3301 TGCGGTGTGA AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC 3361 CATTCAGGCT GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC 3421 AGCTGGCGAA AGGGGG AT GT GCTGCAAGGC GATT AAGTT G GGTAACGCCA GGGTTTTCCC 3481 AGTCACGACG TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA 3541 TCCAGATCGA ATTGGAGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG 3601 TCTCAACCTC CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG 3661 TCATTAGTTC ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG 3721 CCTGGCTGAC CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA 3781 GTAACGCCAA TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC 3841 CACTTGGCAG TACATCAAGT GT AT C AT AT G CCAAGTACGC CCCCTATTGA CGTCAATGAC 3901 GGTAAATGGC CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG 3961 CAGTACATCT ACGTATTAGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC 4021 AATGGGCGTG GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC 4081 AATGGGAGTT TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC 4141 GCCCCATTGA CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT 4201 CGTTTAGTGA ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA 4261 ACTAGGGAAC CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG 4321 TGCCCGTCTG TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG 4381 GAAAATCTCT AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG 4441 ATCTCTCGAC GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA 4501 CTGGTGAGTA CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG 4561 AGCGTCGGTA TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG 4621 GGGAAAGAAA C A AT AT AA AC T A A A AC AT AT AGTTAGGGCA AGCAGGGAGC T AG A ACG ATT 4681 CGCAGTTAAT CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT 4741 ACAACCATCC CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT A AT A CAATAGCAGT 4801 CCTCTATTGT GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT 4861 AGAGGAAGAG CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCAGACCTGGAGG 4921 AGGCAGGAGG CGATATGAGG GACAATTGGA GAAGTGAATT AT AT A A AT AT A A AGT AGT A A 4981 AAATTGAACC ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA 5041 AAAGAGCAGT GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GGAAGCACTA 5101 TGGGCGCAGC GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC 5161 AGCAGCAGAA CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG 5221 TCTGGGGCAT CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GG A A AG AT AC CTAAAGGATC 5281 AACAGCTCCT GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT 5341 GGAATGCTAG TTGGAGTAAT AAATCTCTGG AACAGATTTG GAATAACATG ACCTGGATGG 5401 AGTGGGACAG AG AA ATT A AC A ATT AC AC A A GCTT A AT AC A CTCCTTAATT GAAGAATCGC 5461 AAAACCAGCA AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT 5521 GGAATTGGTT TAACATAACA AATTGGCTGT GGT AT AT AAA ATTATTCATA ATGATAGTAG

5641 AGGGATATTC ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC 5701 AAATGGCAGT ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATT GGGGGG TACAGTGCAG 5761 GGGAAAGAAT AGTAGACATA ATAGCAACAG AC AT AC A A AC T A A AG A ATT A CAAAAACAAA 5821 TTACAAAAAT TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG 5881 CTGAGCATCC GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA 5941 GAAGTTGGGG GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA 6001 CTGGGAAAGT GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A 6061 TATAAGTGCA GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA 6121 GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT 6181 GCCTTGAATT ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG 6241 TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT 6301 GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG 6361 CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA

6541 GGCGGGGCCT GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC 6601 CTGCTCTGGT GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG 6661 CCCGGTCGGC ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA 6721 GCTCAAAATG GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA 6781 AAAGGGCCTT TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT 6841 CCAGGCACCT CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG 6901 GGTTTTATGC GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT

7021 TCAAGCCTCA GACAGTGGTT CAAAGTTTTT TTCTTCCATT TCAGGTGTCG TGAAAACTAC 7081 CCCTCAGAGC CGCCACCATG CTTCTCCTGG TGACAAGCCT TCTGCTCTGT GAGTTACCAC 7141 ACCCAGCATT CCTCCTGATC CCAGACATCC AGATGACACA GACTACATCC TCCCTGTCTG 7201 CCTCTCTGGG AGACAGAGTC ACCATCAGTT GCAGGGCAAG TCAGGACATT AGTAAATATT 7261 T AA ATT GGT A TCAGCAGAAA CCAGATGGAA CTGTTAAACT CCTGATCTAC CATACATCAA 7321 GATTACACTC AGGAGTCCCA TCAAGGTTCA GTGGCAGTGG GTCTGGAACA GATTATTCTC 7381 TCACCATTAG CAACCTGGAG CAAGAAGATA TTGCCACTTA CTTTTGCCAA CAGGGTAATA 7441 CGCTTCCGTA CACGTTCGGA GGGGGGACTA AGTTGGAAAT AACAGGAGGT GGAGGTTCTG 7501 GTGGAGGAGG TTCAGGAGGT GGTGGAAGTG AGGTGAAACT GCAGGAGTCA GGACCTGGCC 7561 TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CAT GC ACT GT CTCAGGGGTC TCATTACCCG 7621 ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG CTGGGAGTAA 7681 TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG ACCATCATCA 7741 AGGACAACTC CAAGAGCCAA GTTTTCTTAA A A AT G A AC AG TCTGCAAACT GAT G AC AC AG 7801 CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG GACTACTGGG 7861 GTCAAGGAAC CTCAGTCACC GTCTCCTCAG G A ATT C AG A A CCCTGAGCCT GCCGTGTACC 7921 AGCTGAAGGA CCCTAGAAGC CAGGACAGCA CCCTGTGCCT GTTCACCGAC TTCGACAGCC 7981 AGATCAACGT GCCCAAGACC ATGGAAAGCG GCACCTTCAT CACCGATAAG ACTGTGCTGG 8041 ACATGAAGGC CATGGACAGC AAGAGCAACG GCGCCATTGC NT GGT CCA AT CAGACCAGCT 8101 TTACCTGCCA AGACATCTTC AAAGAGACAA ACGCCACCTA CCCCAGTTCA GACGTTCCCT 8161 GTGATGCCAC GTTGACTGAG AAAAGCTTTG A A AC AG AT AT GAACCTAAAC TTTCAAAACC 8221 TGTCAGTTAT GGGACTCCGA ATCCTCCTGC TGAAAGTAGC CGGATTTAAC CTGCTCATGA 8281 CGCTGAGGCT GTGGTCCAGT GGCAGCGGCG CTACTAACTT CAGCCTGCTG AAGCAGGCTG 8341 GAGACGTGGA GGAGAACCCT GGACCTGATC TGAGAAATGT GACTCCACCC AAGGTCTCCT 8401 TGTTTGAGCC ATCAAAAGCA GAGATTGCAA ACAAACAAAA GGCTACCCTC GTGTGCTTGG 8461 CCAGGGGCTT CTTCCCTGAC CACGTGGAGC TGAGCTGGTG GGTGAATGGC AAGGAGGTCC 8521 ACAGTGGGGT CAGCACGGAC CCTCAGGCCT ACAAGGAGAG CAATTATAGC TACTGCCTGA 8581 GCAGCCGCCT GAGGGTCTCT GCTACCTTCT GGCACAATCC TCGCAACCAC TTCCGCTGCC 8641 AAGTGCAGTT CCATGGGCTT TCAGAGGAGG ACAAGTGGCC AGAGGGCTCA CCCAAACCTG 8701 TCACACAGAA CATCAGTGCA GAGGCCTGGG GTCGAGCAGA CTGTGGTATT ACCTCAGCAT 8761 CCT AT C A AC A AGGAGTCTTG TCTGCCACCA TCCTCTATGA GATCCTGCTA GGGAAAGCCA 8821 CCCTGTATGC TGTGCTTGTC AGTACACTGG TGGTGATGGC TATGGTCAAA AGAAAGAATT 8881 CATGAGATAT CGAGCATCTT ACCGCCATTT ATACCCATAT TTGTTCTGTT TTTCTTGATT 8941 TGGGTATACA TTTAAATGTT A AT AAA AC A A AAT GGTGGGG C A AT C ATTT A C ATTTTT AGG 9001 GATATGTAAT TACTAGTTCA GGTGTATTGC CACAAGACAA ACATGTTAAG AAACTTTCCC 9061 GTTATTTACG CTCTGTTCCT GTTAATCAAC CTCTGGATTA CAAAATTTGT G AA AG ATT G A 9121 CTGATATTCT TAACTATGTT GCTCCTTTTA CGCTGTGTGG ATATGCTGCT TTATAGCCTC 9181 TGTATCTAGC TATTGCTTCC CGTACGGCTT TCGTTTTCTC CTCCTTGTAT AAATCCTGGT 9241 TGCTGTCTCT TTTAGAGGAG TTGTGGCCCG TTGTCCGTCA ACGTGGCGTG GTGTGCTCTG 9301 TGTTTGCTGA CGCAACCCCC ACTGGCTGGG GCATTGCCAC CACCTGTCAA CTCCTTTCTG 9361 GGACTTTCGC TTTCCCCCTC CCGATCGCCA CGGCAGAACT CATCGCCGCC TGCCTTGCCC 9421 GCTGCTGGAC AGGGGCTAGG TTGCTGGGCA CTGATAATTC CGTGGTGTTG TCAGTACTGG 9481 TACCTTTAAG ACCAATGACT TACAAGGCAG CTGTAGATCT TAGCCACTTT TT A A A AG A A A 9541 AGGGGGGACT GG A AGGGCT A ATTCACTCCC AAAGAAGACA AGATCTGCTT TTTGCCTGTA 9601 CTGGGTCTCT CTGGTTAGAC CAGATCTGAG CCTGGGAGCT CTCTGGCTAA CTAGGGAACC 9661 CACTGCTTAA GCCTCAATAA AGCTTGCCTT GAGTGCTTCA A pLRPO Jet_FMC63 mTRAC_T2 A mTRB C (SEQ ID NO: 162)

1 TG AT CAT AAT C AAGCCAT AT C AC AT CT GT A GAGGTTT ACT T GCTTT AAA A AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT TTCACAAATA AAGC ATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC AT GT CT GG AT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGCAGCTT GGCGTAATCA 361 TGGTCATAGC TGTTTCCTGT GTGAAATTGT TATCCGCTCA CAATTCCACA CAACATACGA 421 GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG TGAGCTAACT CACATTAATT 481 GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT GC ATT AATGA 541 ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC GCTCTTCCGC TTCCTCGCTC 601 ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA CTCAAAGGCG 661 GTAATACGGT T AT CC AC AG A ATCAGGGGAT AACGCAGGAA AGAACATGTG AGCAAAAGGC 721 CAGCAAAAGG CCAGGAACCG TAAAAAGGCC GCGTTGCTGG CGTTTTTCCA TAGGCTCCGC 781 CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA CCCGACAGGA 841 CT AT A A AG AT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC TGTTCCGACC 901 CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC GCTTTCTCAT 961 AGCTCACGCT GT AGGT AT CT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT GGGCTGTGTG 1021 CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG TCTTGAGTCC 1081 AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATTAGCAGA 1141 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 1201 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT

5641 AGGGATATTC ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC 5701 AAATGGCAGT ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATT GGGGGG TACAGTGCAG 5761 GGGAAAGAAT AGTAGACATA ATAGCAACAG AC AT AC A A AC T A A AG A ATT A CAAAAACAAA 5821 TTACAAAAAT TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG 5881 CTGAGCTAGC GGGCGGAGTT AGGGCGGAGC CAATCAGCGT GCGCCGTTCC GAAAGTTGCC 5941 TTTTATGGCT GGGCGGAGAA TGGGCGGTGA ACGCCGATGA TTATATAAGG ACGCGCCGGG 6001 TGTGGCACAG CTAGTTCCGT CGCAGCCGGG ATTTGGGTCG CGGTTCTTGT TTGTTCAGAG 6061 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 6121 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 6181 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT T AGT A A AT AT TT A A ATT GGT 6241 ATCAGCAGAA ACCAGATGGA ACTGTTAAAC TCCTGATCTA CCATACATCA AGATTACACT 6301 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AG ATT ATTCT CT C ACC ATT A 6361 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 6421 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGAGG TGGAGGTTCT GGTGGAGGAG 6481 GTTCAGGAGG TGGTGGAAGT GAGGTGAAAC TGCAGGAGTC AGGACCTGGC CTGGTGGCGC 6541 CCTCACAGAG CCTGTCCGTC ACATGCACTG TCTCAGGGGT CTCATTACCC GACTATGGTG 6601 TAAGCTGGAT TCGCCAGCCT CCACGAAAGG GTCTGGAGTG GCTGGGAGTA ATATGGGGTA 6661 GTGAAACCAC AT ACT AT A AT TCAGCTCTCA AATCCAGACT GACCATCATC AAGGACAACT 6721 CCAAGAGCCA AGTTTTCTTA AAAATGAACA GTCTGCAAAC TGATGACACA GCCATTTACT 6781 ACTGTGCCAA ACATTATTAC TACGGTGGTA GCTATGCTAT GGACTACTGG GGTCAAGGAA 6841 CCTCAGTCAC CGTCTCCTCA GGAATTCAGA ACCCTGAGCC TGCCGTGTAC CAGCTGAAGG 6901 ACCCTAGAAG CCAGGACAGC ACCCTGTGCC TGTTCACCGA CTTCGACAGC CAGATCAACG 6961 TGCCCAAGAC CATGGAAAGC GGCACCTTCA TCACCGATAA GACTGTGCTG GACATGAAGG 7021 CCATGGACAG CAAGAGCAAC GGCGCCATTG CNTGGTCCAA TCAGACCAGC TTTACCTGCC 7081 AAGACATCTT CAAAGAGACA AACGCCACCT ACCCCAGTTC AGACGTTCCC TGTGATGCCA 7141 CGTTGACTGA GAAAAGCTTT GAAACAGATA TGAACCTAAA CTTTCAAAAC CTGTCAGTTA 7201 TGGGACTCCG AATCCTCCTG CT G A A AGT AG CCGGATTTAA CCTGCTCATG ACGCTGAGGC 7261 TGTGGTCCAG TGGCAGCGGC GAGGGCAGAG GAAGTCTGCT AACATGCGGT GACGTCGAGG 7321 AGAATCCTGG ACCTGATCTG AGAAATGTGA CTCCACCCAA GGTCTCCTTG TTTGAGCCAT 7381 CAAAAGCAGA GATTGCAAAC AAACAAAAGG CTACCCTCGT GTGCTTGGCC AGGGGCTTCT 7441 TCCCTGACCA CGTGGAGCTG AGCTGGTGGG TGAATGGCAA GGAGGTCCAC AGTGGGGTCA 7501 GCACGGACCC TCAGGCCTAC AAGGAGAGCA ATTATAGCTA CTGCCTGAGC AGCCGCCTGA 7561 GGGTCTCTGC TACCTTCTGG CACAATCCTC GCAACCACTT CCGCTGCCAA GTGCAGTTCC 7621 ATGGGCTTTC AGAGGAGGAC AAGTGGCCAG AGGGCTCACC CAAACCTGTC ACACAGAACA 7681 TCAGTGCAGA GGCCTGGGGT CGAGCAGACT GTGGTATTAC CTCAGCATCC TATCAACAAG 7741 GAGTCTTGTC TGCCACCATC CTCTATGAGA TCCTGCTAGG GAAAGCCACC CTGTATGCTG 7801 TGCTTGTCAG TACACTGGTG GTGATGGCTA TGGTCAAAAG A A AG A ATT C A TGAGATATCG 7861 AGCATCTTAC CGCCATTTAT ACCCATATTT GTTCTGTTTT TCTTGATTTG GGT AT AC ATT 7921 TAAATGTTAA T A A A AC A A A A TGGTGGGGCA ATCATTTACA TTTTTAGGGA TATGTAATTA 7981 CTAGTTCAGG TGTATTGCCA CAAGACAAAC ATGTTAAGAA ACTTTCCCGT TATTTACGCT 8041 CTGTTCCTGT TAATCAACCT CT GG ATT AC A AAATTTGTGA A AG ATT G ACT GAT ATT CTT A 8101 ACTATGTTGC TCCTTTTACG CTGTGTGGAT ATGCTGCTTT ATAGCCTCTG TATCTAGCTA 8161 TTGCTTCCCG TACGGCTTTC GTTTTCTCCT CCTTGT AT AA ATCCTGGTTG CTGTCTCTTT 8221 TAGAGGAGTT GTGGCCCGTT GTCCGTCAAC GTGGCGTGGT GTGCTCTGTG TTTGCTGACG 8281 CAACCCCCAC TGGCTGGGGC ATTGCCACCA CCTGTCAACT CCTTTCTGGG ACTTTCGCTT 8341 TCCCCCTCCC GATCGCCACG GCAGAACTCA TCGCCGCCTG CCTTGCCCGC TGCTGGACAG 8401 GGGCTAGGTT GCTGGGCACT GATAATTCCG TGGTGTTGTC AGTACTGGTA CCTTTAAGAC 8461 C A AT GACTT A CAAGGCAGCT GT AG AT CTT A GCCACTTTTT AAAAGAAAAG GGGGGACTGG 8521 AAGGGCTAAT TCACTCCCAA AGAAGACAAG ATCTGCTTTT TGCCTGTACT GGGTCTCTCT 8581 GGTTAGACCA GATCTGAGCC TGGGAGCTCT CTGGCTAACT AGGGAACCCA CTGCTTAAGC 8641 CTCAATAAAG CTTGCCTTGA GTGCTTCAA pLRPC FMC63SLmTRAC(82-i37) T2A optiFMC63SLmTRBC_(i23-i73) (SEQ ID NO:163)

1 AAAGCTGAGC ATCCGGCTCC GGTGCCCGTC AGTGGGCAGA GCGCACATCG CCCACAGTCC 61 CCGAGAAGTT GGGGGGAGGG GTCGGCAATT GAACCGGTGC CTAGAGAAGG TGGCGCGGGG 121 TAAACTGGGA AAGTGATGTC GTGTACTGGC TCCGCCTTTT TCCCGAGGGT GGGGGAGAAC

241 CACAGGTAAG TGCCGTGTGT GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT 301 GCGTGCCTTG AATTACTTCC ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT 361 CGGGTTGGAA GTGGGTGGGA GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT 421 GCTTGAGTTG AGGCCTGGCC TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT 481 CGCGCCTGTC TCGCTGCTTT CGATAAGTCT CTAGCCATTT AAAATTTTTG ATGACCTGCT 541 GCGACGCTTT TTTTCTGGCA AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT 601 ATTTCGGTTT TTGGGGCCGC GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG 661 GCGAGGCGGG GCCTGCGAGC GCGGCCACCG AGAATCGGAC GGGGGTAGTC TCAAGCTGGC 721 CGGCCTGCTC TGGTGCCTGG CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG 781 CTGGCCCGGT CGGCACCAGT TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA 841 GGGAGCTCAA AATGGAGGAC GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA 901 AGGAAAAGGG CCTTTCCGTC CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG 961 CCGTCCAGGC ACCTCGATTA GTTCTCGAGC TTTTGGAGTA CGTCGTCTTT AGGTTGGGGG 1021 GAGGGGTTTT ATGCGATGGA GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA 1081 GCTTGGCACT TGATGTAATT CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC 1141 ATTCTCAAGC CTCAGACAGT GGTTCAAAGT TTTTTTCTTC CATTTCAGGT GTCGTGAAAA 1201 CTACCCCTCT AGAGCCGCCA CCATGCTTCT CCTGGTGACA AGCCTTCTGC TCTGTGAGTT 1261 ACCACACCCA GCATTCCTCC TGATCCCAGA CATCCAGATG ACACAGACTA CATCCTCCCT 1321 GTCTGCCTCT CTGGGAGACA GAGTCACCAT CAGTTGCAGG GCAAGTCAGG ACATTAGTAA 1381 ATATTTAAAT TGGTATCAGC AGAAACCAGA TGGAACTGTT AAACTCCTGA TCTACCATAC 1441 ATCAAGATTA CACTCAGGAG TCCCATCAAG GTTCAGTGGC AGTGGGTCTG GAACAGATTA 1501 TTCTCTCACC ATTAGCAACC TGGAGCAAGA AG AT ATT GCC ACTTACTTTT GCCAACAGGG 1561 TAATACGCTT CCGTACACGT TCGGAGGGGG GACTAAGTTG GAAATAACAG GCTCCACCTC 1621 TGGATCCGGC AAGCCCGGAT CTGGCGAGGG ATCCACCAAG GGCGAGGTGA AACTGCAGGA 1681 GTCAGGACCT GGCCTGGTGG CGCCCTCACA GAGCCTGTCC GTCACATGCA CTGTCTCAGG 1741 GGTCTCATTA CCCGACTATG GTGTAAGCTG GATTCGCCAG CCTCCACGAA AGGGTCTGGA 1801 GTGGCTGGGA GTAATATGGG GTAGTGAAAC C AC AT ACT AT A ATT C AGCT C TCAAATCCAG 1861 ACTGACCATC ATCAAGGACA ACTCCAAGAG CCAAGTTTTC TTAAAAATGA ACAGTCTGCA 1921 AACTGATGAC ACAGCCATTT ACTACTGTGC CAAACATTAT TACTACGGTG GTAGCTATGC 1981 T AT GG ACT AC TGGGGTCAAG GAACCTCAGT CACCGTCTCC TCAGCGGCCG CAGGTGGAGG 2041 AGGTTCTGGA GGTGGTGGAT CAGGTGGTGG AGGATCTTTA GAAGGAGCCA CCTACCCCAG 2101 TTCAGACGTT CCCTGTGATG CCACGTTGAC TGAGAAAAGC TTTGAAACAG ATATGAACCT 2161 AAACTTTCAA AACCTGTCAG TTATGGGACT CCGAATCCTC CTGCTGAAAG TAGCCGGATT 2221 TAACCTGCTC ATGACGCTGA GGCTGTGGTC CAGTGGGTCA GGCGAGGGCA GAGGAAGTCT 2281 GCTAACATGC GGTGACGTCG AGGAGAATCC TGGACCTATG CTACTACTTG TGACCTCACT 2341 ATTGTTATGC GAACTCCCTC ATCCCGCATT CTTGCTGATT CCAGACATTC AGATGACTCA 2401 AACAACTTCC AGCCTCTCCG CCTCACTCGG CGACCGCGTA ACAATAAGCT GTCGGGCCTC 2461 GCAAGATATT AGTAAGTACC TGAATTGGTA TCAGCAAAAA CCCGATGGTA CAGTCAAGCT 2521 TCTGATCTAC CATACCAGTC GTCTGCACAG CGGTGTCCCC AGCAGGTTCA GCGGCTCAGG 2581 ATCTGGTACC GATTATTCAC TGACGATTTC CAACCTTGAG CAGGAGGACA TCGCCACCTA 2641 CTTCTGCCAG CAGGGTAATA CTCTGCCGTA CACATTCGGG GGCGGTACCA AGCTCGAGAT 2701 CACGGGTTCA ACAAGCGGTT CTGGCAAGCC AGGCAGCGGC GAGGGGAGTA CAAAGGGGGA 2761 GGTGAAGTTG CAGGAAAGTG GCCCTGGATT GGTGGCCCCG AGCCAGAGTC TGTCTGTCAC 2821 CTGCACAGTT TCCGGAGTAA GTCTGCCTGA TTACGGAGTG TCCTGGATCA GACAGCCACC 2881 TCGAAAGGGC TTGGAGTGGC TTGGGGTCAT TTGGGGCAGT GAAACCACAT ACTACAACAG 2941 CGCTCTTAAG TCCAGGCTCA CTATCATCAA GGACAATTCA AAGAGCCAAG TATTCTTGAA 3001 AATGAATTCC CTGCAGACTG ATGACACCGC TATTTATTAT TGCGCTAAAC ATTATTACTA 3061 TGGAGGTTCT TATGCCATGG ACTACTGGGG GCAGGGTACC TCTGTGACAG TGAGTTCAGC 3121 TGCAGCTGGA GGTGGAGGTA GCGGAGGCGG TGGTAGTGGA GGGGGTGGTT CTCTGGAAGG 3181 TCGAGCAGAC TGTGGTATTA CCTCAGCATC CT AT C A AC A A GGAGTCTTGT CTGCCACCAT 3241 CCTCTATGAG ATCCTGCTAG GGAAAGCCAC CCTGTATGCT GTGCTTGTCA GTACACTGGT 3301 GGTGATGGCT ATGGT CAAAA G A A AG A ATT C ATGAGATATC GAGCATCTTA CCGCCATTTA 3361 TACCCATATT TGTTCTGTTT TTCTTGATTT GGGTATACAT TT A A AT GTT A AT A A A AC A A A

3481 ACAAGACAAA CATGTTAAGA AACTTTCCCG TTATTTACGC TCTGTTCCTG TT AATCAACC 3541 TCTGGATTAC AAAATTTGTG AAAGATTGAC TGATATTCTT AACTATGTTG CTCCTTTTAC 3601 GCTGTGTGGA TATGCTGCTT TATAGCCTCT GTATCTAGCT ATTGCTTCCC GTACGGCTTT 3661 CGTTTTCTCC TCCTTGTATA AATCCTGGTT GCTGTCTCTT TTAGAGGAGT TGTGGCCCGT 3721 TGTCCGTCAA CGTGGCGTGG TGTGCTCTGT GTTTGCTGAC GCAACCCCCA CTGGCTGGGG 3781 CATTGCCACC ACCTGTCAAC TCCTTTCTGG GACTTTCGCT TTCCCCCTCC CGATCGCCAC 3841 GGCAGAACTC ATCGCCGCCT GCCTTGCCCG CTGCTGGACA GGGGCTAGGT TGCTGGGCAC 3901 TGATAATTCC GTGGTGTTGT CAGTACTGGT ACCTTTAAGA CCAATGACTT ACAAGGCAGC 3961 TGTAGATCTT AGCCACTTTT T AAA AG A A A A GGGGGGACTG GAAGGGCTAA TTCACTCCCA 4021 AAGAAGACAA GATCTGCTTT TTGCCTGTAC TGGGTCTCTC TGGTTAGACC AGATCTGAGC 4081 CTGGGAGCTC TCTGGCTAAC TAGGGAACCC ACTGCTTAAG CCTCAATAAA GCTTGCCTTG 4141 AGTGCTTCAA T GAT CAT A AT C AAGCC AT AT CACATCTGTA GAGGTTT ACT T GCTTT A A A A 4201 AACCTCCACA CCTCCCCCTG AACCTGAAAC ATAAAATGAA TGCAATTGTT GTTGTTAACT 4261 TGTTTATTGC AGCTT AT A AT GGTT AC A A AT AAAGCAATAG CATCACAAAT TT C AC A A AT A 4321 AAGCATTTTT TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC 4381 ATGTCTGGAT CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG 4441 CTGGAAGAGG AAGGAGCTTG ATCCAGATCC CG AT CT CG AT CCAGATCCGG ATCGC AGCTT 4501 GGCGTAATCA TGGTCATAGC TGTTTCCTGT GTGAAATTGT TATCCGCTCA CAATTCCACA 4561 CAACATACGA GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG T G AGCT A ACT 4621 CACATTAATT GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT 4681 GCATTAATGA ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC GCTCTTCCGC 4741 TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG T AT C AGCT C A 4801 CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG 4861 AGCAAAAGGC CAGCAAAAGG CCAGGAACCG TAAAAAGGCC GCGTTGCTGG CGTTTTTCCA 4921 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 4981 CCCGACAGGA CTATAAAGAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 5041 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 5101 GCTTTCTCAT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 5161 GGGCTGTGTG CACGAACCCC CCCGGTAAGA CACGACTTAT CGCCACTGGC AGCAGCCACT 5221 GGTAACAGGA TTAGCAGAGC GAGGTATGTA GGCGGTGCTA CAGAGTTCTT GAAGTGGTGG 5281 CCTAACTACG GCTACACTAG AAGAACAGTA TTTGGTATCT GCGCTCTGCT GAAGCCAGTT 5341 ACCTTCGGAA AAAGAGTTGG TAGCTCTTGA TCCGGCAAAC AAACCACCGC TGGTAGCGGT

5461 TTGATCTTTT CTACGGGGTC TGACGCTCAG TGGAACGAAA ACTCACGTTA AGGGATTTTG 5521 GTCATGAGAT T AT C A A A A AG GATCTTCACC TAGATCCTTT T A AATT A A A A ATGAAGTTTT 5581 AAATCAATCT A AAGT AT AT A TGAGTAAACT TGGTCTGACA GTTACCAATG CTTAATCAGT 5641 GAGGCACCTA TCTCAGCGAT CTGTCTATTT CGTTCATCCA TAGTTGCCTG ACTCCCCGTC 5701 GTTGCTAGGT TACTGTCATG AGCGGATACA TATTTGAATG TATTTAGAAA AAT A A AC A A A 5761 AGAGTTTGTA GAAACGCAAA AAGGCCATCC GTCAGGATGG CCTTCTGCTT AATTTGATCG 5821 GTGGCAGTTT ATGGCGGGCG TCCTGCCCGC CACCCTCCGG GCCGTTGCTT CGCAACGTTC 5881 AAATCCGCTC CCGGCGGATT TGTCCTACTC AGGAGAGCGT TCACCGACAA ACAACAGATA 5941 AAACGAAAGG CCCAGTCTTT CGACTGAGCC TTTCGTTTTA TTTGATGCCT GGCAGTTCCC 6001 TACTCTCGCA TGGGTTGCGG CCGCCCGGGC CGTCGACCAA TTCTCATGTT TG AC AGCTT A 6061 TCATCGAATT TCTGCCATTC ATCCGCTTAT TATCACTTAT TCAGGCGTAG CAACCAGGCG 6121 TTTAAGGGCA CCAATAACTG CCTTAAAAAA ATTACGCCCC GCCCTGCCAC TCATCGCAGT 6181 ACTGTTGTAA TTCATTAAGC ATTCTGCCGA CATGGAAGCC ATCACAAACG GCATGATGAA 6241 CCTGAATCGC CAGCGGCATC AGCACCTTGT CGCCTTGCGT ATAATATTTG CCCATGGTGA 6301 AAACGGGGGC GAAGAAGTTG TCCATATTGG CCACGTTTAA ATCAAAACTG GTGAAACTCA 6361 CCCAGGGATT GGCTGAGACG A A A A AC AT AT TCTCAATAAA CCCTTTAGGG AAATAGGCCA 6421 GGTTTTCACC GTAACACGCC AC AT CTTGCG AATATATGTG TAGAAACTGC CGGAAATCGT 6481 CGTGGTATTC ACTCCAGAGC GATGAAAACG TTTCAGTTTG CTCATGGAAA ACGGTGTAAC 6541 AAGGGTGAAC ACTATCCCAT ATCACCAGCT CACCGTCTTT CATTGCCATA CGAAATTCCG 6601 GATGAGCATT CATCAGGCGG GCAAGAATGT GAATAAAGGC CGGATAAAAC TTGTGCTTAT 6661 TTTTCTTTAC GGTCTTTAAA AAGGCCGTAA TATCCAGCTG AACGGTCTGG TTATAGGTAC 6721 ATTGAGCAAC TGACTGAAAT GCCTCAAAAT GTTCTTTACG ATGCCATTGG GAT AT AT C A A

7141 TGCCGTAAAG CACTAAATCG GAACCCTAAA GGGAGCCCCC GATTTAGAGC TTGACGGGGA 7201 AAGCCGGCGA ACGTGGCGAG AAAGGAAGGG AAGAAAGCGAAAGG AGCGGGCGCT AAGGCG 7261 CTGGCAAGTG TAGCGGTCAC GCTGCGCGTA ACCACCACAC CCGCCGCGCT TAATGCGCCG 7321 CTACAGGGCG CGTACTATGG TTGCTTTGAC GTATGCGGTG TGAAATACCG CACAGATGCG 7381 TAAGGAGAAA ATACCGCATC AGGCGCCATT CGCCATTCAG GCTGCGCAAC TGTTGGGAAG 7441 GGCGATCGGT GCGGGCCTCT TCGCTATTAC GCCAGCTGGC GAAAGGGGGA TGTGCTGCAA 7501 GGCGATTAAG TTGGGTAACG CCAGGGTTTT CCCAGTCACG ACGTTGTAAA ACGACGGCCA 7561 GTGAATTGAT CGAGATCGTG ATCCGGATCA AGATCCAGAT CGAATTGGAG GCTACAGTCA 7621 GT GG AG AGG A CTTTCACTGA CTGACTGACT GCGTCTCAAC CTCCTAGGGG ACATTGATTA 7681 TTGACTAGTT ATTAATAGTA ATCAATTACG GGGTCATTAG TTCATAGCCC ATATATGGAG 7741 TTCCGCGTTA CATAACTTAC GGTAAATGGC CCGCCTGGCT GACCGCCCAA CGACCCCCGC 7801 CCATTGACGT CAATAATGAC GTATGTTCCC ATAGTAACGC CAATAGGGAC TTTCCATTGA 7861 CGTCAATGGG TGGAGTATTT ACGGTAAACT GCCCACTTGG CAGTACATCA AGTGTATCAT 7921 ATGCCAAGTA CGCCCCCTAT TGACGTCAAT GACGGTAAAT GGCCCGCCTG GCATTATGCC 7981 CAGTACATGA CCTTATGGGA CTTTCCTACT TGGCAGTACA TCTACGTATT AGTCATCGCT 8041 ATT ACC AT GG TGATGCGGTT TTGGCAGTAC ATCAATGGGC GTGGATAGCG GTTTGACTCA 8101 CGGGGATTTC CAAGTCTCCA CCCCATTGAC GTCAATGGGA GTTTGTTTTG GCACCAAAAT 8161 CAACGGGACT TTCCAAAATG TCGTAACAAC TCCGCCCCAT TGACGCAAAT GGGCGGTAGG 8221 CGTGTACGGT GGGAGGTCTA TATAAGCAGA GCTCGTTTAG TGAACCGGGT CTCTCTGGTT 8281 AGACCAGATC TGAGCCTGGG AGCTCTCTGG CTAACTAGGG AACCCACTGC TTAAGCCTCA 8341 ATAAAGCTTG CCTTGAGTGC TCAAAGTAGT GTGTGCCCGT CTGTTGTGTG ACTCTGGTAA 8401 CTAGAGATCC CTCAGACCCT TTTAGTCAGT GTGGAAAATC TCTAGCAGTG GCGCCCGAAC 8461 AGGGACTTGA AAGCGAAAGT AAAGCCAGAG GAGATCTCTC GACGCAGGAC TCGGCTTGCT 8521 GAAGCGCGCA CGGCAAGAGG CGAGGGGCGG CGACTGGTGA GTACGCCAAA AATTTTGACT 8581 AGCGGAGGCT AGAAGGAGAG AGTAGGGTGC GAGAGCGTCG GTATTAAGCG GGGGAGAATT 8641 AGATAAATGG G A A A A A ATT C GGTTAAGGCC AGGGGGAAAG A A AC A AT AT A A ACT A A A AC A 8701 TATAGTTAGG GCAAGCAGGG AGCTAGAACG ATTCGCAGTT AATCCTGGCC TTTTAGAGAC 8761 ATCAGAAGGC T GT AG AC A A A TACTGGGACA GCTACAACCA TCCCTTCAGA CAGGATCAGA 8821 AGAACTTAGA TC ATT AT AT A ATACAATAGC AGTCCTCTAT TGTGTGCATC AAAGGATAGA 8881 T GT A A A AG AC ACCAAGGAAG CCTTAGATAA GAT AG AGG A A GAGCAAAACA A A AGT A AG A A 8941 AAAGGCACAG CAAGCGATCT TCAGACCTGG AGGAGGCAGG AGGCGATATG AGGGACAATT 9001 GGAGAAGTGA ATT AT AT AAA TAT A A AGT AG T AAA A ATT G A ACCATTAGGA GTAGCACCCA 9061 CCAAGGCAAA GAGAAGAGTG GTGCAGAGAG AAAAAAGAGC AGTGGGAATA GGAGCTTTGT 9121 TCCTTGGGTT CTTGGGAGCA GCAGGAAGCA CTATGGGCGC AGCGTCAATG ACGCTGACGG 9181 TACAGGCCAG AC A ATT ATT G TCT GAT AT AG TGCAGCAGCA GAACAATTTG CTGAGGGCTA 9241 TTGAGGCGCA ACAGCATCTG TTGCAACTCA CAGTCTGGGG CATCAAACAG CTCCAGGCAA 9301 GAATCCTGGC TGTGGAAAGA TACCTAAAGG ATCAACAGCT CCTGGGGATT TGGGGTTGCT 9361 CTGGAAAACT CATTTGCACC ACTGCTGTGC CTTGGAATGC TAGTTGGAGT AAT A A AT CTC 9421 TGGAACAGAT TTGGAATAAC ATGACCTGGA TGGAGTGGGA CAGAGAAATT AACAATTACA 9481 C A AGCTT AAT AC ACTCCTT A ATTGAAGAAT CGCAAAACCA GCAAGAAAAG AAT G A AC A AG 9541 AATTATTGGA ATT AGAT AAA TGGGCAAGTT TGTGGAATTG GTTTAACATA ACAAATTGGC 9601 TGTGGTATAT AAAATTATTC ATAATGATAG TAGGAGGCTT GGTAGGTTTA AGAATAGTTT 9661 TTGCTGTACT TTCTATAGTG AATAGAGTTA GGCAGGGATA TTCACCATTA TCGTTTCAGA 9721 CCCACCTCCC AATCCCGAGG GGACCACGCG TACAAATGGC AGTATTCATC CACAATTTTA 9781 AAAGAAAAGG GGGGATTGGG GGGTACAGTG CAGGGGAAAG AAT AGT AG AC AT AAT AGC A A 9841 CAGACATACA AACTAAAGAA TTACAAAAAC A A ATT AC A A A AATTCAAAAT TTTCGGGTTT 9901 ATTACAGGGA CAGCAGAAAT CCACTTTGG pLRPC FMC63mTRAC_T2A_mTRBC (SEQ ID NO: 164)

1 TGATCATAAT CAAGCCATAT CACATCTGTA GAGGTTTACT TGCTTTAAAA AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTT AT A AT GGTT AC A A AT AAAGCAATAG CAT C AC A A AT TT C AC A A AT A AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC ATGTCTGGAT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGC AGCTT GGCGTAATCA 361 TGGTCATAGC TGTTTCCTGT GTGAAATTGT TATCCGCTCA CAATTCCACA CAACATACGA 421 GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG TGAGCTAACT CACATTAATT 481 GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT GCATTAATGA 541 ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC GCTCTTCCGC TTCCTCGCTC 601 ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA CTCAAAGGCG 661 GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG AGCAAAAGGC 721 CAGCAAAAGG CCAGGAACCG T AAAAAGGCC GCGTTGCTGG CGTTTTTCCA TAGGCTCCGC 781 CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA CCCGACAGGA 841 CT AT A A AG AT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC TGTTCCGACC 901 CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC GCTTTCTCAT 961 AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT GGGCTGTGTG 1021 CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG TCTTGAGTCC 1081 AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATTAGCAGA 1141 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 1201 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT

1321 CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT TTCTACGGGG 1381 TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG ATTATCAAAA 1441 AGGATCTTCA CCTAGATCCT TTTAAATTAA AAATGAAGTT TTAAATCAAT CTAAAGTATA 1501 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 1561 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTTGCTAG GTTACTGTCA 1621 TGAGCGGATA CATATTTGAA TGTATTTAGA AAAATAAACA AAAGAGTTTG TAGAAACGCA 1681 AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT CGGTGGCAGT TTATGGCGGG 1741 CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT TCAAATCCGC TCCCGGCGGA 1801 TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA T AAAACG AAA GGCCCAGTCT 1861 TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC CCTACTCTCG CATGGGTTGC 1921 GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT TATCATCGAA TTTCTGCCAT 1981 TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG CGTTTAAGGG CACCAATAAC 2041 TGCCTTAAAA AAATTACGCC CCGCCCTGCC ACTCATCGCA GTACTGTTGT AATTCATTAA 2101 GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG AACCTGAATC GCCAGCGGCA 2161 TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT GAAAACGGGG GCGAAGAAGT 2221 TGTCCATATT GGCCACGTTT AA AT C A A A AC TGGTGAAACT CACCCAGGGA TTGGCTGAGA 2281 CGAAAAACAT ATT CT C A AT A AACCCTTT AG GGAAATAGGC C AGGTTTT C A CCGTAACACG 2341 CCACATCTTG CGAATATATG TGTAGAAACT GCCGGAAATC GTCGTGGTAT TCACTCCAGA 2401 GCGAT GAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA ACAAGGGTGA ACACTATCCC 2461 ATATCACCAG CTCACCGTCT TTCATTGCCA TACGAAATTC CGGATGAGCA TTCATCAGGC 2521 GGGCAAGAAT GTGAATAAAG GCCGGATAAA ACTTGTGCTT ATTTTTCTTT ACGGTCTTTA 2581 AAAAGGCCGT A AT AT CC AGC TGAACGGTCT GGTTATAGGT ACATTGAGCA ACTGACTGAA 2641 ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC AACGGTGGTA TATCCAGTGA

2761 CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC TCTTACGTGC CGATCAACGT 2821 CTCATTTTCG CCAAAAGTGA CATTAACCTA TAAAAATAGG CGTATCACGA GGCCAGCTTG 2881 GGAAACC AT A AGACCGAGAT AGAGTTGAGT GTTGTTCCAG TTTGGAACAA GAGTCCACTA 2941 TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG TCTATCAGGG CGATGGCCCA 3001 CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA GGTGCCGTAA AGC ACT A A AT 3061 CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG GAAAGCCGGC GAACGTGGCG 3121 AGAAAGGAAG GGAAGAAAGC GAAAGGAGCG GGCGCTAAGG CGCTGGCAAGTGTAGCGGTC 3181 ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC CGCTACAGGG CGCGT ACT AT 3241 GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG CGTAAGGAGA AAATACCGCA 3301 TCAGGCGCCA TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGATCG GTGCGGGCCT 3361 CTTCGCTATT ACGCCAGCTG GCGAAAGGGG GATGTGCTGC AAGGCG ATT A AGTTGGGTAA 3421 CGCCAGGGTT TTCCCAGTCA CGACGTTGTA AAACGACGGC CAGTGAATTG ATCGAGATCG 3481 TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT CAGTGGAGAG GACTTTCACT 3541 GACTGACTGA CTGCGTCTCA ACCTCCTAGG GG AC ATT GAT TATTGACTAG TT ATT A AT AG 3601 TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG AGTTCCGCGT TACATAACTT 3661 ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC GCCCATTGAC GTCAATAATG 3721 ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT GACGTCAATG GGTGGAGTAT 3781 TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC ATATGCCAAG TACGCCCCCT 3841 ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG CCCAGTACAT GACCTTATGG 3901 GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG CTATTACCAT GGTGATGCGG 3961 TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT CACGGGGATT TCCAAGTCTC 4021 CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA ATCAACGGGA CTTTCCAAAA 4081 TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA GGCGTGTACG GTGGGAGGTC 4141 T AT AT AAGC A GAGCTCGTTT AGTGAACCGG GTCTCTCTGG TTAGACCAGA TCTGAGCCTG 4201 GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT CAATAAAGCT TGCCTTGAGT 4261 GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT AACTAGAGAT CCCTCAGACC 4321 CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA ACAGGGACTT GAAAGCGAAA 4381 GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG CTGAAGCGCG CACGGCAAGA 4441 GGCGAGGGGC GGCGACTGGT GAGTACGCCA A A A ATTTT G A CTAGCGGAGG CT AG A AGG AG 4501 AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA TTAGATAAAT GGGAAAAAAT 4561 TCGGTTAAGG CCAGGGGGAA AG A A AC A AT A T A A ACT A A A A CAT AT AGTT A GGGCAAGCAG 4621 GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTTAGAG ACATCAGAAG GCTGTAGACA 4681 AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA GAAGAACTTA GATCATTATA 4741 T AAT AC A AT A GCAGTCCTCT ATT GT GT GCA T C A A AGG AT A GAT GT AAA AG ACACCAAGGA 4801 AGCCTTAGAT AAGATAGAGG AAGAGCAAAA CAAAAGTAAG AAAAAGGCACAGCAAGCGAT 4861 CTTCAGACCT GGAGGAGGCA GGAGGCGAT A TGAGGGACAA TTGGAGAAGT G A ATT AT AT A 4921 AAT AT A A AGT AGTAAAAATT GAACCATTAG GAGTAGCACC CACCAAGGCA AAGAGAAGAG 4981 TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT GTTCCTTGGG TTCTTGGGAG 5041 CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC GGTACAGGCC AGACAATTAT 5101 TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC TATTGAGGCG CAACAGCATC 5161 TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC AAGAATCCTG GCTGTGGAAA 5221 GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG CTCTGGAAAA CTCATTTGCA 5281 CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC TCTGGAACAG ATTTGGAATA 5341 ACATGACCTG GAT GG AGT GG GACAGAGAAA TT AAC A ATT A CACAAGCTTA ATACACTCCT 5401 TAATTGAAGA ATCGCAAAAC CAGCAAGAAA AGAATGAACA AG A ATT ATT G GAATT AG AT A 5461 AATGGGCAAG TTTGTGGAAT TGGTTTAACA T A AC A A ATT G GCTGTGGTAT ATAAAATTAT 5521 T CAT A ATG AT AGTAGGAGGC TTGGTAGGTT T A AG AAT AGT TTTTGCTGTA CTTTCTATAG 5581 TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA GACCCACCTC CCAATCCCGA 5641 GGGGACCACG CGTACAAATG GC AGT ATT C A TCCACAATTT T AAA AG A A A A GGGGGGATTG 5701 GGGGGTACAG TGCAGGGGAA AGAATAGTAG ACATAATAGC AACAGACATA CAAACTAAAG 5761 AATT AC A A A A ACAAATTACA A A A ATT C A A A ATTTTCGGGT TT ATT AC AGG GACAGCAGAA 5821 ATCCACTTTG GAAAGCTGAG CATCCGGCTC CGGTGCCCGT CAGTGGGCAG AGCGCACATC 5881 GCCCACAGTC CCCGAGAAGT TGGGGGGAGG GGTCGGCAAT TGAACCGGTG CCTAGAGAAG 5941 GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG CTCCGCCTTT TTCCCGAGGG

6061 TGCCGCCAGA ACACAGGTAA GTGCCGTGTG TGGTTCCCGC GGGCCTGGCC TCTTTACGGG 6121 TTATGGCCCT TGCGTGCCTT GAATTACTTC CACGCCCCTG GCTGCAGTAC GTGATTCTTG 6181 ATCCCGAGCT TCGGGTTGGA AGTGGGTGGG AGAGTTCGAG GCCTTGCGCT TAAGGAGCCC 6241 CTTCGCCTCG TGCTTGAGTT GAGGCCTGGC CTGGGCGCTG GGGCCGCCGC GTGCGAATCT 6301 GGTGGCACCT TCGCGCCTGT CTCGCTGCTT TCGATAAGTC TCTAGCCATT TAAAATTTTT 6361 GATGACCTGC TGCGACGCTT TTTTTCTGGC AAGATAGTCT TGTAAATGCG GGCCAAGATC 6421 TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA CGGGGCCCGT GCGTCCCAGC 6481 GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC GAGAATCGGA CGGGGGTAGT 6541 CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC GCCGTGTATC GCCCCGCCCT 6601 GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC GGAAAGATGG CCGCTTCCCG 6661 GCCCTGCTGC AGGGAGCTCA AAATGGAGGA CGCGGCGCTC GGGAGAGCGG GCGGGTGAGT 6721 CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT CGCTTCATGT GACTCCACGG 6781 AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG CTTTTGGAGT ACGTCGTCTT 6841 TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA CACTGAGTGG GTGGAGACTG 6901 AAGTTAGGCC AGCTTGGCAC TT GAT GT A AT TCTCCTTGGA ATTTGCCCTT TTTGAGTTTG 6961 GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG TTTTTTTCTT CCATTTCAGG 7021 TGTCGTGAAA ACTACCCCTC TAGAGCCGCC ACCATGCTTC TCCTGGTGAC AAGCCTTCTG 7081 CTCTGTGAGT TACCACACCC AGCATTCCTC CTGATCCCAG ACATCCAGAT GACACAGACT 7141 ACATCCTCCC TGTCTGCCTC TCTGGGAGAC AGAGTCACCA TCAGTTGCAG GGCAAGTCAG 7201 GAC ATT AGT A A AT ATTT AAA TTGGTATCAG CAGAAACCAG ATGGAACTGT TAAACTCCTG 7261 ATCTACCATA CATCAAGATT ACACTCAGGA GTCCCATCAA GGTTCAGTGG CAGTGGGTCT 7321 GGAACAGATT ATTCTCTCAC C ATT AGC A AC CTGGAGCAAG A AG AT ATT GC CACTTACTTT 7381 TGCCAACAGG GTAATACGCT TCCGTACACG TTCGGAGGGG GGACTAAGTT GGAAATAACA 7441 GGAGGTGGAG GTTCTGGTGG AGGAGGTTCA GGAGGTGGTG GAAGTGAGGT GAAACTGCAG 7501 GAGTCAGGAC CTGGCCTGGT GGCGCCCTCA CAGAGCCTGT CCGTCACATG CACTGTCTCA 7561 GGGGTCTCAT TACCCGACTA TGGTGTAAGC TGGATTCGCC AGCCTCCACG AAAGGGTCTG 7621 GAGTGGCTGG G AGT A AT AT G GGGTAGTGAA ACC AC AT ACT ATAATTCAGC TCTCAAATCC 7681 AGACTGACCA TCATCAAGGA CAACTCCAAG AGCCAAGTTT TCTTAAAAAT GAACAGTCTG 7741 CAAACTGATG ACACAGCCAT TTACTACTGT GCCAAACATT ATTACTACGG TGGTAGCTAT 7801 GCTATGGACT ACTGGGGTCA AGGAACCTCA GTCACCGTCT CCTCAGGAAT TCAGAACCCT 7861 GAGCCTGCCG TGTACCAGCT GAAGGACCCT AGAAGCCAGG ACAGCACCCT GTGCCTGTTC 7921 ACCGACTTCG AC AGC C AG AT CAACGTGCCC AAGACCATGG AAAGCGGCAC CTTCATCACC 7981 GATAAGACTG TGCTGGACAT GAAGGCCATG GACAGCAAGA GCAACGGCGC CATTGCNTGG 8041 TCCAATCAGA CCAGCTTTAC CTGCCAAGAC ATCTTCAAAG AGACAAACGC CACCTACCCC 8101 AGTTCAGACG TTCCCTGTGA TGCCACGTTG ACT GAG A A A A GCTTTGAAAC AGATATGAAC 8161 CTAAACTTTC AAAACCTGTC AGTTATGGGA CTCCGAATCC TCCTGCTGAA AGTAGCCGGA 8221 TTTAACCTGC TCATGACGCT GAGGCTGTGG TCCAGTGGCA GCGGCGAGGG CAGAGGAAGT 8281 CTGCTAACAT GCGGTGACGT CGAGGAGAAT CCTGGACCTG ATCTGAGAAA TGTGACTCCA 8341 CCCAAGGTCT CCTTGTTTGA GCCATCAAAA GCAGAGATTG CAAACAAACA AAAGGCTACC 8401 CTCGTGTGCT TGGCCAGGGG CTTCTTCCCT GACCACGTGG AGCTGAGCTG GTGGGTGAAT 8461 GGCAAGGAGG TCCACAGTGG GGTCAGCACG GACCCTCAGG CCTACAAGGA GAGCAATTAT 8521 AGCTACTGCC TGAGCAGCCG CCTGAGGGTC TCTGCTACCT TCTGGCACAA TCCTCGCAAC 8581 CACTTCCGCT GCCAAGTGCA GTTCCATGGG CTTTCAGAGG AGGACAAGTG GCCAGAGGGC 8641 TCACCCAAAC CTGTCACACA GAACATCAGT GCAGAGGCCT GGGGTCGAGC AGACTGTGGT 8701 ATTACCTCAG CATCCTATCA ACAAGGAGTC TTGTCTGCCA CCATCCTCTA TGAGATCCTG 8761 CTAGGGAAAG CCACCCTGTA TGCTGTGCTT GTCAGTACAC TGGTGGTGAT GGCTATGGTC 8821 AAAAGAAAGA ATTCATGAGA TATCGAGCAT CTTACCGCCA TTTATACCCA TATTTGTTCT 8881 GTTTTTCTTG ATTTGGGTAT ACATTTAAAT GTTAATAAAA CAAAATGGTG GGGCAATCAT

9001 AAGAAACTTT CCCGTTATTT ACGCTCTGTT CCTGTTAATC AACCTCTGGA TT AC AAA ATT 9061 TGTGAAAGAT T GACT GAT AT TCTTAACTAT GTTGCTCCTT TTACGCTGTG TGGATATGCT 9121 GCTTTATAGC CTCTGTATCT AGCTATTGCT TCCCGTACGG CTTTCGTTTT CTCCTCCTTG 9181 T AT AAATCCT GGTTGCTGTC TCTTTTAGAG GAGTTGTGGC CCGTTGTCCG TCAACGTGGC 9241 GTGGTGTGCT CTGTGTTTGC TGACGCAACC CCCACTGGCT GGGGCATTGC CACCACCTGT 9301 CAACTCCTTT CTGGGACTTT CGCTTTCCCC CTCCCGATCG CCACGGCAGA ACTCATCGCC 9361 GCCTGCCTTG CCCGCTGCTG GACAGGGGCT AGGTTGCTGG GC ACT GAT A A TTCCGTGGTG 9421 TTGTCAGTAC TGGTACCTTT AAGACCAATG ACTTACAAGG CAGCTGTAGA TCTTAGCCAC 9481 TTTTT AAA AG AAAAGGGGGG ACT GG AAGGG CTAATTCACT CCCAAAGAAG ACAAGATCTG 9541 CTTTTTGCCT GTACTGGGTC TCTCTGGTTA GACCAGATCT GAGCCTGGGA GCTCTCTGGC 9601 TAACTAGGGA ACCCACTGCT TAAGCCTCAA TAAAGCTTGC CTTGAGTGCT TCAA pLRPC FMC63mTRAC_T2A_mTRBC U5 (SEQ ID NO: 165)

1 GACATTGATT ATTGACTAGT TATTAATAGT AATCAATTAC GGGGTCATTA GTTCATAGCC 61 CATATATGGA GTTCCGCGTT ACATAACTTA CGGTAAATGG CCCGCCTGGC TGACCGCCCA 121 ACGACCCCCG CCCATTGACG TCAATAATGA CGTATGTTCC CATAGTAACG CCA AT AGGG A 181 CTTTCCATTG ACGTCAATGG GTGGAGTATT TACGGTAAAC TGCCCACTTG GCAGTACATC 241 AAGTGTATCA TATGCCAAGT ACGCCCCCTA TTGACGTCAA TGACGGTAAA TGGCCCGCCT 301 GGCATTATGC CCAGTACATG ACCTTATGGG ACTTTCCTAC TTGGCAGTAC ATCTACGTAT 361 TAGTCATCGC T ATT ACC AT G GTGATGCGGT TTTGGCAGTA CATCAATGGG CGTGGATAGC 421 GGTTT G ACT C ACGGGGATTT CCAAGTCTCC ACCCCATTGA CGTCAATGGG AGTTTGTTTT 481 GGCACCAAAA TCAACGGGAC TTTCCAAAAT GTCGTAACAA CTCCGCCCCA TTGACGCAAA 541 TGGGCGGTAG GCGTGTACGG TGGGAGGTCT AT AT AAGC AG AGCTCGTTTA GTGAACCGGG 601 TCTCTCTGGT TAGACCAGAT CTGAGCCTGG GAGCTCTCTG GCTAACTAGG GAACCCACTG 661 CTTAAGCCTC AATAAAGCTT GCCTTGAGTG CTCAAAGTAG TGTGTGCCCG TCTGTTGTGT 721 GACTCTGGTA ACT AG AG AT C CCTCAGACCC TTTTAGTCAG TGTGGAAAAT CTCTAGCAGT 781 GGCGCCCGAA CAGGGACTTG AAAGCGAAAG TAAAGCCAGA GGAGATCTCT CGACGCAGGA 841 CTCGGCTTGC TGAAGCGCGC ACGGCAAGAG GCGAGGGGCG GCGACTGGTG AGTACGCCAA 901 AAATTTTGAC T AGCGGAGGC TAGAAGGAGA GAGTAGGGTG CGAGAGCGTC GGTATTAAGC 961 GGGGGAGAAT TAGATAAATG GGAAAAAATT CGGTTAAGGC CAGGGGGAAA GA AAC A AT AT 1021 AAACT AAAAC ATATAGTTAG GGCAAGCAGG GAGCTAGAAC GATTCGCAGT TAATCCTGGC 1081 CTTTTAGAGA CATCAGAAGG CTGTAGACAA ATACTGGGAC AGCTACAACC ATCCCTTCAG 1141 ACAGGATCAG AAGAACTTAG ATCATTATAT A AT AC A AT AG CAGTCCTCTA TTGTGTGCAT 1201 CAAAGGATAG AT GT A A A AG A CACCAAGGAA GCCTT AGAT A AG AT AG AGG A AGAGC AAAAC 1261 AAAAGTAAGA AAAAGGCACA GCAAGCGATC TTCAGACCTG GAGGAGGCAG GAGGCGATAT 1321 GAGGGACAAT TGGAGAAGTG A ATT AT AT A A AT AT A A AGT A GT A A A A ATT G AACCATTAGG 1381 AGTAGCACCC ACCAAGGCAA AGAGAAGAGT GGTGCAGAGA GAAAAAAGAGCAGTGGGAAT 1441 AGGAGCTTTG TTCCTTGGGT TCTTGGGAGC AGCAGGAAGC ACTATGGGCG CAGCGTCAAT 1501 GACGCTGACG GTACAGGCCA GACAATTATT GTCTGATATA GTGCAGCAGC AGAACAATTT 1561 GCTGAGGGCT ATTGAGGCGC AACAGCATCT GTTGCAACTC ACAGTCTGGG GCATCAAACA 1621 GCTCCAGGCA AGAATCCTGG CTGTGGAAAG ATACCTAAAG GATCAACAGC TCCTGGGGAT 1681 TTGGGGTTGC TCTGGAAAAC TCATTTGCAC CACTGCTGTG CCTTGGAATG CTAGTTGGAG 1741 TAATAAATCT CTGGAACAGA TTTGGAATAA CATGACCTGG ATGGAGTGGG ACAGAGAAAT 1801 TAACAATTAC ACAAGCTTAA TACACTCCTT AATTGAAGAA TCGCAAAACC AGCAAGAAAA 1861 GAATGAACAA GAATTATTGG AATT AGAT A A ATGGGCAAGT TTGTGGAATT GGTTTAACAT 1921 AACAAATTGG CTGTGGTATA TAAAATTATT CATAATGATA GTAGGAGGCT TGGTAGGTTT 1981 AAGAAT AGTT TTTGCTGTAC TTTCTATAGT GAATAGAGTT AGGCAGGGAT ATTCACCATT 2041 ATCGTTTCAG ACCCACCTCC CAATCCCGAG GGGACCACGC GTACAAATGG CAGTATTCAT 2101 CCACAATTTT AAAAGAAAAG GGGGGATTGG GGGGTACAGT GCAGGGGAAA GAATAGTAGA 2161 CATAATAGCA ACAGACATAC AAACT AAAGA ATT AC A A A A A CAAATTACAA A A ATT C A A A A 2221 TTTTCGGGTT TATTACAGGG ACAGCAGAAA TCCACTTTGG AAAGCTGAGC ATCCGGCTCC 2281 GGTGCCCGTC AGTGGGCAGA GCGCACATCG CCCACAGTCC CCGAGAAGTT GGGGGGAGGG 2341 GTCGGCAATT GAACCGGTGC CTAGAGAAGG TGGCGCGGGG TAAACTGGGA AAGTGATGTC 2401 GTGTACTGGC TCCGCCTTTT TCCCGAGGGT GGGGGAGAAC CGTATATAAG TGCAGTAGTC 2461 GCCGTGAACG TTCTTTTTCG CAACGGGTTT GCCGCCAGAA CACAGGTAAG TGCCGTGTGT 2521 GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT GCGTGCCTTG AATTACTTCC 2581 ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT CGGGTTGGAA GTGGGTGGGA 2641 GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT GCTTGAGTTG AGGCCTGGCC 2701 TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT CGCGCCTGTC TCGCTGCTTT

2821 AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT ATTTCGGTTT TTGGGGCCGC 2881 GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG GCGAGGCGGG GCCTGCGAGC 2941 GCGGCCACCG AGAATCGGAC GGGGGTAGTC TCAAGCTGGC CGGCCTGCTC TGGTGCCTGG 3001 CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG CTGGCCCGGT CGGCACCAGT 3061 TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA GGGAGCTCAA AATGGAGGAC 3121 GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA AGGAAAAGGG CCTTTCCGTC 3181 CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG CCGTCCAGGC ACCT CG ATT A 3241 GTTCTCGAGC TTTTGGAGTA CGTCGTCTTT AGGTTGGGGG GAGGGGTTTT ATGCGATGGA 3301 GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA GCTTGGCACT TGATGTAATT 3361 CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC ATTCTCAAGC CTCAGACAGT

3481 CCATGCTTCT CCTGGTGACA AGCCTTCTGC TCTGTGAGTT ACCACACCCA GCATTCCTCC 3541 TGATCCCAGA CATCCAGATG ACACAGACTA CATCCTCCCT GTCTGCCTCT CTGGGAGACA 3601 GAGTCACCAT CAGTTGCAGG GCAAGTCAGG ACATTAGTAA ATATTTAAAT TGGTATCAGC 3661 AGAAACCAGA TGGAACTGTT AA ACT CCT G A TCTACCATAC ATCAAGATTA CACTCAGGAG 3721 TCCCATCAAG GTTCAGTGGC AGTGGGTCTG GAACAGATTA TTCTCTCACC ATTAGCAACC 3781 TGGAGCAAGA AGATATTGCC ACTTACTTTT GCCAACAGGG TAATACGCTT CCGTACACGT 3841 TCGGAGGGGG GACTAAGTTG GAAATAACAG GAGGTGGAGG TTCTGGTGGA GGAGGTTCAG 3901 GAGGTGGTGG AAGTGAGGTG AAACTGCAGG AGTCAGGACC TGGCCTGGTG GCGCCCTCAC 3961 AGAGCCTGTC CGTCACATGC ACTGTCTCAG GGGTCTCATT ACCCGACTAT GGTGTAAGCT 4021 GGATTCGCCA GCCTCCACGA AAGGGTCTGG AGTGGCTGGG AGTAATATGG GGTAGTGAAA 4081 CC AC AT ACT A TAATTCAGCT CTCAAATCCA GACTGACCAT CATCAAGGAC AACTCCAAGA 4141 GCCAAGTTTT CTTAAAAATG AACAGTCTGC A A ACT GAT G A CACAGCCATT TACTACTGTG 4201 CCA A AC ATT A TTACTACGGT GGTAGCTATG CTATGGACTA CTGGGGTCAA GGAACCTCAG 4261 TCACCGTCTC CTCAGGAATT CAGAACCCTG AGCCTGCCGT GTACCAGCTG AAGGACCCTA 4321 GAAGCCAGGA CAGCACCCTG TGCCTGTTCA CCGACTTCGA CAGCCAGATC AACGTGCCCA 4381 AGACCATGGA AAGCGGCACC TTCATCACCG AT A AG ACT GT GCTGGACATG AAGGCCATGG 4441 ACAGCAAGAG CAACGGCGCC ATTGCTTGGT CCAATCAGAC CAGCTTTACC TGCCAAGACA 4501 TCTTCAAAGA GACAAACGCC ACCTACCCCA GTTCAGACGT TCCCTGTGAT GCCACGTTGA 4561 CTGAGAAAAG CTTT G A A AC A GATATGAACC T A A ACTTT C A AAACCTGTCA GTTATGGGAC 4621 TCCGAATCCT CCTGCTGAAA GTAGCCGGAT TTAACCTGCT CATGACGCTG AGGCTGTGGT 4681 CCAGTGGCAG CGGCGAGGGC AGAGGAAGTC TGCTAACATG CGGTGACGTC GAGGAGAATC 4741 CTGGACCTGA TCTGAGAAAT GTGACTCCAC CCAAGGTCTC CTTGTTTGAG CCATCAAAAG 4801 CAGAGATTGC AAACAAACAA AAGGCTACCC TCGTGTGCTT GGCCAGGGGC TTCTTCCCTG 4861 ACCACGTGGA GCTGAGCTGG TGGGTGAATG GCAAGGAGGT CCACAGTGGG GTCAGCACGG 4921 ACCCTCAGGC CTACAAGGAG AGCAATTATA GCTACTGCCT GAGCAGCCGC CTGAGGGTCT 4981 CTGCTACCTT CTGGCACAAT CCTCGCAACC ACTTCCGCTG CCAAGTGCAG TTCCATGGGC 5041 TTTCAGAGGA GGACAAGTGG CCAGAGGGCT CACCCAAACC TGTCACACAG AACATCAGTG 5101 CAGAGGCCTG GGGTCGAGCA GACTGTGGTA TTACCTCAGC ATCCTATCAA CAAGGAGTCT 5161 TGTCTGCCAC CATCCTCTAT GAGATCCTGC TAGGGAAAGC CACCCTGTAT GCTGTGCTTG 5221 TCAGTACACT GGTGGTGATG GCTATGGTCA AAAGAAAGAA TTCATGAGAT ATCGAGCATC 5281 TTACCGCCAT TTATACCCAT ATTTGTTCTG TTTTTCTTGA TTTGGGTATA CATTTAAATG

5401 CAGGTGTATT GCCACAAGAC AAACATGTTA AGAAACTTTC CCGTTATTTA CGCTCTGTTC 5461 CTGTTAATCA ACCTCTGGAT TACAAAATTT GTGAAAGATT GACTGATATT CTTAACTATG 5521 TTGCTCCTTT TACGCTGTGT GGATATGCTG CTTTATAGCC TCTGTATCTA GCTATTGCTT 5581 CCCGTACGGC TTTCGTTTTC TCCTCCTTGT ATAAATCCTG GTTGCTGTCT CTTTTAGAGG 5641 AGTTGTGGCC CGTTGTCCGT CAACGTGGCG TGGTGTGCTC TGTGTTTGCT GACGCAACCC 5701 CCACTGGCTG GGGCATTGCC ACCACCTGTC AACTCCTTTC TGGGACTTTC GCTTTCCCCC 5761 TCCCGATCGC CACGGCAGAA CTCATCGCCG CCTGCCTTGC CCGCTGCTGG ACAGGGGCTA 5821 GGTTGCTGGG C ACT GAT A AT TCCGTGGTGT TGTCAGTACT GGTACCTTTA AG ACC A AT G A 5881 CTTACAAGGC AGCTGTAGAT CTTAGCCACT TTTTAAAAGA AAAGGGGGGA CTGGAAGGGC 5941 TAATTCACTC CCAAAGAAGA CAAGATCTGC TTTTTGCCTG TACTGGGTCT CTCTGGTTAG 6001 ACCAGATCTG AGCCTGGGAG CTCTCTGGCT AACTAGGGAA CCCACTGCTT AAGCCTCAAT 6061 AAAGCTTGCC TTGAGTGCTT CAAGTAGTGT GTGCCCGTCT GTTGTGTGAC TCTGGTAACT 6121 AGAGATCCCT CAGACCCTTT T AGTCAGTGT GGAAAATCTC TAGCATGATC ATAATCAAGC 6181 CATATCACAT CTGTAGAGGT TTACTTGCTT TAAAAAACCT CCACACCTCC CCCTGAACCT 6241 GAAACATAAA ATGAATGCAA TTGTTGTTGT TAACTTGTTT ATTGCAGCTT ATAATGGTTA 6301 CAAATAAAGC AATAGCATCA CAAATTTCAC AAATAAAGCA TTTTTTTCAC TGCATTCT AG 6361 TTGTGGTTTG TCCAAACTCA TCAATGTATC TTATCATGTC TGGATCTGCG TCGACACGAA 6421 GAGACGACTG ACTGACTGAC TGGAAAGAGG AAGGGCTGGA AGAGGAAGGA GCTTGATCCA 6481 GATCCCGATC TCGATCCAGA TCCGGATCGC AGCTTGGCGT AATCATGGTC ATAGCTGTTT 6541 CCTGTGTGAA ATTGTTATCC GCTCACAATT CCACACAACA TACGAGCCGG AAGCATAAAG 6601 TGTAAAGCCT GGGGTGCCTA ATGAGTGAGC T A ACT C AC AT TAATTGCGTT GCGCTCACTG 6661 CCCGCTTTCC AGTCGGGAAA CCTGTCGTGC CAGCTGCATT AATGAATCGG CCAACGCGCG 6721 GGGAGAGGCG GTTTGCGTAT TGGGCGCTCT TCCGCTTCCT CGCTCACTGA CTCGCTGCGC 6781 TCGGTCGTTC GGCTGCGGCG AGCGGTATCA GCTCACTCAA AGGCGGTAAT ACGGTTATCC 6841 ACAGAATCAG GGGATAACGC AGGAAAGAAC ATGTGAGCAA AAGGCCAGCAAAAGGCCAGG 6901 AACCGTAAAA AGGCCGCGTT GCTGGCGTTT TTCCATAGGC TCCGCCCCCC TGACGAGCAT 6961 CACAAAAATC GACGCTCAAG TCAGAGGTGG CGAAACCCGA CAGGACTATA AAGATACCAG 7021 GCGTTTCCCC CTGGAAGCTC CCTCGTGCGC TCTCCTGTTC CGACCCTGCC GCTTACCGGA 7081 TACCTGTCCG CCTTTCTCCC TTCGGGAAGC GTGGCGCTTT CTCATAGCTC ACGCTGTAGG 7141 TATCTCAGTT CGGTGTAGGT CGTTCGCTCC AAGCTGGGCT GTGTGCACGA ACCCCCCGTT 7201 CAGCCCGACC GCTGCGCCTT ATCCGGTAAC TATCGTCTTG AGTCCAACCC GGT A AG AC AC 7261 GACTTATCGC CACTGGCAGC AGCCACTGGT AACAGGATTA GCAGAGCGAG GTATGTAGGC 7321 GGTGCTACAG AGTTCTTGAA GTGGTGGCCT AACTACGGCT ACACTAGAAG AACAGTATTT 7381 GGTATCTGCG CTCTGCTGAA GCCAGTTACC TTCGGAAAAA GAGTTGGTAG CTCTTGATCC

7501 AGAAAAAAAG GATCTCAAGA AGATCCTTTG ATCTTTTCTA CGGGGTCTGA CGCTCAGTGG 7561 AACGAAAACT CACGTTAAGG GATTTTGGTC ATGAGATTAT CAAAAAGGAT CTTCACCTAG 7621 ATCCTTTTAA ATT A AAA AT G AAGTTTTAAA TCAATCTAAA GTATATATGA GTAAACTTGG 7681 TCTGACAGTT ACCAATGCTT AATCAGTGAG GCACCTATCT CAGCGATCTG TCTATTTCGT 7741 TCATCCATAG TTGCCTGACT CCCCGTCGTT GCTAGGTTAC TGTCATGAGC GG AT AC AT AT 7801 TTGAATGTAT TT AG A A A A AT AAACAAAAGA GTTTGTAGAA ACGCAAAAAG GCCATCCGTC 7861 AGGATGGCCT TCTGCTTAAT TTGATCGGTG GCAGTTTATG GCGGGCGTCC TGCCCGCCAC 7921 CCTCCGGGCC GTTGCTTCGC AACGTTCAAA TCCGCTCCCG GCGGATTTGT CCTACTCAGG 7981 AGAGCGTTCA CCGACAAACA ACAGATAAAA CGAAAGGCCC AGTCTTTCGA CTGAGCCTTT 8041 CGTTTTATTT GATGCCTGGC AGTTCCCTAC TCTCGCATGG GTTGCGGCCG CCCGGGCCGT 8101 CGACCAATTC TCATGTTTGA CAGCTTATCA TCGAATTTCT GCCATTCATC CGCTTATTAT 8161 CACTTATTCA GGCGTAGCAA CCAGGCGTTT AAGGGCACCA ATAACTGCCT T AAA A A A ATT 8221 ACGCCCCGCC CTGCCACTCA TCGCAGTACT GTTGTAATTC ATTAAGCATT CTGCCGACAT 8281 GGAAGCCATC ACAAACGGCA TGATGAACCT GAATCGCCAG CGGCATCAGC ACCTTGTCGC 8341 CTTGCGTATA ATATTTGCCC ATGGTGAAAA CGGGGGCGAA GAAGTTGTCC ATATTGGCCA 8401 CGTTTAAATC AAAACTGGTG AAACTCACCC AGGG ATT GGC TGAGACGAAA AACATATTCT 8461 CAATAAACCC TTTAGGGAAA TAGGCCAGGT TTTCACCGTA ACACGCCACA TCTTGCGAAT 8521 ATATGTGTAG AAACTGCCGG AAATCGTCGT GGTATTCACT CCAGAGCGAT GAAAACGTTT 8581 CAGTTTGCTC ATGGAAAACG GTGTAACAAG GGTGAACACT ATCCCATATC ACCAGCTCAC 8641 CGTCTTTCAT TGCCATACGA AATTCCGGAT G AGC ATT CAT CAGGCGGGCA AGAATGTGAA 8701 TAAAGGCCGG ATAAAACTTG TGCTTATTTT TCTTTACGGT CTTTAAAAAG GCCGTAATAT 8761 CCAGCTGAAC GGTCTGGTTA T AGGT AC ATT GAGCAACTGA CTGAAATGCC T C A A A AT GTT 8821 CTTTACGATG CCATTGGGAT ATATCAACGG TGGTATATCC AGTGATTTTT TTCTCCATTT 8881 TAGCTTCCTT AGCTCCTGAA AAT CT CG AT A ACTCAAAAAA TACGCCCGGT AGTGATCTTA 8941 TTTCATTATG GTGAAAGTTG GAACCTCTTA CGTGCCGATC AACGTCTCAT TTTCGCCAAA 9001 AGTGACATTA ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC 9061 GAGAT AGAGT TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC 9121 TCCAACGTCA AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA 9181 CCCAAATCAA GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG 9241 AGCCCCCGAT TT AG AGCTT G ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAG 9301 AAAGCGAAAG GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC 9361 ACCACACCCG CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT ATGGTTG CTTTGACGTA 9421 TGCGGTGTGA AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC 9481 C ATT C AGGCT GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC 9541 AGCTGGCGAA AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC 9601 AGTCACGACG TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA 9661 TCCAGATCGA ATTGG AGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG 9721 TCTCAACCTC CTAGGG pLCUS FMC63 mTRAC_P2 A mTRBC (SEQ ID NO: 166)

1 TG AT CAT AAT C AAGCCAT AT C AC AT CT GT A GAGGTTT ACT T GCTTT AAA A AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT A A AGC AAT AG CATC AC A A AT TTCACAAATA AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC ATGTCTGGAT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG AT CGC AGCTT GGTCTTCCGC 361 TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA 421 CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG

541 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 601 CCCGACAGGA CT AT AAA GAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 661 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 721 GCTTT CTC AT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 781 GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GT A ACT AT CG 841 TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG 901 GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA 961 CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG 1021 AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT 1081 TGTTTGCAAG CAGCAGATTA CGCGCAGAAA A A A AGG AT CT C A AG A AG AT C CTTTGATCTT 1141 TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG 1201 GTGAGGCACC TATCTCAGCG ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG 1261 TCGTTGCTAG GTT ACT GT C A TGAGCGGATA CAT ATTT G AA TGTATTTAGA AAAAT AAAC A 1321 AAAGAGTTTG TAGAAACGCA AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT 1381 CGGTGGCAGT TTATGGCGGG CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT 1441 TCAAATCCGC TCCCGGCGGA TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA 1501 TAAAACGAAA GGCCCAGTCT TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC 1561 CCTACTCTCG CATGGGTTGC GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT 1621 TATCATCGAA TTTCTGCCAT TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG 1681 CGTTTAAGGG CACCAATAAC TGCCTTAAAA AAATT ACGCC CCGCCCTGCC ACTCATCGCA 1741 GTACTGTTGT A ATT C ATT A A GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG 1801 AACCTGAATC GCCAGCGGCA TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT 1861 GAAAACGGGG GCGAAGAAGT TGTCCATATT GGCCACGTTT A A AT C A A A AC TGGTGAAACT 1921 CACCCAGGGA TTGGCTGAGA CGAAAAACAT ATTCTCAATA AACCCTTTAG GGAAATAGGC 1981 CAGGTTTT CA CCGTAACACG CCACATCTTG CG A AT AT AT G T GT AG A A ACT GCCGGAAATC 2041 GTCGTGGTAT TCACTCCAGA GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA 2101 ACAAGGGTGA ACACTATCCC AT AT C ACC AG CTCACCGTCT TTCATTGCCA TACGAAATTC 2161 CGGATGAGCA TTCATCAGGC GGGCAAGAAT GTGAAT AAAG GCCGGATAAA ACTTGTGCTT 2221 ATTTTTCTTT ACGGTCTTTA AAAAGGCCGT AATATCCAGC TGAACGGTCT GGTTATAGGT 2281 ACATTGAGCA ACTGACTGAA ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC 2341 AACGGTGGTA TATCCAGTGA TTTTTTTCTC CATTTTAGCT TCCTTAGCTC CTGAAAATCT 2401 CGATAACTCA AAAAATACGC CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC 2461 TCTTACGTGC CGATCAACGT CTCATTTTCG CCAAAAGTGA CATTAACCTA T A A A A AT AGG 2521 CGTATCACGA GGCCAGCTTG GGAAACCATA AGACCGAGAT AGAGTTGAGT GTTGTTCCAG 2581 TTTGGAACAA GAGTCCACTA TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG 2641 TCTATCAGGG CGATGGCCCA CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA 2701 GGTGCCGTAA AGCACTAAAT CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG 2761 GAAAGCCGGC GAACGTGGCG AGAAAGGAAG GGAAGAAAGCG AAAGGAGCGGGCGCT AAGG 2821 CGCTGGCAAG TGTAGCGGTC ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC 2881 CGCTACAGGG CGCGTACTAT GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG 2941 CGTAAGGAGA AAATACATCG TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT 3001 CAGTGGAGAG GACTTTCACT GACTGACTGA CTGCGTCTCA ACCTCCTAGG GGACATTGAT 3061 TATTGACTAG TTATTAATAG TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG 3121 AGTTCCGCGT TACATAACTT ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC 3181 GCCCATTGAC GTCAATAATG ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT 3241 GACGTCAATG GGTGGAGTAT TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC 3301 ATATGCCAAG TACGCCCCCT ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG 3361 CCCAGTACAT GACCTTATGG GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG 3421 CTATTACCAT GGTGATGCGG TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT 3481 CACGGGGATT TCCAAGTCTC CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA 3541 ATCAACGGGA CTTTCCAAAA TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA 3601 GGCGTGTACG GTGGGAGGTC TATATAAGCA GAGCTCGTTT AGTGAACCGG GTCTCTCTGG 3661 TTAGACCAGA TCTGAGCCTG GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT 3721 CAATAAAGCT TGCCTTGAGT GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT 3781 AACTAGAGAT CCCTCAGACC CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA 3841 ACAGGGACTT GAAAGCGAAA GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG 3901 CTGAAGCGCG CACGGCAAGA GGCGAGGGGC GGCGACTGGT GAGTACGCCA AAAATTTTGA 3961 CTAGCGGAGG CTAGAAGGAG AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA 4021 TT AG AT A A AT GGGAAAAAAT TCGGTTAAGG CCAGGGGGAA AG AA AC A AT A T A A ACT A A A A 4081 CATATAGTTA GGGCAAGCAG GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTTAGAG 4141 ACATCAGAAG GCTGTAGACA AATACTGGGA CAGCTACAAC CATCCCTTCA G AC AGG AT C A 4201 GAAGAACTTA GATCATTATA TAATACAATA GCAGTCCTCT ATTGTGTGCA TCAAAGGATA 4261 GATGTAAAAG ACACCAAGGA AGCCTTAGAT AAGATAGAGG AAGAGCAAAA CAAAAGTAAG 4321 AAAAAGGCAC AGCAAGCGAT CTTCAGACCT GGAGGAGGCA GGAGGCGAT A TGAGGGACAA 4381 TTGGAGAAGT G A ATT AT AT A AATATAAAGT AGT AAA A ATT GAACCATTAG GAGTAGCACC 4441 CACCAAGGCA AAGAGAAGAG TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA T AGG AGCTTT 4501 GTTCCTTGGG TTCTTGGGAG CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC 4561 GGTACAGGCC AGACAATTAT TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC 4621 TATTGAGGCG CAACAGCATC T GTT GCA ACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC 4681 AAGAATCCTG GCTGTGGAAA GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG 4741 CTCTGGAAAA CTCATTTGCA CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GT A AT A A AT C 4801 TCTGGAACAG ATTTGGAATA ACATGACCTG GATGGAGTGG GACAGAGAAA TT A AC A ATT A 4861 CACAAGCTTA ATACACTCCT T A ATT G A AG A ATCGCAAAAC CAGCAAGAAA AGAATGAACA 4921 AGAATTATTG GAATTAGATA AATGGGCAAG TTTGTGGAAT T GGTTT A AC A T A AC A A ATT G 4981 GCTGTGGTAT ATAAAATTAT TC AT A AT GAT AGTAGGAGGC TTGGTAGGTT TAAGAATAGT 5041 TTTTGCTGTA CTTTCTATAG TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA 5101 GACCCACCTC CCAATCCCGA GGGGACCACG CGTACAAATG GCAGTATTCA TCCACAATTT 5161 TAAAAGAAAA GGGGGGATTG GGGGGTACAG TGCAGGGGAA AGAATAGTAG ACATAATAGC 5221 AACAGACATA C A A ACT AA AG A ATT AC A A A A AC A A ATT AC A AAAATTCAAA ATTTTCGGGT 5281 TTATTACAGG GACAGCAGAA ATCCACTTTG GAAAGCTGAG CATCCGGCTC CGGTGCCCGT 5341 CAGTGGGCAG AGCGCACATC GCCCACAGTC CCCGAGAAGT T GGGGGG AGG GGTCGGCAAT 5401 TGAACCGGTG CCTAGAGAAG GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG 5461 CTCCGCCTTT TTCCCGAGGG TGGGGGAGAA CCGTATATAA GTGCAGTAGT CGCCGTGAAC

5581 GGGCCTGGCC TCTTTACGGG TTATGGCCCT TGCGTGCCTT GAATTACTTC CACGCCCCTG 5641 GCTGCAGTAC GTGATTCTTG ATCCCGAGCT TCGGGTTGGA AGTGGGTGGG AGAGTTCGAG 5701 GCCTTGCGCT TAAGGAGCCC CTTCGCCTCG TGCTTGAGTT GAGGCCTGGC CTGGGCGCTG 5761 GGGCCGCCGC GTGCGAATCT GGTGGCACCT TCGCGCCTGT CTCGCTGCTT TCGATAAGTC

5881 TGTAAATGCG GGCCAAGATC TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA 5941 CGGGGCCCGT GCGTCCCAGC GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC 6001 GAG A AT CGG A CGGGGGTAGT CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC 6061 GCCGTGTATC GCCCCGCCCT GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC 6121 GGAAAGATGG CCGCTTCCCG GCCCTGCTGC AGGGAGCTCA AAATGGAGGA CGCGGCGCTC 6181 GGGAGAGCGG GCGGGTGAGT CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT 6241 CGCTTCATGT GACTCCACGG AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG 6301 CTTTTGGAGT ACGTCGTCTT TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA 6361 CACTGAGTGG GTGGAGACTG AAGTTAGGCC AGCTTGGCAC TTGATGTAAT TCTCCTTGGA 6421 ATTTGCCCTT TTTGAGTTTG GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG

6541 CCTGGTGACA AGCCTTCTGC TCTGTGAGTT ACCACACCCA GCATTCCTCC TGATCCCAGA 6601 CATCCAGATG ACACAGACTA CATCCTCCCT GTCTGCCTCT CTGGGAGACA GAGTCACCAT 6661 CAGTTGCAGG GCAAGTCAGG ACATTAGTAA ATATTTAAAT TGGTATCAGC AGAAACCAGA 6721 TGGAACTGTT AAACTCCTGA TCTACCATAC ATCAAGATTA CACTCAGGAG TCCCATCAAG 6781 GTTCAGTGGC AGTGGGTCTG GAACAGATTA TTCTCTCACC ATT AGC AACC TGGAGCAAGA 6841 AGATATTGCC ACTTACTTTT GCCAACAGGG TAATACGCTT CCGTACACGT TCGGAGGGGG 6901 GACTAAGTTG GA A AT A AC AG GCTCCACCTC TGGATCCGGC AAGCCCGGAT CTGGCGAGGG 6961 ATCCACCAAG GGCGAGGTGA AACTGCAGGA GTCAGGACCT GGCCTGGTGG CGCCCTCACA 7021 GAGCCTGTCC GTCACATGCA CTGTCTCAGG GGTCTCATTA CCCGACTATG GTGTAAGCTG 7081 GATTCGCCAG CCTCCACGAA AGGGTCTGGA GTGGCTGGGA GTAATATGGG GTAGTGAAAC 7141 CACATACTAT AATTCAGCTC TCAAATCCAG ACTGACCATC ATCAAGGACA ACTCCAAGAG 7201 CCAAGTTTTC TTAAAAATGA ACAGTCTGCA AACTGATGAC ACAGCCATTT ACTACTGTGC 7261 CAAACATTAT TACTACGGTG GTAGCTATGC TATGGACTAC TGGGGTCAAG GAACCTCAGT 7321 CACCGTCTCC TCAATTCAGA ACCCTGAGCC TGCCGTGTAC CAGCTGAAGG ACCCTAGAAG 7381 CCAGGACAGC ACCCTGTGCC TGTTCACCGA CTTCGACAGC CAGATCAACG TGCCCAAGAC 7441 CATGGAAAGC GGCACCTTCA TCACCGATAA GACTGTGCTG GACATGAAGG CCATGGACAG 7501 CAAGAGCAAC GGCGCCATTG CNTGGTCCAA TCAGACCAGC TTTACCTGCC AAGACATCTT 7561 CAAAGAGACA AACGCCACCT ACCCCAGTTC AGACGTTCCC TGTGATGCCA CGTTGACTGA 7621 GAAAAGCTTT GAAACAGATA TGAACCTAAA CTTTCAAAAC CTGTCAGTTA TGGGACTCCG 7681 AATCCTCCTG CTGAAAGTAG CCGGATTT AA CCTGCTCATG ACGCTGAGGC TGTGGTCCAG 7741 TGGCAGCGGC GCTACTAACT TCAGCCTGCT GAAGCAGGCT GGAGACGTGG AGGAGAACCC 7801 TGGACCTATG CTACTACTTG TGACCTCACT ATTGTTATGC GAACTCCCTC ATCCCGCATT 7861 CTTGCTGATT CCAGATCTGA GAAATGTGAC TCCACCCAAG GTCTCCTTGT TTGAGCCATC 7921 AAAAGCAGAG ATTGCAAACA AACAAAAGGC TACCCTCGTG TGCTTGGCCA GGGGCTTCTT 7981 CCCTGACCAC GTGGAGCTGA GCTGGTGGGT GAATGGCAAG GAGGTCCACA GTGGGGTCAG 8041 CACGGACCCT CAGGCCTACA AGGAGAGCAA TTATAGCTAC TGCCTGAGCA GCCGCCTGAG 8101 GGTCTCTGCT ACCTTCTGGC ACAATCCTCG CAACCACTTC CGCTGCCAAG TGCAGTTCCA 8161 TGGGCTTTCA GAGGAGGACA AGTGGCCAGA GGGCTCACCC AAACCTGTCA CACAGAACAT 8221 CAGTGCAGAG GCCTGGGGTC GAGCAGACTG TGGTATTACC TCAGCATCCT ATCAACAAGG 8281 AGTCTTGTCT GCCACCATCC TCTATGAGAT CCTGCTAGGG AAAGCCACCC TGTATGCTGT 8341 GCTTGTCAGT ACACTGGTGG TGATGGCTAT GGTCAAAAGA AAGAATTCAT GAGATATCGA 8401 GCATCTTACC GCCATTTATA CCCATATTTG TTCTGTTTTT CTTGATTTGG GTATACATTT 8461 AAATGTTAAT AAAACAAAAT GGT GGGGC A A TCATTTACAT TTTTAGGGAT AT GT A ATT AC 8521 TAGTTCAGGT GTATTGCCAC AAGACAAACA TGTTAAGAAA CTTTCCCGTT ATTTACGCTC 8581 TGTTCCTGTT AATCAACCTC TGGATTACAA AATTTGTGAA AGATTGACTG ATATTCTTAA 8641 CTATGTTGCT CCTTTTACGC TGTGTGGATA TGCTGCTTTA TAGCCTCTGT ATCTAGCTAT 8701 TGCTTCCCGT ACGGCTTTCG TTTTCTCCTC CTTGTATAAA TCCTGGTTGC TGTCTCTTTT 8761 AGAGGAGTTG TGGCCCGTTG TCCGTCAACG TGGCGTGGTG TGCTCTGTGT TTGCTGACGC 8821 AACCCCCACT GGCTGGGGCA TTGCCACCAC CTGTCAACTC CTTTCTGGGA CTTTCGCTTT 8881 CCCCCTCCCG ATCGCCACGG CAGAACTCAT CGCCGCCTGC CTTGCCCGCT GCTGGACAGG 8941 GGCTAGGTTG CTGGGCACTG ATAATTCCGT GGTGTTGTCA GTACTGGTAC CTTT AAGACC

9061 AGGGCTAATT CACTCCCAAA G A AG AC A AG A TCTGCTTTTT GCCTGTACTG GGTCTCTCTG 9121 GTTAGACCAG ATCTGAGCCT GGGAGCTCTC TGGCTAACTA GGGAACCCAC TGCTTAAGCC 9181 TCAATAAAGC TTGCCTTGAG TGCTTCAAGT AGTGTGTGCC CGTCTGTTGT GTGACTCTGG 9241 T AACT AG AG A TCCCTCAGAC CCTTTTAGTC AGTGTGGAAA AT CTCT AGC A pLCUS FMC63 SLmTRAC_P2A_mTRBC (SEQ ID NO: 167)

1 TGATCATAAT CAAGCCATAT CACATCTGTA GAGGTTTACT TGCTTTAAAA AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTT AT A AT GGTT AC A A AT A A AGC AAT AG CAT C AC A A AT TT C AC A A AT A AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC ATGTCTGGAT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGC AGCTT GGTCTTCCGC 361 TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA 421 CTCAAAGGCG GTAATACGGT T AT CC AC AG A ATCAGGGGAT AACGCAGGAA AGAACATGTG

541 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 601 CCCGACAGGA CT AT AAA GAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 661 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 721 GCTTTCTCAT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 781 GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG 841 TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG 901 GATT AGC AGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA 961 CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG 1021 AAAAAGAGTT GGT AGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT 1081 TGTTTGCAAG CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTT GAT CTT 1141 TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG 1201 GTGAGGCACC TATCTCAGCG ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG 1261 TCGTTGCTAG GTTACTGTCA TGAGCGGATA CATATTTGAA TGTATTTAGA AAAAT AAAC A 1321 AAAGAGTTTG T AGAAACGC A AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT 1381 CGGTGGCAGT TTATGGCGGG CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT 1441 TCAAATCCGC TCCCGGCGGA TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA 1501 TAAAACGAAA GGCCCAGTCT TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC 1561 CCTACTCTCG CATGGGTTGC GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT 1621 TATCATCGAA TTTCTGCCAT TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG 1681 CGTTTAAGGG CACCAATAAC TGCCTTAAAA AAATT ACGCC CCGCCCTGCC ACTCATCGCA 1741 GTACTGTTGT A ATT C ATT A A GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG 1801 AACCTGAATC GCCAGCGGCA TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT 1861 GAAAACGGGG GCGAAGAAGT TGTCCATATT GGCCACGTTT A A AT C A A A AC TGGTGAAACT 1921 CACCCAGGGA TTGGCTGAGA CGAAAAACAT ATTCTCAATA AACCCTTTAG GGAAATAGGC 1981 CAGGTTTT CA CCGTAACACG CCACATCTTG CG A AT AT AT G T GT AG A A ACT GCCGGAAATC 2041 GTCGTGGTAT TCACTCCAGA GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA 2101 ACAAGGGTGA ACACTATCCC AT AT C ACC AG CTCACCGTCT TTCATTGCCA TACGAAATTC 2161 CGGATGAGCA TTCATCAGGC GGGCAAGAAT GTGAATAAAG GCCGGATAAA ACTTGTGCTT 2221 ATTTTTCTTT ACGGTCTTTA AAAAGGCCGT AATATCCAGC TGAACGGTCT GGTTATAGGT 2281 ACATTGAGCA ACTGACTGAA ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC 2341 AACGGTGGTA TATCCAGTGA TTTTTTTCTC CATTTTAGCT TCCTTAGCTC CTGAAAATCT 2401 CGATAACTCA AAAAAT ACGC CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC 2461 TCTTACGTGC CGATCAACGT CTCATTTTCG CCAAAAGTGA CATTAACCTA T AAAAAT AGG 2521 CGTATCACGA GGCCAGCTTG GGAAACCATA AGACCGAGAT AGAGTTGAGT GTTGTTCCAG 2581 TTTGGAACAA GAGTCCACTA TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG 2641 TCTATCAGGG CGATGGCCCA CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA 2701 GGTGCCGTAA AGC ACT AAAT CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG 2761 GAAAGCCGGC GAACGTGGCG AGAAAGGAAG GGAAGAAAGCGAAAGGAGCGGGCGCTAAGG 2821 CGCTGGCAAG TGTAGCGGTC ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC 2881 CGCTACAGGG CGCGT ACT AT GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG 2941 CGTAAGGAGA AAATACATCG TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT 3001 CAGTGGAGAG GACTTTCACT GACTGACTGA CTGCGTCTCA ACCTCCTAGG GGACATTGAT 3061 TATTGACTAG TTATTAATAG TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG 3121 AGTTCCGCGT TACATAACTT ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC 3181 GCCCATTGAC GTCAATAATG ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT 3241 GACGTCAATG GGTGGAGTAT TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC 3301 ATATGCCAAG TACGCCCCCT ATTGACGTCA ATGACGGT AA ATGGCCCGCC TGGCATTATG 3361 CCCAGTACAT GACCTTATGG GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG 3421 CTATTACCAT GGTGATGCGG TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT 3481 CACGGGGATT TCCAAGTCTC CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA 3541 ATCAACGGGA CTTTCCAAAA TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA 3601 GGCGTGTACG GTGGGAGGTC TAT AT A AGC A GAGCTCGTTT AGTGAACCGG GTCTCTCTGG 3661 TTAGACCAGA TCTGAGCCTG GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTT A AGCCT 3721 CAATAAAGCT TGCCTTGAGT GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT 3781 AACTAGAGAT CCCTCAGACC CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA 3841 ACAGGGACTT GAAAGCGAAA GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG 3901 CTGAAGCGCG CACGGCAAGA GGCGAGGGGC GGCGACTGGT GAGTACGCCA AAAATTTTGA 3961 CTAGCGGAGG CT AG A AGG AG AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA 4021 TT AG AT A A AT GGGAAAAAAT TCGGTTAAGG CCAGGGGGAA AGAAACAATA T A A ACT A A A A 4081 CATATAGTTA GGGCAAGCAG GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTTAGAG 4141 ACATCAGAAG GCTGTAGACA AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA 4201 GAAGAACTTA GATCATTATA TAATACAATA GCAGTCCTCT ATTGTGTGCA TCAAAGGATA 4261 GAT GT A A A AG ACACCAAGGA AGCCTTAGAT AAG AT AG AGG AAGAGCAAAA CAAAAGTAAG 4321 AAAAAGGCAC AGCAAGCGAT CTTCAGACCT GGAGGAGGCA GGAGGCGATA TGAGGGACAA 4381 TTGGAGAAGT G A ATT AT AT A AATATAAAGT AGT AAA A ATT GAACCATTAG GAGTAGCACC 4441 CACCAAGGCA AAGAGAAGAG TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA T AGG AGCTTT 4501 GTTCCTTGGG TTCTTGGGAG CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC 4561 GGTACAGGCC AGACAATTAT T GT CT GAT AT AGTGCAGCAG CAGAACAATT TGCTGAGGGC 4621 TATTGAGGCG CAACAGCATC TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC 4681 AAGAATCCTG GCTGTGGAAA GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG 4741 CTCTGGAAAA CTCATTTGCA CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GT A AT A A AT C 4801 TCTGGAACAG ATTTGGAATA ACATGACCTG GATGGAGTGG GACAGAGAAA TT A AC A ATT A 4861 CACAAGCTTA AT AC ACTCCT T A ATT G A AG A ATCGCAAAAC CAGCAAGAAA AGAATGAACA 4921 AGAATTATTG GAATTAGATA AATGGGCAAG TTTGTGGAAT TGGTTTAACA TAACAAATTG 4981 GCTGTGGTAT ATAAAATTAT TC AT A AT GAT AGTAGGAGGC TTGGTAGGTT TAAGAATAGT 5041 TTTTGCTGTA CTTTCTATAG TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA 5101 GACCCACCTC CCAATCCCGA GGGGACCACG CGTACAAATG GCAGTATTCA TCCACAATTT 5161 T AAA AG A A A A GGGGGGATTG GGGGGT AC AG TGCAGGGGAA AGAATAGTAG AC AT A AT AGC 5221 AACAGACATA CAAACTAAAG A ATT AC A A A A AC A A ATT AC A AAAATTCAAA ATTTTCGGGT 5281 TTATTACAGG GACAGCAGAA ATCCACTTTG GAAAGCTGAG CATCCGGCTC CGGTGCCCGT 5341 CAGTGGGCAG AGCGCACATC GCCCACAGTC CCCGAGAAGT T GGGGGG AGG GGTCGGCAAT 5401 TGAACCGGTG CCTAGAGAAG GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG 5461 CTCCGCCTTT TTCCCGAGGG T GGGGG AG A A CCGTATATAA GTGCAGTAGT CGCCGTGAAC

5881 TGTAAATGCG GGCCAAGATC TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA 5941 CGGGGCCCGT GCGTCCCAGC GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC 6001 GAGAATCGGA CGGGGGTAGT CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC 6061 GCCGTGTATC GCCCCGCCCT GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC 6121 GG A A AG AT GG CCGCTTCCCG GCCCTGCTGC AGGGAGCTCA A A AT GG AGG A CGCGGCGCTC 6181 GGGAGAGCGG GCGGGTGAGT CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT 6241 CGCTTCATGT GACTCCACGG AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG 6301 CTTTTGGAGT ACGTCGTCTT TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA 6361 CACTGAGTGG GTGGAGACTG AAGTTAGGCC AGCTTGGCAC TTGATGTAAT TCTCCTTGGA 6421 ATTTGCCCTT TTTGAGTTTG GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG

6541 CCTGGTGACA AGCCTTCTGC TCTGTGAGTT ACCACACCCA GCATTCCTCC TGATCCCAGA 6601 CATCCAGATG ACACAGACTA CATCCTCCCT GTCTGCCTCT CTGGGAGACA GAGTCACCAT 6661 CAGTTGCAGG GCAAGTCAGG ACATTAGTAA ATATTTAAAT TGGTATCAGC AGAAACCAGA 6721 T GG A ACT GTT AAACTCCTGA TCTACCATAC ATCAAGATTA CACTCAGGAG TCCCATCAAG 6781 GTTCAGTGGC AGTGGGTCTG GAACAGATTA TTCTCTCACC ATTAGCAACC TGGAGCAAGA 6841 AGATATTGCC ACTTACTTTT GCCAACAGGG TAATACGCTT CCGTACACGT TCGGAGGGGG 6901 GACTAAGTTG GA A AT A AC AG GCTCCACCTC TGGATCCGGC AAGCCCGGAT CTGGCGAGGG 6961 ATCCACCAAG GGCGAGGTGA AACTGCAGGA GTCAGGACCT GGCCTGGTGG CGCCCTCACA 7021 GAGCCTGTCC GTCACATGCA CTGTCTCAGG GGTCTCATTA CCCGACTATG GTGTAAGCTG 7081 GATTCGCCAG CCTCCACGAA AGGGTCTGGA GTGGCTGGGA GTAATATGGG GTAGTGAAAC 7141 CACATACTAT AATTCAGCTC TCAAATCCAG ACTGACCATC ATCAAGGACA ACTCCAAGAG 7201 CCAAGTTTTC TTAAAAATGA ACAGTCTGCA AACTGATGAC ACAGCCATTT ACTACTGTGC 7261 CAAACATTAT TACTACGGTG GTAGCTATGC TATGGACTAC TGGGGTCAAG GAACCTCAGT 7321 CACCGTCTCC TCAGCTGCCG CAGGAGGCGG TGGCAGTGGT GGGGGAGGAT CTGGCGGAGG 7381 AGGTAGCTTG GAAATTCAGA ACCCTGAGCC TGCCGTGTAC CAGCTGAAGG ACCCTAGAAG 7441 CCAGGACAGC ACCCTGTGCC TGTTCACCGA CTTCGACAGC CAGATCAACG TGCCCAAGAC 7501 CATGGAAAGC GGCACCTTCA TCACCGATAA GACTGTGCTG GACATGAAGG CCATGGACAG 7561 CAAGAGCAAC GGCGCCATTG CNTGGTCCAA TCAGACCAGC TTTACCTGCC AAGACATCTT 7621 CAAAGAGACA AACGCCACCT ACCCCAGTTC AGACGTTCCC TGTGATGCCA CGTTGACTGA 7681 GAAAAGCTTT GAAACAGATA TGAACCTAAA CTTTCAAAAC CTGTCAGTTA TGGGACTCCG 7741 AATCCTCCTG CTGAAAGTAG CCGGATTTAA CCTGCTCATG ACGCTGAGGC TGTGGTCCAG 7801 TGGCAGCGGC GCT ACT AACT TCAGCCTGCT GAAGCAGGCT GGAGACGTGG AGGAGAACCC 7861 TGGACCTATG CTACTACTTG TGACCTCACT ATTGTTATGC GAACTCCCTC ATCCCGCATT 7921 CTTGCTGATT CCAGATCTGA GAAATGTGAC TCCACCCAAG GTCTCCTTGT TTGAGCCATC 7981 AAAAGCAGAG ATTGCAAACA AACAAAAGGC TACCCTCGTG TGCTTGGCCA GGGGCTTCTT 8041 CCCTGACCAC GTGGAGCTGA GCTGGTGGGT GAATGGCAAG GAGGTCCACA GTGGGGTCAG 8101 CACGGACCCT CAGGCCTACA AGGAGAGCAA TTATAGCTAC TGCCTGAGCA GCCGCCTGAG 8161 GGTCTCTGCT ACCTTCTGGC ACAATCCTCG CAACCACTTC CGCTGCCAAG TGCAGTTCCA 8221 TGGGCTTTCA GAGGAGGACA AGTGGCCAGA GGGCTCACCC AAACCTGTCA CACAGAACAT 8281 CAGTGCAGAG GCCTGGGGTC GAGCAGACTG TGGTATTACC TCAGCATCCT ATCAACAAGG 8341 AGTCTTGTCT GCCACCATCC TCTATGAGAT CCTGCTAGGG AAAGCCACCC TGTATGCTGT 8401 GCTTGTCAGT ACACTGGTGG TGATGGCTAT GGTCAAAAGA A AG A ATT CAT GAGATATCGA 8461 GCATCTTACC GCCATTTATA CCCATATTTG TTCTGTTTTT CTTGATTTGG GTATACATTT 8521 AAATGTTAAT AAAACAAAAT GGTGGGGCAA TCATTTACAT TTTTAGGGAT AT GT A ATT AC 8581 TAGTTCAGGT GTATTGCCAC AAGACAAACA TGTTAAGAAA CTTTCCCGTT ATTTACGCTC 8641 TGTTCCTGTT AATCAACCTC TGGATTACAA AATTTGTGAA AGATTGACTG ATATTCTTAA 8701 CTATGTTGCT CCTTTTACGC TGTGTGGATA TGCTGCTTTA TAGCCTCTGT ATCTAGCTAT 8761 TGCTTCCCGT ACGGCTTTCG TTTTCTCCTC CTTGTATAAA TCCTGGTTGC TGTCTCTTTT 8821 AGAGGAGTTG TGGCCCGTTG TCCGTCAACG TGGCGTGGTG TGCTCTGTGT TTGCTGACGC 8881 AACCCCCACT GGCTGGGGCA TTGCCACCAC CTGTCAACTC CTTTCTGGGA CTTTCGCTTT 8941 CCCCCTCCCG ATCGCCACGG CAGAACTCAT CGCCGCCTGC CTTGCCCGCT GCTGGACAGG 9001 GGCTAGGTTG CTGGGCACTG ATAATTCCGT GGTGTTGTCA GTACTGGTAC CTTTAAGACC

9121 AGGGCTAATT CACTCCCAAA G A AG AC A AG A TCTGCTTTTT GCCTGTACTG GGTCTCTCTG 9181 GTTAGACCAG ATCTGAGCCT GGGAGCTCTC TGGCT A ACT A GGGAACCCAC TGCTT A AGCC 9241 TCAATAAAGC TTGCCTTGAG TGCTTCAAGT AGTGTGTGCC CGTCTGTTGT GTGACTCTGG 9301 TAACTAGAGA TCCCTCAGAC CCTTTTAGTC AGTGTGGAAA ATCTCTAGCA pLCUS FMC63 SLmTRAC_P2 A FMC63 SLmTRB C (SEQ ID NO:168)

1 TG AT CAT AAT C AAGCCAT AT C AC AT CT GT A GAGGTTT ACT T GCTTT AAA A AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT TTCACAAATA AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC AT GT CT GG AT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG AT CGC AGCTT GGTCTTCCGC 361 TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA 421 CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG

541 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 601 CCCGACAGGA CT AT AAA GAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 661 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 721 GCTTT CTC AT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 781 GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GT A ACT AT CG 841 TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG 901 GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA 961 CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG 1021 AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT 1081 TGTTTGCAAG CAGCAGATTA CGCGCAGAAA A A A AGG AT CT C A AG A AG AT C CTTTGATCTT 1141 TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG 1201 GTGAGGCACC TATCTCAGCG ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG 1261 TCGTTGCTAG GTT ACT GT C A TGAGCGGATA CAT ATTT G AA TGTATTTAGA AAAAT AAAC A 1321 AAAGAGTTTG TAGAAACGCA AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT 1381 CGGTGGCAGT TTATGGCGGG CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT 1441 TCAAATCCGC TCCCGGCGGA TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA 1501 TAAAACGAAA GGCCCAGTCT TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC 1561 CCTACTCTCG CATGGGTTGC GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT 1621 TATCATCGAA TTTCTGCCAT TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG 1681 CGTTTAAGGG CACCAATAAC TGCCTTAAAA AAATTACGCC CCGCCCTGCC ACTCATCGCA 1741 GTACTGTTGT A ATT C ATT A A GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG 1801 AACCTGAATC GCCAGCGGCA TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT 1861 GAAAACGGGG GCGAAGAAGT TGTCCATATT GGCCACGTTT A A AT C A A A AC TGGTGAAACT 1921 CACCCAGGGA TTGGCTGAGA CGAAAAACAT ATTCTCAATA AACCCTTTAG GGAAATAGGC 1981 CAGGTTTTCA CCGTAACACG CCACATCTTG CGAATATATG TGTAGAAACT GCCGGAAATC 2041 GTCGTGGTAT TCACTCCAGA GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA 2101 ACAAGGGTGA ACACTATCCC AT AT C ACC AG CTCACCGTCT TTCATTGCCA TACGAAATTC 2161 CGGATGAGCA TTCATCAGGC GGGCAAGAAT GTGAAT AAAG GCCGGATAAA ACTTGTGCTT 2221 ATTTTTCTTT ACGGTCTTTA AAAAGGCCGT AATATCCAGC TGAACGGTCT GGTTATAGGT 2281 ACATTGAGCA ACTGACTGAA ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC 2341 AACGGTGGT A TATCCAGTGA TTTTTTTCTC CATTTTAGCT TCCTTAGCTC CTGAAAATCT 2401 CGATAACTCA AAAAATACGC CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC 2461 TCTTACGTGC CGATCAACGT CTCATTTTCG CCAAAAGTGA CATTAACCTA T A A A A AT AGG 2521 CGTATCACGA GGCCAGCTTG GGAAACCATA AGACCGAGAT AGAGTTGAGT GTTGTTCCAG 2581 TTTGGAACAA GAGTCCACTA TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG 2641 TCTATCAGGG CGATGGCCCA CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA 2701 GGTGCCGTAA AGCACTAAAT CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG 2761 GAAAGCCGGC GAACGTGGCG AGAAAGGAAG GGAAGAAAGCG AAAGGAGCGGGCGCT AAGG 2821 CGCTGGCAAG TGTAGCGGTC ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC 2881 CGCTACAGGG CGCGTACTAT GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG 2941 CGT AAGG AG A AAATACATCG TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT 3001 CAGTGGAGAG GACTTTCACT GACTGACTGA CTGCGTCTCA ACCTCCTAGG GGACATTGAT 3061 TATTGACTAG TTATTAATAG TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG 3121 AGTTCCGCGT TACATAACTT ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC 3181 GCCCATTGAC GTCAATAATG ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT 3241 GACGTCAATG GGTGGAGTAT TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC 3301 ATATGCCAAG TACGCCCCCT ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG 3361 CCCAGTACAT GACCTTATGG GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG 3421 CTATTACCAT GGTGATGCGG TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT 3481 CACGGGGATT TCCAAGTCTC CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA 3541 ATCAACGGGA CTTTCCAAAA TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA 3601 GGCGTGTACG GTGGGAGGTC TATATAAGCA GAGCTCGTTT AGTGAACCGG GTCTCTCTGG 3661 TTAGACCAGA TCTGAGCCTG GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT 3721 CAATAAAGCT TGCCTTGAGT GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT 3781 AACTAGAGAT CCCTCAGACC CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA 3841 ACAGGGACTT GAAAGCGAAA GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG 3901 CTGAAGCGCG CACGGCAAGA GGCGAGGGGC GGCGACTGGT GAGTACGCCA AAAATTTTGA 3961 CTAGCGGAGG CTAGAAGGAG AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA 4021 TT AG AT A A AT GGGAAAAAAT TCGGTTAAGG CCAGGGGGAA AG AA AC A AT A T A A ACT A A A A 4081 CATATAGTTA GGGCAAGCAG GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTTAGAG 4141 ACATCAGAAG GCTGTAGACA AATACTGGGA CAGCTACAAC CATCCCTTCA G AC AGG AT C A 4201 GAAGAACTTA GATCATTATA TAATACAATA GCAGTCCTCT ATTGTGTGCA TCAAAGGATA 4261 GATGTAAAAG ACACCAAGGA AGCCTTAGAT AAGATAGAGG AAGAGCAAAA CAAAAGTAAG 4321 AAAAAGGCAC AGCAAGCGAT CTTCAGACCT GGAGGAGGCA GGAGGCGAT A TGAGGGACAA 4381 TTGGAGAAGT G A ATT AT AT A AATATAAAGT AGT AAA A ATT GAACCATTAG GAGTAGCACC 4441 CACCAAGGCA AAGAGAAGAG TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT 4501 GTTCCTTGGG TTCTTGGGAG CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC 4561 GGTACAGGCC AGACAATTAT TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC 4621 TATTGAGGCG CAACAGCATC T GTT GCA ACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC 4681 AAGAATCCTG GCTGTGGAAA GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG 4741 CTCTGGAAAA CTCATTTGCA CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC 4801 TCTGGAACAG ATTTGGAATA ACATGACCTG GATGGAGTGG GACAGAGAAA TT A AC A ATT A 4861 CACAAGCTTA ATACACTCCT T A ATT G A AG A ATCGCAAAAC CAGCAAGAAA AGAATGAACA 4921 AGAATTATTG GAATTAGATA AATGGGCAAG TTTGTGGAAT T GGTTT A AC A T A AC A A ATT G 4981 GCTGTGGTAT ATAAAATTAT TC AT A AT GAT AGTAGGAGGC TTGGTAGGTT TAAGAATAGT 5041 TTTTGCTGTA CTTTCTATAG TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA 5101 GACCCACCTC CCAATCCCGA GGGGACCACG CGTACAAATG GC AGT ATT C A TCCACAATTT 5161 TAAAAGAAAA GGGGGGATTG GGGGGTACAG TGCAGGGGAA AGAATAGTAG ACATAATAGC 5221 AACAGACATA C A A ACT AA AG A ATT AC A A A A AC A A ATT AC A AAAATTCAAA ATTTTCGGGT 5281 TTATTACAGG GACAGCAGAA ATCCACTTTG GAAAGCTGAG CATCCGGCTC CGGTGCCCGT 5341 CAGTGGGCAG AGCGCACATC GCCCACAGTC CCCGAGAAGT TGGGGGGAGG GGTCGGCAAT 5401 TGAACCGGTG CCT AG AG A AG GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG 5461 CTCCGCCTTT TTCCCGAGGG TGGGGGAGAA CCGTATATAA GTGCAGTAGT CGCCGTGAAC

5881 TGTAAATGCG GGCCAAGATC TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA 5941 CGGGGCCCGT GCGTCCCAGC GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC 6001 GAG A AT CGG A CGGGGGTAGT CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC 6061 GCCGTGTATC GCCCCGCCCT GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC 6121 GG A A AG AT GG CCGCTTCCCG GCCCTGCTGC AGGGAGCTCA A A AT GG AGG A CGCGGCGCTC 6181 GGGAGAGCGG GCGGGTGAGT CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT 6241 CGCTTCATGT GACTCCACGG AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG 6301 CTTTTGGAGT ACGTCGTCTT TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA 6361 CACTGAGTGG GTGGAGACTG AAGTTAGGCC AGCTTGGCAC TTGATGTAAT TCTCCTTGGA 6421 ATTTGCCCTT TTTGAGTTTG GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG

6541 CCTGGTGACA AGCCTTCTGC TCTGTGAGTT ACCACACCCA GCATTCCTCC TGATCCCAGA 6601 CATCCAGATG ACACAGACTA CATCCTCCCT GTCTGCCTCT CTGGGAGACA GAGTCACCAT 6661 CAGTTGCAGG GCAAGTCAGG ACATTAGTAA ATATTTAAAT TGGTATCAGC AGAAACCAGA 6721 TGGAACTGTT AAACTCCTGA TCTACCATAC ATCAAGATTA CACTCAGGAG TCCCATCAAG 6781 GTTCAGTGGC AGTGGGTCTG GAACAGATTA TTCTCTCACC ATT AGC AACC TGGAGCAAGA 6841 AGATATTGCC ACTTACTTTT GCCAACAGGG TAATACGCTT CCGTACACGT TCGGAGGGGG 6901 GACTAAGTTG GAAATAACAG GCTCCACCTC TGGATCCGGC AAGCCCGGAT CTGGCGAGGG 6961 ATCCACCAAG GGCGAGGTGA AACTGCAGGA GTCAGGACCT GGCCTGGTGG CGCCCTCACA 7021 GAGCCTGTCC GTCACATGCA CTGTCTCAGG GGTCTCATTA CCCGACTATG GTGTAAGCTG 7081 GATTCGCCAG CCTCCACGAA AGGGTCTGGA GTGGCTGGGA GTAATATGGG GTAGTGAAAC 7141 CACATACTAT AATTCAGCTC TCAAATCCAG ACTGACCATC ATCAAGGACA ACTCCAAGAG 7201 CCAAGTTTTC TTAAAAATGA ACAGTCTGCA AACTGATGAC ACAGCCATTT ACTACTGTGC 7261 CAAAC ATT AT TACTACGGTG GTAGCTATGC TATGGACTAC TGGGGTCAAG GAACCTCAGT 7321 CACCGTCTCC TCAGCTGCCG CAGGAGGCGG TGGCAGTGGT GGGGGAGGAT CTGGCGGAGG 7381 AGGTAGCTTG G AA ATT C AG A ACCCTGAGCC TGCCGTGTAC CAGCTGAAGG ACCCTAGAAG 7441 CCAGGACAGC ACCCTGTGCC TGTTCACCGA CTTCGACAGC CAGATCAACG TGCCCAAGAC 7501 CATGGAAAGC GGCACCTTCA TCACCGATAA GACTGTGCTG GACATGAAGG CCATGGACAG 7561 CAAGAGCAAC GGCGCCATTG CNTGGTCCAA TCAGACCAGC TTTACCTGCC A AG AC AT CTT 7621 CAAAGAGACA AACGCCACCT ACCCCAGTTC AGACGTTCCC TGTGATGCCA CGTTGACTGA 7681 GAAAAGCTTT G AA AC AG AT A TGAACCTAAA CTTTCAAAAC CTGTCAGTTA TGGGACTCCG 7741 AATCCTCCTG CTGAAAGTAG CCGGATTTAA CCTGCTCATG ACGCTGAGGC TGTGGTCCAG 7801 TGGCAGCGGC GCTACTAACT TCAGCCTGCT GAAGCAGGCT GGAGACGTGG AGGAGAACCC 7861 TGGACCTATG CTACTACTTG TGACCTCACT ATTGTTATGC GAACTCCCTC ATCCCGCATT 7921 CTTGCTGATT CCAGACATTC AGATGACTCA AACAACTTCC AGCCTCTCCG CCTCACTCGG 7981 CGACCGCGTA AC A AT A AGCT GTCGGGCCTC GCAAGATATT AGTAAGTACC T G A ATT GGT A 8041 TCAGCAAAAA CCCGATGGTA CAGTCAAGCT TCTGATCTAC CATACCAGTC GTCTGCACAG 8101 CGGTGTCCCC AGCAGGTTCA GCGGCTCAGG ATCTGGTACC GATTATTCAC TGACGATTTC 8161 CAACCTTGAG CAGGAGGACA TCGCCACCTA CTTCTGCCAG CAGGGTAATA CTCTGCCGTA 8221 CACATTCGGG GGCGGTACCA AGCTCGAGAT CACGGGTTCA ACAAGCGGTT CTGGCAAGCC 8281 AGGCAGCGGC G AGGGGAGT A CAAAGGGGGA GGTGAAGTTG CAGGAAAGTG GCCCTGGATT 8341 GGTGGCCCCG AGCCAGAGTC TGTCTGTCAC CTGCACAGTT TCCGGAGTAA GTCTGCCTGA 8401 TTACGGAGTG TCCTGGATCA GACAGCCACC TCGAAAGGGC TTGGAGTGGC TTGGGGTCAT 8461 TTGGGGCAGT GAAACCACAT ACT AC A AC AG CGCTCTTAAG TCCAGGCTCA CTATCATCAA 8521 GGACAATTCA AAGAGCCAAG TATTCTTGAA AATGAATTCC CTGCAGACTG ATGACACCGC 8581 TATTTATTAT TGCGCTAAAC ATTATTACTA TGGAGGTTCT TATGCCATGG ACTACTGGGG 8641 GCAGGGTACC TCTGTGACAG TGAGTTCAGC TGCAGCTGGA GGTGGAGGTA GCGGAGGCGG 8701 TGGTAGTGGA GGGGGTGGTT CTCTGGAAGA TCTGAGAAAT GTGACTCCAC CCAAGGTCTC 8761 CTTGTTTGAG CCATCAAAAG CAGAGATTGC AAACAAACAA AAGGCTACCC TCGTGTGCTT 8821 GGCCAGGGGC TTCTTCCCTG ACCACGTGGA GCTGAGCTGG TGGGTGAATG GCAAGGAGGT 8881 CCACAGTGGG GTCAGCACGG ACCCTCAGGC CTACAAGGAG AGC A ATT AT A GCTACTGCCT 8941 GAGCAGCCGC CTGAGGGTCT CTGCTACCTT CTGGCACAAT CCTCGCAACC ACTTCCGCTG 9001 CCAAGTGCAG TTCCATGGGC TTTCAGAGGA GGACAAGTGG CCAGAGGGCT CACCCAAACC 9061 TGTCACACAG AACATCAGTG CAGAGGCCTG GGGTCGAGCA GACTGTGGTA TTACCTCAGC 9121 ATCCTATCAA CAAGGAGTCT TGTCTGCCAC CATCCTCTAT GAGATCCTGC TAGGGAAAGC 9181 CACCCTGTAT GCTGTGCTTG TCAGTACACT GGTGGTGATG GCTATGGTCA AAAGAAAGAA 9241 TTCATGAGAT ATCGAGCATC TTACCGCCAT TTATACCCAT ATTTGTTCTG TTTTTCTTGA

9361 GGGATATGTA ATTACTAGTT CAGGTGTATT GCCACAAGAC AAACATGTTA AGAAACTTTC 9421 CCGTTATTTA CGCTCTGTTC CTGTTAATCA ACCTCT GG AT TACAAAATTT GTGAAAGATT 9481 GACTGATATT CTTAACTATG TTGCTCCTTT TACGCTGTGT GGATATGCTG CTTTATAGCC 9541 TCTGTATCTA GCTATTGCTT CCCGTACGGC TTTCGTTTTC TCCTCCTTGT ATAAATCCTG 9601 GTTGCTGTCT CTTTTAGAGG AGTTGTGGCC CGTTGTCCGT CAACGTGGCG TGGTGTGCTC 9661 TGTGTTTGCT GACGCAACCC CCACTGGCTG GGGCATTGCC ACCACCTGTC AACTCCTTTC 9721 TGGGACTTTC GCTTTCCCCC TCCCGATCGC CACGGCAGAA CTCATCGCCG CCTGCCTTGC 9781 CCGCTGCTGG ACAGGGGCTA GGTTGCTGGG CACTGATAAT TCCGTGGTGT TGTCAGTACT 9841 GGTACCTTTA AG ACC A AT G A CTTACAAGGC AGCTGTAGAT CTTAGCCACT TTTTAAAAGA 9901 AAAGGGGGGA CTGGAAGGGC TAATTCACTC CCAAAGAAGA CAAGATCTGC TTTTTGCCTG 9961 TACTGGGTCT CTCTGGTTAG ACCAGATCTG AGCCTGGGAG CTCTCTGGCT AACTAGGGAA 10021 CCCACTGCTT AAGCCTCAAT AAAGCTTGCC TTGAGTGCTT CAAGTAGTGT GTGCCCGTCT 10081 GTTGTGTGAC TCTGGTAACT AGAGATCCCT CAGACCCTTT TAGTCAGTGT GGAAAATCTC 10141 TAGCA pLKaUS FMC63 mTR AC P2 A FMC63 mTRB C (SEQ ID NO: 169)

1 CTCGCTGCGC TCGGTCGTTC GGCTGCGGCG AGCGGTATCA GCT C ACT C A A AGGCGGTAAT 61 ACGGTTATCC ACAGAATCAG GGGATAACGC AGGAAAGAAC ATGTGAGCAA AAGGCCAGCA 121 AAAGGCCAGG AACCGT AAAA AGGCCGCGTT GCTGGCGTTT TTCCAT AGGC TCCGCCCCCC 181 TGACGAGCAT CACAAAAATC GACGCTCAAG TCAGAGGTGG CGAAACCCGA CAGGACTATA 241 AAGATACCAG GCGTTTCCCC CTGGAAGCTC CCTCGTGCGC TCTCCTGTTC CGACCCTGCC 301 GCTTACCGGA TACCTGTCCG CCTTTCTCCC TTCGGGAAGC GTGGCGCTTT CTCATAGCTC 361 ACGCTGTAGG TATCTCAGTT CGGTGTAGGT CGTTCGCTCC AAGCTGGGCT GTGTGCACGA 421 ACCCCCCGTT CAGCCCGACC GCTGCGCCTT ATCCGGTAAC TATCGTCTTG AGTCCAACCC 481 GGTAAGACAC GACTTATCGC CACTGGCAGC AGCCACTGGT AACAGGATTA GCAGAGCGAG 541 GTATGTAGGC GGTGCTACAG AGTTCTTGAA GTGGTGGCCT AACTACGGCT ACACTAGAAG 601 AACAGTATTT GGTATCTGCG CTCTGCTGAA GCCAGTTACC TT CGG A A A A A GAGTTGGTAG

721 GATTACGCGC AGAAAAAAAG GATCTCAAGA AGATCCTTTG ATCTTTTCTA CGGGGTCTGA 781 CGCTCAGTGG AACGAAAACT CACGTTAAGG GATTTTGGTC ATGAGTTAAT TAACTTGCGC 841 CGTCCCGTCA AGTCAGCGTA ATGCTCTGCC AGTGTTACAA CCA ATT A ACC AATTCTGATT 901 AGAAAAACTC ATCGAGCATC AAATGAAACT GCAATTTATT CACATCAGGA TTATCAATAC 961 CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA CTCACCGAGG CAGTTCCATA 1021 GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG TCCAACATCA ATACAACCTA 1081 TTAATTTCCC CTCGTCAAAA AT AAGGTT AT CAAGTGAGAA ATCACCATGA GTGACGACTG 1141 AATCCGGTGA GAATGGCAAA AGTTTATGCA TTTCTTTCCA GACTTGTTCA ACAGGCCAGC 1201 CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC GTTATTCATT CGTGATTGCG 1261 CCTGAGCAAG ACGAAAT ACG CGATCGCTGT TAAAAGGACA ATT AC A A AC A GGAATCGAAT 1321 GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT TTCACCTGAA TCAGGATATT

1441 CAGGAGTACG GATAAAATGC TTGATGGTCG GAAGAGGCAT AAATTCCGTC AGCCAGTTTA 1501 GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC TTTGCCATGT TTCAGAAACA 1561 ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT CGCACCTGAT TGCCCGACAT 1621 TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT GTTGGAATTT AATCGCGGCC 1681 TCGACGTTTC CCGTTGAATA TGGCT CAT A A CACCCCTTGT ATTACTGTTT ATGTAAGCAG 1741 ACAGTTTTAT TGTTCATGAT GATATATTTT TATCTTGTGC A AT GT A AC AT CAGAGATTTT 1801 GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA ACCTATAAAA ATAGGCGTAT 1861 CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT TGAGTGTTGT TCCAGTTTGG 1921 AACAAGAGTC CACTATTAAA GAACGTGGAC TCCAACGTCA AAGGGCGAAA AACCGTCTAT 1981 CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA GTTTTTTGGG GTCGAGGTGC 2041 CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG 2101 CCGGCGAACG TGGCGAGAAA GGAAGGGAAG AAAGCGAAAG GAGCGGGCGCTAAGGCGCTG 2161 GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG CCGCGCTTAA TGCGCCGCTA 2221 CAGGGCGCGT ACTATGGTTG CTTTGACGTA TGCGGTGTGA AATACCGCAC AGATGCGTAA 2281 GG AG AAA AT A CATCGTGATC CGGATCAAGA TCCAGATCGA ATTGGAGGCT ACAGTCAGTG 2341 GAGAGGACTT TCACTGACTG ACTGACTGCG TCTCAACCTC CTAGGGGACA TTGATTATTG 2401 ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC ATAGCCCATA TATGGAGTTC 2461 CGCGTT AC AT AACTT ACGGT AAATGGCCCG CCTGGCTGAC CGCCCAACGA CCCCCGCCCA 2521 TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA TAGGGACTTT CCATTGACGT 2581 CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG T AC AT C A AGT GT AT CAT AT G 2641 CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC CCGCCTGGCA TTATGCCCAG 2701 TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT ACGTATTAGT CATCGCTATT 2761 ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG GATAGCGGTT TGACTCACGG 2821 GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT TGTTTTGGCA CCAAAATCAA 2881 CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA CGC A A AT GGG CGGTAGGCGT 2941 GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTTAGTGA ACCGGGTCTC TCTGGTTAGA 3001 CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA 3061 AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG TTGTGTGACT CT GGT A ACT A 3121 GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT AGCAGTGGCG CCCGAACAGG 3181 GACTT G A A AG CG A A AGT AAA GCCAGAGGAG ATCTCTCGAC GCAGGACTCG GCTTGCTGAA 3241 GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA CGCCAAAAAT TTTGACTAGC 3301 GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA TTAAGCGGGG GAGAATTAGA 3361 T AA AT GGG A A AAAATTCGGT TAAGGCCAGG GGGAAAGAAA C A AT AT A A AC T A A A AC AT AT 3421 AGTTAGGGCA AGCAGGGAGC TAGAACGATT CGCAGTTAAT CCTGGCCTTT TAGAGACATC 3481 AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC CTTCAGACAG GATCAGAAGA 3541 ACTTAGATCA TT AT AT A AT A CAATAGCAGT CCTCTATTGT GTGCATCAAA GGATAGATGT 3601 AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG CAAAACAAAAGTAAGAAAAA 3661 GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG CGATATGAGG GACAATTGGA 3721 GAAGTGAATT ATATAAATAT A A AGT AGT A A AAATTGAACC ATT AGG AGT A GCACCCACCA 3781 AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT GGGAATAGGA GCTTTGTTCC 3841 TTGGGTTCTT GGGAGCAGCA GGAAGCACTA TGGGCGCAGC GTCAATGACG CTGACGGTAC 3901 AGGCCAGACA ATTATTGTCT GATATAGTGC AGCAGCAGAA CAATTTGCTG AGGGCTATTG 3961 AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT CAAACAGCTC CAGGCAAGAA 4021 TCCTGGCTGT GGAAAGATAC CTAAAGGATC AACAGCTCCT GGGGATTTGG GGTTGCTCTG 4081 GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG TTGGAGTAAT AAATCTCTGG 4141 AACAGATTTG GAATAACATG ACCTGGATGG AGT GGG AC AG AG A A ATT AAC A ATT AC AC A A 4201 GCTTAATACA CTCCTTAATT GAAGAATCGC AAAACCAGCA AGAAAAGAAT GAACAAGAAT 4261 TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT T AAC AT AAC A AATTGGCTGT 4321 GGT AT AT A A A ATTATTCATA ATGATAGTAG GAGGCTTGGT AGGTTTAAGA ATAGTTTTTG 4381 CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC ACCATTATCG TTTCAGACCC 4441 ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT ATTCATCCAC A ATTTT A A A A 4501 GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT AGTAGACATA ATAGCAACAG 4561 AC AT AC A A AC T A A AG A ATT A CAAAAACAAA TTACAAAAAT TCAAA ATTTT CGGGTTTATT 4621 ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC GGCTCCGGTG CCCGTCAGTG 4681 GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG GGAGGGGTCG GCAATTGAAC 4741 CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA CTGGGAAAGT GATGTCGTGT ACTGGCTCCG 4801 CCTTTTTCCC GAGGGTGGGG GAGAACCGTA TAT A AGT GCA GTAGTCGCCG TGAACGTTCT 4861 TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC 4921 TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT ACTTCCACGC CCCTGGCTGC 4981 AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT 5041 GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC 5101 GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG

5221 ATGCGGGCCA AGATCTGCAC ACT GGT ATTT CGGTTTTTGG GGCCGCGGGC GGCGACGGGG 5281 CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT GCGAGCGCGG CCACCGAGAA 5341 TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT GCCTGGCCTC GCGCCGCCGT 5401 GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC ACCAGTTGCG TGAGCGGAAA 5461 GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG GAGGACGCGG CGCTCGGGAG 5521 AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT TCCGTCCTCA GCCGTCGCTT 5581 CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT CGATTAGTTC TCGAGCTTTT 5641 GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC GATGGAGTTT CCCCACACTG 5701 AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT GTAATTCTCC TTGGAATTTG

5821 TTCTTCCATT TCAGGTGTCG T GA A A ACT AC CCCTCAGAGC CGCCACCATG CTTCTCCTGG 5881 TGACAAGCCT TCTGCTCTGT GAGTTACCAC ACCCAGCATT CCTCCTGATC CCAGACATCC 5941 AGATGACACA GACTACATCC TCCCTGTCTG CCTCTCTGGG AGACAGAGTC ACCATCAGTT 6001 GCAGGGCAAG TCAGGACATT AGT A A AT ATT TAAATTGGTA TCAGCAGAAA CCAGATGGAA 6061 CTGTTAAACT CCTGATCTAC CATACATCAA GATTACACTC AGGAGTCCCA TCAAGGTTCA 6121 GTGGCAGTGG GTCTGGAACA GATTATTCTC TC ACC ATT AG CAACCTGGAG CAAGAAGATA 6181 TTGCCACTTA CTTTTGCCAA CAGGGTAATA CGCTTCCGTA CACGTTCGGA GGGGGG ACT A 6241 AGTTGGAAAT AACAGGCTCC ACCTCTGGAT CCGGCAAGCC CGGATCTGGC GAGGGATCCA 6301 CCAAGGGCGA GGTGAAACTG CAGGAGTCAG GACCTGGCCT GGTGGCGCCC TCACAGAGCC 6361 TGTCCGTCAC ATGCACTGTC TCAGGGGTCT CATTACCCGA CTATGGTGTA AGCTGGATTC 6421 GCCAGCCTCC ACGAAAGGGT CTGGAGTGGC TGGGAGTAAT ATGGGGTAGT GAAACCACAT 6481 ACT AT A ATT C AGCTCTCAAA TCCAGACTGA CCATCATCAA GGACAACTCC AAGAGCCAAG 6541 TTTTCTTAAA AATGAACAGT CTGCAAACTG ATGACACAGC CATTTACTAC TGTGCCAAAC 6601 ATT ATT ACT A CGGTGGTAGC TATGCTATGG ACTACTGGGG TCAAGGAACC TCAGTCACCG 6661 TCTCCTCAAT TCAGAACCCT GAGCCTGCCG TGTACCAGCT GAAGGACCCT AGAAGCCAGG 6721 ACAGCACCCT GTGCCTGTTC ACCGACTTCG ACAGCCAGAT CAACGTGCCC AAGACCATGG 6781 AAAGCGGCAC CTTCATCACC GATAAGACTG TGCTGGACAT GAAGGCCATG GACAGCAAGA 6841 GCAACGGCGC CATTGCNTGG TCCAATCAGA CCAGCTTTAC CTGCCAAGAC ATCTTCAAAG 6901 AGACAAACGC CACCTACCCC AGTTCAGACG TTCCCTGTGA TGCCACGTTG ACTGAGAAAA 6961 GCTTTGAAAC AGATATGAAC CTAAACTTTC AAAACCTGTC AGTTATGGGA CTCCGAATCC 7021 TCCTGCTGAA AGTAGCCGGA TTTAACCTGC TCATGACGCT GAGGCTGTGG TCCAGTGGCA 7081 GCGGCGCTAC TAACTTCAGC CTGCTGAAGC AGGCTGGAGA CGTGGAGGAG AACCCTGGAC 7141 CTATGCTACT ACTTGTGACC TCACTATTGT TATGCGAACT CCCTCATCCC GCATTCTTGC 7201 T GATT CC AG A CATTCAGATG ACT C AA AC A A CTTCCAGCCT CTCCGCCTCA CTCGGCGACC 7261 GCGTAACAAT AAGCTGTCGG GCCTCGCAAG AT ATT AGT AA GTACCTGAAT TGGTATCAGC 7321 AAAAACCCGA TGGTACAGTC AAGCTTCTGA TCTACCATAC CAGTCGTCTG CACAGCGGTG 7381 TCCCCAGCAG GTTCAGCGGC TCAGGATCTG GTACCGATTA TTCACTGACG ATTTCCAACC 7441 TTGAGCAGGA GGACATCGCC ACCTACTTCT GCCAGCAGGG TAATACTCTG CCGTACACAT 7501 TCGGGGGCGG TACCAAGCTC GAGATCACGG GTTCAACAAG CGGTTCTGGC AAGCCAGGCA 7561 GCGGCGAGGG GAGTACAAAG GGGGAGGTGA AGTTGCAGGA AAGTGGCCCT GGATTGGTGG 7621 CCCCGAGCCA GAGTCTGTCT GTCACCTGCA CAGTTTCCGG AGTAAGTCTG CCTGATTACG 7681 GAGTGTCCTG GAT C AG AC AG CCACCTCGAA AGGGCTTGGA GTGGCTTGGG GTCATTTGGG 7741 GCAGTGAAAC C AC AT ACT AC AACAGCGCTC TTAAGTCCAG GCTCACTATC ATCAAGGACA 7801 ATT C A A AG AG CCAAGTATTC TTGAAAATGA ATTCCCTGCA GACTGATGAC ACCGCTATTT 7861 ATTATTGCGC TAAACATTAT TACTATGGAG GTTCTTATGC CATGGACTAC TGGGGGCAGG 7921 GTACCTCTGT GACAGTGAGT TCAGATCTGA GAAATGTGAC TCCACCCAAG GTCTCCTTGT 7981 TTGAGCCATC AAAAGCAGAG ATT GCA A AC A AACAAAAGGC TACCCTCGTG TGCTTGGCCA 8041 GGGGCTTCTT CCCTGACCAC GTGGAGCTGA GCTGGTGGGT GAATGGCAAG GAGGTCCACA 8101 GTGGGGTCAG CACGGACCCa CAGGCCTACA AGGAGAGCAA TTATAGCTAC TGCCTGAGCA 8161 GCCGCCTGAG GGTCTCTGCT ACCTT CTGGC ACAATCCTCG CAACCACTTC CGCTGCCAAG 8221 TGCAGTTCCA TGGGCTTTCA GAGGAGGACA AGTGGCCAGA GGGCTCACCC AAACCTGTCA 8281 CACAGAACAT C AGT GC AG AG GCCTGGGGTC G AGC AG ACT G TGGTATTACC TCAGCATCCT 8341 ATCAACAAGG AGTCTTGTCT GCCACCATCC TCTATGAGAT CCTGCTAGGG AAAGCCACCC 8401 TGTATGCTGT GCTTGTCAGT ACACTGGTGG TGATGGCTAT GGTCAAAAGA AAGAATTCAT

8521 GTATACATTT AAATGTTAAT AAAACAAAAT GGTGGGGCAA TCATTTACAT TTTTAGGGAT 8581 AT GT A ATT AC TAGTTCAGGT GTATTGCCAC AAGACAAACA TGTTAAGAAA CTTTCCCGTT 8641 ATTTACGCTC TGTTCCTGTT AATCAACCTC TGGATTACAA AATTTGTGAA AGATTGACTG 8701 ATATTCTTAA CTATGTTGCT CCTTTTACGC TGTGTGGATA TGCTGCTTTA TAGCCTCTGT 8761 AT CT AGCT AT TGCTTCCCGT ACGGCTTTCG TTTTCTCCTC CTT GT AT A A A TCCTGGTTGC 8821 TGTCTCTTTT AGAGGAGTTG TGGCCCGTTG TCCGTCAACG TGGCGTGGTG TGCTCTGTGT 8881 TTGCTGACGC AACCCCCACT GGCTGGGGCA TTGCCACCAC CTGTCAACTC CTTTCTGGGA 8941 CTTTCGCTTT CCCCCTCCCG ATCGCCACGG C AG A ACT CAT CGCCGCCTGC CTTGCCCGCT 9001 GCTGGACAGG GGCTAGGTTG CTGGGCACTG ATAATTCCGT GGTGTTGTCA GTACTGGTAC 9061 CTTT A AG ACC AATGACTTAC AAGGCAGCTG T AG AT CTT AG CCACTTTTTA AAAGAAAAGG

9541 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACT CAT C A AT GTATCTTATC ATGTCTGGAT 9601 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 9661 AAGGAGCTTG ATCCAGATCC CG AT CT CG AT CCAGATCCGG ATCGCAGCTT GGTCTTCCGC 9721 TTCCTCGCTC ACTGA pLRPO FMC63 endoL TRBC1(126-177) (SEQ ID NO: 170)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TT AT CA AT AC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTT AT GCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GAT AAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG AC AGTTTT AT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAGATAGAGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT AT GGTT G CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGGATGT GCTGCAAGGC GATT AAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT T C ACT G ACT G ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA T A AT G ACGT A TGTTCCCATA GTAACGCCAA 1861 TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGT ATT AGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC C ATT G ACGT C AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTT AGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG G A A A AT CTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC T AG A ACG ATT CGCAGTTAAT 2761 CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TTATATAATA CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG G AC A ATT GG A G A AGTGA ATT AT AT AA AT AT A A AGT AGT AA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GG A AGC ACT A TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGC AGC AG AA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GG AA AG AT AC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT AAATCTCTGG AACAGATTTG GAATAACATG ACCTGGATGG AGTGGGACAG 3481 AG A A ATT A AC A ATT AC AC A A GCTT A AT AC A CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 TAACATAACA AATTGGCTGT GGTATATAAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT 3781 ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGTAGACATA ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A T AT A AGT GCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACTGGTATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 5281 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT T AGT A A AT AT TTAAATTGGT 5341 ATCAGCAGAA ACCAGATGGA ACTGTTAAAC TCCTGATCTA CCATACATCA AGATTACACT 5401 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AGATTATTCT CTCACCATTA 5461 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 5521 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGCTC CACCTCTGGA TCCGGCAAGC 5581 CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA GGACCTGGCC 5641 TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CAT GC ACT GT CTCAGGGGTC TCATTACCCG 5701 ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG CTGGGAGTAA 5761 TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG ACCATCATCA 5821 AGGACAACTC CAAGAGCCAA GTTTTCTTAA AAATGAACAG TCTGCAAACT GATGACACAG 5881 CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG GACTACTGGG 5941 GTCAAGGAAC CTCAGTCACC GTCTCCTCAG GAT GGGGT AG AGCAGACTGT GGCTTTACCT 6001 CGGTGTCCTA CCAGCAAGGG GTCCTGTCTG CCACCATCCT CTATGAGATC CTGCTAGGGA 6061 AGGCCACCCT GTATGCTGTG CTGGTCAGCG CCCTTGTGTT GATGGCCATG GT C A AG AG A A

6181 TTGATTTGGG TATACATTTA AATGTTAATA AAACAAAATG GTGGGGCAAT CATTTACATT 6241 TTTAGGGATA T GT A ATT ACT AGTTCAGGTG T ATT GCC AC A AGACAAACAT GTTAAGAAAC 6301 TTTCCCGTTA TTTACGCTCT GTTCCTGTTA ATCAACCTCT GGATTACAAA ATTTGTGAAA 6361 GATTGACTGA TATTCTTAAC TATGTTGCTC CTTTTACGCT GTGTGGATAT GCTGCTTTAT 6421 AGCCTCTGTA TCTAGCTATT GCTTCCCGTA CGGCTTTCGT TTTCTCCTCC TT GT AT A A AT 6481 CCTGGTTGCT GTCTCTTTTA GAGGAGTTGT GGCCCGTTGT CCGTCAACGT GGCGTGGTGT 6541 GCTCTGTGTT TGCTGACGCA ACCCCCACTG GCTGGGGCAT TGCCACCACC TGTCAACTCC 6601 TTTCTGGGAC TTTCGCTTTC CCCCTCCCGA TCGCCACGGC AGAACTCATC GCCGCCTGCC 6661 TTGCCCGCTG CTGGACAGGG GCTAGGTTGC TGGGCACTGA TAATTCCGTG GTGTTGTCAG 6721 T ACT GGT ACC TTTAAGACCA ATGACTTACA AGGCAGCTGT AGATCTT AGC CACTTTTTAA 6781 AAGAAAAGGG GGGACTGGAA GGGCTAATTC ACTCCCAAAG AAGACAAGAT CTGCTTTTTG 6841 CCTGTACTGG GTCTCTCTGG TT AG ACC AG A TCTGAGCCTG GGAGCTCTCT GGCTAACTAG 6901 GGAACCCACT GCTTAAGCCT CAATAAAGCT TGCCTTGAGT GCTTCAATGA TCATAATCAA 6961 GCCATATCAC ATCTGTAGAG GTTTACTTGC TTTAAAAAAC CTCCACACCT CCCCCTGAAC 7021 CTGAAACATA AAATGAATGC AATTGTTGTT GTTAACTTGT TT ATT GC AGC TTATAATGGT

7141 AGTTGTGGTT TGTCCAAACT CATCAATGTA TCTTATCATG TCTGGATCTG CGTCGACACG 7201 AAGAGACGAC TGACTGACTG ACTGGAAAGA GGAAGGGCTG GAAGAGGAAG GAGCTTGATC 7261 CAGATCCCGA TCTCGATCCA GATCCGGATC GCAGCTTGGC GTAATCATGG TCATAGCTGT 7321 TTCCTGTGTG AA ATT GTT AT CCGCTCACAA TTCCACACAA CATACGAGCC GG A AGC AT A A 7381 AGTGTAAAGC CTGGGGTGCC TAATGAGTGA GCTAACTCAC ATTAATTGCG TTGCGCTCAC 7441 TGCCCGCTTT CCAGTCGGGA AACCTGTCGT GCCAGCTGCA TT A AT G A AT C GGCCAACGCG 7501 CGGGGAGAGG CGGTTTGCGT ATTGGGCGCT CTTCCGCTTC CTCGCTCACT GACTCGCTGC 7561 GCTCGGTCGT TCGGCTGCGG CGAGCGGTAT CAGCTCACTC AAAGGCGGTA ATACGGTTAT 7621 CCACAGAATC AGGGGAT AAC GCAGGAAAGA ACATGTGAGC AAAAGGCCAG CAAAAGGCCA 7681 GGAACCGTAA AAAGGCCGCG TTGCTGGCGT TTTTCCATAG GCTCCGCCCC CCTGACGAGC 7741 AT C AC A A A A A TCGACGCTCA AGTCAGAGGT GGCGAAACCC GACAGGACTA TAAAGATACC 7801 AGGCGTTTCC CCCTGGAAGC TCCCTCGTGC GCTCTCCTGT TCCGACCCTG CCGCTTACCG 7861 GATACCTGTC CGCCTTTCTC CCTTCGGGAA GCGTGGCGCT TTCTCATAGC TCACGCTGTA 7921 GGTATCTCAG TTCGGTGTAG GTCGTTCGCT CCAAGCTGGG CTGTGTGCAC GAACCCCCCG 7981 TTCAGCCCGA CCGCTGCGCC TTATCCGGTA ACTATCGTCT TGAGTCCAAC CCGGTAAGAC 8041 ACGACTTATC GCCACTGGCA GCAGCCACTG GTAACAGGAT TAGCAGAGCG AGGTATGTAG 8101 GCGGTGCTAC AGAGTTCTTG AAGTGGTGGC CTAACTACGG CT AC ACT AG A AGAACAGTAT 8161 TTGGTATCTG CGCTCTGCTG AAGCCAGTTA CCTTCGGAAA AAGAGTTGGT AGCTCTTGAT

8281 GCAGAAAAAA AGGATCTCAA GAAGATCCTT TGATCTTTTC TACGGGGTCT GACGCTCAGT 8341 GGAACGAAAA CTCACGTTAA GGGATTTTGG TC AT GAG ATT ATCAAAAAGG ATCTTCACCT 8401 AGATCCTTTT AA ATT A AAA A TGAAGTTTTA AATCAATCTA A AGT AT AT AT GAGTAAACTT 8461 GGTCTGACAG TTACCAATGC TTAATCAGTG AGGCACCTAT CTCAGCGATC TGTCTATTTC 8521 GTTCATCCAT AGTTGCCTGA CTCCCCGTCG TGTAGATAAC TACGATACGG GAGGGCTTAC 8581 CATCTGGCCC CAGTGCTGCA ATGATACCGC AGCTTGGGAA ACCATAAGAG CTGAAGCCAG 8641 TTACCTTCGG AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG 8701 GTGGTTTTTT TGTTTGCAAG CAGCAGATTA CGCGCAGAAA A A A AGG AT CT C A AG A AG AT C 8761 CTTTGATCTT TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT 8821 TGGTCATGAG CTTGCGCCGT CCCGTCAAGT CAGCGTAATG CTCTGCCAGT GTTACAA pLRPO FMC63 SL TRBC1(131-177) (SEQ ID NO: 171)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC AAATGAAACT GCAATTTATT 61 CACATCAGGA TTATCAATAC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG AT CCT GGT AT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTT AT GCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GAT AAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG AC AGTTTT AT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAGATAGAGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT AT GGTT G CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGGATGT GCTGCAAGGC GATT AAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT T C ACT G ACT G ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA 1861 TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCT GGC A TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGTATTAGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTTAGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG G A A A AT CTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC T AG A ACG ATT CGCAGTTAAT 2761 CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TTATATAATA CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG G AC A ATT GG A GAAGTGAATT AT AT AA AT AT AAAGTAGTAA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GGAAGCACTA TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGCAGCAGAA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GG AA AG AT AC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT AAATCTCTGG AACAGATTTG GAATAACATG ACCTGGATGG AGTGGGACAG 3481 AG A A ATT A AC A ATT AC AC A A GCTT A AT AC A CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 TAACATAACA AATTGGCTGT GGTATATAAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT 3781 ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGTAGACATA ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A T AT A AGT GCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACTGGTATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 5281 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT TAGTAAATAT TTAAATTGGT 5341 ATCAGCAGAA ACCAGATGGA ACT GTT A A AC TCCTGATCTA CC AT AC AT C A AGATTACACT 5401 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AGATTATTCT CTCACCATTA 5461 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 5521 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGCTC CACCTCTGGA TCCGGCAAGC 5581 CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA GGACCTGGCC 5641 TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CAT GC ACT GT CTCAGGGGTC TCATTACCCG 5701 ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG CTGGGAGTAA 5761 TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG ACCATCATCA 5821 AGGACAACTC CAAGAGCCAA GTTTTCTTAA AAATGAACAG TCTGCAAACT GATGACACAG 5881 CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG GACTACTGGG 5941 GTCAAGGAAC CTCAGTCACC GTCTCCTCAG CaGCtGCaGG aGGTGGAGGt AGTGGTGGTG 6001 GaGGtTCTGG aGGTGGaGGT AGtCTaGAaT GTGGCTTTAC CTCGGTGTCC TACCAGCAAG 6061 GGGTCCTGTC TGCCACCATC CTCTATGAGA TCCTGCTAGG GAAGGCCACC CTGTATGCTG 6121 TGCTGGTCAG CGCCCTTGTG TTGATGGCCA TGGTCAAGAG AAAGGATTTC TGAGATATCG 6181 AGCATCTTAC CGCCATTTAT ACCCATATTT GTTCTGTTTT TCTTGATTTG GGTATACATT 6241 T AA AT GTT AA T A A A AC A A A A TGGTGGGGCA ATCATTTACA TTTTT AGGG A TATGTAATTA 6301 CTAGTTCAGG TGTATTGCCA CAAGACAAAC AT GTT AAGA A ACTTTCCCGT TATTTACGCT 6361 CTGTTCCTGT TAATCAACCT CTGGATTACA AAATTTGTGA AAGATTGACT GATATTCTTA 6421 ACT AT GTT GC TCCTTTTACG CTGTGTGGAT ATGCTGCTTT AT AGCCTCTG TATCTAGCTA 6481 TTGCTTCCCG TACGGCTTTC GTTTTCTCCT CCTTGTATAA ATCCTGGTTG CTGTCTCTTT 6541 TAGAGGAGTT GTGGCCCGTT GTCCGTCAAC GTGGCGTGGT GTGCTCTGTG TTTGCTGACG 6601 CAACCCCCAC TGGCTGGGGC ATTGCCACCA CCTGTCAACT CCTTTCTGGG ACTTTCGCTT 6661 TCCCCCTCCC GATCGCCACG GCAGAACTCA TCGCCGCCTG CCTTGCCCGC TGCTGGACAG 6721 GGGCTAGGTT GCTGGGCACT GATAATTCCG TGGTGTTGTC AGTACTGGTA CCTTT A AG AC 6781 CAATGACTTA CAAGGCAGCT GTAGATCTTA GCCACTTTTT AAAAGAAAAG GGGGGACTGG 6841 AAGGGCTAAT TCACTCCCAA AGAAGACAAG ATCTGCTTTT TGCCTGTACT GGGTCTCTCT 6901 GGTTAGACCA GATCTGAGCC TGGGAGCTCT CTGGCTAACT AGGGAACCCA CTGCTTAAGC 6961 CTCAATAAAG CTTGCCTTGA GTGCTTCAAT GATCATAATC AAGCCATATC ACATCTGTAG 7021 AGGTTTACTT GCTTT AAA A A ACCTCCACAC CTCCCCCTGA ACCTGAAACA TAAAATGAAT 7081 GCAATTGTTG TTGTTAACTT GTTTATTGCA GCTTATAATG GTTACAAATA AAGCAATAGC 7141 ATCACAAATT TCACAAATAA AGCATTTTTT TCACTGCATT CTAGTTGTGG TTTGTCCAAA 7201 CTC AT C A AT G TATCTTATCA TGTCTGGATC TGCGTCGACA CGAAGAGACG ACTGACTGAC 7261 TGACTGGAAA GAGGAAGGGC TGGAAGAGGA AGGAGCTTGA TCCAGATCCC GATCTCGATC 7321 CAGATCCGGA TCGCAGCTTG GCGTAATCAT GGTCATAGCT GTTTCCTGTG T G A A ATT GTT 7381 ATCCGCTCAC AATTCCACAC AACATACGAG CCGGAAGCAT AAAGTGTAAA GCCTGGGGTG 7441 CCTAATGAGT GAGCTAACTC ACATTAATTG CGTTGCGCTC ACTGCCCGCT TTCCAGTCGG 7501 GAAACCTGTC GTGCCAGCTG C ATT AAT G A A TCGGCCAACG CGCGGGGAGA GGCGGTTTGC 7561 GTATTGGGCG CTCTTCCGCT TCCTCGCTCA CTGACTCGCT GCGCTCGGTC GTTCGGCTGC 7621 GGCGAGCGGT ATCAGCTCAC TCAAAGGCGG T AAT ACGGTT AT CC AC AG A A TCAGGGGATA 7681 ACGCAGGAAA GAACATGTGA GCAAAAGGCC AGCAAAAGGC CAGGAACCGTAAAAAGGCCG 7741 CGTTGCTGGC GTTTTTCCAT AGGCTCCGCC CCCCTGACGA GCATCACAAA AATCGACGCT 7801 CAAGTCAGAG GTGGCGAAAC CCGACAGGAC T AT A A AG AT A CCAGGCGTTT CCCCCTGGAA 7861 GCTCCCTCGT GCGCTCTCCT GTTCCGACCC TGCCGCTTAC CGGATACCTG TCCGCCTTTC 7921 TCCCTTCGGG AAGCGTGGCG CTTTCTCATA GCTCACGCTG TAGGTATCTC AGTTCGGTGT 7981 AGGTCGTTCG CTCCAAGCTG GGCTGTGTGC ACGAACCCCC CGTTCAGCCC GACCGCTGCG 8041 CCTTATCCGG TAACTATCGT CTTGAGTCCA ACCCGGTAAG ACACGACTTA TCGCCACTGG 8101 CAGCAGCCAC TGGTAACAGG ATT AGC AG AG CGAGGTATGT AGGCGGTGCT ACAGAGTTCT 8161 TGAAGTGGTG GCCTAACTAC GGCTACACTA GAAGAACAGT ATTTGGTATC TGCGCTCTGC 8221 TGAAGCCAGT TACCTTCGGA AAAAGAGTTG GTAGCTCTTG ATCCGGCAAA CAAACCACCG 8281 CTGGTAGCGG TGGTTTTTTT GTTTGCAAGC AGCAGATTAC GCGCAGAAAA AAAGGATCTC 8341 AAGAAGATCC TTTGATCTTT TCTACGGGGT CTGACGCTCA GTGGAACGAA AACTCACGTT 8401 AAGGGATTTT GGTCATGAGA TT AT C A A A A A GGATCTTCAC CTAGATCCTT TT AA ATT AAA 8461 AATGAAGTTT TAAATCAATC TAAAGTATAT ATGAGTAAAC TTGGTCTGAC AGTTACCAAT 8521 GCTTAATCAG TGAGGCACCT ATCTCAGCGA TCTGTCTATT TCGTTCATCC ATAGTTGCCT 8581 GACTCCCCGT CGTGTAGATA ACTACGATAC GGGAGGGCTT ACCATCTGGC CCCAGTGCTG 8641 CAATGATACC GCAGCTTGGG AAACCATAAG AGCTGAAGCC AGTTACCTTC GGAAAAAGAG 8701 TTGGTAGCTC TTGATCCGGC AAACAAACCA CCGCTGGTAG CGGTGGTTTT TTTGTTTGCA 8761 AGC AGC AG AT TACGCGCAGA AAAAAAGGAT CTCAAGAAGA TCCTTTGATC TTTTCTACGG 8821 GGTCTGACGC TCAGTGGAAC GAAAACTCAC GTTAAGGGAT TTTGGTCATG AGCTTGCGCC 8881 GTCCCGTCAA GTCAGCGTAA TGCTCTGCCA GTGTTACAA pLRPO FMC63 endoL TRBC1 (SEQ ID NO: 172)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TTATCAATAC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG AT CCT GGT AT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTTATGCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GATAAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GT CT G ACC AT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGT AAC AT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAGATAGAGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT AT GGTT G CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGG AT GT GCTGCAAGGC GATT AAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT T C ACT G ACT G ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA T A AT G ACGT A TGTTCCCATA GTAACGCCAA 1861 TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGT ATT AGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC C ATT G ACGT C AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTTAGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG G A A A AT CTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC TAGAACGATT CGCAGTTAAT 2761 CCTGGCCTTT T AG AG AC AT C AGAAGGCTGT AG AC A A AT AC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TTATATAATA CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG GACAATTGGA GAAGTGAATT AT AT AA AT AT AAAGTAGTAA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GGAAGCACTA TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGCAGCAGAA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GGAAAGATAC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG G A A A ACT CAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT AAATCTCTGG AACAGATTTG GAATAACATG ACCTGGATGG AGTGGGACAG 3481 AG A A ATT A AC A ATT AC AC A A GCTT A AT AC A CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 TAACATAACA AATTGGCTGT GGTATATAAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT 3781 ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGTAGACATA ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A T AT A AGT GCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACTGGTATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 5281 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT TAGTAAATAT TTAAATTGGT 5341 ATCAGCAGAA ACCAGATGGA ACT GTT A A AC TCCTGATCTA CC AT AC AT C A AGATTACACT 5401 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AGATTATTCT CTCACCATTA 5461 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 5521 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGCTC CACCTCTGGA TCCGGCAAGC 5581 CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA GGACCTGGCC 5641 TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CAT GC ACT GT CTCAGGGGTC TCATTACCCG 5701 ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG CTGGGAGTAA 5761 TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG ACCATCATCA 5821 AGGACAACTC CAAGAGCCAA GTTTTCTTAA A A AT G A AC AG T CT GCA A ACT GAT G AC AC AG 5881 CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG GACTACTGGG 5941 GTCAAGGAAC CTCAGTCACC GTCTCCTCAG GAGTAGAGGA CCTGAACAAG GTGTTCCCAC 6001 CCGAGGTCGC TGTGTTTGAG CCATCAGAAG CAGAGATCTC CCACACCCAA AAGGCCACtC 6061 TaGTaTGtCT aGCtACAGGC TTCTTCCCTG ACCACGTGGA GCTGAGCTGG TGGGTGAATG 6121 GGAAGGAGGT GCACAGTGGG GTCAGCACGG ACCCGCAGCC aCTtAAaGAa CAGCCaGCtC 6181 TCAATGACTC CAGATACTGt CTaAGCAGtC GaCTtAGaGT CTCGGCtACa TTtTGGCAaA 6241 AtCCtCGaAA CCACTTCCGC TGTCAAGTCC AGTTCTACGG GCTCTCGGAG AATGACGAGT 6301 GGACCCAGGA TAGGGCCAAA CCCGTCACCC AGATCGTCAG CGCCGAGGCC TGGGGTAGAG 6361 CAGACTGTGG CTTTACCTCG GTGTCCTACC AGCAAGGGGT CCTGTCTGCC ACCATCCTCT 6421 ATGAGATCCT GCTAGGGAAG GCCACCCTGT ATGCTGTGCT GGTCAGCGCC CTTGTGTTGA 6481 TGGCCATGGT CAAGAGAAAG GATTTCTGAG ATATCGAGCA TCTTACCGCC ATTTATACCC 6541 ATATTTGTTC TGTTTTTCTT GATTTGGGTA TACATTTAAA T GTT A AT AAA ACAAAATGGT 6601 GGGGCAATCA TTTACATTTT TAGGGATATG T A ATT ACT AG TTCAGGTGTA TTGCCACAAG 6661 ACAAACATGT TAAGAAACTT TCCCGTTATT TACGCTCTGT TCCTGTTAAT CAACCTCTGG 6721 ATT AC A A A AT TTGTGAAAGA TT G ACT GAT A TTCTTAACTA TGTTGCTCCT TTTACGCTGT 6781 GTGGATATGC TGCTTTATAG CCTCTGTATC TAGCTATTGC TTCCCGTACG GCTTTCGTTT 6841 TCTCCTCCTT GTATAAATCC TGGTTGCTGT CTCTTTTAGA GGAGTTGTGG CCCGTTGTCC 6901 GTCAACGTGG CGTGGTGTGC TCTGTGTTTG CTGACGCAAC CCCCACTGGC TGGGGCATTG 6961 CCACCACCTG TCAACTCCTT TCTGGGACTT TCGCTTTCCC CCTCCCGATC GCCACGGCAG 7021 AACTCATCGC CGCCTGCCTT GCCCGCTGCT GGACAGGGGC TAGGTTGCTG GGCACTGATA 7081 ATTCCGTGGT GTTGTCAGTA CTGGTACCTT TAAGACCAAT GACTTACAAG GCAGCTGTAG 7141 ATCTTAGCCA CTTTTTAAAA GAAAAGGGGG GACTGGAAGG GCTAATTCAC TCCCAAAGAA 7201 GACAAGATCT GCTTTTTGCC TGTACTGGGT CTCTCTGGTT AGACCAGATC TGAGCCTGGG 7261 AGCTCTCTGG CTAACTAGGG AACCCACTGC TTAAGCCTCA ATAAAGCTTG CCTTGAGTGC 7321 TTCAATGATC ATAATCAAGC CATATCACAT CTGTAGAGGT TTACTTGCTT TAAAAAACCT 7381 CCACACCTCC CCCTGAACCT GAAACATAAA ATGAATGCAA TTGTTGTTGT TAACTTGTTT 7441 ATTGCAGCTT ATAATGGTTA CAAATAAAGC AATAGCATCA CAAATTTCAC AAATAAAGCA

7561 TGGATCTGCG TCGACACGAA GAGACGACTG ACTGACTGAC TGGAAAGAGG AAGGGCTGGA 7621 AGAGGAAGGA GCTTGATCCA GATCCCGATC TCGATCCAGA TCCGGATCGC AGCTTGGCGT 7681 AATCATGGTC ATAGCTGTTT CCTGTGTGAA ATTGTTATCC GCTCACAATT CCACACAACA 7741 TACGAGCCGG AAGCATAAAG TGTAAAGCCT GGGGTGCCTA ATGAGTGAGC TAACTCACAT 7801 TAATTGCGTT GCGCTCACTG CCCGCTTTCC AGTCGGGAAA CCTGTCGTGC CAGCTGCATT 7861 AATGAATCGG CCAACGCGCG GGGAGAGGCG GTTTGCGTAT TGGGCGCTCT TCCGCTTCCT 7921 CGCTCACTGA CTCGCTGCGC TCGGTCGTTC GGCTGCGGCG AGCGGTATCA GCTCACTCAA 7981 AGGCGGTAAT ACGGTTATCC ACAGAATCAG GGGATAACGC AGGAAAGAAC ATGTGAGCAA 8041 AAGGCCAGCA AAAGGCCAGG AACCGTAAAA AGGCCGCGTT GCTGGCGTTT TTCCATAGGC 8101 TCCGCCCCCC TGACGAGCAT C AC A A A A AT C GACGCTCAAG TCAGAGGTGG CGAAACCCGA 8161 CAGGACTATA AAGATACCAG GCGTTTCCCC CTGGAAGCTC CCTCGTGCGC TCTCCTGTTC 8221 CGACCCTGCC GCTTACCGGA TACCTGTCCG CCTTTCTCCC TTCGGGAAGC GTGGCGCTTT 8281 CTCATAGCTC ACGCTGTAGG TATCTCAGTT CGGTGTAGGT CGTTCGCTCC AAGCTGGGCT 8341 GTGTGCACGA ACCCCCCGTT CAGCCCGACC GCTGCGCCTT ATCCGGTAAC TATCGTCTTG 8401 AGTCCAACCC GGTAAGACAC GACTTATCGC CACTGGCAGC AGCCACTGGT AACAGGATTA 8461 GCAGAGCGAG GTATGTAGGC GGTGCTACAG AGTTCTTGAA GTGGTGGCCT AACTACGGCT 8521 ACACTAGAAG AACAGTATTT GGTATCTGCG CTCTGCTGAA GCCAGTTACC TTCGGAAAAA 8581 GAGTTGGTAG CTCTTGATCC GGCAAACAAA CCACCGCTGG TAGCGGTGGT TTTTTTGTTT 8641 GCAAGCAGCA GATTACGCGC AGAAAAAAAG GATCTCAAGA AGATCCTTTG ATCTTTTCTA 8701 CGGGGTCTGA CGCTCAGTGG AACGAAAACT CACGTTAAGG GATTTTGGTC ATGAGATTAT 8761 CAAAAAGGAT CTTCACCTAG ATCCTTTTAA ATTAAAAATG AAGTTTTAAA TCAATCTAAA 8821 GTATATATGA GTAAACTTGG TCTGACAGTT ACCAATGCTT AATCAGTGAG GCACCTATCT 8881 CAGCGATCTG TCTATTTCGT TCATCCATAG TTGCCTGACT CCCCGTCGTG TAGATAACTA 8941 CGATACGGGA GGGCTTACCA TCTGGCCCCA GTGCTGCAAT GATACCGCAG CTTGGGAAAC 9001 CATAAGAGCT GAAGCCAGTT ACCTTCGGAA AAAGAGTTGG TAGCTCTTGA TCCGGCAAAC 9061 AAACCACCGC TGGTAGCGGT GGTTTTTTTG TTTGCAAGCA GCAGATTACG CGCAGAAAAA 9121 AAGGATCTCA AGAAGATCCT TTGATCTTTT CTACGGGGTC TGACGCTCAG TGGAACGAAA 9181 ACTCACGTTA AGGGATTTTG GTCATGAGCT TGCGCCGTCC CGTCAAGTCA GCGTAATGCT 9241 CTGCCAGTGT TACAA pLRPO V5-TRAC(94-140) T2APuroR (SEQ ID NO: 173)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TT AT CA AT AC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTT AT GCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GAT AAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG AC AGTTTT AT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAGATAGAGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT AT GGTT G CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT T C ACT G ACT G ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTT ACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA 1861 TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGT ATT AGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTT AGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC T AG A ACG ATT CGCAGTTAAT 2761 CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT AAT A CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG G AC A ATT GG A GAAGTGAATT AT AT AA AT AT AAAGTAGTAA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GG A AGC ACT A TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGC AGC AG AA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GG AA AG AT AC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT AAATCTCTGG AACAGATTTG GAATAACATG ACCTGGATGG AGTGGGACAG 3481 AG A A ATT A AC A ATT AC AC A A GCTT A AT AC A CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 T AAC AT A AC A A ATT GGCT GT GGT AT AT AAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT 3781 ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGTAGACATA ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 T CA A AATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A T AT A AGT GCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACT GGT ATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAggtaag cctatcccta accctctcct cggtctcgat tctacgGGAT

5281 GCGACGT AAA ACTGGTGGAA AAGTCCTTCG AG ACT GAT AC AAACTTGAAC TTT CA AA ACT 5341 TGAGCGTGAT CGGCTTTCGG ATATTGCTGC TCAAGGTGGC CGGTTTCAAT CTGCTGATGA 5401 CACTTAGGCT TTGGTCGTCC GGCAGCGGCG AGGGCAGAGG AAGTCTGCTA ACATGCGGTG 5461 ACGTCGAGGA GAATCCTGGC CCAATGACCG AGTACAAGCC CACGGTGCGC CTCGCCACCC 5521 GCGACGACGT CCCCAGGGCC GTACGCACCC TCGCCGCCGC GTTCGCCGAC TACCCCGCCA 5581 CGCGCCACAC CGTCGATCCG GACCGCCACA TCGAGCGGGT CACCGAGCTG CAAGAACTCT 5641 TCCTCACGCG CGTCGGGCTC GACATCGGCA AGGTGTGGGT CGCGGACGAC GGCGCCGCGG 5701 TGGCGGTCTG GACCACGCCG GAGAGCGTCG AAGCGGGGGC GGTGTTCGCC GAGATCGGCC 5761 CGCGCATGGC CGAGTTGAGC GGTTCCCGGC TGGCCGCGCA GCAACAGATG GAAGGCCTCC 5821 TGGCGCCGCA CCGGCCCAAG GAGCCCGCGT GGTTCCTGGC CACCGTCGGC GTCTCGCCCG 5881 ACCACCAGGG CAAGGGTCTG GGCAGCGCCG TCGTGCTCCC CGGAGTGGAG GCGGCCGAGC 5941 GCGCCGGGGT GCCCGCCTTC CTGGAGACCT CCGCGCCCCG CAACCTCCCC TTCTACGAGC 6001 GGCTCGGCTT CACCGTCACC GCCGACGTCG AGGTGCCCGA AGGACCGCGC ACCTGGTGCA 6061 TGACCCGCAA GCCCGGTGCC TGAGATATCG AGCATCTTAC CGCCATTTAT ACCCATATTT 6121 GTTCTGTTTT TCTTGATTTG GGTATACATT TAAATGTTAA T AAA AC A A A A TGGTGGGGCA 6181 ATCATTTACA TTTTTAGGGA TATGTAATTA CTAGTTCAGG TGTATTGCCA CAAGACAAAC 6241 AT GTT AAG A A ACTTTCCCGT TATTTACGCT CTGTTCCTGT TAATCAACCT CTGGATT AC A 6301 AAATTTGTGA AAGATTGACT GATATTCTTA ACTATGTTGC TCCTTTTACG CTGTGTGGAT 6361 ATGCTGCTTT ATAGCCTCTG TATCTAGCTA TTGCTTCCCG TACGGCTTTC GTTTTCTCCT 6421 CCTTGTATAA ATCCTGGTTG CTGTCTCTTT TAGAGGAGTT GTGGCCCGTT GTCCGTCAAC 6481 GTGGCGTGGT GTGCTCTGTG TTTGCTGACG CAACCCCCAC TGGCTGGGGC ATTGCCACCA 6541 CCTGTCAACT CCTTTCTGGG ACTTTCGCTT TCCCCCTCCC GATCGCCACG GCAGAACTCA 6601 TCGCCGCCTG CCTTGCCCGC TGCTGGACAG GGGCTAGGTT GCTGGGCACT GATAATTCCG 6661 TGGTGTTGTC AGTACTGGTA CCTTT AAGAC CAATGACTTA CAAGGCAGCT GTAGATCTTA

7081 TCACTGCATT CTAGTTGTGG TTTGTCCAAA CTCATCAATG TATCTTATCA TGTCTGGATC 7141 TGCGTCGACA CGAAGAGACG ACTGACTGAC TGACTGGAAA GAGGAAGGGC TGGAAGAGGA 7201 AGGAGCTTGA TCCAGATCCC GATCTCGATC CAGATCCGGA TCGCAGCTTG GCGTAATCAT 7261 GGTCATAGCT GTTTCCTGTG TGAAATTGTT ATCCGCTCAC AATTCCACAC AAC AT ACGAG 7321 CCGGAAGCAT AAAGTGTAAA GCCTGGGGTG CCTAATGAGT GAGCTAACTC AC ATT A ATT G 7381 CGTTGCGCTC ACTGCCCGCT TTCCAGTCGG GAAACCTGTC GTGCCAGCTG CATTAATGAA 7441 TCGGCCAACG CGCGGGGAGA GGCGGTTTGC GTATTGGGCG CTCTTCCGCT TCCTCGCTCA 7501 CTGACTCGCT GCGCTCGGTC GTTCGGCTGC GGCGAGCGGT ATCAGCTCAC TCAAAGGCGG 7561 TAATACGGTT ATCCACAGAA TCAGGGGATA ACGCAGGAAA GAACATGTGA GCAAAAGGCC

7681 CCCCTGACGA GCATCACAAA AATCGACGCT CAAGTCAGAG GTGGCGAAAC CCGACAGGAC 7741 T AT A A AG AT A CCAGGCGTTT CCCCCTGGAA GCTCCCTCGT GCGCTCTCCT GTTCCGACCC 7801 TGCCGCTTAC CGGATACCTG TCCGCCTTTC TCCCTTCGGG AAGCGTGGCG CTTTCTCATA 7861 GCTCACGCTG TAGGTATCTC AGTTCGGTGT AGGTCGTTCG CTCCAAGCTG GGCTGTGTGC 7921 ACGAACCCCC CGTTCAGCCC GACCGCTGCG CCTTATCCGG T A ACT AT CGT CTTGAGTCCA 7981 ACCCGGTAAG ACACGACTTA TCGCCACTGG CAGCAGCCAC TGGTAACAGG ATTAGCAGAG 8041 CGAGGTATGT AGGCGGTGCT ACAGAGTTCT TGAAGTGGTG GCCTAACTAC GGCTACACTA 8101 GAAGAACAGT ATTTGGTATC TGCGCTCTGC TGAAGCCAGT TACCTTCGGA AAAAGAGTTG

8221 AGCAGATTAC GCGCAGAAAA AAAGGATCTC AAGAAGATCC TTTGATCTTT TCTACGGGGT 8281 CTGACGCTCA GTGGAACGAA AACTCACGTT AAGGGATTTT GGTCATGAGA TTATCAAAAA 8341 GGATCTTCAC CTAGATCCTT TTAAATTAAA AATGAAGTTT TAAATCAATC TAAAGTATAT 8401 ATGAGTAAAC TTGGTCTGAC AGTTACCAAT GCTTAATCAG TGAGGCACCT ATCTCAGCGA 8461 TCTGTCTATT TCGTTCATCC ATAGTTGCCT GACTCCCCGT CGTGTAGATA ACTACGATAC 8521 GGGAGGGCTT ACCATCTGGC CCCAGTGCTG CAATGATACC GCAGCTTGGG AAACC AT AAG 8581 AGCTGAAGCC AGTTACCTTC GGAAAAAGAG TTGGTAGCTC TTGATCCGGC AAACAAACCA 8641 CCGCTGGTAG CGGTGGTTTT TTTGTTTGCA AGCAGCAGAT TACGCGCAGA AAAAAAGGAT 8701 CTCAAGAAGA TCCTTTGATC TTTTCTACGG GGTCTGACGC TCAGTGGAAC GAAAACTCAC 8761 GTTAAGGGAT TTTGGTCATG AGCTTGCGCC GTCCCGTCAA GTCAGCGTAA TGCTCTGCCA 8821 GTGTTACAA pLRPO V5-TRAC(7-140) T2APuroR (SEQ ID NO: 174)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TT AT CA AT AC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA ATAAGGTTAT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTT AT GCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA TCAGGATATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GAT AAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG AC AGTTTT AT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT AT GGTT G CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGG AT GT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT T C ACT G ACT G ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA T A AT G ACGT A TGTTCCCATA GTAACGCCAA 1861 TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGT ATT AGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC C ATT G ACGT C AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTT AGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG G A A A AT CTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA 2701 C A AT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC T AG A ACG ATT CGCAGTTAAT 2761 CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT AAT A CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG G AC A ATT GG A G A AGTGA ATT AT AT AA AT AT A A AGT AGT AA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GG A AGC ACT A TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGC AGC AG AA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GG AA AG AT AC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT AAATCTCTGG AACAGATTTG G A AT A AC AT G ACCTGGATGG AGT GGG AC AG 3481 AG A A ATT A AC A ATT AC AC A A GCTTAATACA CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 T AAC AT A AC A A ATT GGCT GT GGT AT AT AAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TAT AGTGA AT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT 3781 ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGTAGACATA ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A T AT A AGT GCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACTGGTATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5281 CTGTGTACCA GCTCAGGGAT TCCAAGAGTT CAGATAAGTC AGTGTGCCTG TTCACCGACT 5341 TTGATAGTCA GACCAATGTC TCACAGTCTA AAGACTCGGA TGTGTACATC ACCGATAAGA 5401 CAGTCCTCGA CATGCGAAGC ATGGATTTTA AG AGT A ATT C AGCCGTGGCC TGGTCCAACA 5461 AGT CAGATTT CGCCTGCGCC AACGCCTTCA AT AACT C A AT CATTCCCGAA GAT AC ATTTT 5521 TCCCCTCCCC CGAGTCTTCG TGTGATGTTA AACTTGTGGA GAAATCTTTC GAAACTGATA 5581 CAAACCTCAA TTTCCAGAAC TTGAGCGTCA TAGGATTTAG AATCCTCCTC TTAAAGGTTG 5641 CTGGCTTTAA CTTACTGATG ACACTCCGAC TCTGGAGCTC CGGCAGCGGC GAGGGCAGAG 5701 GAAGTCTGCT AACATGCGGT GACGTCGAGG AGAATCCTGG CCCAATGACC GAGTACAAGC 5761 CCACGGTGCG CCTCGCCACC CGCGACGACG TCCCCAGGGC CGTACGCACC CTCGCCGCCG 5821 CGTTCGCCGA CTACCCCGCC ACGCGCCACA CCGTCGATCC GGACCGCCAC ATCGAGCGGG 5881 TCACCGAGCT GCAAGAACTC TTCCTCACGC GCGTCGGGCT CGACATCGGC AAGGTGTGGG 5941 TCGCGGACGA CGGCGCCGCG GTGGCGGTCT GGACCACGCC GGAGAGCGTC GAAGCGGGGG 6001 CGGTGTTCGC CGAGATCGGC CCGCGCATGG CCGAGTTGAG CGGTTCCCGG CTGGCCGCGC 6061 AGCAACAGAT GGAAGGCCTC CTGGCGCCGC ACCGGCCCAA GGAGCCCGCG TGGTTCCTGG 6121 CCACCGTCGG CGTCTCGCCC GACCACCAGG GCAAGGGTCT GGGCAGCGCC GTCGTGCTCC 6181 CCGGAGTGGA GGCGGCCGAG CGCGCCGGGG TGCCCGCCTT CCTGGAGACC TCCGCGCCCC 6241 GCAACCTCCC CTTCT ACGAG CGGCTCGGCT TCACCGTCAC CGCCGACGTC GAGGTGCCCG 6301 AAGGACCGCG CACCTGGTGC ATGACCCGCA AGCCCGGTGC CTGAGATATC GAGCATCTTA 6361 CCGCCATTTA TACCCATATT TGTTCTGTTT TTCTTGATTT GGGTATACAT TTAAATGTTA

6481 GTGTATTGCC ACAAGACAAA CATGTTAAGA AACTTTCCCG TTATTTACGC TCTGTTCCTG 6541 TT A AT C A ACC TCTGGATTAC AAAATTTGTG AAAGATTGAC TGATATTCTT A ACT AT GTT G 6601 CTCCTTTTAC GCTGTGTGGA TATGCTGCTT TATAGCCTCT GTATCTAGCT ATTGCTTCCC 6661 GTACGGCTTT CGTTTTCTCC TCCTTGTATA AATCCTGGTT GCTGTCTCTT TTAGAGGAGT 6721 TGTGGCCCGT TGTCCGTCAA CGTGGCGTGG TGTGCTCTGT GTTTGCTGAC GCAACCCCCA 6781 CTGGCTGGGG CATTGCCACC ACCTGTCAAC TCCTTTCTGG GACTTTCGCT TTCCCCCTCC 6841 CGATCGCCAC GGCAGAACTC ATCGCCGCCT GCCTTGCCCG CTGCTGGACA GGGGCTAGGT 6901 TGCTGGGCAC TGATAATTCC GTGGTGTTGT CAGTACTGGT ACCTTTAAGA CCAATGACTT 6961 ACAAGGCAGC TGTAGATCTT AGCCACTTTT TAAAAGAAAA GGGGGGACTG GAAGGGCTAA 7021 TTCACTCCCA AAGAAGACAA GATCTGCTTT TTGCCTGTAC TGGGTCTCTC TGGTTAGACC 7081 AGATCTGAGC CTGGGAGCTC TCTGGCTAAC TAGGGAACCC ACTGCTTAAG CCTCAATAAA 7141 GCTTGCCTTG AGTGCTTCAA T GAT CAT A AT CAAGCCATAT CACATCTGTA G AGGTTT ACT 7201 TGCTTTAAAA AACCTCCACA CCTCCCCCTG AACCTGAAAC AT AAAATGAA TGCAATTGTT 7261 GTT GTT A ACT TGTTTATTGC AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT 7321 TTCACAAATA AAGCATTTTT TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACT CAT C A AT 7381 GTATCTTATC ATGTCTGGAT CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA 7441 AGAGGAAGGG CTGGAAGAGG AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG 7501 ATCGCAGCTT GGCGTAATCA TGGTCATAGC TGTTTCCTGT GTGAAATTGT TATCCGCTCA 7561 CAATTCCACA CAACATACGA GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG 7621 TGAGCTAACT CACATTAATT GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT 7681 CGTGCCAGCT GCATTAATGA ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC 7741 GCTCTTCCGC TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG 7801 TATCAGCTCA CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA 7861 AGAACATGTG AGCAAAAGGC CAGCAAAAGG CCAGGAACCG TAAAAAGGCC GCGTTGCTGG

7981 GGTGGCGAAA CCCGACAGGA CT AT A A AG AT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG 8041 TGCGCTCTCC TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG 8101 GAAGCGTGGC GCTTTCTCAT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC 8161 GCTCCAAGCT GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG 8221 GTAACTATCG TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA 8281 CTGGTAACAG GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT 8341 GGCCTAACTA CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG 8401 TTACCTTCGG AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG 8461 GTGGTTTTTT TGTTTGCAAG CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC 8521 CTTTGATCTT TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT 8581 TGGTCATGAG ATTATCAAAA AGGATCTTCA CCTAGATCCT TTTAAATTAA AAATGAAGTT 8641 TTAAATCAAT CTAAAGTATA TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA 8701 GTGAGGCACC TATCTCAGCG ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG 8761 TCGTGTAGAT AACTACGATA CGGGAGGGCT TACCATCTGG CCCCAGTGCT GCAATGATAC 8821 CGCAGCTTGG GAAACC AT AA GAGCTGAAGC CAGTTACCTT CGGAAAAAGA GTTGGTAGCT 8881 CTTGATCCGG CAAACAAACC ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC AAGCAGCAGA 8941 TTACGCGCAG AAAAAAAGGA TCTCAAGAAG ATCCTTTGAT CTTTTCTACG GGGTCTGACG 9001 CTCAGTGGAA CGAAAACTCA CGTTAAGGGA TTTTGGTCAT GAGCTTGCGC CGTCCCGTCA 9061 AGTCAGCGTA ATGCTCTGCC AGTGTTACAA pLRPO FMC63 endoL TRBC1(126-177) T2AW trEGFR (SEQ ID NO:175)

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 5281 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT TAGTAAATAT TTAAATTGGT 5341 ATCAGCAGAA ACCAGATGGA ACT GTT A A AC TCCTGATCTA CC AT AC AT C A AGATTACACT 5401 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AGATTATTCT CTCACCATTA 5461 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 5521 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGCTC CACCTCTGGA TCCGGCAAGC 5581 CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA GGACCTGGCC 5641 TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CAT GC ACT GT CTCAGGGGTC TCATTACCCG 5701 ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG CTGGGAGTAA 5761 TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG ACCATCATCA 5821 AGGACAACTC CAAGAGCCAA GTTTTCTTAA AAATGAACAG TCTGCAAACT GATGACACAG 5881 CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG GACTACTGGG 5941 GTCAAGGAAC CTCAGTCACC GTCTCCTCAG GAT GGGGT AG AGCAGACTGT GGCTTTACCT 6001 CGGTGTCCTA CCAGCAAGGG GTCCTGTCTG CCACCATCCT CTATGAGATC CTGCTAGGGA 6061 AGGCCACCCT GTATGCTGTG CTGGTCAGCG CCCTTGTGTT GATGGCCATG GT C A AG AG A A 6121 AGGATTTCGG GTCAGGCGAG GGCAGAGGAA GTCTGCTAAC ATGCGGTGAC GTCGAGGAGA 6181 ATCCTGGACC TATGCTTCTC CTGGTGACAA GCCTTCTGCT CTGTGAGTTA CCACACCCAG 6241 CATTCCTCCT GATCCCACGC AAAGTGTGTA ACGGAATAGG TATTGGTGAA TTT A A AG ACT 6301 CACTCTCCAT AAATGCTACG A AT ATT AA AC ACTTCAAAAA CTGCACCTCC ATCAGTGGCG 6361 ATCTCCACAT CCTGCCGGTG GCATTTAGGG GTGACTCCTT CACACATACT CCTCCTCTGG 6421 ATCCACAGGA ACT GG AT ATT CTGAAAACCG TAAAGGAAAT CACAGGGTTT TTGCTGATTC 6481 AGGCTTGGCC TGAAAACAGG ACGGACCTCC ATGCCTTTGA GAACCTAGAA ATCATACGCG 6541 GCAGGACCAA GCAACATGGT CAGTTTTCTC TTGCAGTCGT CAGCCTGAAC AT A AC AT CCT 6601 TGGGATTACG CTCCCTCAAG GAGATAAGTG ATGGAGATGT GATAATTTCA GGAAACAAAA 6661 ATTTGTGCTA T GCA A AT AC A ATAAACTGGA AAAAACTGTT TGGGACCTCC GGTCAGAAAA 6721 CCAAAATTAT AAGCAACAGA GGT G A A A AC A GCTGCAAGGC CACAGGCCAG GTCTGCCATG 6781 CCTTGTGCTC CCCCGAGGGC TGCTGGGGCC CGGAGCCCAG GGACTGCGTC TCTTGCCGGA 6841 ATGTCAGCCG AGGCAGGGAA TGCGTGGACA AGTGCAACCT TCTGGAGGGT GAGCCAAGGG 6901 AGTTTGTGGA GAACTCTGAG TGCATACAGT GCCACCCAGA GTGCCTGCCT CAGGCCATGA 6961 ACATCACCTG CACAGGACGG GGACCAGACA ACTGTATCCA GTGTGCCCAC TACATTGACG 7021 GCCCCCACTG CGTCAAGACC TGCCCGGCAG GAGTCATGGG AGAAAACAAC ACCCTGGTCT 7081 GGAAGTACGC AGACGCCGGC CATGTGTGCC ACCTGTGCCA TCCAAACTGC ACCTACGGAT 7141 GCACTGGGCC AGGTCTTGAA GGCTGTCCAA CGAATGGGCC TAAGATCCCG TCCATCGCCA 7201 CTGGGATGGT GGGGGCCCTC CTCTTGCTGC TGGTGGTGGC CCTGGGGATC GGCCTCTTCA 7261 TGTGAGATAT CGAGCATCTT ACCGCCATTT ATACCCATAT TTGTTCTGTT TTTCTTGATT 7321 TGGGTATACA TTTAAATGTT A AT AAA AC A A AAT GGTGGGG CAATCATTTA CATTTTTAGG 7381 GATATGTAAT TACTAGTTCA GGTGTATTGC CACAAGACAA ACATGTTAAG AAACTTTCCC 7441 GTTATTTACG CTCTGTTCCT GTTAATCAAC CTCTGGATTA CAAAATTTGT GAAAGATTGA 7501 CTGATATTCT TAACTATGTT GCTCCTTTTA CGCTGTGTGG AT AT GCTGCT TTATAGCCTC 7561 TGTATCTAGC TATTGCTTCC CGTACGGCTT TCGTTTTCTC CTCCTTGTAT AAATCCTGGT 7621 TGCTGTCTCT TTTAGAGGAG TTGTGGCCCG TTGTCCGTCA ACGTGGCGTG GTGTGCTCTG 7681 TGTTTGCTGA CGCAACCCCC ACTGGCTGGG GCATTGCCAC CACCTGTCAA CTCCTTTCTG 7741 GGACTTTCGC TTTCCCCCTC CCGATCGCCA CGGCAGAACT CATCGCCGCC TGCCTTGCCC 7801 GCTGCTGGAC AGGGGCTAGG TTGCTGGGCA CT GAT A ATT C CGTGGTGTTG TCAGTACTGG 7861 TACCTTTAAG ACCAATGACT TACAAGGCAG CTGTAGATCT TAGCCACTTT TT A A A AG A A A 7921 AGGGGGGACT GG A AGGGCT A ATTCACTCCC AAAGAAGACA AGATCTGCTT TTTGCCTGTA 7981 CTGGGTCTCT CTGGTTAGAC CAGATCTGAG CCTGGGAGCT CTCTGGCTAA CTAGGGAACC 8041 CACTGCTTAA GCCTCAATAA AGCTTGCCTT GAGTGCTTCA ATGATCATAA TCAAGCCATA 8101 TCACATCTGT AGAGGTTTAC TTGCTTT AAA AAACCTCCAC ACCTCCCCCT GAACCTGAAA 8161 CAT AA AAT G A ATGCAATTGT TGTTGTTAAC TTGTTTATTG CAGCTTATAA TGGTTACAAA 8221 TAAAGCAATA GCATCACAAA TTT C AC A A AT AAAGCATTTT TTTCACTGCA TTCTAGTTGT 8281 GGTTTGTCCA AACTCATCAA TGTATCTTAT CATGTCTGGA TCTGCGTCGA CACGAAGAGA 8341 CGACTGACTG ACTGACTGGA AAGAGGAAGG GCTGGAAGAG GAAGGAGCTT GATCCAGATC 8401 CCGATCTCGA TCCAGATCCG GATCGCAGCT TGGCGTAATC ATGGTCATAG CTGTTTCCTG 8461 TGTGAAATTG TTATCCGCTC ACAATTCCAC ACAACATACG AGCCGGAAGC ATAAAGTGTA 8521 AAGCCTGGGG TGCCTAATGA GTGAGCTAAC TC AC ATT A AT TGCGTTGCGC TCACTGCCCG 8581 CTTTCCAGTC GGGAAACCTG TCGTGCCAGC TGCATTAATG AATCGGCCAA CGCGCGGGGA 8641 GAGGCGGTTT GCGTATTGGG CGCTCTTCCG CTTCCTCGCT CACTGACTCG CTGCGCTCGG 8701 TCGTTCGGCT GCGGCGAGCG GTATCAGCTC ACTCAAAGGC GGTAATACGG TT AT CC AC AG 8761 AATCAGGGGA TAACGCAGGA AAGAACATGT GAGCAAAAGG CCAGCAAAAGGCCAGGAACC

8881 AAAATCGACG CTCAAGTCAG AGGTGGCGAA ACCCGACAGG ACT AT A A AG A TACCAGGCGT 8941 TTCCCCCTGG AAGCTCCCTC GTGCGCTCTC CTGTTCCGAC CCTGCCGCTT ACCGGATACC 9001 TGTCCGCCTT TCTCCCTTCG GGAAGCGTGG CGCTTTCTCA TAGCTCACGC TGTAGGTATC 9061 TCAGTTCGGT GTAGGTCGTT CGCTCCAAGC TGGGCTGTGT GCACGAACCC CCCGTTCAGC 9121 CCGACCGCTG CGCCTTATCC GGT A ACT AT C GTCTTGAGTC CAACCCGGTA AGACACGACT 9181 TATCGCCACT GGCAGCAGCC ACTGGTAACA GGATTAGCAG AGCGAGGTAT GTAGGCGGTG 9241 CTACAGAGTT CTTGAAGTGG TGGCCTAACT ACGGCTACAC TAGAAGAACA GTATTTGGTA 9301 TCTGCGCTCT GCTGAAGCCA GTTACCTTCG GAAAAAGAGT TGGTAGCTCT TGATCCGGCA 9361 AACAAACCAC CGCTGGTAGC GGTGGTTTTT TTGTTTGCAA GCAGCAGATT ACGCGCAGAA 9421 AAAAAGGATC TCAAGAAGAT CCTTTGATCT TTTCTACGGG GTCTGACGCT CAGTGGAACG 9481 AAAACTCACG TT AAGGGATT TTGGTCATGA GATTATCAAA AAGGATCTTC ACCTAGATCC 9541 TTTTAAATTA AAAATGAAGT TTTAAATCAA TCTAAAGTAT AT AT G AGT A A ACTTGGTCTG 9601 ACAGTTACCA ATGCTTAATC AGTGAGGCAC CTATCTCAGC GATCTGTCTA TTTCGTTCAT 9661 CCATAGTTGC CTGACTCCCC GTCGTGTAGA T A ACT ACG AT ACGGGAGGGC TTACCATCTG 9721 GCCCCAGTGC TGCAATGATA CCGCAGCTTG GGAAACCATA AGAGCTGAAG CCAGTTACCT 9781 TCGGAAAAAG AGTTGGTAGC TCTTGATCCG GCAAACAAAC CACCGCTGGT AGCGGTGGTT 9841 TTTTTGTTTG CAAGCAGCAG ATTACGCGCA GAAAAAAAGG ATCTCAAGAA GATCCTTTGA 9901 TCTTTTCTAC GGGGTCTGAC GCTCAGTGGA ACGAAAACTC ACGTTAAGGG ATTTTGGTCA 9961 TGAGCTTGCG CCGTCCCGTC AAGTCAGCGT AATGCTCTGC CAGTGTTACA A pLRPO FMC63-TCRbetal (37GRK) (SEQ ID NO: 176)

1 CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT GCAATTTATT 61 CACATCAGGA TT AT CA AT AC CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA 121 CTCACCGAGG CAGTTCCATA GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG 181 TCCAACATCA ATACAACCTA TTAATTTCCC CTCGTCAAAA AT AAGGTT AT CAAGTGAGAA 241 ATCACCATGA GTGACGACTG AATCCGGTGA GAATGGCAAA AGTTTATGCA TTTCTTTCCA 301 GACTTGTTCA ACAGGCCAGC CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC 361 GTTATTCATT CGTGATTGCG CCTGAGCAAG ACGAAATACG CGATCGCTGT TAAAAGGACA 421 ATT AC AA AC A GGAATCGAAT GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT 481 TTCACCTGAA T C AGG AT ATT CTTCTAATAC CTGGAATGCT GTTTTTCCGG GGATCGCAGT 541 GGTGAGTAAC CATGCATCAT CAGGAGTACG GATAAAATGC TTGATGGTCG GAAGAGGCAT 601 AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC 661 TTTGCCATGT TTCAGAAACA ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT 721 CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT 781 GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT 841 ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT TATCTTGTGC 901 AATGTAACAT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA 961 ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT 1021 TGAGTGTTGT TCCAGTTTGG AACAAGAGTC C ACT ATT AAA GAACGTGGAC TCCAACGTCA 1081 AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA 1141 GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT 1201 TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAGAAAGCGAAAG 1261 GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG 1321 CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACTATGGTTG CTTTGACGTA TGCGGTGTGA 1381 AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC CATTCAGGCT 1441 GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC AGCTGGCGAA 1501 AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC AGTCACGACG 1561 TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA TCCAGATCGA 1621 ATTGGAGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG TCTCAACCTC 1681 CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC 1741 ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTT ACGGT AAATGGCCCG CCTGGCTGAC 1801 CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA 1861 TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG 1921 TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC 1981 CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT 2041 ACGT ATT AGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG 2101 GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT 2161 TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA 2221 CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTT AGTGA 2281 ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC 2341 CCACTGCTTA AGCCT CAAT A AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG 2401 TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT 2461 AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC 2521 GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA 2581 CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA 2641 TTAAGCGGGG GAGAATTAGA TAAATGGGAA A A A ATT CGGT TAAGGCCAGG GGGAAAGAAA 2701 CAAT AT A A AC TAAAACATAT AGTTAGGGCA AGCAGGGAGC TAGAACGATT CGCAGTTAAT 2761 CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC 2821 CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT AAT A CAATAGCAGT CCTCTATTGT 2881 GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG 2941 CAAAACAAAA GT A AG AAA AA GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG 3001 CGATATGAGG GACAATTGGA GAAGTGAATT AT AT AA AT AT AAAGTAGTAA AAATTGAACC 3061 ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT 3121 GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GG A AGC ACT A TGGGCGCAGC 3181 GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC AGC AGC AG AA 3241 CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT 3301 CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GGAAAGATAC CTAAAGGATC AACAGCTCCT 3361 GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG 3421 TTGGAGTAAT A AAT CTCTGG AACAGATTTG G A AT A AC AT G ACCTGGATGG AGT GGG AC AG 3481 AG A A ATT A AC A ATT AC AC A A GCTTAATACA CTCCTTAATT GAAGAATCGC AAAACCAGCA 3541 AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT 3601 TAACATAACA A ATT GGCT GT GGT AT AT AAA ATTATTCATA ATGATAGTAG GAGGCTTGGT 3661 AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TAT AGTGA AT AGAGTTAGGC AGGGATATTC 3721 ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC A A AT GGC AGT 3781 ATTCATCCAC AATTTTAAAA GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT 3841 AGT AG AC AT A ATAGCAACAG AC AT AC A AAC T A A AG A ATT A CAAAAACAAA TTACAAAAAT 3901 TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC 3961 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 4021 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA CTGGGAAAGT 4081 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A TATAAGTGCA 4141 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 4201 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 4261 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 4321 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 4381 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC 4441 TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA CGCTTTTTTT 4501 CTGGCAAGAT AGTCTTGTAA ATGCGGGCCA AGATCTGCAC ACT GGT ATTT CGGTTTTTGG 4561 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 4621 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 4681 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 4741 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 4801 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 4861 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 4921 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 4981 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT 5041 GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC TCAAGCCTCA

5161 CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 5221 TCCTCCTGAT CCCAGACATC CAGATGACAC AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG 5281 GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT T AGT A A AT AT TT A A ATT GGT 5341 ATCAGCAGAA ACCAGATGGA ACTGTTAAAC TCCTGATCTA CCATACATCA AGATTACACT 5401 CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AG ATT ATTCT CT C ACC ATT A 5461 GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT 5521 ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGCTC CACCTCTGGA TCCGGCAAGC 5581 CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA GGACCTGGCC 5641 TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CATGCACTGT CTCAGGGGTC TCATTACCCG 5701 ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG CTGGGAGTAA 5761 TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG ACCATCATCA 5821 AGGACAACTC CAAGAGCCAA GTTTTCTTAA AAATGAACAG TCTGCAAACT GATGACACAG 5881 CC ATTT ACT A CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG GACTACTGGG 5941 GTCAAGGAAC CTCAGTCACC GTCTCCTCAG CGGCCGCAGG TGGAGGAGGT TCTGGAGGTG 6001 GAGGTTCAGG TGGAGGTGGT TCACTCGAGC TGGGAGCAGG CCCAGTGGAT TCTGGAGTCA 6061 CACAAACCCC AAAGCACCTG ATCACAGCAA CTGGACAGCG AGTGACGCTG AGATGCTCCC 6121 CTAGGTCTGG AGACCTCTCT GTGTCATGGT ACCAACAGAG CCTGGACCAG GGCCTCCAGT 6181 TCCTCATTCA GT ATT AT AAT GGAGAAGAGA GAGCAAAAGG AAACATTCTT GAACGATTCT 6241 CCGCACAACA GTTCCCTGAC TTGCACTCTG AACTAAACCT GAGCTCTCTG GAGCTGGGGG 6301 ACTCAGCTTT GTATTTCTGT GCCAGCAGCC CCCGGACAGG CCTGAACACT GAAGCTTTCT 6361 TTGGACAAGG CACCAGACTC ACAGTTGTAG AGGACCTGAA CAAGGTGTTC CCACCCGAGG 6421 TCGCTGTGTT TGAGCCATCA GAAGCAGAGA TCTCCCACAC CCAAAAGGCC ACACTGGTGT 6481 GCCTGGCCAC AGGCTTCTTC CCCGACCACG TGGAGCTGAG CTGGTGGGTG A AT GGG A AGG 6541 AGGTGCACAG TGGGGTCAGC ACGGACCCGC AGCCCCTCAA GGAGCAGCCC GCCCTCAATG 6601 ACTCCAGATA CTGCCTGAGC AGCCGCCTGA GGGTCTCGGC CACCTTCTGG CAGAACCCCC 6661 GCA AC CACTT CCGCTGTCAA GTCCAGTTCT ACGGGCTCTC GGAGAATGAC GAGTGGACCC 6721 AGGATAGGGC CAAACCCGTC ACCCAGATCG TCAGCGCCGA GGCCTGGGGT AGAGCAGACT 6781 GTGGCTTTAC CTCGGTGTCC TACCAGCAAG GGGTCCTGTC TGCCACCATC CTCTATGAGA 6841 TCCTGCTAGG GAAGGCCACC CTGTATGCTG TGCTGGTCAG CGCCCTTGTG TTGATGGCCA 6901 TGGTCAAGAG AAAGGATTTC TGATAAGATA TCGAGCATCT TACCGCCATT TATACCCATA 6961 TTTGTTCTGT TTTTCTTGAT TTGGGTATAC ATTTAAATGT T A AT A A A AC A AAATGGTGGG 7021 GCAATCATTT ACATTTTTAG GGATATGTAA TTACTAGTTC AGGTGTATTG CCACAAGACA 7081 AACATGTTAA GAAACTTTCC CGTTATTTAC GCTCTGTTCC TGTTAATCAA CCTCTGGATT 7141 ACAAAATTTG TGAAAGATTG ACT GAT ATT C TTAACTATGT TGCTCCTTTT ACGCTGTGTG 7201 GATATGCTGC TTTATAGCCT CTGTATCTAG CTATTGCTTC CCGTACGGCT TTCGTTTTCT 7261 CCTCCTTGTA TAAATCCTGG TTGCTGTCTC TTTTAGAGGA GTTGTGGCCC GTTGTCCGTC 7321 AACGTGGCGT GGTGTGCTCT GTGTTTGCTG ACGCAACCCC CACTGGCTGG GGCATTGCCA 7381 CCACCTGTCA ACTCCTTTCT GGGACTTTCG CTTTCCCCCT CCCGATCGCC ACGGCAGAAC 7441 T CAT CGCCGC CTGCCTTGCC CGCTGCTGGA CAGGGGCTAG GTTGCTGGGC ACTGATAATT 7501 CCGTGGTGTT GTCAGTACTG GTACCTTTAA GACCAATGAC TTACAAGGCA GCTGTAGATC 7561 TTAGCCACTT TTT A A A AG A A AAGGGGGGAC TGGAAGGGCT A ATT C ACT CC CAAAGAAGAC 7621 AAGATCTGCT TTTTGCCTGT ACTGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC 7681 TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTTC 7741 AATGATCATA ATCAAGCCAT ATCACATCTG T AG AGGTTT A CTTGCTTTAA AAAACCTCCA 7801 CACCTCCCCC TGAACCTGAA AC AT A A A AT G AATGCAATTG TTGTTGTTAA CTTGTTTATT 7861 GC AGCTT AT A ATGGTTACAA ATAAAGCAAT AGCATCACAA ATTTCACAAA TAAAGCATTT 7921 TTTTCACTGC ATTCTAGTTG TGGTTTGTCC AAACTCATCA ATGTATCTTA TCATGTCTGG 7981 ATCTGCGTCG ACACGAAGAG ACGACTGACT GACTGACTGG AAAGAGGAAG GGCTGGAAGA 8041 GGAAGGAGCT T GAT CC AG AT CCCGATCTCG ATCCAGATCC GGATCGCAGC TTGGCGTAAT 8101 CATGGTCATA GCTGTTTCCT GTGTGAAATT GTTATCCGCT CACAATTCCA CACAACATAC 8161 GAGCCGGAAG CATAAAGTGT AAAGCCTGGG GTGCCTAATG AGTGAGCTAA CTCACATTAA 8221 TTGCGTTGCG CTCACTGCCC GCTTTCCAGT CGGGAAACCT GTCGTGCCAG CTGCATTAAT 8281 GAATCGGCCA ACGCGCGGGG AGAGGCGGTT TGCGTATTGG GCGCTCTTCC GCTTCCTCGC 8341 TCACTGACTC GCTGCGCTCG GTCGTTCGGC TGCGGCGAGC GGTATCAGCT CACTCAAAGG 8401 CGGTAATACG GTTATCCACA GAATCAGGGG ATAACGCAGG AAAGAACATG TGAGCAAAAG

8521 GCCCCCCTGA CGAGCATCAC A A A A AT CG AC GCTCAAGTCA GAGGTGGCGA AACCCGACAG 8581 GACTATAAAG ATACCAGGCG TTTCCCCCTG GAAGCTCCCT CGTGCGCTCT CCTGTTCCGA 8641 CCCTGCCGCT TACCGGATAC CTGTCCGCCT TTCTCCCTTC GGGAAGCGTG GCGCTTTCTC 8701 ATAGCTCACG CTGTAGGTAT CTCAGTTCGG TGTAGGTCGT TCGCTCCAAG CTGGGCTGTG 8761 TGCACGAACC CCCCGTTCAG CCCGACCGCT GCGCCTTATC CGGTAACTAT CGTCTTGAGT 8821 CCAACCCGGT AAGACACGAC TTATCGCCAC TGGCAGCAGC CACTGGTAAC AGGATTAGCA 8881 GAGCGAGGTA TGTAGGCGGT GCTACAGAGT TCTTGAAGTG GTGGCCTAAC TACGGCTACA 8941 CTAGAAGAAC AGTATTTGGT ATCTGCGCTC TGCTGAAGCC AGTTACCTTC GGAAAAAGAG 9001 TTGGTAGCTC TTGATCCGGC AAACAAACCA CCGCTGGTAG CGGTGGTTTT TTTGTTTGCA 9061 AGCAGCAGAT TACGCGCAGA AAAAAAGGAT CTCAAGAAGA TCCTTTGATC TTTTCTACGG 9121 GGTCTGACGC TCAGTGGAAC GAAAACTCAC GTTAAGGGAT TTTGGTCATG AGATTATCAA 9181 AAAGGATCTT CACCTAGATC CTTTTAAATT AAAAATGAAG TTTTAAATCA ATCTAAAGTA 9241 TATATGAGTA AACTTGGTCT GACAGTTACC AATGCTTAAT CAGTGAGGCA CCTATCTCAG 9301 CGATCTGTCT ATTTCGTTCA TCCATAGTTG CCTGACTCCC CGTCGTGTAG ATAACTACGA 9361 TACGGGAGGG CTTACCATCT GGCCCCAGTG CTGCAATGAT ACCGCAGCTT GGGAAACCAT 9421 AAGAGCTGAA GCCAGTTACC TT CGG A A A A A GAGTTGGTAG CTCTTGATCC GGCAAACAAA

9541 GATCTCAAGA AGATCCTTTG ATCTTTTCTA CGGGGTCTGA CGCTCAGTGG AACGAAAACT 9601 CACGTTAAGG GATTTTGGTC ATGAGCTTGC GCCGTCCCGT CAAGTCAGCG T AAT GCTCTG 9661 CCAGTGTTAC AA pLRPO FMC63-HAP 17(1-258) (SEQ ID NO:177)

1 ATATGAGTAA ACTTGGTCTG ACAGTTACCA ATGCTTAATC AGTGAGGCAC CTATCTCAGC 61 GATCTGTCTA TTTCGTTCAT CCATAGTTGC CTGACTCCCC GTCGTGTAGA T A ACT ACG AT 121 ACGGGAGGGC TTACCATCTG GCCCCAGTGC TGCAATGATA CCGCAGCTTG GGAAACCATA 181 AGAGCTGAAG CCAGTTACCT TCGGAAAAAG AGTTGGTAGC TCTTGATCCG GCAAACAAAC 241 CACCGCTGGT AGCGGTGGTT TTTTTGTTTG CAAGCAGCAG ATTACGCGCA GAAAAAAAGG 301 ATCTCAAGAA GATCCTTTGA TCTTTTCTAC GGGGTCTGAC GCTCAGTGGA ACGAAAACTC 361 ACGTTAAGGG ATTTTGGTCA TGAGCTTGCG CCGTCCCGTC AAGTCAGCGT A AT GCTCTGC 421 CAGTGTTACA ACCAATTAAC CAATTCTGAT T AG A A A A ACT CATCGAGCAT CAAATGAAAC

961 GGGATCGCAG TGGTGAGTAA CCATGCATCA TCAGGAGTAC GG AT A A A AT G CTTGATGGTC 1021 GGAAGAGGCA TAAATTCCGT CAGCCAGTTT AGTCTGACCA TCTCATCTGT AAC AT C ATT G 1081 GCAACGCTAC CTTTGCCATG TTTCAGAAAC AACTCTGGCG CATCGGGCTT CCCATACAAG 1141 CGATAGATTG TCGCACCTGA TTGCCCGACA TTATCGCGAG CCCATTTATA CCCATATAAA 1201 TCAGCATCCA TGTTGGAATT TAATCGCGGC CTCGACGTTT CCCGTTGAAT ATGGCTCATA 1261 ACACCCCTTG TATTACTGTT TATGTAAGCA GACAGTTTTA TTGTTCATGA TGATATATTT 1321 TTATCTTGTG CAATGT AAC A TCAGAGATTT TGAGACACAA CGTGGCTTTC CCCCCCCCCC 1381 CCATGACATT AACCTATAAA AATAGGCGTA TCACGAGGCC AGCTTGGGAA ACCATAAGAC 1441 CGAGATAGAG TTGAGTGTTG TTCCAGTTTG GAACAAGAGT CC ACT ATT A A AGAACGTGGA 1501 CTCCAACGTC AAAGGGCGAA AAACCGTCTA TCAGGGCGAT GGCCCACTAC GTGAACCATC

1621 GAGCCCCCGA TTTAGAGCTT GACGGGGAAA GCCGGCGAAC GTGGCGAGAA AGGAAGGGAA 1681 GAAAGCGAAA GGAGCGGGCG CTAAGGCGCT GGCAAGTGTA GCGGTCACGC TGCGCGTAAC 1741 CACCACACCC GCCGCGCTTA ATGCGCCGCT ACAGGGCGCG TACTATGGTT GCTTTGACGT 1801 ATGCGGTGTG AAATACCGCA CAGATGCGTA AGGAGAAAAT ACCGCATCAG GCGCCATTCG 1861 CCATTCAGGC TGCGCAACTG TTGGGAAGGG CGATCGGTGC GGGCCTCTTC GCTATTACGC 1921 CAGCTGGCGA A AGGGGG AT G TGCTGCAAGG CGATTAAGTT GGGTAACGCC AGGGTTTTCC 1981 CAGTCACGAC GTTGTAAAAC GACGGCCAGT GAATTGATCG AGATCGTGAT CCGGATCAAG 2041 ATCCAGATCG AATTGGAGGC TACAGTCAGT GGAGAGGACT TTCACTGACT GACTGACTGC 2101 GTCTCAACCT CCTAGGGGAC ATTGATTATT G ACT AGTT AT T A AT AGT A AT CAATTACGGG 2161 GTC ATT AGTT CATAGCCCAT AT AT GG AGTT CCGCGTTACA TAACTTACGG TAAATGGCCC 2221 GCCTGGCTGA CCGCCCAACG ACCCCCGCCC ATTGACGTCA AT A AT G ACGT ATGTTCCCAT 2281 AGTAACGCCA ATAGGGACTT TCCATTGACG TCAATGGGTG GAGTATTTAC GGTAAACTGC 2341 CCACTTGGCA GTACATCAAG TGTATCATAT GCCAAGTACG CCCCCTATTG ACGTCAATGA 2401 CGGTAAATGG CCCGCCTGGC ATTATGCCCA GTACATGACC TT AT GGG ACT TTCCTACTTG 2461 GCAGTACATC T ACGT ATT AG TCATCGCTAT TACCATGGTG ATGCGGTTTT GGCAGTACAT 2521 CAATGGGCGT GGATAGCGGT TTGACTCACG GGGATTTCCA AGTCTCCACC CCATTGACGT 2581 CAATGGGAGT TTGTTTTGGC ACCAAAATCA ACGGGACTTT CCAAAATGTC GTAACAACTC 2641 CGCCCCATTG ACGCAAATGG GCGGTAGGCG TGTACGGTGG GAGGTCTATA TAAGCAGAGC 2701 TCGTTTAGTG AACCGGGTCT CTCTGGTTAG ACCAGATCTG AGCCTGGGAG CTCTCTGGCT 2761 AACTAGGGAA CCCACTGCTT AAGCCTCAAT AAAGCTTGCC TTGAGTGCTC AAAGTAGTGT 2821 GTGCCCGTCT GTTGTGTGAC TCTGGTAACT AGAGATCCCT CAGACCCTTT T AGT C AGT GT 2881 GGAAAATCTC TAGCAGTGGC GCCCGAACAG GGACTTGAAA GCGAAAGTAA AGCCAGAGGA 2941 GATCTCTCGA CGCAGGACTC GGCTTGCTGA AGCGCGCACG GCAAGAGGCG AGGGGCGGCG 3001 ACTGGTGAGT ACGCCAAAAA TTTTGACTAG CGGAGGCTAG AAGGAGAGAG TAGGGTGCGA 3061 GAGCGTCGGT ATTAAGCGGG GGAGAATTAG ATAAATGGGA AAAAATTCGG TTAAGGCCAG 3121 GGGGAAAGAA ACAATATAAA CTAAAACATA TAGTTAGGGC AAGCAGGGAG CTAGAACGAT 3181 TCGCAGTTAA TCCTGGCCTT TT AG AG AC AT CAGAAGGCTG T AG AC A A AT A CTGGGACAGC 3241 TACAACCATC CCTTCAGACA GGATCAGAAG AACTTAGATC ATTATATAAT ACAATAGCAG 3301 TCCTCTATTG TGTGCATCAA AGG AT AG AT G T A A A AGAC AC CAAGGAAGCC TT AG AT A AG A 3361 TAGAGGAAGA GCAAAACAAA AGTAAGAAAA AGGCACAGCA AGCGATCTTC AGACCTGGAG 3421 GAGGCAGGAG GCGATATGAG GGACAATTGG AG A AGT G A AT TAT AT A A AT A TAAAGTAGTA 3481 AAAATTGAAC CATTAGGAGT AGCACCCACC AAGGCAAAGA GAAGAGTGGT GCAGAGAGAA 3541 AAAAGAGCAG TGGGAATAGG AGCTTTGTTC CTTGGGTTCT TGGGAGCAGC AGGAAGCACT 3601 ATGGGCGCAG CGTCAATGAC GCTGACGGTA CAGGCCAGAC AATTATTGTC T GAT AT AGT G 3661 CAGCAGCAGA ACAATTTGCT GAGGGCTATT GAGGCGCAAC AGCATCTGTT GCAACTCACA 3721 GTCTGGGGCA TCAAACAGCT CCAGGCAAGA ATCCTGGCTG TGGAAAGATA CCTAAAGGAT 3781 CAACAGCTCC TGGGGATTTG GGGTTGCTCT GGAAAACTCA TTTGCACCAC TGCTGTGCCT 3841 TGGAATGCTA GTTGGAGTAA TAAATCTCTG GAACAGATTT GGAATAACAT GACCTGGATG 3901 GAGTGGGACA GAG A A ATT A A CAATTACACA AGCTTAATAC ACTCCTTAAT TGAAGAATCG 3961 CAAAACCAGC AAGAAAAGAA T G A AC A AG A A TTATTGGAAT T AG AT A A AT G GGCAAGTTTG 4021 TGGAATTGGT TTAACATAAC AAATTGGCTG TGGTATATAA AATTATTCAT AATGATAGTA 4081 GGAGGCTTGG T AGGTTT A AG A AT AGTTTTT GCTGTACTTT CTATAGTGAA TAGAGTTAGG 4141 CAGGGATATT C ACC ATT AT C GTTTCAGACC CACCTCCCAA TCCCGAGGGG ACCACGCGTA 4201 CAAATGGCAG TATTCATCCA CAATTTTAAA AGAAAAGGGG GGATTGGGGG GTACAGTGCA 4261 GGGGAAAGAA TAGTAGACAT AATAGCAACA GACATACAAA CT A A AG A ATT ACAAAAACAA 4321 ATT AC A A A A A TTCAAAATTT TCGGGTTTAT TACAGGGACA GCAGAAATCC ACTTTGGAAA 4381 GCTGAGCATC CGGCTCCGGT GCCCGTCAGT GGGCAGAGCG CACATCGCCC ACAGTCCCCG 4441 AGAAGTTGGG GGGAGGGGTC GGCAATTGAA CCGGTGCCTA GAGAAGGTGG CGCGGGGTAA 4501 ACTGGGAAAG TGATGTCGTG TACTGGCTCC GCCTTTTTCC CGAGGGTGGG GGAGAACCGT 4561 ATATAAGTGC AGTAGTCGCC GTGAACGTTC TTTTTCGCAA CGGGTTTGCC GCCAGAACAC 4621 AGGTAAGTGC CGTGTGTGGT TCCCGCGGGC CTGGCCTCTT TACGGGTTAT GGCCCTTGCG 4681 TGCCTTGAAT TACTTCCACG CCCCTGGCTG CAGTACGTGA TTCTTGATCC CGAGCTTCGG 4741 GTTGGAAGTG GGTGGGAGAG TTCGAGGCCT TGCGCTTAAG GAGCCCCTTC GCCTCGTGCT 4801 TGAGTTGAGG CCTGGCCTGG GCGCTGGGGC CGCCGCGTGC GAATCTGGTG GCACCTTCGC 4861 GCCTGTCTCG CTGCTTTCGA TAAGTCTCTA GCCATTTAAA ATTTTTGATG ACCTGCTGCG

4981 TCGGTTTTTG GGGCCGCGGG CGGCGACGGG GCCCGTGCGT CCCAGCGCAC ATGTTCGGCG 5041 AGGCGGGGCC TGCGAGCGCG GCCACCGAGA ATCGGACGGG GGTAGTCTCA AGCTGGCCGG 5101 CCTGCTCTGG TGCCTGGCCT CGCGCCGCCG TGTATCGCCC CGCCCTGGGC GGCAAGGCTG 5161 GCCCGGTCGG CACCAGTTGC GTGAGCGGAA AGATGGCCGC TTCCCGGCCC TGCTGCAGGG 5221 AGCTCAAAAT GGAGGACGCG GCGCTCGGGA GAGCGGGCGG GTGAGTCACC CACACAAAGG 5281 AAAAGGGCCT TTCCGTCCTC AGCCGTCGCT T CAT GT G ACT CCACGGAGTA CCGGGCGCCG 5341 TCCAGGCACC TCGATTAGTT CTCGAGCTTT TGGAGTACGT CGTCTTTAGG TTGGGGGGAG 5401 GGGTTTTATG CGATGGAGTT TCCCCACACT GAGTGGGTGG AGACTGAAGT TAGGCCAGCT 5461 TGGCACTTGA TGTAATTCTC CTTGGAATTT GCCCTTTTTG AGTTTGGATC TTGGTTCATT 5521 CTCAAGCCTC AGACAGTGGT TCAAAGTTTT TTTCTTCCAT TTCAGGTGTC GTGAAAACTA 5581 CCCCTCTAGA GCCGCCACCA TGCTTCTCCT GGTGACAAGC CTTCTGCTCT GTGAGTTACC 5641 ACACCCAGCA TTCCTCCTGA TCCCAGACAT CCAGATGACA CAGACTACAT CCTCCCTGTC 5701 TGCCTCTCTG GGAGACAGAG TCACCATCAG TTGCAGGGCA AGTCAGGACA TTAGTAAATA 5761 TTTAAATTGG TATCAGCAGA A ACC AG AT GG A ACT GTT AAA CTCCTGATCT ACCATACATC 5821 AAGATTACAC TCAGGAGTCC CATCAAGGTT CAGTGGCAGT GGGTCTGGAA CAGATTATTC 5881 TCTCACCATT AGCAACCTGG AGCAAGAAGA TATTGCCACT TACTTTTGCC A AC AGGGT A A 5941 TACGCTTCCG TACACGTTCG GAGGGGGGAC TAAGTTGGAA ATAACAGGCT CCACCTCTGG 6001 ATCCGGCAAG CCCGGATCTG GCGAGGGATC CACCAAGGGC GAGGTGAAAC TGCAGGAGTC 6061 AGGACCTGGC CTGGTGGCGC CCTCACAGAG CCTGTCCGTC ACATGCACTG TCTCAGGGGT 6121 CTCATTACCC GACTATGGTG TAAGCTGGAT TCGCCAGCCT CCACGAAAGG GTCTGGAGTG 6181 GCTGGGAGTA ATATGGGGTA GTGAAACCAC AT ACT AT A AT TCAGCTCTCA AATCCAGACT 6241 GACCATCATC AAGGACAACT CCAAGAGCCA AGTTTTCTTA A A A AT G A AC A GTCTGCAAAC 6301 TGATGACACA GCCATTTACT ACTGTGCCAA ACATTATTAC TACGGTGGTA GCTATGCTAT 6361 GGACTACTGG GGTCAAGGAA CCTCAGTCAC CGTCTCCTCA GCGGCCGCAG GTGGAGGAGG 6421 TTCTGGAGGT GGTGGATCAG GTGGTGGAGG ATCTCTAGAA GT G A AT GG AG AGAATGTGGA 6481 GCAGCATCCT TCAACCCTGA GTGTCCAGGA GGGAGACAGC GCTGTTATCA AGTGTACTTA 6541 TTCAGACAGT GCCTCAAACT ACTTCCCTTG GTATAAGCAA GAACTTGGAA AAAGACCTCA 6601 GCTTATTATA GACATTCGTT CAAATGTGGG CGAAAAGAAA GACCAACGAA TTGCTGTTAC 6661 ATTGAACAAG ACAGCCAAAC ATTTCTCCCT GCACATCACA GAGACCCAAC CTGAAGACTC 6721 GGCTGTCTAC TTCTGTGCAG CAAGTAGGAA GGACTCTGGG GGTTACCAGA AAGTT ACCTT 6781 TGGAACTGGA ACAAAGCTCC AAGTCATCCC AAATATCCAG AACCCTGACC CTGCCGTGTA 6841 CCAGCTGAGA G ACT CT AA AT CCAGTGACAA GTCTGTCTGC CTATTCACCG ATTTTGATTC 6901 T CA A AC A A AT GTGTCACAAA GTAAGGATTC TGATGTGTAT ATCACAGACA AAACTGTGCT 6961 AGACATGAGG TCTATGGACT TCAAGAGCAA CAGTGCTGTG GCCTGGAGCA ACAAATCTGA 7021 CTTTGCATGT GCAAACGCCT TCAACAACAG CATTATTCCA GAAGACACCT TCTTCCCCAG 7081 CCCAGAAAGT TCCTGTGATG TCAAGCTGGT CGAGAAAAGC TTTGAAACAG ATACGAACCT 7141 AAACTTTCAA AACCTGTCAG TGATTGGGTT CCGAATCCTC CTCCTGAAAG TGGCCGGGTT 7201 TAATCTGCTC ATGACGCTGC GGCTGTGGTC CAGCTGATAA GATATCGAGC ATCTTACCGC 7261 CATTTATACC CATATTTGTT CTGTTTTTCT TGATTTGGGT ATACATTTAA ATGTTAATAA 7321 AACAAAATGG TGGGGCAATC ATTTACATTT TTAGGGATAT GT A ATT ACTA GTTCAGGTGT 7381 ATTGCCACAA GACAAACATG TTAAGAAACT TTCCCGTTAT TTACGCTCTG TTCCTGTTAA 7441 TCAACCTCTG GATT AC A A A A TTTGTGAAAG ATT GACT GAT ATTCTTAACT ATGTTGCTCC 7501 TTTTACGCTG TGTGGATATG CTGCTTTATA GCCTCTGTAT CTAGCTATTG CTTCCCGTAC 7561 GGCTTTCGTT TTCTCCTCCT TGTATAAATC CTGGTTGCTG TCTCTTTTAG AGGAGTTGTG 7621 GCCCGTTGTC CGTCAACGTG GCGTGGTGTG CTCTGTGTTT GCTGACGCAA CCCCCACTGG 7681 CTGGGGCATT GCCACCACCT GTCAACTCCT TTCTGGGACT TTCGCTTTCC CCCTCCCGAT 7741 CGCCACGGCA GAACTCATCG CCGCCTGCCT TGCCCGCTGC TGGACAGGGG CTAGGTTGCT 7801 GGGCACTGAT AATTCCGTGG TGTTGTCAGT ACTGGTACCT TTAAGACCAA TGACTTACAA 7861 GGCAGCTGTA GATCTTAGCC ACTTTTTAAA AGAAAAGGGG GGACTGGAAG GGCTAATTCA 7921 CTCCCAAAGA AGACAAGATC TGCTTTTTGC CTGTACTGGG TCTCTCTGGT TAGACCAGAT 7981 CTGAGCCTGG GAGCTCTCTG GCTAACTAGG GAACCCACTG CTTAAGCCTC AATAAAGCTT 8041 GCCTTGAGTG CTTCAATGAT CATAATCAAG CCATATCACA TCTGTAGAGG TTTACTTGCT 8101 TTAAAAAACC TCCACACCTC CCCCTGAACC T G A A AC AT A A AATGAATGCA ATTGTTGTTG 8161 TTAACTTGTT TATTGCAGCT TATAATGGTT ACAAATAAAG CAATAGCATC ACAAATTTCA

8281 CTTATCATGT CTGGATCTGC GTCGACACGA AGAGACGACT GACTGACTGA CTGGAAAGAG 8341 GAAGGGCTGG AAGAGGAAGG AGCTTGATCC AGATCCCGAT CTCGATCCAG ATCCGGATCG 8401 CAGCTTGGCG T A AT CAT GGT CAT AGCT GTT TCCTGTGTGA AATTGTTATC CGCTCACAAT 8461 TCCACACAAC ATACGAGCCG GAAGCATAAA GTGTAAAGCC TGGGGTGCCT AATGAGTGAG 8521 CTAACTCACA TTAATTGCGT TGCGCTCACT GCCCGCTTTC CAGTCGGGAA ACCTGTCGTG 8581 CCAGCTGCAT TAATGAATCG GCCAACGCGC GGGGAGAGGC GGTTTGCGTA TTGGGCGCTC 8641 TTCCGCTTCC TCGCTCACTG ACTCGCTGCG CTCGGTCGTT CGGCTGCGGC GAGCGGTATC 8701 AGCTC ACT CA AAGGCGGT AA TACGGTTATC CACAGAATCA GGGGATAACG CAGGAAAGAA 8761 CATGTGAGCA AAAGGCCAGC AAAAGGCCAG GAACCGTAAA AAGGCCGCGT TGCTGGCGTT 8821 TTTCCATAGG CTCCGCCCCC CTGACGAGCA TC AC AAA A AT CGACGCTCAA GTCAGAGGTG 8881 GCGAAACCCG ACAGGACTAT A A AG AT ACC A GGCGTTTCCC CCTGGAAGCT CCCTCGTGCG 8941 CTCTCCTGTT CCGACCCTGC CGCTTACCGG ATACCTGTCC GCCTTTCTCC CTTCGGGAAG 9001 CGTGGCGCTT TCTCATAGCT CACGCTGTAG GTATCTCAGT TCGGTGTAGG TCGTTCGCTC 9061 CAAGCTGGGC TGTGTGCACG AACCCCCCGT TCAGCCCGAC CGCTGCGCCT TATCCGGTAA 9121 CTATCGTCTT GAGTCCAACC CGGTAAGACA CGACTTATCG CCACTGGCAG CAGCCACTGG 9181 T AAC AGG ATT AGCAGAGCGA GGTATGTAGG CGGTGCTACA GAGTTCTTGA AGTGGTGGCC 9241 TAACTACGGC TACACTAGAA GAACAGTATT TGGTATCTGC GCTCTGCTGA AGCCAGTTAC 9301 CTTCGGAAAA AGAGTTGGTA GCTCTTGATC CGGCAAACAA ACCACCGCTG GTAGCGGTGG 9361 TTTTTTTGTT TGCAAGCAGC AGATTACGCG CAGAAAAAAA GGATCTCAAG AAGATCCTTT 9421 GATCTTTTCT ACGGGGTCTG ACGCTCAGTG GAACGAAAAC TCACGTTAAG GGATTTTGGT 9481 CATGAGATTA T C A A A A AGG A TCTTCACCTA GATCCTTTTA A ATT AAA A AT G A AGTTTT AA 9541 ATCAATCTAA AGTAT pLRPO FMC63-HAP 17(35-258) (SEQ ID NO: 178)

1 TATGAGT AAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 61 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTGTAGAT AACTACGATA 121 CGGGAGGGCT TACCATCTGG CCCCAGTGCT GCAATGATAC CGCAGCTTGG G A A ACC AT A A 181 GAGCTGAAGC CAGTTACCTT CGGAAAAAGA GTTGGTAGCT CTTGATCCGG CAAACAAACC 241 ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC AAGCAGCAGA TTACGCGCAG AAAAAAAGGA 301 TCTCAAGAAG ATCCTTTGAT CTTTTCTACG GGGTCTGACG CTCAGTGGAA CGAAAACTCA 361 CGTTAAGGGA TTTTGGTCAT GAGCTTGCGC CGTCCCGTCA AGTCAGCGTA ATGCTCTGCC 421 AGTGTTACAA CCAATTAACC A ATT CT GATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT

961 GGATCGCAGT GGTGAGTAAC CATGCATCAT CAGGAGTACG GATAAAATGC TTGATGGTCG 1021 GAAGAGGCAT AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG 1081 CAACGCTACC TTTGCCATGT TT C AG A A AC A ACTCTGGCGC ATCGGGCTTC CCATACAAGC 1141 GATAGATTGT CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT 1201 CAGCATCCAT GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTT GA AT A TGGCT CAT A A 1261 CACCCCTTGT ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT 1321 TATCTTGTGC A AT GT A AC AT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC 1381 CATGACATTA ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC 1441 GAGATAGAGT TGAGTGTTGT TCCAGTTTGG AACAAGAGTC CACTATTAAA GAACGTGGAC 1501 TCCAACGTCA AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA 1561 CCCAAATCAA GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG 1621 AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAG 1681 AAAGCGAAAG GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC 1741 ACCACACCCG CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACTATGGTTG CTTTGACGTA 1801 TGCGGTGTGA AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC 1861 C ATT C AGGCT GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC 1921 AGCTGGCGAA AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC 1981 AGTCACGACG TTGT AAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA 2041 TCCAGATCGA ATTGGAGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG 2101 TCTCAACCTC CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG 2161 TCATTAGTTC ATAGCCCATA TATGGAGTTC CGCGTT AC AT A ACTT ACGGT AAATGGCCCG 2221 CCTGGCTGAC CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA 2281 GTAACGCCAA TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC 2341 CACTTGGCAG TACATCAAGT GTATCATATG CCAAGTACGC CCCCTATTGA CGTCAATGAC 2401 GGTAAATGGC CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG 2461 CAGTACATCT ACGTATTAGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC 2521 AATGGGCGTG GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC 2581 AATGGGAGTT TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC 2641 GCCCCATTGA CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT 2701 CGTTTAGTGA ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA 2761 ACT AGGGAAC CCACTGCTTA AGCCTC AAT A AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG 2821 TGCCCGTCTG TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG 2881 GAAAATCTCT AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG 2941 ATCTCTCGAC GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA 3001 CTGGTGAGTA CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG 3061 AGCGTCGGTA TTAAGCGGGG GAGAATTAGA T A A AT GGG A A AAAATTCGGT TAAGGCCAGG 3121 GGGAAAGAAA CAATATAAAC TAAAACATAT AGTTAGGGCA AGCAGGGAGC TAGAACGATT 3181 CGCAGTTAAT CCTGGCCTTT T AG AG AC AT C AGAAGGCTGT AG AC A AAT AC TGGGACAGCT 3241 ACAACCATCC CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT A AT A CAATAGCAGT 3301 CCTCTATTGT GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT 3361 AGAGGAAGAG CAAAACAAAA GT A AG A A A A A GGCACAGCAA GCGATCTTCAGACCTGGAGG 3421 AGGCAGGAGG CGATATGAGG GACAATTGGA GAAGTGAATT AT AT A A AT AT AAAGTAGTAA 3481 AAATTGAACC ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGT GGTG CAGAGAGAAA 3541 AAAGAGCAGT GGGAATAGGA GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GGAAGCACTA 3601 TGGGCGCAGC GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC 3661 AGCAGCAGAA CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG C A ACT C AC AG 3721 TCTGGGGCAT CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GGAAAGATAC CTAAAGGATC 3781 AACAGCTCCT GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT 3841 GGAATGCTAG TTGGAGTAAT AAATCTCTGG A AC AGATTT G G A AT A AC AT G ACCTGGATGG 3901 AGTGGGACAG AG AA ATT A AC A ATT AC AC A A GCTTAATACA CTCCTTAATT GAAGAATCGC 3961 AAAACCAGCA AGAAAAGAAT GAACAAGAAT TATTGGAATT AG AT A A AT GG GCAAGTTTGT 4021 GGAATTGGTT TAACATAACA AATTGGCTGT GGT AT AT AAA ATTATTCATA ATGATAGTAG 4081 GAGGCTTGGT AGGTTTAAGA ATAGTTTTTG CTGTACTTTC TATAGTGAAT AGAGTTAGGC 4141 AGGGATATTC ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC 4201 AAATGGCAGT ATTCATCCAC AATTTTAAAA GAAAAGGGGG GATTGGGGGG TACAGTGCAG 4261 GGGAAAGAAT AGTAGACATA ATAGCAACAG AC AT AC A A AC T A A AG A ATT A CAAAAACAAA 4321 TT AC A A A A AT T C A A A ATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG 4381 CTGAGCATCC GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA 4441 GAAGTTGGGG GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA 4501 CTGGGAAAGT GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG GAGAACCGTA 4561 TATAAGTGCA GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA 4621 GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT 4681 GCCTTGAATT ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG 4741 TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT 4801 GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG 4861 CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA

5041 GGCGGGGCCT GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC 5101 CTGCTCTGGT GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG 5161 CCCGGTCGGC ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA 5221 GCTCAAAATG GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA 5281 AAAGGGCCTT TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT 5341 CCAGGCACCT CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT T GGGGGG AGG 5401 GGTTTTATGC GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT 5461 GGCACTTGAT GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC 5521 TCAAGCCTCA GACAGTGGTT CAAAGTTTTT TTCTTCCATT TCAGGTGTCG T G A A A ACT AC 5581 CCCTCTAGAG CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA 5641 CACCCAGCAT TCCTCCTGAT CCCAGACATC CAGATGACAC AGACTACATC CTCCCTGTCT 5701 GCCTCTCTGG GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT TAGTAAATAT 5761 TTAAATTGGT ATCAGCAGAA ACCAGATGGA ACTGTTAAAC TCCTGATCTA CCATACATCA 5821 AGATTACACT CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AGATTATTCT 5881 CTCACCATTA GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA ACAGGGTAAT 5941 ACGCTTCCGT ACACGTTCGG AGGGGGGACT AAGTT GG A A A TAACAGGCTC CACCTCTGGA 6001 TCCGGCAAGC CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA 6061 GGACCTGGCC TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CATGCACTGT CTCAGGGGTC 6121 TCATTACCCG ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG 6181 CTGGGAGTAA TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG 6241 ACCATCATCA AGGACAACTC CAAGAGCCAA GTTTTCTTAA AAATGAACAG TCTGCAAACT 6301 GATGACACAG CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG 6361 GACTACTGGG GTCAAGGAAC CTCAGTCACC GTCTCCTCAG CGGCCGCAGG TGGAGGAGGT 6421 TCTGGAGGTG GTGGATCAGG TGGTGGAGGA TCTCTAGAAG AAAAGAAAGA CCAACGAATT 6481 GCTGTTACAT TGAACAAGAC AGCCAAACAT TTCTCCCTGC ACATCACAGA GACCCAACCT 6541 GAAGACTCGG CTGTCTACTT CTGTGCAGCA AGTAGGAAGG ACTCTGGGGG TTACCAGAAA 6601 GTTACCTTTG GAACTGGAAC AAAGCTCCAA GTCATCCCAA ATATCCAGAA CCCTGACCCT 6661 GCCGTGTACC AGCTGAGAGA CTCTAAATCC AGTGACAAGT CTGTCTGCCT ATTCACCGAT 6721 TTTGATTCTC AAACAAATGT GTCACAAAGT AAGGATTCTG ATGTGTATAT CACAGACAAA 6781 ACTGTGCTAG ACATGAGGTC TATGGACTTC AAGAGCAACA GTGCTGTGGC CTGGAGCAAC 6841 AAATCTGACT TTGCATGTGC AAACGCCTTC AACAACAGCA TTATTCCAGA AGACACCTTC 6901 TTCCCCAGCC CAGAAAGTTC CTGTGATGTC AAGCTGGTCG AGAAAAGCTT TG A A AC AG AT 6961 ACGAACCTAA ACTTTCAAAA CCTGTCAGTG ATTGGGTTCC GAATCCTCCT CCTGAAAGTG 7021 GCCGGGTTTA ATCTGCTCAT GACGCTGCGG CTGTGGTCCA GCTGATAAGA TATCGAGCAT 7081 CTTACCGCCA TTTATACCCA TATTTGTTCT GTTTTTCTTG ATTT GGGTAT AC ATTT A A AT 7141 GTT A AT A A A A CAAAATGGTG GGGCAATCAT TTACATTTTT AGGGATATGT AATTACTAGT 7201 TCAGGTGTAT TGCCACAAGA CAAACATGTT AAGAAACTTT CCCGTTATTT ACGCTCTGTT 7261 CCTGTTAATC AACCTCTGGA TTACAAAATT TGTGAAAGAT TG ACT GAT AT TCTTAACTAT 7321 GTTGCTCCTT TTACGCTGTG TGGATATGCT GCTTTATAGC CTCTGTATCT AGCTATTGCT 7381 TCCCGTACGG CTTTCGTTTT CTCCTCCTTG TATAAATCCT GGTTGCTGTC TCTTTTAGAG 7441 GAGTTGTGGC CCGTTGTCCG TCAACGTGGC GTGGTGTGCT CTGTGTTTGC TGACGCAACC 7501 CCCACTGGCT GGGGCATTGC CACCACCTGT CAACTCCTTT CTGGGACTTT CGCTTTCCCC 7561 CTCCCGATCG CCACGGCAGA ACTCATCGCC GCCTGCCTTG CCCGCTGCTG GACAGGGGCT 7621 AGGTTGCTGG GCACTGATAA TTCCGTGGTG TTGTCAGTAC TGGTACCTTT AAGACCAATG 7681 ACTTACAAGG CAGCTGTAGA TCTTAGCCAC TTTTT AAA AG AAAAGGGGGG ACT GG A AGGG

8101 CAATGTATCT TATCATGTCT GGATCTGCGT CGACACGAAG AGACGACTGA CTGACTGACT 8161 GGAAAGAGGA AGGGCTGGAA GAGGAAGGAG CTTGATCCAG ATCCCGATCT CGATCCAGAT 8221 CCGGATCGCA GCTTGGCGTA ATCATGGTCA TAGCTGTTTC CTGTGTGAAA TTGTTATCCG 8281 CTCACAATTC CACACAACAT ACGAGCCGGA AGC AT A A AGT GTAAAGCCTG GGGTGCCTAA 8341 TGAGTGAGCT AACTCACATT AATTGCGTTG CGCTCACTGC CCGCTTTCCA GTCGGGAAAC 8401 CTGTCGTGCC AGCTGCATTA ATGAATCGGC CAACGCGCGG GGAGAGGCGG TTTGCGTATT 8461 GGGCGCTCTT CCGCTTCCTC GCTCACTGAC TCGCTGCGCT CGGTCGTTCG GCTGCGGCGA 8521 GCGGTATCAG CTCACTCAAA GGCGGTAATA CGGTTATCCA CAGAATCAGG GGATAACGCA 8581 GGAAAGAACA TGTGAGCAAA AGGCCAGCAA AAGGCCAGGA ACCGT AAAAA GGCCGCGTTG 8641 CTGGCGTTTT TCCATAGGCT CCGCCCCCCT GACGAGCATC ACAAAAATCG ACGCTCAAGT 8701 CAGAGGTGGC GAAACCCGAC AGGACTATAA AGATACCAGG CGTTTCCCCC TGGAAGCTCC 8761 CTCGTGCGCT CTCCTGTTCC GACCCTGCCG CTT ACCGGAT ACCTGTCCGC CTTTCTCCCT 8821 TCGGGAAGCG TGGCGCTTTC TCATAGCTCA CGCTGTAGGT ATCTCAGTTC GGTGTAGGTC 8881 GTTCGCTCCA AGCTGGGCTG TGTGCACGAA CCCCCCGTTC AGCCCGACCG CTGCGCCTTA 8941 TCCGGTAACT ATCGTCTTGA GTCCAACCCG GT A AG AC ACG ACTTATCGCC ACTGGCAGCA 9001 GCCACTGGTA ACAGGATTAG CAGAGCGAGG TATGTAGGCG GTGCTACAGA GTTCTTGAAG 9061 TGGTGGCCTA ACTACGGCTA CACTAGAAGA ACAGTATTTG GTATCTGCGC TCTGCTGAAG 9121 CCAGTTACCT TCGGAAAAAG AGTTGGTAGC TCTTGATCCG GCAAACAAAC CACCGCTGGT 9181 AGCGGTGGTT TTTTTGTTTG CAAGCAGCAG ATTACGCGCA GAAAAAAAGG ATCTCAAGAA 9241 GATCCTTTGA TCTTTTCTAC GGGGTCTGAC GCTCAGTGGA ACGAAAACTC ACGTTAAGGG 9301 ATTTTGGTCA TGAGATTATC AAAAAGGATC TTCACCTAGA TCCTTTTAAA TT A A A A AT G A 9361 AGTTTT A A AT C A AT CT A A AG TATA pLRPO FMC63-HAP 17(79-258) (SEQ ID NO: 179)

961 GGGATCGCAG TGGTGAGTAA CCATGCATCA TCAGGAGTAC GG AT A A A AT G CTTGATGGTC 1021 GGAAGAGGCA TAAATTCCGT CAGCCAGTTT AGTCTGACCA TCTCATCTGT AACATCATTG 1081 GCAACGCTAC CTTTGCCATG TTTCAGAAAC AACTCTGGCG CATCGGGCTT CCCATACAAG 1141 CGATAGATTG TCGCACCTGA TTGCCCGACA TTATCGCGAG CCCATTTATA CCCATATAAA 1201 TCAGCATCCA TGTTGGAATT TAATCGCGGC CTCGACGTTT CCCGTTGAAT ATGGCTCATA 1261 ACACCCCTTG TATTACTGTT TATGTAAGCA GACAGTTTTA TTGTTCATGA TGATATATTT 1321 TTATCTTGTG CAATGT AAC A TCAGAGATTT TGAGACACAA CGTGGCTTTC CCCCCCCCCC 1381 CCATGACATT AACCTATAAA AATAGGCGTA TCACGAGGCC AGCTTGGGAA ACCATAAGAC 1441 CGAGATAGAG TTGAGTGTTG TTCC AGTTT G GAACAAGAGT CC ACT ATT A A AGAACGTGGA 1501 CTCCAACGTC AAAGGGCGAA AAACCGTCTA TCAGGGCGAT GGCCCACTAC GTGAACCATC

1621 GAGCCCCCGA TTTAGAGCTT GACGGGGAAA GCCGGCGAAC GTGGCGAGAA AGGAAGGGAA 1681 GAAAGCGAAA GGAGCGGGCG CTAAGGCGCT GGCAAGTGTA GCGGTCACGC TGCGCGTAAC 1741 CACCACACCC GCCGCGCTTA ATGCGCCGCT ACAGGGCGCG TACTATGGTT GCTTTGACGT 1801 ATGCGGTGTG AAATACCGCA CAGATGCGTA AGGAGAAAAT ACCGCATCAG GCGCCATTCG 1861 CCATTCAGGC TGCGCAACTG TTGGGAAGGG CGATCGGTGC GGGCCTCTTC GCTATTACGC 1921 CAGCTGGCGA A AGGGGG AT G TGCTGCAAGG CGATTAAGTT GGGTAACGCC AGGGTTTTCC 1981 CAGTCACGAC GTTGTAAAAC GACGGCCAGT GAATTGATCG AGATCGTGAT CCGGATCAAG 2041 ATCCAGATCG AATTGGAGGC TACAGTCAGT GGAGAGGACT TTCACTGACT GACTGACTGC 2101 GTCTCAACCT CCTAGGGGAC ATTGATTATT G ACT AGTT AT T A AT AGT A AT CAATTACGGG 2161 GTC ATT AGTT CATAGCCCAT AT AT GG AGTT CCGCGTTACA TAACTTACGG TAAATGGCCC 2221 GCCTGGCTGA CCGCCCAACG ACCCCCGCCC ATTGACGTCA AT A AT G ACGT ATGTTCCCAT 2281 AGTAACGCCA ATAGGGACTT TCCATTGACG TCAATGGGTG GAGTATTTAC GGTAAACTGC 2341 CCACTTGGCA GTACATCAAG TGTATCATAT GCCAAGTACG CCCCCTATTG ACGTCAATGA 2401 CGGTAAATGG CCCGCCTGGC ATTATGCCCA GTACATGACC TT AT GGG ACT TTCCTACTTG 2461 GCAGTACATC T ACGT ATT AG TCATCGCTAT TACCATGGTG ATGCGGTTTT GGCAGTACAT 2521 CAATGGGCGT GGATAGCGGT TTGACTCACG GGGATTTCCA AGTCTCCACC CCATTGACGT 2581 CAATGGGAGT TTGTTTTGGC ACCAAAATCA ACGGGACTTT CCAAAATGTC GTAACAACTC 2641 CGCCCCATTG ACGCAAATGG GCGGTAGGCG TGTACGGTGG GAGGTCTATA TAAGCAGAGC 2701 TCGTTTAGTG AACCGGGTCT CTCTGGTTAG ACCAGATCTG AGCCTGGGAG CTCTCTGGCT 2761 AACTAGGGAA CCCACTGCTT AAGCCTCAAT AAAGCTTGCC TTGAGTGCTC AAAGTAGTGT 2821 GTGCCCGTCT GTTGTGTGAC TCTGGTAACT AGAGATCCCT CAGACCCTTT T AGT C AGT GT 2881 GGAAAATCTC TAGCAGTGGC GCCCGAACAG GGACTTGAAA GCGAAAGTAA AGCCAGAGGA 2941 GATCTCTCGA CGCAGGACTC GGCTTGCTGA AGCGCGCACG GCAAGAGGCG AGGGGCGGCG 3001 ACTGGTGAGT ACGCCAAAAA TTTTGACTAG CGGAGGCTAG AAGGAGAGAG TAGGGTGCGA 3061 GAGCGTCGGT ATTAAGCGGG GGAGAATTAG ATAAATGGGA AAAAATTCGG TTAAGGCCAG 3121 GGGGAAAGAA ACAATATAAA CT A A A AC AT A TAGTTAGGGC AAGCAGGGAG CTAGAACGAT 3181 TCGCAGTTAA TCCTGGCCTT TT AG AG AC AT CAGAAGGCTG T AG AC A A AT A CTGGGACAGC 3241 TACAACCATC CCTTCAGACA GGATCAGAAG AACTTAGATC ATTATATAAT ACAATAGCAG 3301 TCCTCTATTG TGTGCATCAA AGG AT AG AT G T A A A AGAC AC CAAGGAAGCC TT AG AT A AG A 3361 TAGAGGAAGA GCAAAACAAA AGTAAGAAAA AGGCACAGCA AGCGATCTTC AGACCTGGAG 3421 GAGGCAGGAG GCGATATGAG GGACAATTGG AG A AGT G A AT TAT AT A A AT A TAAAGTAGTA 3481 AAAATTGAAC CATTAGGAGT AGCACCCACC AAGGCAAAGA GAAGAGTGGT GCAGAGAGAA 3541 AAAAGAGCAG TGGGAATAGG AGCTTTGTTC CTTGGGTTCT TGGGAGCAGC AGGAAGCACT 3601 ATGGGCGCAG CGTCAATGAC GCTGACGGTA CAGGCCAGAC AATTATTGTC T GAT AT AGT G 3661 CAGCAGCAGA ACAATTTGCT GAGGGCTATT GAGGCGCAAC AGCATCTGTT GCAACTCACA 3721 GTCTGGGGCA TCAAACAGCT CCAGGCAAGA ATCCTGGCTG TGGAAAGAT A CCTAAAGGAT 3781 CAACAGCTCC TGGGGATTTG GGGTTGCTCT GGAAAACTCA TTTGCACCAC TGCTGTGCCT 3841 TGGAATGCTA GTTGGAGTAA TAAATCTCTG GAACAGATTT GGAATAACAT GACCTGGATG 3901 GAGTGGGACA GAG A A ATT A A CAATTACACA AGCTTAATAC ACTCCTTAAT TGAAGAATCG 3961 CAAAACCAGC AAGAAAAGAA TGAACAAGAA TTATTGGAAT T AG AT A A AT G GGCAAGTTTG 4021 TGGAATTGGT TTAACATAAC AAATTGGCTG TGGTATATAA AATTATTCAT A AT GAT AGT A 4081 GGAGGCTTGG T AGGTTT A AG A AT AGTTTTT GCTGTACTTT CTATAGTGAA TAGAGTTAGG 4141 CAGGGATATT C ACC ATT AT C GTTTCAGACC CACCTCCCAA TCCCGAGGGG ACCACGCGTA 4201 CAAATGGCAG TATTCATCCA CAATTTTAAA AGAAAAGGGG GGATTGGGGG GTACAGTGCA 4261 GGGGAAAGAA TAGTAGACAT A AT AGC A AC A G AC AT AC A A A CT A A AG A ATT ACAAAAACAA 4321 ATT AC A A A A A TTCAAAATTT TCGGGTTTAT TACAGGGACA GCAGAAATCC ACTTTGGAAA 4381 GCTGAGCATC CGGCTCCGGT GCCCGTCAGT GGGCAGAGCG CACATCGCCC ACAGTCCCCG 4441 AGAAGTTGGG GGGAGGGGTC GGCAATTGAA CCGGTGCCTA GAGAAGGTGG CGCGGGGTAA 4501 ACTGGGAAAG TGATGTCGTG TACTGGCTCC GCCTTTTTCC CGAGGGTGGG GGAGAACCGT 4561 ATATAAGTGC AGTAGTCGCC GTGAACGTTC TTTTTCGCAA CGGGTTTGCC GCCAGAACAC 4621 AGGTAAGTGC CGTGTGTGGT TCCCGCGGGC CTGGCCTCTT TACGGGTTAT GGCCCTTGCG 4681 TGCCTTGAAT TACTTCCACG CCCCTGGCTG CAGTACGTGA TTCTTGATCC CGAGCTTCGG 4741 GTTGGAAGTG GGTGGGAGAG TTCGAGGCCT TGCGCTTAAG GAGCCCCTTC GCCTCGTGCT 4801 TGAGTTGAGG CCTGGCCTGG GCGCTGGGGC CGCCGCGTGC GAATCTGGTG GCACCTTCGC 4861 GCCTGTCTCG CTGCTTTCGA TAAGTCTCTA GCCATTTAAA ATTTTTGATG ACCTGCTGCG

4981 TCGGTTTTTG GGGCCGCGGG CGGCGACGGG GCCCGTGCGT CCCAGCGCAC ATGTTCGGCG 5041 AGGCGGGGCC TGCGAGCGCG GCCACCGAGA ATCGGACGGG GGTAGTCTCA AGCTGGCCGG 5101 CCTGCTCTGG TGCCTGGCCT CGCGCCGCCG TGTATCGCCC CGCCCTGGGC GGCAAGGCTG 5161 GCCCGGTCGG CACCAGTTGC GTGAGCGGAA AGATGGCCGC TTCCCGGCCC TGCTGCAGGG 5221 AGCTCAAAAT GGAGGACGCG GCGCTCGGGA GAGCGGGCGG GTGAGTCACC CACACAAAGG 5281 AAAAGGGCCT TTCCGTCCTC AGCCGTCGCT T CAT GT G ACT CCACGGAGTA CCGGGCGCCG 5341 TCCAGGCACC TCGATTAGTT CTCGAGCTTT TGGAGTACGT CGTCTTTAGG TTGGGGGGAG 5401 GGGTTTTATG CGATGGAGTT TCCCCACACT GAGTGGGTGG AGACTGAAGT TAGGCCAGCT 5461 TGGCACTTGA TGTAATTCTC CTTGGAATTT GCCCTTTTTG AGTTTGGATC TTGGTTCATT 5521 CTCAAGCCTC AGACAGTGGT TCAAAGTTTT TTTCTTCCAT TTCAGGTGTC GTGAAAACTA 5581 CCCCTCTAGA GCCGCCACCA TGCTTCTCCT GGTGACAAGC CTTCTGCTCT GTGAGTTACC 5641 ACACCCAGCA TTCCTCCTGA TCCCAGACAT CCAGATGACA CAGACTACAT CCTCCCTGTC 5701 TGCCTCTCTG GGAGACAGAG TCACCATCAG TTGCAGGGCA AGTCAGGACA TTAGTAAATA 5761 TTTAAATTGG T AT C AGC AG A A ACC AG AT GG A ACT GTT AAA CTCCTGATCT ACCATACATC 5821 AAGATTACAC TCAGGAGTCC CATCAAGGTT CAGTGGCAGT GGGTCTGGAA CAGATTATTC 5881 TCTCACCATT AGCAACCTGG AGCAAGAAGA TATTGCCACT TACTTTTGCC A AC AGGGT A A 5941 TACGCTTCCG TACACGTTCG GAGGGGGGAC TAAGTTGGAA ATAACAGGCT CCACCTCTGG 6001 ATCCGGCAAG CCCGGATCTG GCGAGGGATC CACCAAGGGC GAGGTGAAAC TGCAGGAGTC 6061 AGGACCTGGC CTGGTGGCGC CCTCACAGAG CCTGTCCGTC ACATGCACTG TCTCAGGGGT 6121 CTCATTACCC GACTATGGTG TAAGCTGGAT TCGCCAGCCT CCACGAAAGG GTCTGGAGTG 6181 GCT GGGAGT A ATATGGGGTA GTGAAACCAC AT ACT AT A AT TCAGCTCTCA AATCCAGACT 6241 GACCATCATC AAGGACAACT CCAAGAGCCA AGTTTTCTTA AAAATGAACA GTCTGCAAAC 6301 TGATGACACA GCCATTTACT ACTGTGCCAA ACATTATTAC TACGGTGGTA GCTATGCTAT 6361 GGACTACTGG GGTCAAGGAA CCTCAGTCAC CGTCTCCTCA GCGGCCGCAG GTGGAGGAGG 6421 TTCTGGAGGT GGTGGATCAG GTGGTGGAGG ATCTCTAGAA TACCAGAAAG TTACCTTTGG 6481 AACTGGAACA AAGCTCCAAG TCATCCCAAA TATCCAGAAC CCTGACCCTG CCGTGTACCA 6541 GCT GAGAGAC TCTAAATCCA GTGACAAGTC TGTCTGCCTA TTCACCGATT TTGATTCTCA 6601 AACAAATGTG TCACAAAGTA AGGATTCTGA TGTGTATATC ACAGACAAAA CTGTGCTAGA 6661 CATGAGGTCT ATGGACTTCA AGAGCAACAG TGCTGTGGCC TGGAGCAACA AATCTGACTT 6721 TGCATGTGCA AACGCCTTCA ACAACAGCAT TATTCCAGAA GACACCTTCT TCCCCAGCCC 6781 AGAAAGTTCC TGTGATGTCA AGCTGGTCGA GAAAAGCTTT GAAACAGATA CGAACCTAAA 6841 CTTT C A A A AC CTGTCAGTGA TTGGGTTCCG AATCCTCCTC CTGAAAGTGG CCGGGTTTAA 6901 TCTGCTCATG ACGCTGCGGC TGTGGTCCAG CTGATAAGAT ATCGAGCATC TTACCGCCAT 6961 TTATACCCAT ATTTGTTCTG TTTTTCTTGA TTTGGGTATA CATTTAAATG TTAATAAAAC 7021 AAA AT GGTGG GGC A AT C ATT TACATTTTTA GGGATATGTA ATT ACT AGTT CAGGTGTATT 7081 GCCACAAGAC AAACATGTTA AGAAACTTTC CCGTTATTTA CGCTCTGTTC CTGTTAATCA 7141 ACCTCTGGAT TACAAAATTT GTGAAAGATT GACTGATATT CTTAACTATG TTGCTCCTTT 7201 TACGCTGTGT GGATATGCTG CTTTATAGCC TCTGTATCTA GCTATTGCTT CCCGTACGGC 7261 TTTCGTTTTC TCCTCCTTGT ATAAATCCTG GTTGCTGTCT CTTTTAGAGG AGTTGTGGCC 7321 CGTTGTCCGT CAACGTGGCG TGGTGTGCTC TGTGTTTGCT GACGCAACCC CCACTGGCTG 7381 GGGCATTGCC ACCACCTGTC AACTCCTTTC TGGGACTTTC GCTTTCCCCC TCCCGATCGC 7441 CACGGCAGAA CTCATCGCCG CCTGCCTTGC CCGCTGCTGG ACAGGGGCTA GGTTGCTGGG 7501 CACTGATAAT TCCGTGGTGT TGTCAGTACT GGTACCTTTA AGACCAATGA CTTACAAGGC 7561 AGCTGTAGAT CTTAGCCACT TTTTAAAAGA AAAGGGGGGA CTGGAAGGGC TAATTCACTC

7981 ATCATGTCTG GATCTGCGTC GACACGAAGA GACGACTGAC TGACTGACTG GAAAGAGGAA 8041 GGGCTGGAAG AGGAAGGAGC TTGATCCAGA TCCCGATCTC GATCCAGATC CGGATCGCAG 8101 CTTGGCGTAA TCATGGTCAT AGCTGTTTCC TGTGTGAAAT TGTTATCCGC TCACAATTCC 8161 ACACAACATA CGAGCCGGAA GCATAAAGTG TAAAGCCTGG GGTGCCTAAT GAGTGAGCTA 8221 ACTCACATTA ATTGCGTTGC GCTCACTGCC CGCTTTCCAG TCGGGAAACC TGTCGTGCCA 8281 GCT GC ATT A A TGAATCGGCC AACGCGCGGG GAGAGGCGGT TTGCGTATTG GGCGCTCTTC 8341 CGCTTCCTCG CTCACTGACT CGCTGCGCTC GGTCGTTCGG CTGCGGCGAG CGGTATCAGC 8401 TCACTCAAAG GCGGTAATAC GGTTATCCAC AGAATCAGGG GATAACGCAG GAAAGAACAT 8461 GTGAGCAAAA GGCCAGCAAA AGGCCAGGAA CCGTAAAAAG GCCGCGTTGC TGGCGTTTTT 8521 CCATAGGCTC CGCCCCCCTG ACGAGCATCA C A A A A AT CG A CGCTCAAGTC AGAGGTGGCG 8581 AAACCCGACA GGACTATAAA GATACCAGGC GTTTCCCCCT GGAAGCTCCC TCGTGCGCTC 8641 TCCTGTTCCG ACCCTGCCGC TTACCGGATA CCTGTCCGCC TTTCTCCCTT CGGGAAGCGT 8701 GGCGCTTTCT CAT AGCT C AC GCTGTAGGTA TCTCAGTTCG GTGTAGGTCG TTCGCTCCAA 8761 GCTGGGCTGT GTGCACGAAC CCCCCGTTCA GCCCGACCGC TGCGCCTTAT CCGGTAACTA 8821 TCGTCTTGAG TCCAACCCGG TAAGACACGA CTTATCGCCA CTGGCAGCAG CCACTGGTAA 8881 CAGGATTAGC AGAGCGAGGT ATGTAGGCGG TGCTACAGAG TTCTTGAAGT GGTGGCCTAA 8941 CTACGGCTAC ACTAGAAGAA CAGTATTTGG TATCTGCGCT CTGCTGAAGC CAGTTACCTT 9001 CGGAAAAAGA GTTGGTAGCT CTTGATCCGG CAAACAAACC ACCGCTGGTA GCGGTGGTTT 9061 TTTTGTTTGC AAGCAGCAGA TTACGCGCAG AAAAAAAGGA TCTCAAGAAG ATCCTTTGAT 9121 CTTTTCTACG GGGTCTGACG CTCAGTGGAA CGAAAACTCA CGTTAAGGGA TTTTGGTCAT 9181 GAGATTATCA AAAAGGATCT TCACCTAGAT CCTTTTAAAT TAAAAATGAA GTTTTAAATC 9241 AATCTAAAGT AT pLRPC FMC63 -T CRbeta 1 (CRISPR Resistant) (SEQ ID NO: 180)

241 CACAGGTAAG TGCCGTGTGT GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT 301 GCGTGCCTTG AATTACTTCC ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT 361 CGGGTTGGAA GTGGGTGGGA GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT 421 GCTTGAGTTG AGGCCTGGCC TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT 481 CGCGCCTGTC TCGCTGCTTT CGATAAGTCT CTAGCCATTT AAAATTTTTG ATGACCTGCT 541 GCGACGCTTT TTTTCTGGCA AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT 601 ATTTCGGTTT TTGGGGCCGC GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG 661 GCGAGGCGGG GCCTGCGAGC GCGGCCACCG AGAATCGGAC GGGGGTAGTC TCAAGCTGGC 721 CGGCCTGCTC TGGTGCCTGG CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG 781 CTGGCCCGGT CGGCACCAGT TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA 841 GGGAGCTCAA AATGGAGGAC GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA 901 AGGAAAAGGG CCTTTCCGTC CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG 961 CCGTCCAGGC ACCTCGATTA GTTCTCGAGC TTTTGGAGTA CGTCGTCTTT AGGTTGGGGG 1021 GAGGGGTTTT ATGCGATGGA GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA 1081 GCTTGGCACT TGATGTAATT CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC 1141 ATTCTCAAGC CTCAGACAGT GGTTCAAAGT TTTTTTCTTC CATTTCAGGT GTCGTGAAAA 1201 CTACCCCTCT AGAGCCGCCA CCATGCTTCT CCTGGTGACA AGCCTTCTGC TCTGTGAGTT 1261 ACCACACCCA GCATTCCTCC TGATCCCAGA CATCCAGATG ACACAGACTA CATCCTCCCT 1321 GTCTGCCTCT CTGGGAGACA GAGTCACCAT CAGTTGCAGG GCAAGTCAGG ACATTAGTAA 1381 ATATTTAAAT TGGTATCAGC AGAAACCAGA TGGAACTGTT AAACTCCTGA TCTACCATAC 1441 ATCAAGATTA CACTCAGGAG TCCCATCAAG GTTCAGTGGC AGTGGGTCTG GAACAGATTA 1501 TTCTCTCACC ATTAGCAACC TGGAGCAAGA AG AT ATT GCC ACTTACTTTT GCCAACAGGG 1561 TAATACGCTT CCGTACACGT TCGGAGGGGG GACTAAGTTG GAAATAACAG GCTCCACCTC 1621 TGGATCCGGC AAGCCCGGAT CTGGCGAGGG ATCCACCAAG GGCGAGGTGA AACTGCAGGA 1681 GTCAGGACCT GGCCTGGTGG CGCCCTCACA GAGCCTGTCC GTCACATGCA CTGTCTCAGG 1741 GGTCTCATTA CCCGACTATG GTGTAAGCTG GATTCGCCAG CCTCCACGAA AGGGTCTGGA 1801 GTGGCTGGGA GTAATATGGG GTAGTGAAAC C AC AT ACT AT A ATT C AGCT C TCAAATCCAG 1861 ACTGACCATC ATCAAGGACA ACTCCAAGAG CCAAGTTTTC TTAAAAATGA ACAGTCTGCA 1921 AACTGATGAC ACAGCCATTT ACTACTGTGC CAAACATTAT TACTACGGTG GTAGCTATGC 1981 T AT GG ACT AC TGGGGTCAAG GAACCTCAGT CACCGTCTCC TCAGCGGCCG CAGGTGGAGG 2041 AGGTTCTGGA GGTGGAGGTT CAGGTGGAGG TGGTTCACTC GAGCTGGGAG CAGGCCCAGT 2101 GGATTCTGGA GTCACACAAA CCCCAAAGCA CCTGATCACA GCAACTGGAC AGCGAGTGAC 2161 GCTGAGATGC TCCCCTAGGT CTGGAGACCT CTCTGTGTCA TGGTACCAAC AGAGCCTGGA 2221 CCAGGGCCTC CAGTTCCTCA TTCAGTATTA TAATGGAGAA GAGAGAGCAA AAGGAAACAT 2281 TCTTGAACGA TTCTCCGCAC AACAGTTCCC TGACTTGCAC TCTGAACTAA ACCTGAGCTC 2341 TCTGGAGCTG GGGGACTCAG CTTTGTATTT CTGTGCCAGC AGCCCCCGGA CAGGCCTGAA 2401 CACTGAAGCT TTCTTTGGAC AAGGCACCAG ACTCACAGTT GTAGAGGACC TGAACAAGGT 2461 GTTCCCACCC GAGGTCGCTG TGTTTGAGCC ATCAGAAGCA GAGATCTCCC ACACCCAAAA 2521 GGCCACgCTa GTaTGtCTaG CtACAGGCTT CTTCCCCGAC CACGTGGAGC TGAGCTGGTG 2581 GGTGAATGGG AAGGAGGTGC ACAGTGGGGT CAGCACGGAC CCGCAGCCCC TCAAGGAGCA 2641 GCCCGCCCTC AATGACTCCA GATACTGCCT GAGCAGCCGC CTGAGGGTCT CGGCCACCTT 2701 CTGGCAGAAC CCCCGCAACC ACTTCCGCTG TCAAGTCCAG TTCTACGGGC TCTCGGAGAA 2761 TGACGAGTGG ACCCAGGATA GGGCCAAACC CGTCACCCAG ATCGTCAGCG CCGAGGCCTG 2821 GGGTAGAGCA GACTGTGGCT TTACCTCGGT GTCCTACCAG CAAGGGGTCC TGTCTGCCAC 2881 CATCCTCTAT GAGATCCTGC TAGGGAAGGC CACCCTGTAT GCTGTGCTGG TCAGCGCCCT 2941 TGTGTTGATG GCCATGGTCA AGAGAAAGGA TTTCTGATAA GATATCGAGC ATCTTACCGC 3001 CATTTATACC CATATTTGTT CTGTTTTTCT TGATTTGGGT ATACATTTAA ATGTTAATAA 3061 AACAAAATGG TGGGGCAATC ATTTACATTT TTAGGGATAT GT A ATT ACTA GTTCAGGTGT 3121 ATTGCCACAA GACAAACATG TTAAGAAACT TTCCCGTTAT TTACGCTCTG TTCCTGTTAA 3181 TCAACCTCTG GATT AC A A A A TTTGTGAAAG ATT GACT GAT ATTCTTAACT ATGTTGCTCC 3241 TTTTACGCTG TGTGGATATG CTGCTTTATA GCCTCTGTAT CTAGCTATTG CTTCCCGTAC 3301 GGCTTTCGTT TTCTCCTCCT TGTATAAATC CTGGTTGCTG TCTCTTTTAG AGGAGTTGTG 3361 GCCCGTTGTC CGTCAACGTG GCGTGGTGTG CTCTGTGTTT GCTGACGCAA CCCCCACTGG 3421 CTGGGGCATT GCCACCACCT GTCAACTCCT TTCTGGGACT TTCGCTTTCC CCCTCCCGAT 3481 CGCCACGGCA GAACTCATCG CCGCCTGCCT TGCCCGCTGC TGGACAGGGG CTAGGTTGCT 3541 GGGCACTGAT AATTCCGTGG TGTTGTCAGT ACTGGTACCT TTAAGACCAA TGACTTACAA 3601 GGCAGCTGTA GATCTTAGCC ACTTTTTAAA AGAAAAGGGG GGACTGGAAG GGCTAATTCA

4021 CTTATCATGT CTGGATCTGC GTCGACACGA AGAGACGACT GACTGACTGA CTGGAAAGAG 4081 GAAGGGCTGG AAGAGGAAGG AGCTTGATCC AGATCCCGAT CTCGATCCAG ATCCGGATCG 4141 CAGCTTGGCG T A AT CAT GGT CAT AGCT GTT TCCTGTGTGA AATTGTTATC CGCTCACAAT 4201 TCCACACAAC ATACGAGCCG GAAGCATAAA GTGTAAAGCC TGGGGTGCCT AATGAGTGAG 4261 CTAACTCACA TTAATTGCGT TGCGCTCACT GCCCGCTTTC CAGTCGGGAA ACCTGTCGTG 4321 CCAGCTGCAT TAATGAATCG GCCAACGCGC GGGGAGAGGC GGTTTGCGTA TTGGGCGCTC 4381 TTCCGCTTCC TCGCTCACTG ACTCGCTGCG CTCGGTCGTT CGGCTGCGGC GAGCGGTATC 4441 AGCTC ACT CA AAGGCGGT AA TACGGTTATC CACAGAATCA GGGGATAACG CAGGAAAGAA 4501 CATGTGAGCA AAAGGCCAGC AAAAGGCCAG GAACCGTAAA AAGGCCGCGT TGCTGGCGTT 4561 TTTCCATAGG CTCCGCCCCC CTGACGAGCA TC AC AAA A AT CGACGCTCAA GTCAGAGGTG 4621 GCGAAACCCG ACAGGACTAT A A AG AT ACC A GGCGTTTCCC CCTGGAAGCT CCCTCGTGCG 4681 CTCTCCTGTT CCGACCCTGC CGCTTACCGG ATACCTGTCC GCCTTTCTCC CTTCGGGAAG 4741 CGTGGCGCTT TCTCATAGCT CACGCTGTAG GTATCTCAGT TCGGTGTAGG TCGTTCGCTC 4801 CAAGCTGGGC TGTGTGCACG AACCCCCCCG GTAAGACACG ACTTATCGCC ACTGGCAGCA 4861 GCCACTGGTA ACAGGATTAG CAGAGCGAGG TATGTAGGCG GTGCTACAGA GTTCTTGAAG 4921 TGGTGGCCTA ACTACGGCTA CACTAGAAGA ACAGTATTTG GTATCTGCGC TCTGCTGAAG 4981 CCAGTTACCT TCGGAAAAAG AGTTGGTAGC TCTTGATCCG GCAAACAAAC CACCGCTGGT 5041 AGCGGTGGTT TTTTTGTTTG CAAGCAGCAG ATTACGCGCA GAAAAAAAGG ATCTCAAGAA 5101 GATCCTTTGA TCTTTTCTAC GGGGTCTGAC GCTCAGTGGA ACGAAAACTC ACGTTAAGGG 5161 ATTTTGGTCA TGAGATTATC AAAAAGGATC TTCACCTAGA TCCTTTTAAA TT A A A A AT G A 5221 AGTTTT A A AT C A AT CT A A AG TATATATGAG TAAACTTGGT CTGACAGTTA CCAATGCTTA 5281 ATCAGTGAGG CACCTATCTC AGCGATCTGT CTATTTCGTT CATCCATAGT TGCCTGACTC 5341 CCCGTCGTTG CT AGGTT ACT GTCATGAGCG GATACATATT TGAATGTATT T AG A A A A AT A 5401 AACAAAAGAG TTTGTAGAAA CGCAAAAAGG CCATCCGTCA GGATGGCCTT CTGCTTAATT 5461 TGATCGGTGG CAGTTTATGG CGGGCGTCCT GCCCGCCACC CTCCGGGCCG TTGCTTCGCA 5521 ACGTT C AA AT CCGCTCCCGG CGGATTTGTC CTACTCAGGA GAGCGTTCAC CGACAAACAA 5581 CAGATAAAAC GAAAGGCCCA GTCTTTCGAC TGAGCCTTTC GTTTTATTTG ATGCCTGGCA 5641 GTTCCCTACT CTCGCATGGG TTGCGGCCGC CCGGGCCGTC GACCAATTCT CATGTTTGAC 5701 AGCTTATCAT CGAATTTCTG CCATTCATCC GCTTATTATC ACTTATTCAG GCGTAGCAAC 5761 CAGGCGTTTA AGGGCACCAA TAACTGCCTT A A A A A A ATT A CGCCCCGCCC TGCCACTCAT 5821 CGCAGTACTG TTGTAATTCA TTAAGCATTC TGCCGACATG GAAGCCATCA CAAACGGCAT 5881 GATGAACCTG AATCGCCAGC GGCATCAGCA CCTTGTCGCC TTGCGTATAA TATTTGCCCA 5941 TGGTGAAAAC GGGGGCGAAG AAGTTGTCCA T ATT GGCC AC GTTTAAATCA AAACTGGTGA 6001 AACTCACCCA GGGATTGGCT GAGACGAAAA ACATATTCTC AATAAACCCT TTAGGGAAAT 6061 AGGCC AGGTT TTCACCGTAA CACGCCACAT CTTGCGAATA TATGTGTAGA AACTGCCGGA 6121 AATCGTCGTG GTATTCACTC CAGAGCGATG AAAACGTTTC AGTTTGCTCA TGGAAAACGG 6181 TGTAACAAGG GTGAACACTA TCCCATATCA CC AGCTC ACC GTCTTTCATT GCCATACGAA 6241 ATTCCGGATG AGCATTCATC AGGCGGGCAA GAATGTGAAT AAAGGCCGGA TAAAACTTGT 6301 GCTTATTTTT CTTTACGGTC TTTAAAAAGG CCGTAATATC CAGCTGAACG GTCTGGTTAT 6361 AGGTACATTG AGCAACTGAC TGAAATGCCT CAAAATGTTC TTTACGATGC CATTGGGATA 6421 T AT C A ACGGT GGTATATCCA GTGATTTTTT TCTCCATTTT AGCTTCCTTA GCTCCTGAAA 6481 ATCTCGATAA CTCAAAAAAT ACGCCCGGTA GTGATCTTAT TTCATTATGG TGAAAGTTGG 6541 AACCTCTTAC GTGCCGATCA ACGTCTCATT TTCGCCAAAA GTGACATTAA CCTATAAAAA 6601 TAGGCGTATC ACGAGGCCAG CTTGGGAAAC CATAAGACCG AGATAGAGTT GAGTGTTGTT 6661 CCAGTTTGGA ACAAGAGTCC ACT ATT AA AG AACGTGGACT CCAACGTCAA AGGGCGAAAA 6721 ACCGTCTATC AGGGCGATGG CCCACTACGT G A ACC AT C AC CCAAATCAAG TTTTTTGGGG 6781 TCGAGGTGCC GTAAAGCACT AAATCGGAAC CCTAAAGGGA GCCCCCGATT TAGAGCTTGA 6841 CGGGGAAAGC CGGCGAACGT GGCGAGAAAG GAAGGGAAGAAAGCGAAAGGAGCGGGCGCT 6901 AAGGCGCTGG CAAGTGTAGC GGTCACGCTG CGCGTAACCA CCACACCCGC CGCGCTT AAT 6961 GCGCCGCTAC AGGGCGCGTA CTATGGTTGC TTTGACGTAT GCGGTGTGAA ATACCGCACA 7021 GATGCGTAAG GAG A A A AT AC CGCATCAGGC GCCATTCGCC ATTCAGGCTG CGCAACTGTT 7081 GGGAAGGGCG ATCGGTGCGG GCCTCTTCGC TATTACGCCA GCTGGCGAAA GGGGGATGTG 7141 CTGCAAGGCG ATTAAGTTGG GTAACGCCAG GGTTTTCCCA GTCACGACGT TGTAAAACGA 7201 CGGCCAGTGA ATTGATCGAG ATCGTGATCC GGATCAAGAT CCAGATCGAA TTGGAGGCTA 7261 CAGTCAGTGG AGAGGACTTT CACTGACTGA CTGACTGCGT CTCAACCTCC TAGGGGACAT 7321 TGATTATTGA CTAGTTATTA ATAGTAATCA ATTACGGGGT CATTAGTTCA TAGCCCATAT 7381 ATGGAGTTCC GCGTT ACAT A ACTTACGGTA AATGGCCCGC CTGGCTGACC GCCCAACGAC 7441 CCCCGCCCAT TGACGTCAAT AATGACGTAT GTTCCCATAG TAACGCCAAT AGGGACTTTC 7501 CATTGACGTC AATGGGTGGA GTATTTACGG T AAACTGCCC ACTTGGCAGT ACATCAAGTG 7561 TATCATATGC CAAGTACGCC CCCTATTGAC GTCAATGACG GTAAATGGCC CGCCTGGCAT 7621 TATGCCCAGT ACATGACCTT ATGGGACTTT CCTACTTGGC AGTACATCTA CGTATTAGTC 7681 AT CGCT ATT A CCATGGTGAT GCGGTTTTGG CAGTACATCA ATGGGCGTGG AT AGCGGTTT 7741 GACTCACGGG GATTTCCAAG TCTCCACCCC ATTGACGTCA ATGGGAGTTT GTTTTGGCAC 7801 CAAAATCAAC GGGACTTTCC AAAATGTCGT AACAACTCCG CCCCATTGAC GCAAATGGGC 7861 GGTAGGCGTG TACGGTGGGA GGTCTATATA AGCAGAGCTC GTTTAGTGAA CCGGGTCTCT 7921 CTGGTTAGAC CAGATCTGAG CCTGGGAGCT CTCTGGCTAA CTAGGGAACC CACTGCTTAA 7981 GCCTCAATAA AGCTTGCCTT GAGTGCTCAA AGTAGTGTGT GCCCGTCTGT TGTGTGACTC 8041 TGGTAACTAG AGATCCCTCA GACCCTTTTA GTCAGTGTGG AAAATCTCTA GCAGTGGCGC 8101 CCGAACAGGG ACTTGAAAGC GAAAGTAAAG CCAGAGGAGA TCTCTCGACG CAGGACTCGG 8161 CTTGCTGAAG CGCGCACGGC AAGAGGCGAG GGGCGGCGAC TGGTGAGTAC GCCAAAAATT 8221 TTGACTAGCG GAGGCTAGAA GGAGAGAGTA GGGTGCGAGA GCGTCGGTAT TAAGCGGGGG 8281 AGAATTAGAT AAATGGGAAA A A ATT CGGTT AAGGCCAGGG GGAAAGAAAC AAT AT A AACT 8341 AAA AC AT AT A GTTAGGGCAA GCAGGGAGCT AGAACGATTC GCAGTTAATC CTGGCCTTTT 8401 AGAGACATCA G AAGGCTGT A G ACAA AT ACT GGGACAGCTA CAACCATCCC TTCAGACAGG 8461 ATCAGAAGAA CTTAGATCAT TATATAATAC AATAGCAGTC CTCTATTGTG TGCATCAAAG 8521 GATAGATGTA AAAGACACCA AGGAAGCCTT AGATAAGATA GAGGAAGAGC AAAACAAAAG 8581 TAAGAAAAAG GCACAGCAAG CGATCTTCAG ACCTGGAGGA GGCAGGAGGC GAT ATGAGGG 8641 ACAATTGGAG AAGTGAATTA TAT A A AT AT A AAGTAGTAAA AATTGAACCA TTAGGAGTAG 8701 CACCCACCAA GGCAAAGAGA AGAGTGGTGC AGAGAGAAAA A AG AGC AGT GGGA AT AGG AG 8761 CTTTGTTCCT TGGGTTCTTG GGAGCAGCAG GAAGCACTAT GGGCGCAGCG TCAATGACGC 8821 TGACGGTACA GGCCAGACAA TTATTGTCTG ATATAGTGCA GCAGCAGAAC AATTTGCTGA 8881 GGGCTATTGA GGCGCAACAG CATCTGTTGC AACT C AC AGT CTGGGGCATC AAACAGCTCC 8941 AGGCAAGAAT CCTGGCTGTG GAAAGATACC TAAAGGATCA ACAGCTCCTG GGGATTTGGG 9001 GTTGCTCTGG AAAACTCATT TGCACCACTG CTGTGCCTTG GAATGCTAGT TGGAGTAATA 9061 AATCTCTGGA ACAGATTTGG AATAACATGA CCTGGATGGA GTGGGACAGA G A A ATT A AC A 9121 ATTACACAAG CTTAATACAC TCCTTAATTG AAGAATCGCA AAACCAGCAA GAAAAGAATG 9181 AACAAGAATT ATT GG A ATT A GATAAATGGG CAAGTTTGTG G A ATT GGTTT A AC AT A AC A A 9241 ATTGGCTGTG GTATATAAAA TTATTCATAA TGATAGTAGG AGGCTTGGTA GGTTT AAGAA

9361 TTCAGACCCA CCTCCCAATC CCGAGGGGAC CACGCGTACA AATGGCAGTA TT CAT CC AC A 9421 ATTTTAAAAG AAAAGGGGGG ATTGGGGGGT ACAGTGCAGG GGAAAGAATA GTAGACATAA 9481 TAGCAACAGA CATACAAACT A A AG A ATT AC AAAAACAAAT TACAAAAATT CAAAATTTTC 9541 GGGTTTATTA CAGGGACAGC AGAAATCCAC TTTGG pLRPO FMC63 TRDC T2AW FMC63op TRGC1 (SEQ ID NO: 181)

1 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 61 ATCTGTCTAT TTCGTTCATC CAT AGTT GCC TGACTCCCCG TCGTGTAGAT AACTACGATA 121 CGGGAGGGCT TACCATCTGG CCCCAGTGCT GCAATGATAC CGCAGCTTGG GAAACCATAA 181 GAGCTGAAGC CAGTTACCTT CGGAAAAAGA GTTGGTAGCT CTTGATCCGG CAAACAAACC 241 ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC AAGCAGCAGA TTACGCGCAG AAAAAAAGGA 301 TCTCAAGAAG ATCCTTTGAT CTTTTCTACG GGGTCTGACG CTCAGTGGAA CGAAAACTCA 361 CGTTAAGGGA TTTTGGTCAT GAGCTTGCGC CGTCCCGTCA AGTCAGCGTA ATGCTCTGCC 421 AGTGTTACAA CCAATTAACC AATTCTGATT AGAAAAACTC ATCGAGCATC A A AT G A A ACT

961 GGATCGCAGT GGTGAGTAAC CAT GC AT CAT CAGGAGTACG GAT AAAATGC TTGATGGTCG 1021 GAAGAGGCAT AAATTCCGTC AGCCAGTTTA GTCTGACCAT CTCATCTGTA ACATCATTGG 1081 CAACGCTACC TTTGCCATGT TT C AG A A AC A ACTCTGGCGC ATCGGGCTTC CCATACAAGC 1141 GATAGATTGT CGCACCTGAT TGCCCGACAT TATCGCGAGC CCATTTATAC CCATATAAAT 1201 CAGCATCCAT GTTGGAATTT AATCGCGGCC TCGACGTTTC CCGTTGAATA TGGCTCATAA 1261 CACCCCTTGT ATTACTGTTT ATGTAAGCAG ACAGTTTTAT TGTTCATGAT GATATATTTT 1321 TATCTTGTGC A AT GT A AC AT CAGAGATTTT GAGACACAAC GTGGCTTTCC CCCCCCCCCC 1381 CATGACATTA ACCTATAAAA ATAGGCGTAT CACGAGGCCA GCTTGGGAAA CCATAAGACC 1441 GAGATAGAGT TGAGTGTTGT TCCAGTTTGG AACAAGAGTC CACTATTAAA GAACGTGGAC 1501 TCCAACGTCA AAGGGCGAAA AACCGTCTAT CAGGGCGATG GCCCACTACG TGAACCATCA 1561 CCCAAATCAA GTTTTTTGGG GTCGAGGTGC CGTAAAGCAC TAAATCGGAA CCCTAAAGGG 1621 AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG CCGGCGAACG TGGCGAGAAA GGAAGGGAAG 1681 AAAGCGAAAG GAGCGGGCGC TAAGGCGCTG GCAAGTGTAG CGGTCACGCT GCGCGTAACC 1741 ACCACACCCG CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT ACT ATGGTTG CTTTGACGTA 1801 TGCGGTGTGA AATACCGCAC AGATGCGTAA GGAGAAAATA CCGCATCAGG CGCCATTCGC 1861 C ATT C AGGCT GCGCAACTGT TGGGAAGGGC GATCGGTGCG GGCCTCTTCG CTATTACGCC 1921 AGCTGGCGAA AGGGGGATGT GCTGCAAGGC GATTAAGTTG GGTAACGCCA GGGTTTTCCC 1981 AGTCACGACG TTGTAAAACG ACGGCCAGTG AATTGATCGA GATCGTGATC CGGATCAAGA 2041 TCCAGATCGA ATTGGAGGCT ACAGTCAGTG GAGAGGACTT TCACTGACTG ACTGACTGCG 2101 TCTCAACCTC CTAGGGGACA TTGATTATTG ACTAGTTATT AATAGTAATC AATTACGGGG 2161 TCATTAGTTC ATAGCCCATA TATGGAGTTC CGCGTTACAT AACTTACGGT AAATGGCCCG 2221 CCTGGCTGAC CGCCCAACGA CCCCCGCCCA TTGACGTCAA TAATGACGTA TGTTCCCATA 2281 GTAACGCCAA TAGGGACTTT CCATTGACGT CAATGGGTGG AGTATTTACG GTAAACTGCC 2341 CACTTGGCAG TACATCAAGT GT AT C AT AT G CCAAGTACGC CCCCTATTGA CGTCAATGAC 2401 GGTAAATGGC CCGCCTGGCA TTATGCCCAG TACATGACCT TATGGGACTT TCCTACTTGG 2461 CAGTACATCT ACGTATTAGT CATCGCTATT ACCATGGTGA TGCGGTTTTG GCAGTACATC 2521 AATGGGCGTG GATAGCGGTT TGACTCACGG GGATTTCCAA GTCTCCACCC CATTGACGTC 2581 AATGGGAGTT TGTTTTGGCA CCAAAATCAA CGGGACTTTC CAAAATGTCG TAACAACTCC 2641 GCCCCATTGA CGCAAATGGG CGGTAGGCGT GTACGGTGGG AGGTCTATAT AAGCAGAGCT 2701 CGTTTAGTGA ACCGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA 2761 ACTAGGGAAC CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG 2821 TGCCCGTCTG TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT AGTCAGTGTG 2881 GAAAATCTCT AGCAGTGGCG CCCGAACAGG GACTTGAAAG CGAAAGTAAA GCCAGAGGAG 2941 ATCTCTCGAC GCAGGACTCG GCTTGCTGAA GCGCGCACGG CAAGAGGCGA GGGGCGGCGA 3001 CTGGTGAGTA CGCCAAAAAT TTTGACTAGC GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG 3061 AGCGTCGGTA TTAAGCGGGG GAGAATTAGA TAAATGGGAA AAAATTCGGT TAAGGCCAGG 3121 GGGAAAGAAA C A AT AT AA AC T A A A AC AT AT AGTTAGGGCA AGCAGGGAGC T AG A ACG ATT 3181 CGCAGTTAAT CCTGGCCTTT TAGAGACATC AGAAGGCTGT AGACAAATAC TGGGACAGCT 3241 ACAACCATCC CTTCAGACAG GATCAGAAGA ACTTAGATCA TT AT AT A AT A CAATAGCAGT 3301 CCTCTATTGT GTGCATCAAA GGATAGATGT AAAAGACACC AAGGAAGCCT TAGATAAGAT 3361 AGAGGAAGAG CAAAACAAAA GTAAGAAAAA GGCACAGCAA GCGATCTTCAGACCTGGAGG 3421 AGGCAGGAGG CGATATGAGG GACAATTGGA GAAGTGAATT AT AT A A AT AT A A AGT AGT A A 3481 AAATTGAACC ATTAGGAGTA GCACCCACCA AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA 3541 AAAGAGCAGT GGG A AT AGG A GCTTTGTTCC TTGGGTTCTT GGGAGCAGCA GG A AGC ACT A 3601 TGGGCGCAGC GTCAATGACG CTGACGGTAC AGGCCAGACA ATTATTGTCT GATATAGTGC 3661 AGCAGCAGAA CAATTTGCTG AGGGCTATTG AGGCGCAACA GCATCTGTTG CAACTCACAG 3721 TCTGGGGCAT CAAACAGCTC CAGGCAAGAA TCCTGGCTGT GG A A AG AT AC CTAAAGGATC 3781 AACAGCTCCT GGGGATTTGG GGTTGCTCTG GAAAACTCAT TTGCACCACT GCTGTGCCTT 3841 GGAATGCTAG TTGGAGTAAT AAATCTCTGG AACAGATTTG G A AT A AC AT G ACCTGGATGG 3901 AGTGGGACAG AG AA ATT A AC A ATT AC AC A A GCTTAATACA CTCCTTAATT GAAGAATCGC 3961 AAAACCAGCA AGAAAAGAAT GAACAAGAAT TATTGGAATT AGATAAATGG GCAAGTTTGT 4021 GGAATTGGTT T AAC AT A AC A AATTGGCTGT GGT AT AT AAA ATTATTCATA ATGATAGTAG 4081 GAGGCTTGGT AGGTTTAAGA ATAGTTTTTG CTGTACTTTC T AT AGT G A AT AGAGTTAGGC 4141 AGGGATATTC ACCATTATCG TTTCAGACCC ACCTCCCAAT CCCGAGGGGA CCACGCGTAC 4201 AAATGGCAGT ATTCATCCAC A ATTTT AAA A GAAAAGGGGG GATTGGGGGG TACAGTGCAG 4261 GGGAAAGAAT AGTAGACATA AT AGC AAC AG AC AT AC A A AC T A A AG A ATT A CAAAAACAAA 4321 TT AC A A A A AT T C A A A ATTTT CGGGTTTATT ACAGGGACAG C AG A A AT CCA CTTTGGAAAG 4381 CTGAGCATCC GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA 4441 GAAGTTGGGG GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA 4501 CTGGGAAAGT GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG G AG AACCGT A 4561 TATAAGTGCA GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA 4621 GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT 4681 GCCTTGAATT ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG 4741 TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT 4801 GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG 4861 CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG CCATTTAAAA TTTTTGATGA CCTGCTGCGA

5041 GGCGGGGCCT GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC 5101 CTGCTCTGGT GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG 5161 CCCGGTCGGC ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA 5221 GCTCAAAATG GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA 5281 AAAGGGCCTT TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT 5341 CCAGGCACCT CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG 5401 GGTTTTATGC GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT 5461 GGCACTTGAT GTAATTCTCC TTGGAATTTG CCCTTTTTGA GTTTGGATCT TGGTTCATTC 5521 TCAAGCCTCA GACAGTGGTT CAAAGTTTTT TTCTTCCATT TCAGGTGTCG TGAAAACTAC 5581 CCCTCTAGAG CCGCCACCAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA 5641 CACCCAGCAT TCCTCCTGAT CCCAGACATC CAGATGACAC AGACTACATC CTCCCTGTCT 5701 GCCTCTCTGG GAGACAGAGT CACCATCAGT TGCAGGGCAA GTCAGGACAT TAGTAAATAT 5761 TTAAATTGGT ATCAGCAGAA ACCAGATGGA ACTGTTAAAC TCCTGATCTA CCATACATCA 5821 AGATTACACT CAGGAGTCCC ATCAAGGTTC AGTGGCAGTG GGTCTGGAAC AGATTATTCT 5881 CTCACCATTA GCAACCTGGA GCAAGAAGAT ATTGCCACTT ACTTTTGCCA AC AGGGT A AT 5941 ACGCTTCCGT ACACGTTCGG AGGGGGGACT AAGTTGGAAA TAACAGGCTC CACCTCTGGA 6001 TCCGGCAAGC CCGGATCTGG CGAGGGATCC ACCAAGGGCG AGGTGAAACT GCAGGAGTCA 6061 GGACCTGGCC TGGTGGCGCC CTCACAGAGC CTGTCCGTCA CATGCACTGT CTCAGGGGTC 6121 TCATTACCCG ACTATGGTGT AAGCTGGATT CGCCAGCCTC CACGAAAGGG TCTGGAGTGG 6181 CTGGGAGT A A TATGGGGTAG TGAAACCACA TACTATAATT CAGCTCTCAA ATCCAGACTG 6241 ACCATCATCA AGGACAACTC CAAGAGCCAA GTTTTCTTAA AAATGAACAG TCTGCAAACT 6301 GATGACACAG CCATTTACTA CTGTGCCAAA CATTATTACT ACGGTGGTAG CTATGCTATG 6361 GACTACTGGG GTCAAGGAAC CTCAGTCACC GTCTCCTCAG CGGCCGCAGG TGGAGGAGGT 6421 TCTGGAGGTG GTGGATCAGG TGGTGGAGGA TCTTTAGAAA GTCAGCCTCA TACCAAACCA 6481 TCCGTTTTTG T C AT G AAA A A T GG A AC A A AT GTCGCTTGTC TGGTGAAGGA ATTCTACCCC 6541 AAGGATATAA GAATAAATCT CGTGTCATCC AAGAAGATAA CAGAGTTTGA TCCTGCTATT 6601 GTCATCTCTC CCAGTGGGAA GTACAATGCT GTCAAGCTTG GTAAATATGA AGATTCAAAT 6661 TCAGTGACAT GTTCAGTTCA ACACGACAAT AAAACTGTGC ACTCCACTGA CTTTGAAGTG 6721 AAGACAGATT CTACAGATCA CGTAAAACCA AAGGAAACTG AAAACACAAA GCAACCTTCA 6781 AAGAGCTGCC ATAAACCCAA AGCCATAGTT CATACCGAGA AGGT G A AC AT GATGTCCCTC 6841 ACAGTGCTTG GGCTACGAAT GCTGTTTGCA AAGACTGTTG CCGTCAATTT TCTCTTGACT 6901 GCCAAGTTAT TTTTCTTGGG GTCAGGCGAG GGCAGAGGAA GTCTGCTAAC ATGCGGTGAC 6961 GTCGAGGAGA ATCCTGGACC T AT GCT ACT A CTTGTGACCT CACTATTGTT ATGCGAACTC 7021 CCTCATCCCG CATTCTTGCT GATTCCAGAC ATTCAGATGA CTCAAACAAC TTCCAGCCTC 7081 TCCGCCTCAC TCGGCGACCG CGTAACAATA AGCTGTCGGG CCTCGCAAGA TATTAGTAAG 7141 TACCTGAATT GGTATCAGCA AAAACCCGAT GGTACAGTCA AGCTTCTGAT CTACCATACC 7201 AGTCGTCTGC ACAGCGGTGT CCCCAGCAGG TTCAGCGGCT CAGGATCTGG TACCGATTAT 7261 TCACTGACGA TTTCCAACCT TGAGCAGGAG GACATCGCCA CCTACTTCTG CCAGCAGGGT 7321 AATACTCTGC CGTACACATT CGGGGGCGGT ACCAAGCTCG AGATCACGGG TTCAACAAGC 7381 GGTTCTGGCA AGCCAGGCAG CGGCGAGGGG AGTACAAAGG GGGAGGTGAA GTTGCAGGAA 7441 AGTGGCCCTG GATTGGTGGC CCCGAGCCAG AGTCTGTCTG TCACCTGCAC AGTTTCCGGA 7501 GTAAGTCTGC CTGATTACGG AGTGTCCTGG ATCAGACAGC CACCTCGAAA GGGCTTGGAG 7561 TGGCTTGGGG TCATTTGGGG CAGTGAAACC ACATACTACA ACAGCGCTCT TAAGTCCAGG 7621 CTCACTATCA TCAAGGACAA TTCAAAGAGC CAAGTATTCT TGAAAATGAA TTCCCTGCAG 7681 ACTGATGACA CCGCTATTTA TTATTGCGCT A A AC ATT ATT ACTATGGAGG TTCTTATGCC 7741 AT GG ACT ACT GGGGGCAGGG TACCTCTGTG ACAGTGAGTT CAGCTGCAGC TGGAGGTGGA 7801 GGTAGCGGAG GCGGTGGTAG TGGAGGGGGT GGTTCTCTGG AAGATAAACA ACTTGATGCA 7861 GATGTTTCCC CCAAGCCCAC TATTTTTCTT CCTTCAATTG CT G A A AC AAA GCTCCAGAAG

7981 CAAGAAAAGA AGAGCAACAC GATTCTGGGA TCCCAGGAGG GGAACACCAT GAAGACTAAC 8041 GACACATACA TGAAATTTAG CTGGTTAACG GTGCCAGAAA AGTCACTGGA CAAAGAACAC 8101 AGATGTATCG TCAGACATGA G AAT A AT AAA AACGGAGTTG ATCAAGAAAT TATCTTTCCT 8161 CCA AT A A AG A C AG AT GT CAT CACAATGGAT CCCAAAGACA ATT GTT C A A A AG AT GCA A AT 8221 GAT AC ACT AC TGCTGCAGCT CACAAACACC TCTGCATATT ACATGTACCT CCTCCTGCTC 8281 CTCAAGAGTG TGGTCTATTT TGCCATCATC ACCTGCTGTC TGCTTAGAAG AACGGCTTTC 8341 TGCTGCAATG GAG AG A A AT C ATAATGAGAT ATCGAGCATC TTACCGCCAT TTATACCCAT

8461 GGCAATCATT TACATTTTTA GGGATATGTA ATT ACT AGTT CAGGTGTATT GCCACAAGAC 8521 AAACATGTTA AGAAACTTTC CCGTTATTTA CGCTCTGTTC CTGTTAATCA ACCTCTGGAT 8581 TACAAAATTT GTGAAAGATT GACTGATATT CTTAACTATG TTGCTCCTTT TACGCTGTGT 8641 GGATATGCTG CTTTATAGCC TCTGTATCTA GCTATTGCTT CCCGTACGGC TTTCGTTTTC 8701 TCCTCCTTGT ATAAATCCTG GTTGCTGTCT CTTTTAGAGG AGTTGTGGCC CGTTGTCCGT 8761 CAACGTGGCG TGGTGTGCTC TGTGTTTGCT GACGCAACCC CCACTGGCTG GGGCATTGCC 8821 ACCACCTGTC AACTCCTTTC TGGGACTTTC GCTTTCCCCC TCCCGATCGC CACGGCAGAA 8881 CTCATCGCCG CCTGCCTTGC CCGCTGCTGG ACAGGGGCTA GGTTGCTGGG C ACT GAT A AT 8941 TCCGTGGTGT TGTCAGTACT GGT ACCTTT A AGACCAATGA CTTACAAGGC AGCTGTAGAT 9001 CTTAGCCACT TTTTAAAAGA AAAGGGGGGA CTGGAAGGGC TAATTCACTC CCAAAGAAGA 9061 CAAGATCTGC TTTTTGCCTG TACTGGGTCT CTCTGGTTAG ACCAGATCTG AGCCTGGGAG 9121 CTCTCTGGCT AACTAGGGAA CCCACTGCTT AAGCCT C A AT AAAGCTTGCC TTGAGTGCTT 9181 CAATGATCAT AATCAAGCCA TATCACATCT GTAGAGGTTT ACTTGCTTTA AAAAACCTCC 9241 ACACCTCCCC CTGAACCTGA A AC AT A A A AT G A AT GCA ATT GTT GTT GTT A ACTTGTTTAT 9301 TGCAGCTTAT AATGGTTACA AATAAAGCAA TAGCATCACA AATTTCACAA ATAAAGCATT 9361 TTTTTCACTG CATTCTAGTT GTGGTTTGTC CAAACTCATC AATGTATCTT ATCATGTCTG 9421 GATCTGCGTC GACACGAAGA GACGACTGAC TGACTGACTG GAAAGAGGAA GGGCTGGAAG 9481 AGGAAGGAGC TTGATCCAGA TCCCGATCTC GATCCAGATC CGGATCGCAG CTTGGCGTAA 9541 TCATGGTCAT AGCTGTTTCC TGTGTGAAAT TGTTATCCGC TCACAATTCC ACACAACATA 9601 CGAGCCGGAA GCATAAAGTG TAAAGCCTGG GGTGCCTAAT GAGTGAGCTA ACTCACATTA 9661 ATTGCGTTGC GCTCACTGCC CGCTTTCCAG TCGGGAAACC TGTCGTGCCA GCTGCATTAA 9721 TGAATCGGCC AACGCGCGGG GAGAGGCGGT TTGCGTATTG GGCGCTCTTC CGCTTCCTCG 9781 CTC ACT G ACT CGCTGCGCTC GGTCGTTCGG CTGCGGCGAG CGGTATCAGC TCACTCAAAG 9841 GCGGTAATAC GGTTATCCAC AGAATCAGGG GATAACGCAG GAAAGAACAT GTGAGCAAAA 9901 GGCCAGCAAA AGGCCAGGAA CCGTAAAAAG GCCGCGTTGC TGGCGTTTTT CCATAGGCTC 9961 CGCCCCCCTG ACGAGCATCA CAAAAATCGA CGCTCAAGTC AGAGGTGGCG AAACCCGACA 10021 GG ACT AT AAA GATACCAGGC GTTTCCCCCT GGAAGCTCCC TCGTGCGCTC TCCTGTTCCG 10081 ACCCTGCCGC TTACCGGATA CCTGTCCGCC TTTCTCCCTT CGGGAAGCGT GGCGCTTTCT 10141 CATAGCTCAC GCTGTAGGTA TCTCAGTTCG GTGTAGGTCG TTCGCTCCAA GCTGGGCTGT 10201 GTGCACGAAC CCCCCGTTCA GCCCGACCGC TGCGCCTTAT CCGGTAACTA TCGTCTTGAG 10261 TCCAACCCGG TAAGACACGA CTTATCGCCA CTGGCAGCAG CCACTGGTAA CAGGATTAGC 10321 AGAGCGAGGT ATGTAGGCGG TGCTACAGAG TTCTTGAAGT GGTGGCCTAA CTACGGCTAC 10381 ACTAGAAGAA CAGTATTTGG TATCTGCGCT CTGCTGAAGC CAGTTACCTT CGGAAAAAGA 10441 GTTGGTAGCT CTTGATCCGG CAAACAAACC ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC 10501 AAGCAGCAGA TTACGCGCAG AAAAAAAGGA TCTCAAGAAG ATCCTTTGAT CTTTTCTACG 10561 GGGTCTGACG CTCAGTGGAA CGAAAACTCA CGTTAAGGGA TTTTGGTCAT GAGATTATCA 10621 AAAAGGATCT TCACCTAGAT CCTTTTAAAT T AAA A AT G A A GTTTTAAATC A AT CT A AAGT 10681 ATA pLKaUS FMC63 TRDC P2AW FMC63op TRGC1 (SEQ ID NO: 182)

1 TGATCATAAT C AAGCCAT AT C AC AT CT GT A GAGGTTT ACT T GCTTT AAA A AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT TTCACAAATA AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC AT GT CT GG AT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGCAGCTT GGTCTTCCGC 361 TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA 421 CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG

541 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 601 CCCGACAGGA CT AT AAA GAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 661 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 721 GCTTT CTC AT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 781 GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GT A ACT AT CG 841 TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG 901 GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA 961 CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG 1021 AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT 1081 TGTTTGCAAG CAGCAGATTA CGCGCAGAAA A A A AGG AT CT C A AG A AG AT C CTTTGATCTT 1141 TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG 1201 TT A ATT A ACT TGCGCCGTCC CGTCAAGTCA GCGTAATGCT CTGCCAGTGT TACAACCAAT 1261 TAACCAATTC T GATT AG AAA A ACT CAT CG A GCATCAAATG A A ACT GC AAT TTATTCACAT 1321 CAGGATTATC A AT ACC AT AT TTTTGAAAAA GCCGTTTCTG TAATGAAGGA GAAAACTCAC 1381 CGAGGCAGTT CCATAGGATG GCAAGATCCT GGTATCGGTC TGCGATTCCG ACTCGTCCAA 1441 CATCAATACA ACCT ATT AAT TTCCCCTCGT CAAAAATAAG GTTATCAAGT GAGAAATCAC 1501 CATGAGTGAC GACTGAATCC GGTGAGAATG GCAAAAGTTT ATGCATTTCT TTCCAGACTT 1561 GTTCAACAGG CCAGCC ATT A CGCTCGTCAT CAAAATCACT CGCATCAACC AAACCGTTAT 1621 TCATTCGTGA TTGCGCCTGA GCAAGACGAA ATACGCGATC GCTGTTAAAA GGACAATTAC 1681 AAACAGGAAT CGAATGCAAC CGGCGCAGGA ACACTGCCAG CGCATCAACA ATATTTTCAC 1741 CTGAATCAGG ATATTCTTCT AATACCTGGA ATGCTGTTTT TCCGGGGATC GCAGTGGTGA 1801 GTAACCATGC ATCATCAGGA GTACGGATAA AATGCTTGAT GGTCGGAAGA GGCATAAATT 1861 CCGTCAGCCA GTTTAGTCTG ACCATCTCAT CT GT A AC AT C ATTGGCAACG CTACCTTTGC 1921 CATGTTTCAG AAACAACTCT GGCGCATCGG GCTTCCCATA CAAGCGATAG ATTGTCGCAC 1981 CTGATTGCCC GACATTATCG CGAGCCCATT TATACCCATA TAAATCAGCA TCCATGTTGG 2041 AATTTAATCG CGGCCTCGAC GTTTCCCGTT GAATATGGCT CATAACACCC CTTGTATTAC 2101 TGTTTATGTA AGCAGACAGT TTTATTGTTC ATGATGATAT ATTTTTATCT TGTGCAATGT 2161 AACATCAGAG ATTTT GAG AC ACAACGTGGC TTTCCCCCCC CCCCCCATGA CATTAACCTA 2221 T AAA AAT AGG CGTATCACGA GGCCAGCTTG GGAAACCATA AGACCGAGAT AGAGTTGAGT 2281 GTTGTTCCAG TTTGGAACAA GAGTCCACTA TTAAAGAACG TGGACTCCAA CGTCAAAGGG 2341 CGAAAAACCG TCTATCAGGG CGATGGCCCA CTACGTGAAC CATCACCCAA ATCAAGTTTT 2401 TTGGGGTCGA GGTGCCGTAA AGCACTAAAT CGGAACCCTA AAGGGAGCCC CCGATTTAGA 2461 GCTTGACGGG GAAAGCCGGC GAACGTGGCG AGAAAGGAAGGGAAGAAAGCGAAAGGAGCG 2521 GGCGCTAAGG CGCTGGCAAG TGTAGCGGTC ACGCTGCGCG TAACCACCAC ACCCGCCGCG 2581 CTTAATGCGC CGCTACAGGG CGCGTACTAT GGTTGCTTTG ACGTATGCGG TGTGAAATAC 2641 CGCACAGATG CGTAAGGAGA AAATACATCG TGATCCGGAT CAAGATCCAG ATCGAATTGG 2701 AGGCTACAGT CAGTGGAGAG GACTTTCACT GACTGACTGA CTGCGTCTCA ACCTCCTAGG 2761 GG AC ATT GAT TATTGACTAG TT ATT AAT AG T AAT C A ATT A CGGGGTCATT AGTTCATAGC 2821 CCATATATGG AGTTCCGCGT TACATAACTT ACGGTAAATG GCCCGCCTGG CTGACCGCCC 2881 AACGACCCCC GCCCATTGAC GTCAATAATG ACGTATGTTC CCATAGTAAC GCCAATAGGG 2941 ACTTTCCATT GACGTCAATG GGTGGAGTAT TT ACGGT AAA CTGCCCACTT GGCAGTACAT 3001 CAAGTGTATC ATATGCCAAG TACGCCCCCT ATTGACGTCA ATGACGGTAA ATGGCCCGCC 3061 TGGCATTATG CCCAGTACAT GACCTTATGG GACTTTCCTA CTTGGCAGTA CATCTACGTA 3121 TTAGTCATCG CT ATT ACC AT GGTGATGCGG TTTTGGCAGT ACATCAATGG GCGTGGATAG 3181 CGGTTTGACT CACGGGGATT TCCAAGTCTC CACCCCATTG ACGTCAATGG GAGTTTGTTT 3241 TGGCACCAAA ATCAACGGGA CTTT CCA A A A TGTCGTAACA ACTCCGCCCC ATTGACGCAA 3301 ATGGGCGGTA GGCGTGTACG GTGGGAGGTC TATATAAGCA GAGCTCGTTT AGTGAACCGG 3361 GTCTCTCTGG TTAGACCAGA TCTGAGCCTG GGAGCTCTCT GGCTAACTAG GGAACCCACT 3421 GCTT AAGCCT CAATAAAGCT TGCCTTGAGT GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG 3481 TGACTCTGGT AACTAGAGAT CCCTCAGACC CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG 3541 TGGCGCCCGA ACAGGGACTT GAAAGCGAAA GTAAAGCCAG AGGAGATCTC TCGACGCAGG 3601 ACTCGGCTTG CTGAAGCGCG CACGGCAAGA GGCGAGGGGC GGCGACTGGT GAGTACGCCA 3661 AAAATTTTGA CTAGCGGAGG CTAGAAGGAG AGAGTAGGGT GCGAGAGCGT CGGTATTAAG 3721 CGGGGGAGAA TT AG AT A A AT GGGAAAAAAT TCGGTTAAGG CCAGGGGGAA AG A A AC A AT A 3781 TAAACTAAAA CATATAGTTA GGGCAAGCAG GGAGCTAGAA CGATTCGCAG TTAATCCTGG 3841 CCTTTTAGAG ACATCAGAAG GCTGTAGACA AATACTGGGA CAGCTACAAC CATCCCTTCA 3901 GACAGGATCA GAAGAACTTA GATCATTATA T A AT AC A AT A GCAGTCCTCT ATTGTGTGCA 3961 TCAAAGGATA GATGTAAAAG ACACCAAGGA AGCCTTAGAT AAGATAGAGG AAGAGCAAAA 4021 CAAAAGT AAG AAAAAGGCAC AGCAAGCGAT CTTCAGACCT GGAGGAGGCA GGAGGCGATA 4081 TGAGGGACAA TTGGAGAAGT G A ATT AT AT A A AT AT A A AGT AGT A A A A ATT GAACCATTAG 4141 GAGTAGCACC CACCAAGGCA AAGAGAAGAG TGGTGCAGAG AGAAAAAAGAGCAGTGGGAA 4201 TAGGAGCTTT GTTCCTTGGG TTCTTGGGAG CAGCAGGAAG CACTATGGGC GCAGCGTCAA 4261 TGACGCTGAC GGTACAGGCC AGACAATTAT TGTCTGATAT AGTGCAGCAG CAGAACAATT 4321 TGCTGAGGGC TATTGAGGCG CAACAGCATC TGTTGCAACT CACAGTCTGG GGCATCAAAC 4381 AGCTCCAGGC AAGAATCCTG GCTGTGGAAA GATACCTAAA GGATCAACAG CTCCTGGGGA 4441 TTTGGGGTTG CTCTGGAAAA CTCATTTGCA CCACTGCTGT GCCTTGGAAT GCTAGTTGGA 4501 GTAATAAATC TCTGGAACAG ATTT GG A AT A ACATGACCTG GATGGAGTGG GACAGAGAAA 4561 TT A AC A ATT A CACAAGCTTA ATACACTCCT TAATTGAAGA ATCGCAAAAC CAGCAAGAAA 4621 AGAATGAACA AG A ATT ATT G G A ATT AG AT A A AT GGGC A AG TTTGTGGAAT TGGTTT AAC A 4681 TAACAAATTG GCTGTGGTAT ATAAAATTAT TCATAATGAT AGTAGGAGGC TTGGTAGGTT 4741 T AAG A AT AGT TTTTGCTGTA CTTTCTATAG TGAATAGAGT TAGGCAGGGA TATTCACCAT 4801 TATCGTTTCA GACCCACCTC CCAATCCCGA GGGGACCACG CGTACAAATG GC AGT ATT C A 4861 TCCACAATTT TAAAAGAAAA GGGGGGATTG GGGGGTACAG TGCAGGGGAA AGAATAGTAG 4921 ACATAATAGC AACAGACATA C A A ACT A A AG A ATT AC A A A A AC A A ATT AC A AAAATTCAAA 4981 ATTTTCGGGT TTATTACAGG GACAGCAGAA ATCCACTTTG GAAAGCTGAG CATCCGGCTC 5041 CGGTGCCCGT CAGTGGGCAG AGCGCACATC GCCCACAGTC CCCGAGAAGT TGGGGGGAGG 5101 GGTCGGCAAT TGAACCGGTG CCTAGAGAAG GTGGCGCGGG GTAAACTGGG AAAGTGATGT 5161 CGTGTACTGG CTCCGCCTTT TTCCCGAGGG TGGGGGAGAA CCGTATATAA GTGCAGTAGT 5221 CGCCGTGAAC GTTCTTTTTC GCAACGGGTT TGCCGCCAGA ACACAGGTAA GTGCCGTGTG 5281 TGGTTCCCGC GGGCCTGGCC TCTTTACGGG TTATGGCCCT TGCGTGCCTT GAATTACTTC 5341 CACGCCCCTG GCTGCAGTAC GTGATTCTTG ATCCCGAGCT TCGGGTTGGA AGTGGGTGGG 5401 AGAGTTCGAG GCCTTGCGCT TAAGGAGCCC CTTCGCCTCG TGCTTGAGTT GAGGCCTGGC 5461 CTGGGCGCTG GGGCCGCCGC GTGCGAATCT GGTGGCACCT TCGCGCCTGT CTCGCTGCTT 5521 TCGATAAGTC TCTAGCCATT TAAAATTTTT GATGACCTGC TGCGACGCTT TTTTTCTGGC 5581 AAGATAGTCT TGTAAATGCG GGCCAAGATC TGCACACTGG TATTTCGGTT TTTGGGGCCG 5641 CGGGCGGCGA CGGGGCCCGT GCGTCCCAGC GCACATGTTC GGCGAGGCGG GGCCTGCGAG 5701 CGCGGCCACC GAGAATCGGA CGGGGGTAGT CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG 5761 GCCTCGCGCC GCCGTGTATC GCCCCGCCCT GGGCGGCAAG GCTGGCCCGG TCGGCACCAG 5821 TTGCGTGAGC GGAAAGATGG CCGCTTCCCG GCCCTGCTGC AGGGAGCTCA AAATGGAGGA 5881 CGCGGCGCTC GGGAGAGCGG GCGGGTGAGT CACCCACACA AAGGAAAAGG GCCTTTCCGT 5941 CCTCAGCCGT CGCTTCATGT GACTCCACGG AGTACCGGGC GCCGTCCAGG CACCTCGATT 6001 AGTTCTCGAG CTTTTGGAGT ACGTCGTCTT TAGGTTGGGG GGAGGGGTTT TATGCGATGG 6061 AGTTTCCCCA CACTGAGTGG GTGGAGACTG AAGTTAGGCC AGCTTGGCAC TTGATGTAAT 6121 TCTCCTTGGA ATTTGCCCTT TTTGAGTTTG GATCTTGGTT CATTCTCAAG CCTCAGACAG 6181 TGGTTCAAAG TTTTTTTCTT CCATTTCAGG TGTCGTGAAA ACTACCCCTC AGAGCCGCCA 6241 CCATGCTTCT CCTGGTGACA AGCCTTCTGC TCTGTGAGTT ACCACACCCA GCATTCCTCC 6301 TGATCCCAGA CATCCAGATG ACACAGACTA CATCCTCCCT GTCTGCCTCT CTGGGAGACA 6361 GAGTCACCAT CAGTTGCAGG GCAAGTCAGG ACATTAGTAA ATATTTAAAT TGGTATCAGC 6421 AGAAACCAGA TGGAACTGTT AAACTCCTGA TCTACCATAC ATCAAGATTA CACTCAGGAG 6481 TCCCATCAAG GTTCAGTGGC AGTGGGTCTG G A AC AG ATT A TTCTCTCACC ATT AGC AACC 6541 TGGAGCAAGA AGATATTGCC ACTTACTTTT GCCAACAGGG TAATACGCTT CCGTACACGT 6601 TCGGAGGGGG GACTAAGTTG GAAATAACAG GCTCCACCTC TGGATCCGGC AAGCCCGGAT 6661 CTGGCGAGGG ATCCACCAAG GGCGAGGTGA AACTGCAGGA GTCAGGACCT GGCCTGGTGG 6721 CGCCCTCACA GAGCCTGTCC GTCACATGCA CTGTCTCAGG GGTCTCATTA CCCGACTATG 6781 GTGTAAGCTG GATTCGCCAG CCTCCACGAA AGGGTCTGGA GTGGCTGGGA GTAATATGGG 6841 GTAGTGAAAC CACATACTAT AATTCAGCTC TCAAATCCAG ACTGACCATC ATCAAGGACA 6901 ACTCCAAGAG CCAAGTTTTC TTAAAAATGA ACAGTCTGCA AACTGATGAC ACAGCCATTT 6961 ACTACTGTGC CAAACATTAT TACTACGGTG GTAGCTATGC TATGGACTAC TGGGGTCAAG 7021 GAACCTCAGT CACCGTCTCC TCAGCGGCCG CAGGTGGAGG AGGTTCTGGA GGTGGTGGAT 7081 CAGGTGGTGG AGGATCTTTA GAAAGTCAGC CTCATACCAA ACCATCCGTT TTTGTCATGA 7141 AAAATGGAAC AAATGTCGCT TGTCTGGTGA AGGAATTCTA CCCCAAGGAT AT A AG A AT A A 7201 ATCTCGTGTC ATCCAAGAAG ATAACAGAGT TTGATCCTGC TATTGTCATC TCTCCCAGTG 7261 GGAAGTACAA TGCTGTCAAG CTT GGT A A AT AT G A AG ATT C AAATTCAGTG ACATGTTCAG 7321 TTCAACACGA CAATAAAACT GTGCACTCCA CTGACTTTGA AGTGAAGACA GATTCTACAG 7381 ATCACGTAAA ACCAAAGGAA ACT G A A A AC A CAAAGCAACC TTCAAAGAGC TGCCATAAAC 7441 CCAAAGCCAT AGTTCATACC GAGAAGGTGA ACATGATGTC CCTCACAGTG CTTGGGCTAC 7501 GAATGCTGTT TGCAAAGACT GTTGCCGTCA ATTTTCTCTT GACTGCCAAG TTATTTTTCT 7561 TGGGGTCAGG CGCTACTAAC TTCAGCCTGC TGAAGCAGGC TGGAGACGTG GAGGAGAACC 7621 CTGGACCTAT GCTACTACTT GTGACCTCAC TATTGTTATG CGAACTCCCT CATCCCGCAT 7681 TCTTGCTGAT TCCAGACATT CAGATGACTC AAACAACTTC CAGCCTCTCC GCCTCACTCG 7741 GCGACCGCGT AACAATAAGC TGTCGGGCCT CGCAAGATAT TAGTAAGTAC CTGAATTGGT 7801 ATCAGCAAAA ACCCGATGGT ACAGTCAAGC TTCTGATCTA CCATACCAGT CGTCTGCACA 7861 GCGGTGTCCC CAGCAGGTTC AGCGGCTCAG GATCTGGTAC CGATTATTCA CTGACGATTT 7921 CCAACCTTGA GCAaGAGGAC ATCGCCACCT ACTTCTGCCA GCAGGGTAAT ACTCTGCCGT 7981 ACACATTCGG GGGCGGTACC AAGCTCGAGA TCACGGGTTC AACAAGCGGT TCTGGCAAGC 8041 CAGGCAGCGG CGAGGGGAGT ACAAAGGGGG AGGTGAAGTT GCAGGAAAGT GGCCCTGGAT 8101 TGGTGGCCCC GAGCCAGAGT CTGTCTGTCA CCTGCACAGT TTCCGGAGTA AGTCTGCCTG 8161 ATTACGGAGT GTCCTGGATC AGACAGCCAC CTCGAAAGGG CTTGGAGTGG CTTGGGGTCA 8221 TTTGGGGCAG TGAAACCACA TACTACAACA GCGCTCTTAA GTCCAGGCTC ACTATCATCA 8281 AGGACAATTC AAAGAGCCAA GTATTCTTGA AAATGAATTC CCTGCAGACT GATGACACCG 8341 CTATTTATTA TTGCGCTAAA CATTATTACT ATGGAGGTTC TTATGCCATG GACTACTGGG 8401 GGCAGGGTAC CTCTGTGACA GTGAGTTCAG CTGCAGCTGG AGGTGGAGGT AGCGGAGGCG 8461 GTGGTAGTGG AGGGGGTGGT TCTCTGGAAG AT A A AC A ACT TGATGCAGAT GTTTCCCCCA 8521 AGCCCACTAT TTTTCTTCCT TCAATTGCTG AAACAAAGCT CCAGAAGGCT GG A AC AT ACC 8581 TTTGTCTTCT TGAGAAATTT TTCCCTGATG TTATTAAGAT ACATTGGCAA GAAAAGAAGA 8641 GCAACACGAT TCTGGGATCC CAGGAGGGGA ACACCATGAA GACTAACGAC AC AT AC AT G A 8701 AATTTAGCTG GTTAACGGTG CCAGAAAAGT CACTGGACAA AGAACACAGA TGTATCGTCA 8761 GACATGAGAA TAATAAAAAC GGAGTTGATC A AG A A ATT AT CTTTCCTCCA ATAAAGACAG 8821 ATGTCATCAC AATGGATCCC AAAGACAATT GTTCAAAAGA TGCAAATGAT AC ACT ACT GC 8881 TGCAGCTCAC AAACACCTCT GCATATTACA TGTACCTCCT CCTGCTCCTC AAGAGTGTGG 8941 TCTATTTTGC CATCATCACC TGCTGTCTGC TT AG A AG A AC GGCTTTCTGC TGCAATGGAG 9001 AG A A AT CAT A ATGAGATATC GAGCATCTTA CCGCCATTTA TACCCATATT TGTTCTGTTT 9061 TTCTTGATTT GGGTATACAT TTAAATGTTA AT A A A AC A A A ATGGTGGGGC AATCATTTAC 9121 ATTTTTAGGG AT AT GT A ATT ACTAGTTCAG GTGTATTGCC ACAAGACAAA CAT GTT A AG A 9181 AACTTTCCCG TTATTTACGC TCTGTTCCTG TTAATCAACC TCTGGATTAC AAAATTTGTG 9241 AA AG ATT G AC TGATATTCTT AACTATGTTG CTCCTTTTAC GCTGTGTGGA TATGCTGCTT 9301 TATAGCCTCT GTATCTAGCT ATTGCTTCCC GTACGGCTTT CGTTTTCTCC TCCTTGTATA 9361 AATCCTGGTT GCTGTCTCTT TTAGAGGAGT TGTGGCCCGT TGTCCGTCAA CGTGGCGTGG 9421 TGTGCTCTGT GTTTGCTGAC GCAACCCCCA CTGGCTGGGG CATTGCCACC ACCTGTCAAC 9481 TCCTTTCTGG GACTTTCGCT TTCCCCCTCC CGATCGCCAC GGCAGAACTC ATCGCCGCCT 9541 GCCTTGCCCG CTGCTGGACA GGGGCTAGGT TGCTGGGCAC T GAT A ATT CC GTGGTGTTGT 9601 CAGTACTGGT ACCTTTAAGA CCAATGACTT ACAAGGCAGC TGTAGATCTT AGCCACTTTT 9661 TAAAAGAAAA GGGGGGACTG GAAGGGCTAA TTCACTCCCA AAGAAGACAA GATCTGCTTT 9721 TTGCCTGTAC TGGGTCTCTC TGGTTAGACC AGATCTGAGC CTGGGAGCTC TCTGGCTAAC 9781 TAGGGAACCC ACTGCTTAAG CCTCAATAAA GCTTGCCTTG AGTGCTTCAA GTAGTGTGTG 9841 CCCGTCTGTT GTGTGACTCT GGTAACTAGA GATCCCTCAG ACCCTTTTAG TCAGTGTGGA 9901 AAATCTCTAG CA pLRPC TRDC T2AW FMC63op TRGC1 (SEQ ID NO: 183)

241 CACAGGTAAG TGCCGTGTGT GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT 301 GCGTGCCTTG AATTACTTCC ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT 361 CGGGTTGGAA GTGGGTGGGA GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT 421 GCTTGAGTTG AGGCCTGGCC TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT 481 CGCGCCTGTC TCGCTGCTTT CGATAAGTCT CTAGCCATTT AAAATTTTTG ATGACCTGCT 541 GCGACGCTTT TTTTCTGGCA AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT 601 ATTTCGGTTT TTGGGGCCGC GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG 661 GCGAGGCGGG GCCTGCGAGC GCGGCCACCG AGAATCGGAC GGGGGTAGTC TCAAGCTGGC 721 CGGCCTGCTC TGGTGCCTGG CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG 781 CTGGCCCGGT CGGCACCAGT TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA 841 GGGAGCTCAA AATGGAGGAC GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA 901 AGGAAAAGGG CCTTTCCGTC CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG 961 CCGTCCAGGC ACCTCGATTA GTTCTCGAGC TTTTGGAGTA CGTCGTCTTT AGGTTGGGGG 1021 GAGGGGTTTT ATGCGATGGA GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA 1081 GCTTGGCACT TGATGTAATT CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC 1141 ATTCTCAAGC CTCAGACAGT GGTTCAAAGT TTTTTTCTTC CATTTCAGGT GTCGTGAAAA 1201 CTACCCCTCT AGAGCCGCCA CCATGCTTCT CCTGGTGACA AGCCTTCTGC TCTGTGAGTT 1261 ACCACACCCA GCATTCCTCC TGATCCCAAG TCAGCCTCAT ACCAAACCAT CCGTTTTTGT 1321 CATGAAAAAT GGAACAAATG TCGCTTGTCT GGTGAAGGAA TTCTACCCCA AGGATATAAG 1381 AATAAATCTC GTGTCATCCA AGAAGATAAC AG AGTTT GAT CCTGCTATTG TCATCTCTCC 1441 CAGTGGGAAG TACAATGCTG TCAAGCTTGG TAAATATGAA GATTCAAATT CAGTGACATG 1501 TTCAGTTCAA CACGACAATA AAACTGTGCA CTCCACTGAC TTTGAAGTGA AGACAGATTC 1561 TACAGATCAC GTAAAACCAA AGGAAACTGA AAACACAAAG CAACCTTCAA AGAGCTGCCA 1621 TAAACCCAAA GCCATAGTTC ATACCGAGAA GGTGAACATG ATGTCCCTCA CAGTGCTTGG 1681 GCTACGAATG CTGTTTGCAA AGACTGTTGC CGTCAATTTT CTCTTGACTG CC AAGTT ATT 1741 TTTCTTGGGG TCAGGCGAGG GCAGAGGAAG TCTGCTAACA TGCGGTGACG TCGAGGAGAA 1801 TCCTGGACCT AT GCT ACT AC TTGTGACCTC ACTATTGTTA TGCGAACTCC CTCATCCCGC 1861 ATTCTTGCTG ATTCCAGACA TTCAGATGAC TCAAACAACT TCCAGCCTCT CCGCCTCACT 1921 CGGCGACCGC GTAACAATAA GCTGTCGGGC CTCGCAAGAT ATTAGTAAGT ACCTGAATTG 1981 GTATCAGCAA AAACCCGATG GTACAGTCAA GCTTCTGATC TACCATACCA GTCGTCTGCA 2041 CAGCGGTGTC CCCAGCAGGT TCAGCGGCTC AGGATCTGGT ACCGATTATT CACTGACGAT 2101 TTCCAACCTT GAGCAGGAGG ACATCGCCAC CTACTTCTGC CAGCAGGGTA ATACTCTGCC 2161 GTACACATTC GGGGGCGGTA CCAAGCTCGA GATCACGGGT TCAACAAGCG GTTCTGGCAA 2221 GCCAGGCAGC GGCGAGGGGA GTACAAAGGG GGAGGTGAAG TTGCAGGAAA GTGGCCCTGG 2281 ATTGGTGGCC CCGAGCCAGA GTCTGTCTGT CACCTGCACA GTTTCCGGAG TAAGTCTGCC 2341 TGATTACGGA GTGTCCTGGA TCAGACAGCC ACCTCGAAAG GGCTTGGAGT GGCTTGGGGT 2401 CATTTGGGGC AGTGAAACCA CAT ACT AC A A CAGCGCTCTT AAGTCCAGGC TCACTATCAT 2461 CAAGGACAAT TCAAAGAGCC AAGTATTCTT GAAAATGAAT TCCCTGCAGA CTGATGACAC 2521 CGCTATTTAT TATTGCGCTA AACATTATTA CTATGGAGGT TCTTATGCCA TGGACTACTG 2581 GGGGCAGGGT ACCTCTGTGA CAGTGAGTTC AGCTGCAGCT GGAGGTGGAG GTAGCGGAGG 2641 CGGTGGTAGT GGAGGGGGTG GTTCTCTGGA AGATAAACAA CTTGATGCAG ATGTTTCCCC 2701 C A AGC CC ACT ATTTTTCTTC CTTCAATTGC T G A A AC A A AG CTCCAGAAGG CTGGAACATA 2761 CCTTTGTCTT CTTGAGAAAT TTTTCCCTGA TGTTATTAAG AT AC ATTGGC AAGAAAAGAA 2821 GAGCAACACG ATTCTGGGAT CCCAGGAGGG GAACACCATG AAGACTAACG ACACATACAT 2881 GAAATTTAGC TGGTTAACGG TGCCAGAAAA GTCACTGGAC AAAGAACACA GATGTATCGT 2941 CAGACATGAG A AT A AT A AAA ACGGAGTTGA TC A AG A A ATT ATCTTTCCTC CAATAAAGAC 3001 AGATGTCATC ACAATGGATC CCAAAGACAA TTGTTCAAAA GATGCAAATG ATACACTACT 3061 GCTGCAGCTC ACAAACACCT CTGCATATTA CATGTACCTC CTCCTGCTCC TCAAGAGTGT 3121 GGTCTATTTT GCCATCATCA CCTGCTGTCT GCTTAGAAGA ACGGCTTTCT GCTGCAATGG 3181 AGAGAAATCA T A AT GAG AT A TCGAGCATCT TACCGCCATT TAT ACC CAT A TTTGTTCTGT 3241 TTTTCTTGAT TTGGGTATAC ATTTAAATGT T AAT A A A AC A AAATGGTGGG GCAATCATTT

3361 GAAACTTTCC CGTTATTTAC GCTCTGTTCC TGTTAATCAA CCTCTGGATT ACAAAATTTG 3421 TGAAAGATTG ACTGATATTC TTAACTATGT TGCTCCTTTT ACGCTGTGTG GATATGCTGC 3481 TTTATAGCCT CTGTATCTAG CTATTGCTTC CCGTACGGCT TTCGTTTTCT CCTCCTTGTA 3541 TAAATCCTGG TTGCTGTCTC TTTTAGAGGA GTTGTGGCCC GTTGTCCGTC AACGTGGCGT 3601 GGTGTGCTCT GTGTTTGCTG ACGCAACCCC CACTGGCTGG GGCATTGCCA CCACCTGTCA 3661 ACTCCTTTCT GGGACTTTCG CTTTCCCCCT CCCGATCGCC ACGGCAGAAC TCATCGCCGC 3721 CTGCCTTGCC CGCTGCTGGA CAGGGGCTAG GTTGCTGGGC ACTGATAATT CCGTGGTGTT 3781 GTCAGTACTG GTACCTTTAA GACCAATGAC TTACAAGGCA GCTGTAGATC TTAGCCACTT 3841 TTT AAA AG A A AAGGGGGGAC TGGAAGGGCT AATTCACTCC CAAAGAAGAC AAGATCTGCT 3901 TTTTGCCTGT ACTGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA 3961 ACT AGGGAAC CCACTGCTTA AGCCTC AAT A A AGCTT GCCT TGAGTGCTTC AATGATCATA 4021 ATCAAGCCAT ATCACATCTG TAGAGGTTTA CTTGCTTTAA AAAACCTCCA CACCTCCCCC 4081 TGAACCTGAA AC AT A A A AT G AATGCAATTG TTGTTGTTAA CTTGTTTATT GC AGCTT AT A 4141 AT GGTT AC A A AT AAAGC AAT AGCATCACAA ATTTCACAAA TAAAGCATTT TTTTCACTGC 4201 ATTCTAGTTG TGGTTTGTCC AAACTCATCA ATGTATCTTA TCATGTCTGG ATCTGCGTCG 4261 ACACGAAGAG ACGACTGACT GACTGACTGG AAAGAGGAAG GGCTGGAAGA GGAAGGAGCT 4321 TGATCCAGAT CCCGATCTCG ATCCAGATCC GGATCGCAGC TTGGCGTAAT CATGGTCATA 4381 GCTGTTTCCT GTGTGAAATT GTTATCCGCT CACAATTCCA CACAACATAC GAGCCGGAAG 4441 CATAAAGTGT AAAGCCTGGG GTGCCTAATG AGTGAGCTAA CT C AC ATT A A TTGCGTTGCG 4501 CTCACTGCCC GCTTTCCAGT CGGGAAACCT GTCGTGCCAG CTGCATTAAT GAATCGGCCA 4561 ACGCGCGGGG AGAGGCGGTT TGCGTATTGG GCGCTCTTCC GCTTCCTCGC TCACTGACTC 4621 GCTGCGCTCG GTCGTTCGGC TGCGGCGAGC GGTATCAGCT CACTCAAAGG CGGTAATACG 4681 GTTATCCACA GAATCAGGGG ATAACGCAGG AAAGAACATG TGAGCAAAAG GCCAGCAAAA

4801 CGAGCATCAC AAAAATCGAC GCTCAAGTCA GAGGTGGCGA AACCCGACAG GACTATAAAG 4861 ATACCAGGCG TTTCCCCCTG GAAGCTCCCT CGTGCGCTCT CCTGTTCCGA CCCTGCCGCT 4921 TACCGGATAC CTGTCCGCCT TTCTCCCTTC GGGAAGCGTG GCGCTTTCTC ATAGCTCACG 4981 CTGTAGGTAT CTCAGTTCGG TGTAGGTCGT TCGCTCCAAG CTGGGCTGTG TGCACGAACC 5041 CCCCCGGT AA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATT AGC AG A 5101 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 5161 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT 5221 GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT TGTTTGCAAG 5281 CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT TTCTACGGGG 5341 TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG ATTATCAAAA 5401 AGGATCTTCA CCTAGATCCT TTT AA ATT A A AAATGAAGTT TTAAATCAAT CTAAAGTATA 5461 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 5521 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTTGCTAG GTTACTGTCA 5581 TGAGCGGATA CATATTTGAA TGTATTTAGA AAAATAAACA AAAGAGTTTG TAGAAACGCA 5641 AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT CGGTGGCAGT TTATGGCGGG 5701 CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT TCAAATCCGC TCCCGGCGGA 5761 TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA TAAAACGAAA GGCCCAGTCT 5821 TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC CCTACTCTCG CATGGGTTGC 5881 GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT TATCATCGAA TTTCTGCCAT 5941 TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG CGTTTAAGGG CACCAATAAC 6001 TGCCTT A A A A AAATTACGCC CCGCCCTGCC ACT CAT CGC A GT ACTGTTGT A ATT C ATT A A 6061 GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG AACCTGAATC GCCAGCGGCA 6121 TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT GAAAACGGGG GCGAAGAAGT 6181 TGTCCATATT GGCCACGTTT AA AT C A A A AC TGGTGAAACT CACCCAGGGA TTGGCTGAGA 6241 CGAAAAACAT ATTCTCAATA AACCCTTTAG GGAAATAGGC CAGGTTTTCA CCGTAACACG 6301 CCACATCTTG CG A AT AT AT G T GT AG A A ACT GCCGGAAATC GTCGTGGTAT T C ACT CC AG A 6361 GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA ACAAGGGTGA ACACTATCCC 6421 ATATCACCAG CTCACCGTCT TTCATTGCCA TACGAAATTC CGGATGAGCA TTCATCAGGC 6481 GGGCAAGAAT GTGAATAAAG GCCGGATAAA ACTTGTGCTT ATTTTTCTTT ACGGTCTTTA 6541 AAAAGGCCGT AATATCCAGC TGAACGGTCT GGTTATAGGT ACATTGAGCA ACTGACTGAA 6601 AT GCCT C A A A ATGTTCTTTA CGATGCCATT GGGATATATC AACGGTGGTA TATCCAGTGA

6721 CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC TCTTACGTGC CGATCAACGT 6781 CTCATTTTCG CCAAAAGTGA CATTAACCTA TAAAAATAGG CGTATCACGA GGCCAGCTTG 6841 GGAAACCATA AGACCGAGAT AGAGTTGAGT GTTGTTCCAG TTTGGAACAA GAGTCCACTA 6901 TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG TCTATCAGGG CGATGGCCCA 6961 CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA GGTGCCGTAA AGCACTAAAT 7021 CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG GAAAGCCGGC GAACGTGGCG 7081 AGAAAGGAAG GGAAGAAAGC GAAAGGAGCG GGCGCTAAGG CGCTGGCAAGTGTAGCGGTC 7141 ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC CGCTACAGGG CGCGTACTAT 7201 GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG CGT AAGGAGA AAATACCGCA 7261 TCAGGCGCCA TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGATCG GTGCGGGCCT 7321 CTTCGCTATT ACGCCAGCTG GCGAAAGGGG GATGTGCTGC AAGGCG ATT A AGTTGGGTAA 7381 CGCCAGGGTT TTCCCAGTCA CGACGTTGTA AAACGACGGC CAGTGAATTG ATCGAGATCG 7441 TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT CAGTGGAGAG GACTTTCACT 7501 GACTGACTGA CTGCGTCTCA ACCTCCTAGG GG AC ATT GAT TATTGACTAG TT ATT A AT AG 7561 TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG AGTTCCGCGT TACATAACTT 7621 ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC GCCCATTGAC GTCAATAATG 7681 ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT GACGTCAATG GGTGGAGTAT 7741 TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC ATATGCCAAG TACGCCCCCT 7801 ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG CCCAGTACAT GACCTTATGG 7861 GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG CTATTACCAT GGTGATGCGG 7921 TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT CACGGGGATT TCCAAGTCTC 7981 CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA ATCAACGGGA CTTTCCAAAA 8041 TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA GGCGTGTACG GTGGGAGGTC 8101 TATATAAGCA GAGCTCGTTT AGTGAACCGG GTCTCTCTGG TTAGACCAGA TCTGAGCCTG 8161 GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT CAATAAAGCT TGCCTTGAGT 8221 GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT AACTAGAGAT CCCTCAGACC 8281 CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA ACAGGGACTT GAAAGCGAAA 8341 GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG CTGAAGCGCG CACGGCAAGA 8401 GGCGAGGGGC GGCGACTGGT GAGTACGCCA AAAATTTTGA CTAGCGGAGG CTAGAAGGAG 8461 AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA TT AG AT AA AT GGGAAAAAAT 8521 TCGGTTAAGG CCAGGGGGAA AGAAACAATA T A A ACT A A A A CATATAGTTA GGGCAAGCAG 8581 GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTT AG AG ACATCAGAAG GCTGTAGACA 8641 AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA GAAGAACTTA GATCATTATA 8701 TAATACAATA GCAGTCCTCT ATTGTGTGCA TCAAAGGATA GATGTAAAAG ACACCAAGGA 8761 AGCCTT AG AT A AG AT AG AGG AAGAGCAAAA CAAAAGTAAG AAAAAGGCACAGCAAGCGAT 8821 CTTCAGACCT GGAGGAGGCA GGAGGCGATA TGAGGGACAA TTGGAGAAGT G A ATT AT AT A 8881 AAT AT A A AGT AGTAAAAATT G A ACC ATT AG GAGTAGCACC CACCAAGGCA AAGAGAAGAG 8941 TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT GTTCCTTGGG TTCTTGGGAG 9001 CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC GGTACAGGCC AGACAATTAT 9061 TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC TATTGAGGCG CAACAGCATC 9121 TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC AAGAATCCTG GCTGTGGAAA 9181 GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG CTCTGGAAAA CTCATTTGCA 9241 CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC TCTGGAACAG ATTTGGAATA 9301 ACATGACCTG GATGGAGTGG GACAGAGAAA TTAACAATTA CACAAGCTTA ATACACTCCT 9361 TAATTGAAGA ATCGCAAAAC CAGCAAGAAA AGAATGAACA AG A ATT ATT G GAATT AG AT A 9421 AATGGGCAAG TTTGTGGAAT TGGTTTAACA T A AC A A ATT G GCTGTGGTAT ATAAAATTAT 9481 T CAT A ATG AT AGTAGGAGGC TTGGTAGGTT T A AG AAT AGT TTTTGCTGTA CTTTCTATAG 9541 TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA GACCCACCTC CCAATCCCGA 9601 GGGGACCACG CGTACAAATG GCAGTATTCA TCCACAATTT TAAAAGAAAA GGGGGGATTG 9661 GGGGGTACAG TGCAGGGGAA AGAATAGTAG AC AT AAT AGC AACAGACATA C A A ACT AA AG 9721 AATT AC A A A A AC AA ATT AC A A A A ATT C A A A ATTTTCGGGT TT ATT AC AGG GACAGCAGAA 9781 ATCCACTTTG G pLRPC FMC63 TRDC T2AW TRGC1 (SEQ ID NO: 184)

1 AAAGCTGAGC ATCCGGCTCC GGTGCCCGTC AGTGGGCAGA GCGCACATCG CCCACAGTCC 61 CCGAGAAGTT GGGGGGAGGG GTCGGCAATT GAACCGGTGC CT AG AG A AGG TGGCGCGGGG 121 TAAACTGGGA AAGTGATGTC GTGTACTGGC TCCGCCTTTT TCCCGAGGGT GGGGGAGAAC

241 CACAGGTAAG TGCCGTGTGT GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT 301 GCGTGCCTTG AATTACTTCC ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT 361 CGGGTTGGAA GTGGGTGGGA GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT 421 GCTTGAGTTG AGGCCTGGCC TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT 481 CGCGCCTGTC TCGCTGCTTT CGATAAGTCT CTAGCCATTT AAAATTTTTG ATGACCTGCT 541 GCGACGCTTT TTTTCTGGCA AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT 601 ATTTCGGTTT TTGGGGCCGC GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG 661 GCGAGGCGGG GCCTGCGAGC GCGGCCACCG AGAATCGGAC GGGGGTAGTC TCAAGCTGGC 721 CGGCCTGCTC TGGTGCCTGG CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG 781 CTGGCCCGGT CGGCACCAGT TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA 841 GGGAGCTCAA AATGGAGGAC GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA 901 AGGAAAAGGG CCTTTCCGTC CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG 961 CCGTCCAGGC ACCTCGATTA GTTCTCGAGC TTTTGGAGTA CGTCGTCTTT AGGTTGGGGG 1021 GAGGGGTTTT ATGCGATGGA GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA 1081 GCTTGGCACT TGATGTAATT CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC 1141 ATTCTCAAGC CTCAGACAGT GGTTCAAAGT TTTTTTCTTC CATTTCAGGT GTCGTGAAAA 1201 CTACCCCTCT AGAGCCGCCA CCATGCTTCT CCTGGTGACA AGCCTTCTGC TCTGTGAGTT 1261 ACCACACCCA GCATTCCTCC TGATCCCAGA CATCCAGATG ACACAGACTA CATCCTCCCT 1321 GTCTGCCTCT CTGGGAGACA GAGTCACCAT CAGTTGCAGG GCAAGTCAGG AC ATT AGT A A 1381 ATATTTAAAT TGGTATCAGC AGAAACCAGA TGGAACTGTT AAACTCCTGA TCTACCATAC 1441 ATCAAGATTA CACTCAGGAG TCCCATCAAG GTTCAGTGGC AGTGGGTCTG GAACAGATTA 1501 TTCTCTCACC ATTAGCAACC TGGAGCAAGA AG AT ATT GCC ACTTACTTTT GCCAACAGGG 1561 TAATACGCTT CCGTACACGT TCGGAGGGGG GACTAAGTTG GAAATAACAG GCTCCACCTC 1621 TGGATCCGGC AAGCCCGGAT CTGGCGAGGG ATCCACCAAG GGCGAGGTGA AACTGCAGGA 1681 GTCAGGACCT GGCCTGGTGG CGCCCTCACA GAGCCTGTCC GTCACATGCA CTGTCTCAGG 1741 GGTCTCATTA CCCGACTATG GTGTAAGCTG GATTCGCCAG CCTCCACGAA AGGGTCTGGA 1801 GTGGCTGGGA GTAATATGGG GT AGT G A A AC C AC AT ACT AT A ATT C AGCT C TCAAATCCAG 1861 ACTGACCATC ATCAAGGACA ACTCCAAGAG CCAAGTTTTC TTAAAAATGA ACAGTCTGCA 1921 AACTGATGAC ACAGCCATTT ACT ACTGTGC C A A AC ATT AT TACTACGGTG GTAGCTATGC 1981 TATGGACTAC TGGGGTCAAG GAACCTCAGT CACCGTCTCC TCAGCGGCCG CAGGTGGAGG 2041 AGGTTCTGGA GGTGGTGGAT CAGGTGGTGG AGGATCTTTA GAAAGTCAGC CTCATACCAA 2101 ACCATCCGTT TTTGT CATGA A A A AT GG A AC AAATGTCGCT TGTCTGGTGA AGGAATTCTA 2161 CCCCAAGGAT AT A AG A AT A A ATCTCGTGTC ATCCAAGAAG ATAACAGAGT TTGATCCTGC 2221 TATTGTCATC TCTCCCAGTG GGAAGTACAA TGCTGTCAAG CTTGGTAAAT ATGAAGATTC 2281 AAATTCAGTG ACATGTTCAG TTCAACACGA CAATAAAACT GTGCACTCCA CTGACTTTGA 2341 AGTGAAGACA GATTCTACAG ATCACGTAAA ACCAAAGGAA ACTGAAAACA CAAAGCAACC 2401 TTCAAAGAGC T GCC AT A A AC CCAAAGCCAT AGTTCATACC GAGAAGGTGA AC AT GAT GT C 2461 CCTCACAGTG CTTGGGCTAC GAATGCTGTT TGCAAAGACT GTTGCCGTCA ATTTTCTCTT 2521 GACTGCCAAG TTATTTTTCT TGGGGTCAGG CGAGGGCAGA GGAAGTCTGC TAACATGCGG 2581 TGACGTCGAG GAGAATCCTG GACCTATGCT ACTACTTGTG ACCT C ACT AT TGTTATGCGA 2641 ACTCCCTCAT CCCGCATTCT TGCTGATTCC AGATAAACAA CTTGATGCAG ATGTTTCCCC 2701 C A AGC CC ACT ATTTTTCTTC CTTCAATTGC T G A A AC A A AG CTCCAGAAGG CTGGAACATA 2761 CCTTTGTCTT CTTGAGAAAT TTTTCCCTGA TGTTATTAAG ATACATTGGC AAGAAAAGAA 2821 GAGCAACACG ATTCTGGGAT CCCAGGAGGG GAACACCATG AAGACTAACG ACACATACAT 2881 GAAATTTAGC TGGTTAACGG TGCCAGAAAA GTCACTGGAC AAAGAACACA GATGTATCGT 2941 CAGACATGAG A AT A AT A AAA ACGGAGTTGA TC A AG A A ATT ATCTTTCCTC CAATAAAGAC 3001 AGATGTCATC ACAATGGATC CCAAAGACAA TTGTTCAAAA GATGCAAATG ATACACTACT 3061 GCTGCAGCTC ACAAACACCT CTGCATATTA CATGTACCTC CTCCTGCTCC TCAAGAGTGT 3121 GGTCTATTTT GCCATCATCA CCTGCTGTCT GCTTAGAAGA ACGGCTTTCT GCTGCAATGG 3181 AGAGAAATCA T A AT GAG AT A TCGAGCATCT TACCGCCATT T AT ACC CAT A TTTGTTCTGT 3241 TTTTCTTGAT TTGGGTATAC ATTTAAATGT T AAT A A A AC A AAATGGTGGG GCAATCATTT

3361 GAAACTTTCC CGTTATTTAC GCTCTGTTCC TGTTAATCAA CCTCTGGATT ACAAAATTTG 3421 TGAAAGATTG ACTGATATTC TTAACTATGT TGCTCCTTTT ACGCTGTGTG GATATGCTGC 3481 TTTATAGCCT CTGTATCTAG CTATTGCTTC CCGTACGGCT TTCGTTTTCT CCTCCTTGTA 3541 TAAATCCTGG TTGCTGTCTC TTTTAGAGGA GTTGTGGCCC GTTGTCCGTC AACGTGGCGT 3601 GGTGTGCTCT GTGTTTGCTG ACGCAACCCC CACTGGCTGG GGCATTGCCA CCACCTGTCA 3661 ACTCCTTTCT GGGACTTTCG CTTTCCCCCT CCCGATCGCC ACGGCAGAAC TCATCGCCGC 3721 CTGCCTTGCC CGCTGCTGGA CAGGGGCTAG GTTGCTGGGC ACTGATAATT CCGTGGTGTT 3781 GTCAGTACTG GT ACCTTT A A GACCAATGAC TTACAAGGCA GCTGTAGATC TTAGCCACTT 3841 TTT AAA AG A A AAGGGGGGAC TGGAAGGGCT AATTCACTCC CAAAGAAGAC AAGATCTGCT 3901 TTTTGCCTGT ACTGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC TCTCTGGCTA 3961 ACT AGGGAAC CCACTGCTTA AGCCTC AAT A AAGCTTGCCT TGAGTGCTTC AATGATCATA 4021 ATCAAGCCAT ATCACATCTG TAGAGGTTTA CTTGCTTTAA AAAACCTCCA CACCTCCCCC 4081 TGAACCTGAA AC AT A A A AT G AATGCAATTG TTGTTGTTAA CTTGTTTATT GC AGCTT AT A 4141 ATGGTTACAA AT AAAGC AAT AGCATCACAA ATTTCACAAA TAAAGCATTT TTTTCACTGC 4201 ATTCTAGTTG TGGTTTGTCC AAACTCATCA ATGTATCTTA TCATGTCTGG ATCTGCGTCG 4261 ACACGAAGAG ACGACTGACT GACTGACTGG AAAGAGGAAG GGCTGGAAGA GGAAGGAGCT 4321 TGATCCAGAT CCCGATCTCG ATCCAGATCC GGATCGCAGC TTGGCGTAAT CATGGTCATA 4381 GCTGTTTCCT GTGTGAAATT GTTATCCGCT CACAATTCCA CACAACATAC GAGCCGGAAG 4441 CATAAAGTGT AAAGCCTGGG GTGCCTAATG AGTGAGCTAA CTCACATTAA TTGCGTTGCG 4501 CTCACTGCCC GCTTTCCAGT CGGGAAACCT GTCGTGCCAG CTGCATTAAT GAATCGGCCA 4561 ACGCGCGGGG AGAGGCGGTT TGCGTATTGG GCGCTCTTCC GCTTCCTCGC TCACTGACTC 4621 GCTGCGCTCG GTCGTTCGGC TGCGGCGAGC GGTATCAGCT CACTCAAAGG CGGTAATACG 4681 GTTATCCACA GAATCAGGGG AT AACGC AGG A A AG A AC AT G TGAGCAAAAG GCCAGCAAAA

4801 CGAGCATCAC AAAAATCGAC GCTCAAGTCA GAGGTGGCGA AACCCGACAG GACTATAAAG 4861 ATACCAGGCG TTTCCCCCTG GAAGCTCCCT CGTGCGCTCT CCTGTTCCGA CCCTGCCGCT 4921 TACCGGATAC CTGTCCGCCT TTCTCCCTTC GGGAAGCGTG GCGCTTTCTC ATAGCTCACG 4981 CTGTAGGTAT CTCAGTTCGG TGTAGGTCGT TCGCTCCAAG CTGGGCTGTG TGCACGAACC 5041 CCCCCGGT AA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATTAGCAGA 5101 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 5161 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT 5221 GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT TGTTTGCAAG 5281 CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT TTCTACGGGG 5341 TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG ATTATCAAAA 5401 AGGATCTTCA CCTAGATCCT TTTAAATTAA AAATGAAGTT TTAAATCAAT CTAAAGTATA 5461 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 5521 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTTGCTAG GTTACTGTCA 5581 TGAGCGGATA CATATTTGAA TGTATTTAGA AAAATAAACA AAAGAGTTTG TAGAAACGCA 5641 AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT CGGTGGCAGT TTATGGCGGG 5701 CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT TCAAATCCGC TCCCGGCGGA 5761 TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA TAAAACGAAA GGCCCAGTCT 5821 TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC CCTACTCTCG CATGGGTTGC 5881 GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT TATCATCGAA TTTCTGCCAT 5941 TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG CGTTTAAGGG CACCAATAAC 6001 TGCCTTAAAA AAATTACGCC CCGCCCTGCC ACTCATCGCA GTACTGTTGT AATTCATTAA 6061 GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG AACCTGAATC GCCAGCGGCA 6121 TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT GAAAACGGGG GCGAAGAAGT 6181 TGTCCATATT GGCCACGTTT AA AT C A A A AC TGGTGAAACT CACCCAGGGA TTGGCTGAGA 6241 CGAAAAACAT ATT CT C A AT A AACCCTTT AG GGAAATAGGC C AGGTTTT C A CCGTAACACG 6301 CCACATCTTG CGAATATATG TGTAGAAACT GCCGGAAATC GTCGTGGTAT TCACTCCAGA 6361 GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA ACAAGGGTGA ACACTATCCC 6421 ATATCACCAG CTCACCGTCT TTCATTGCCA TACGAAATTC CGGATGAGCA TTCATCAGGC 6481 GGGCAAGAAT GTGAATAAAG GCCGGATAAA ACTTGTGCTT ATTTTTCTTT ACGGTCTTTA 6541 AAAAGGCCGT A AT AT CC AGC TGAACGGTCT GGTTATAGGT ACATTGAGCA ACTGACTGAA 6601 ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC AACGGTGGTA TATCCAGTGA

6721 CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC TCTTACGTGC CGATCAACGT 6781 CTCATTTTCG CCAAAAGTGA CATTAACCTA TAAAAATAGG CGTATCACGA GGCCAGCTTG 6841 GGAAACC AT A AGACCGAGAT AGAGTTGAGT GTTGTTCCAG TTTGGAACAA GAGTCCACTA 6901 TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG TCTATCAGGG CGATGGCCCA 6961 CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA GGTGCCGTAA AGC ACT A A AT 7021 CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG GAAAGCCGGC GAACGTGGCG 7081 AGAAAGGAAG GGAAGAAAGC GAAAGGAGCG GGCGCTAAGG CGCTGGCAAGTGTAGCGGTC 7141 ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC CGCTACAGGG CGCGTACTAT 7201 GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG CGTAAGGAGA AAATACCGCA 7261 TCAGGCGCCA TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGATCG GTGCGGGCCT 7321 CTTCGCTATT ACGCCAGCTG GCGAAAGGGG GATGTGCTGC AAGGCG ATT A AGTTGGGTAA 7381 CGCCAGGGTT TTCCCAGTCA CGACGTTGTA AAACGACGGC CAGTGAATTG ATCGAGATCG 7441 TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT CAGTGGAGAG GACTTTCACT 7501 GACTGACTGA CTGCGTCTCA ACCTCCTAGG GGACATTGAT TATTGACTAG TT ATT A AT AG 7561 TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG AGTTCCGCGT TACATAACTT 7621 ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC GCCCATTGAC GTCAATAATG 7681 ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT GACGTCAATG GGTGGAGTAT 7741 TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC ATATGCCAAG TACGCCCCCT 7801 ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG CCC AGT AC AT GACCTTATGG 7861 GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG CTATTACCAT GGTGATGCGG 7921 TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT CACGGGGATT TCCAAGTCTC 7981 CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA ATCAACGGGA CTTTCCAAAA 8041 TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA GGCGTGTACG GTGGGAGGTC 8101 T AT AT AAGC A GAGCTCGTTT AGTGAACCGG GTCTCTCTGG TTAGACCAGA TCTGAGCCTG 8161 GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT CAATAAAGCT TGCCTTGAGT 8221 GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT AACTAGAGAT CCCTCAGACC 8281 CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA ACAGGGACTT GAAAGCGAAA 8341 GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG CTGAAGCGCG CACGGCAAGA 8401 GGCGAGGGGC GGCGACTGGT GAGTACGCCA A A A ATTTT G A CTAGCGGAGG CT AG A AGG AG 8461 AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA TTAGATAAAT GGGAAAAAAT 8521 TCGGTTAAGG CCAGGGGGAA AGAAACAATA T A A ACT A A A A CATATAGTTA GGGCAAGCAG 8581 GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTT AG AG ACATCAGAAG GCTGTAGACA 8641 AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA GAAGAACTTA GATCATTATA 8701 T AAT AC A AT A GCAGTCCTCT ATT GT GT GCA T C A A AGG AT A GAT GT AAA AG ACACCAAGGA 8761 AGCCTTAGAT AAGATAGAGG AAGAGCAAAA CAAAAGTAAG AAAAAGGCACAGCAAGCGAT 8821 CTTCAGACCT GGAGGAGGCA GGAGGCGATA TGAGGGACAA TTGGAGAAGT G A ATT AT AT A 8881 AAT AT A A AGT AGTAAAAATT G A ACC ATT AG GAGTAGCACC CACCAAGGCA AAGAGAAGAG 8941 TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT GTTCCTTGGG TTCTTGGGAG 9001 CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC GGTACAGGCC AGACAATTAT 9061 TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC TATTGAGGCG CAACAGCATC 9121 TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC AAGAATCCTG GCTGTGGAAA 9181 GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG CTCTGGAAAA CTCATTTGCA 9241 CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC TCTGGAACAG ATTTGGAATA 9301 ACATGACCTG GAT GG AGT GG GACAGAGAAA TT AAC A ATT A C AC AAGCTT A ATACACTCCT 9361 TAATTGAAGA ATCGCAAAAC CAGCAAGAAA AGAATGAACA AG A ATT ATT G GAATT AG AT A 9421 AATGGGCAAG TTTGTGGAAT TGGTTTAACA T A AC A A ATT G GCTGTGGTAT ATAAAATTAT 9481 T CAT A ATG AT AGTAGGAGGC TTGGTAGGTT T A AG AAT AGT TTTTGCTGTA CTTTCTATAG 9541 TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA GACCCACCTC CCAATCCCGA 9601 GGGGACCACG CGTACAAATG GCAGTATTCA TCCACAATTT T AAA AG A A A A GGGGGGATTG 9661 GGGGGTACAG TGCAGGGGAA AGAATAGTAG ACATAATAGC AAC AG AC AT A CAAACTAAAG 9721 AATT AC A A A A AC AA ATT AC A A A A ATT C A A A ATTTTCGGGT TT ATT AC AGG GACAGCAGAA 9781 ATCCACTTTG G pLRPCU TRDC T2AW FMC63op TRGC1 (SEQ ID NO: 185)

1 GACATTGATT ATT G ACT AGT TATTAATAGT A AT C A ATT AC GGGGTCATTA GTTCATAGCC 61 CATATATGGA GTTCCGCGTT ACATAACTTA CGGTAAATGG CCCGCCTGGC TGACCGCCCA 121 ACGACCCCCG CCCATTGACG TCAATAATGA CGTATGTTCC CATAGTAACG CCAATAGGGA 181 CTTTCCATTG ACGTCAATGG GTGGAGTATT TACGGTAAAC TGCCCACTTG GCAGTACATC 241 AAGTGTATCA TATGCCAAGT ACGCCCCCTA TTGACGTCAA TGACGGTAAA TGGCCCGCCT 301 GGCATTATGC CCAGTACATG ACCTTATGGG ACTTTCCTAC TTGGCAGTAC ATCTACGTAT 361 TAGTCATCGC T ATT ACC AT G GTGATGCGGT TTTGGCAGTA CATCAATGGG CGTGGATAGC 421 GGTTTGACTC ACGGGGATTT CCAAGTCTCC ACCCCATTGA CGTCAATGGG AGTTTGTTTT 481 GGCACCAAAA TCAACGGGAC TTTCCAAAAT GTCGTAACAA CTCCGCCCCA TTGACGCAAA 541 TGGGCGGTAG GCGTGTACGG TGGGAGGTCT ATATAAGCAG AGCTCGTTTA GTGAACCGGG 601 TCTCTCTGGT TAGACCAGAT CTGAGCCTGG GAGCTCTCTG GCTAACTAGG GAACCCACTG 661 CTTAAGCCTC A AT A A AGCTT GCCTTGAGTG CTCAAAGTAG TGTGTGCCCG TCTGTTGTGT 721 GACTCTGGTA ACTAGAGATC CCTCAGACCC TTTTAGTCAG TGTGGAAAAT CTCTAGCAGT 781 GGCGCCCGAA CAGGGACTTG AAAGCGAAAG TAAAGCCAGA GGAGATCTCT CGACGCAGGA 841 CTCGGCTTGC TGAAGCGCGC ACGGCAAGAG GCGAGGGGCG GCGACTGGTG AGTACGCCAA 901 AAATTTTGAC TAGCGGAGGC TAGAAGGAGA GAGTAGGGTG CGAGAGCGTC GGTATTAAGC 961 GGGGGAGAAT TAGATAAATG GGAAAAAATT CGGTTAAGGC CAGGGGGAAA GA AAC A AT AT 1021 AAACT AAAAC ATATAGTTAG GGCAAGCAGG GAGCTAGAAC GATTCGCAGT TAATCCTGGC 1081 CTTTTAGAGA CATCAGAAGG CTGTAGACAA ATACTGGGAC AGCTACAACC ATCCCTTCAG 1141 ACAGGATCAG AAGAACTTAG ATCATTATAT A AT AC A AT AG CAGTCCTCTA TTGTGTGCAT 1201 CAAAGGATAG ATGTAAAAGA CACCAAGGAA GCCTTAGATA AGATAGAGGA AGAGC AAAAC 1261 AAAAGTAAGA AAAAGGCACA GCAAGCGATC TTCAGACCTG GAGGAGGCAG GAGGCGATAT 1321 GAGGGACAAT TGGAGAAGTG A ATT AT AT A A AT AT A A AGT A GT A A A A ATT G AACCATTAGG 1381 AGTAGCACCC ACCAAGGCAA AGAGAAGAGT GGTGCAGAGA GAAAAAAGAGCAGTGGGAAT 1441 AGGAGCTTTG TTCCTTGGGT TCTTGGGAGC AGCAGGAAGC ACTATGGGCG CAGCGTCAAT 1501 GACGCTGACG GTACAGGCCA GACAATTATT GTCTGATATA GTGCAGCAGC AGAACAATTT 1561 GCTGAGGGCT ATTGAGGCGC AACAGCATCT GTTGCAACTC ACAGTCTGGG GCATCAAACA 1621 GCTCCAGGCA AGAATCCTGG CTGTGGAAAG ATACCTAAAG GATCAACAGC TCCTGGGGAT 1681 TTGGGGTTGC TCTGGAAAAC TCATTTGCAC CACTGCTGTG CCTTGGAATG CTAGTTGGAG 1741 TAATAAATCT CTGGAACAGA TTTGGAATAA CATGACCTGG ATGGAGTGGG ACAGAGAAAT 1801 TAACAATTAC ACAAGCTTAA TACACTCCTT AATTGAAGAA TCGCAAAACC AGCAAGAAAA 1861 GAATGAACAA GAATTATTGG AATT AG AT A A ATGGGCAAGT TT GT GG A ATT GGTTT AAC AT 1921 AACAAATTGG CTGTGGTATA TAAAATTATT CATAATGATA GTAGGAGGCT TGGTAGGTTT 1981 AAGAAT AGTT TTTGCTGTAC TTTCTATAGT GAATAGAGTT AGGCAGGGAT ATTCACCATT 2041 ATCGTTTCAG ACCCACCTCC CAATCCCGAG GGGACCACGC GTACAAATGG CAGTATTCAT 2101 CCACAATTTT AAAAGAAAAG GGGGGATTGG GGGGTACAGT GCAGGGGAAA GAATAGTAGA 2161 CAT AAT AGC A ACAGACATAC AAACT AAAGA ATT AC A A A A A C A A ATT AC A A A A ATT C A A A A 2221 TTTTCGGGTT TATTACAGGG ACAGCAGAAA TCCACTTTGG AAAGCTGAGC ATCCGGCTCC 2281 GGTGCCCGTC AGTGGGCAGA GCGCACATCG CCCACAGTCC CCGAGAAGTT GGGGGGAGGG 2341 GTCGGCAATT GAACCGGTGC CTAGAGAAGG TGGCGCGGGG TAAACTGGGA AAGTGATGTC 2401 GTGTACTGGC TCCGCCTTTT TCCCGAGGGT GGGGGAGAAC CGTATATAAG TGCAGTAGTC 2461 GCCGTGAACG TTCTTTTTCG CAACGGGTTT GCCGCCAGAA CACAGGTAAG TGCCGTGTGT 2521 GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT GCGTGCCTTG AATTACTTCC 2581 ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT CGGGTTGGAA GTGGGTGGGA 2641 GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT GCTTGAGTTG AGGCCTGGCC 2701 TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT CGCGCCTGTC TCGCTGCTTT

2821 AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT ATTTCGGTTT TTGGGGCCGC 2881 GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG GCGAGGCGGG GCCTGCGAGC 2941 GCGGCCACCG AG A AT CGG AC GGGGGTAGTC TCAAGCTGGC CGGCCTGCTC TGGTGCCTGG 3001 CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG CTGGCCCGGT CGGCACCAGT 3061 TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA GGGAGCTCAA AATGGAGGAC 3121 GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA AGGAAAAGGG CCTTTCCGTC 3181 CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG CCGTCCAGGC ACCTCGATTA 3241 GTTCTCGAGC TTTTGGAGT A CGTCGTCTTT AGGTT GGGGG GAGGGGTTTT ATGCGATGGA 3301 GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA GCTTGGCACT TGATGTAATT 3361 CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC ATTCTCAAGC CTCAGACAGT

3481 CATGCTTCTC CTGGTGACAA GCCTTCTGCT CTGTGAGTTA CCACACCCAG CATTCCTCCT 3541 GATCCCAAGT CAGCCTCATA CCAAACCATC CGTTTTTGTC ATGAAAAATG G A AC AA AT GT 3601 CGCTTGTCTG GTGAAGGAAT TCTACCCCAA GGATATAAGA ATAAATCTCG TGTCATCCAA 3661 GAAGATAACA GAGTTTGATC CTGCTATTGT CATCTCTCCC AGTGGGAAGT ACAATGCTGT 3721 CAAGCTTGGT AAATATGAAG ATTCAAATTC AGTGACATGT TCAGTTCAAC ACGACAATAA 3781 AACTGTGCAC TCCACTGACT TTGAAGTGAA GACAGATTCT ACAGATCACG T A A A ACC A A A 3841 GGAAACTGAA AACACAAAGC AACCTTCAAA GAGCTGCCAT AAACCCAAAG CCATAGTTCA 3901 TACCGAGAAG GTGAACATGA TGTCCCTCAC AGTGCTTGGG CTACGAATGC TGTTTGCAAA 3961 GACTGTTGCC GTCAATTTTC TCTTGACTGC CAAGTTATTT TTCTTGGGGT CAGGCGAGGG 4021 CAGAGGAAGT CTGCT AAC AT GCGGTGACGT CGAGGAGAAT CCTGGACCTA TGCTACTACT 4081 TGTGACCTCA CTATTGTTAT GCGAACTCCC TCATCCCGCA TTCTTGCTGA TTCCAGACAT 4141 T CAGAT G ACT CAAACAACTT CCAGCCTCTC CGCCTCACTC GGCGACCGCG T A AC A AT A AG 4201 CTGTCGGGCC TCGCAAGATA TTAGTAAGTA CCTGAATTGG TATCAGCAAA AACCCGATGG 4261 TACAGTCAAG CTTCTGATCT ACC AT ACC AG TCGTCTGCAC AGCGGTGTCC CCAGC AGGTT 4321 CAGCGGCTCA GGATCTGGTA CCGATTATTC ACTGACGATT TCCAACCTTG AGCAGGAGGA 4381 CATCGCCACC TACTTCTGCC AGCAGGGTAA TACTCTGCCG TACACATTCG GGGGCGGTAC 4441 CAAGCTCGAG ATCACGGGTT CAACAAGCGG TTCTGGCAAG CCAGGCAGCG GCGAGGGGAG 4501 TACAAAGGGG GAGGTGAAGT TGCAGGAAAG TGGCCCTGGA TTGGTGGCCC CGAGCCAGAG 4561 TCTGTCTGTC ACCTGCACAG TTTCCGGAGT AAGTCTGCCT GATTACGGAG TGTCCTGGAT 4621 CAGACAGCCA CCTCGAAAGG GCTTGGAGTG GCTTGGGGTC ATTTGGGGCA GTGAAACCAC 4681 ATACTACAAC AGCGCTCTTA AGTCCAGGCT CACTATCATC AAGGACAATT CAAAGAGCCA 4741 AGTATTCTTG AAAATGAATT CCCTGCAGAC TGATGACACC GCTATTTATT ATTGCGCTAA 4801 ACATTATTAC TATGGAGGTT CTTATGCCAT GGACTACTGG GGGCAGGGTA CCTCTGTGAC 4861 AGTGAGTTCA GCTGCAGCTG GAGGTGGAGG TAGCGGAGGC GGTGGTAGTG GAGGGGGTGG 4921 TTCTCTGGAA GATAAACAAC TTGATGCAGA TGTTTCCCCC AAGCCCACTA TTTTTCTTCC 4981 TTCAATTGCT GAAACAAAGC TCCAGAAGGC TGGAACATAC CTTTGTCTTC TTGAGAAATT 5041 TTTCCCTGAT GTTATTAAGA TACATTGGCA AGAAAAGAAG AGCAACACGA TTCTGGGATC 5101 CCAGGAGGGG A AC ACC AT G A AG ACT AACGA C AC AT AC AT G AAATTTAGCT GGTTAACGGT 5161 GCCAGAAAAG TCACTGGACA AAGAACACAG ATGTATCGTC AGACATGAGA ATAATAAAAA 5221 CGGAGTTGAT CAAGAAATTA TCTTTCCTCC AAT A A AG AC A GATGTCATCA CAATGGATCC 5281 CAAAGACAAT TGTTCAAAAG ATGCAAATGA T AC ACT ACT G CTGCAGCTCA CAAACACCTC 5341 TGCATATTAC ATGTACCTCC TCCTGCTCCT CAAGAGTGTG GTCTATTTTG CCATCATCAC 5401 CTGCTGTCTG CTT AG A AG A A CGGCTTTCTG CTGCAATGGA GAGAAATCAT AAT GAG AT AT 5461 CGAGCATCTT ACCGCCATTT ATACCCATAT TTGTTCTGTT TTTCTTGATT TGGGTATACA 5521 TTTAAATGTT AAT AAA AC A A AATGGTGGGG CAATCATTTA CATTTTTAGG GATATGTAAT 5581 T ACT AGTT C A GGTGTATTGC CACAAGACAA ACATGTTAAG AAACTTTCCC GTTATTTACG 5641 CTCTGTTCCT GTTAATCAAC CTCTGGATTA CAAAATTTGT GAAAGATTGA CTGATATTCT 5701 TAACTATGTT GCTCCTTTTA CGCTGTGTGG ATATGCTGCT TTATAGCCTC TGTATCTAGC 5761 TATTGCTTCC CGTACGGCTT TCGTTTTCTC CTCCTTGTAT AAATCCTGGT TGCTGTCTCT 5821 TTTAGAGGAG TTGTGGCCCG TTGTCCGTCA ACGTGGCGTG GTGTGCTCTG TGTTTGCTGA 5881 CGCAACCCCC ACTGGCTGGG GCATTGCCAC CACCTGTCAA CTCCTTTCTG GGACTTTCGC 5941 TTTCCCCCTC CCGATCGCCA CGGCAGAACT CATCGCCGCC TGCCTTGCCC GCTGCTGGAC 6001 AGGGGCT AGG TTGCTGGGCA CTGATAATTC CGTGGTGTTG TCAGTACTGG T ACCTTT AAG 6061 ACCAATGACT TACAAGGCAG CTGTAGATCT TAGCCACTTT TT AAAAGAAA AGGGGGGACT 6121 GGAAGGGCTA ATTCACTCCC AAAGAAGACA AGATCTGCTT TTTGCCTGTA CTGGGTCTCT 6181 CTGGTTAGAC CAGATCTGAG CCTGGGAGCT CTCTGGCTAA CTAGGGAACC C ACT GCTT A A 6241 GCCTCAATAA AGCTTGCCTT GAGTGCTTCA AGTAGTGTGT GCCCGTCTGT TGTGTGACTC 6301 TGGTAACTAG AGATCCCTCA GACCCTTTTA GTCAGTGTGG AAAATCTCTA GCATGATCAT 6361 AATCAAGCCA TATCACATCT GTAGAGGTTT ACTTGCTTTA AAAAACCTCC ACACCTCCCC 6421 CTGAACCTGA A AC AT A A A AT GAATGCAATT GTTGTTGTTA ACTTGTTTAT TGCAGCTTAT 6481 AATGGTTACA AATAAAGCAA TAGCATCACA AATTTCACAA AT AAAGCATT TTTTTCACTG 6541 CATTCTAGTT GTGGTTTGTC CAAACTCATC AAT GT AT CTT ATCATGTCTG GATCTGCGTC 6601 GACACGAAGA GACGACTGAC TGACTGACTG GAAAGAGGAA GGGCTGGAAGAGGAAGGAGC 6661 TTGATCCAGA TCCCGATCTC GATCCAGATC CGGATCGCAG CTTGGCGTAA TCATGGTCAT 6721 AGCTGTTTCC TGTGTGAAAT TGTTATCCGC TCACAATTCC ACACAACATA CGAGCCGGAA 6781 GCATAAAGTG TAAAGCCTGG GGTGCCTAAT GAGTGAGCTA ACTC AC ATT A ATT GCGTT GC 6841 GCTCACTGCC CGCTTTCCAG TCGGGAAACC TGTCGTGCCA GCTGCATTAA TGAATCGGCC 6901 AACGCGCGGG GAGAGGCGGT TTGCGTATTG GGCGCTCTTC CGCTTCCTCG CTCACTGACT 6961 CGCTGCGCTC GGTCGTTCGG CTGCGGCGAG CGGTATCAGC TC ACTC A A AG GCGGTAATAC 7021 GGTTATCCAC AGAATCAGGG GATAACGCAG GAAAGAACAT GTGAGCAAAA GGCCAGCAAA 7081 AGGCCAGGAA CCGTAAAAAG GCCGCGTTGC TGGCGTTTTT CCATAGGCTC CGCCCCCCTG 7141 ACGAGCATCA CAAAAATCGA CGCTCAAGTC AGAGGTGGCG AAACCCGACA GGACTATAAA 7201 GATACCAGGC GTTTCCCCCT GGAAGCTCCC TCGTGCGCTC TCCTGTTCCG ACCCTGCCGC 7261 TT ACCGGAT A CCTGTCCGCC TTTCTCCCTT CGGGAAGCGT GGCGCTTTCT CAT AGCT C AC 7321 GCTGTAGGTA TCTCAGTTCG GTGTAGGTCG TTCGCTCCAA GCTGGGCTGT GTGCACGAAC 7381 CCCCCGTTCA GCCCGACCGC TGCGCCTTAT CCGGTAACTA TCGTCTTGAG TCCAACCCGG 7441 TAAGACACGA CTTATCGCCA CTGGCAGCAG CCACTGGTAA CAGGATTAGC AGAGCGAGGT 7501 ATGTAGGCGG TGCTACAGAG TTCTTGAAGT GGTGGCCTAA CTACGGCTAC ACTAGAAGAA 7561 CAGTATTTGG TATCTGCGCT CTGCTGAAGC CAGTTACCTT CGGAAAAAGA GTTGGTAGCT 7621 CTTGATCCGG CAAACAAACC ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC AAGCAGCAGA 7681 TTACGCGCAG AAAAAAAGGA TCTCAAGAAG ATCCTTTGAT CTTTTCTACG GGGTCTGACG 7741 CTCAGTGGAA CGAAAACTCA CGTTAAGGGA TTTTGGTCAT G AG ATT AT C A A A A AGG AT CT 7801 TCACCTAGAT CCTTTTAAAT TAAAAATGAA GTTTTAAATC AATCTAAAGT ATATATGAGT 7861 AAACTTGGTC TGACAGTTAC CAATGCTT AA TCAGTGAGGC ACCTATCTCA GCGATCTGTC 7921 TATTTCGTTC ATCCATAGTT GCCTGACTCC CCGTCGTTGC TAGGTTACTG TCATGAGCGG 7981 ATACATATTT GAATGTATTT AGAAAAATAA ACAAAAGAGT TTGTAGAAAC GCAAAAAGGC 8041 CATCCGTCAG GATGGCCTTC TGCTTAATTT GATCGGTGGC AGTTTATGGC GGGCGTCCTG 8101 CCCGCCACCC TCCGGGCCGT TGCTTCGCAA CGTTCAAATC CGCTCCCGGC GGATTTGTCC 8161 TACTCAGGAG AGCGTTCACC GACAAACAAC AG AT A A A ACG AAAGGCCCAG TCTTTCGACT 8221 GAGCCTTTCG TTTTATTTGA TGCCTGGCAG TTCCCTACTC TCGCATGGGT TGCGGCCGCC 8281 CGGGCCGTCG ACCAATTCTC ATGTTTGACA GCTTATCATC GAATTTCTGC CATTCATCCG 8341 CTTATTATCA CTTATTCAGG CGTAGCAACC AGGCGTTTAA GGGCACCAAT A ACT GCCTT A 8401 AAA A A ATT AC GCCCCGCCCT GCCACTCATC GCAGTACTGT TGTAATTCAT TAAGCATTCT 8461 GCCGACATGG AAGCCATCAC AAACGGCATG ATGAACCTGA ATCGCCAGCG GCATCAGCAC 8521 CTTGTCGCCT TGCGTATAAT ATTTGCCCAT GGTGAAAACG GGGGCGAAGA AGTTGTCCAT 8581 ATTGGCCACG TTTAAATCAA AACTGGTGAA ACTCACCCAG GGATTGGCTG AGACGAAAAA 8641 CATATTCTCA AT AAACCCTT TAGGGAAATA GGCCAGGTTT TCACCGTAAC ACGCCACATC 8701 TTGCGAATAT ATGTGTAGAA ACTGCCGGAA ATCGTCGTGG TATTCACTCC AGAGCGATGA 8761 AA ACGTTT C A GTTTGCTCAT GGAAAACGGT GTAACAAGGG TGAACACTAT CCCATATCAC 8821 CAGCTCACCG TCTTTCATTG CCATACGAAA TTCCGGATGA GCATTCATCA GGCGGGCAAG

8941 CGTAATATCC AGCTGAACGG TCTGGTTATA GGTACATTGA GCAACTGACT GAAATGCCTC 9001 AAAATGTTCT TTACGATGCC ATTGGGATAT ATCAACGGTG GTATATCCAG TGATTTTTTT 9061 CTCCATTTTA GCTTCCTTAG CTCCTGAAAA T CT CG AT A AC T C A A A A A AT A CGCCCGGTAG 9121 TGATCTTATT TCATTATGGT GAAAGTTGGA ACCTCTTACG TGCCGATCAA CGTCTCATTT 9181 TCGCCAAAAG TGACATTAAC CTATAAAAAT AGGCGTATCA CGAGGCCAGC TTGGGAAACC 9241 ATAAGACCGA GATAGAGTTG AGTGTTGTTC CAGTTTGGAA CAAGAGTCCA CT ATT A A AG A 9301 ACGTGGACTC CAACGTCAAA GGGCGAAAAA CCGTCTATCA GGGCGATGGC CCACTACGTG

9421 CTAAAGGGAG CCCCCGATTT AGAGCTTGAC GGGGAAAGCC GGCGAACGTG GCGAGAAAGG 9481 AAGGGAAGAA AGCGAAAGGA GCGGGCGCTA AGGCGCTGGC AAGTGTAGCG GTCACGCTGC 9541 GCGTAACCAC CACACCCGCC GCGCTTAATG CGCCGCTACA GGGCGCGTAC TATGGTTGCT 9601 TTGACGTATG CGGTGTGAAA TACCGCACAG ATGCGTAAGG AGAAAATACC GCATCAGGCG 9661 CCATTCGCCA TTCAGGCTGC GCAACTGTTG GGAAGGGCGA TCGGTGCGGG CCTCTTCGCT 9721 ATTACGCCAG CTGGCGAAAG GGGGATGTGC TGCAAGGCGA TTAAGTTGGG TAACGCCAGG 9781 GTTTTCCCAG TCACGACGTT GTAAAACGAC GGCCAGTGAA TTGATCGAGA TCGTGATCCG 9841 GAT C A AG AT C CAGATCGAAT TGGAGGCTAC AGTCAGTGGA GAGGACTTTC ACTGACTGAC 9901 TGACTGCGTC TCAACCTCCT AGGG pLRPC TRDC P2AW FMC63op TRGC1 (SEQ ID NO: 186)

1 TGATCATAAT CAAGCCATAT CACATCTGTA GAGGTTTACT TGCTTTAAAA AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT TTCACAAATA AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC AT GT CT GG AT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGCAGCTT GGCGTAATCA 361 TGGTCATAGC TGTTTCCTGT GT G AA ATT GT TATCCGCTCA C A ATT CC AC A CAACATACGA 421 GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG TGAGCTAACT CACATTAATT 481 GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT GC ATT AATGA 541 ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC GCTCTTCCGC TTCCTCGCTC 601 ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA CTCAAAGGCG 661 GTAATACGGT T AT CC AC AG A ATCAGGGGAT AACGCAGGAA AGAACATGTG AGCAAAAGGC 721 CAGCAAAAGG CCAGGAACCG TAAAAAGGCC GCGTTGCTGG CGTTTTTCCA TAGGCTCCGC 781 CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA CCCGACAGGA 841 CT AT A A AG AT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC TGTTCCGACC 901 CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC GCTTTCTCAT 961 AGCTCACGCT GT AGGT AT CT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT GGGCTGTGTG 1021 CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG TCTTGAGTCC 1081 AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATTAGCAGA 1141 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 1201 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT

1321 CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT TTCTACGGGG 1381 TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG ATTATCAAAA 1441 AGGATCTTCA CCTAGATCCT TTTAAATTAA AAATGAAGTT TTAAATCAAT CTAAAGTATA 1501 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 1561 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTTGCTAG GTTACTGTCA 1621 TGAGCGGATA CATATTTGAA TGTATTTAGA AAAATAAACA AAAGAGTTTG TAGAAACGCA 1681 AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT CGGTGGCAGT TTATGGCGGG 1741 CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT TCAAATCCGC TCCCGGCGGA 1801 TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA TAAAACGAAA GGCCCAGTCT 1861 TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC CCTACTCTCG CATGGGTTGC 1921 GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT TATCATCGAA TTTCTGCCAT 1981 TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG CGTTTAAGGG CACCAATAAC 2041 TGCCTT A A A A AAATTACGCC CCGCCCTGCC ACT CAT CGC A GT ACTGTTGT A ATT C ATT A A 2101 GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG AACCTGAATC GCCAGCGGCA 2161 TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT GAAAACGGGG GCGAAGAAGT 2221 TGTCCATATT GGCCACGTTT AA AT C A A A AC TGGTGAAACT CACCCAGGGA TTGGCTGAGA 2281 CGAAAAACAT ATTCTCAATA AACCCTTTAG GGAAATAGGC CAGGTTTTCA CCGTAACACG 2341 CCACATCTTG CG A AT AT AT G T GT AG A A ACT GCCGGAAATC GTCGTGGTAT T C ACT CC AG A 2401 GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA ACAAGGGTGA ACACTATCCC 2461 ATATCACCAG CTCACCGTCT TTCATTGCCA TACGAAATTC CGGATGAGCA TTCATCAGGC 2521 GGGCAAGAAT GT G A AT A A AG GCCGGAT AAA ACTTGTGCTT ATTTTTCTTT ACGGTCTTTA 2581 AAAAGGCCGT AATATCCAGC TGAACGGTCT GGTTATAGGT ACATTGAGCA ACTGACTGAA 2641 AT GCCT C A A A ATGTTCTTTA CGATGCCATT GGGATATATC AACGGTGGTA TATCCAGTGA

2761 CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC TCTTACGTGC CGATCAACGT 2821 CTCATTTTCG CCAAAAGTGA CATTAACCTA TAAAAATAGG CGTATCACGA GGCCAGCTTG 2881 GGAAACCATA AGACCGAGAT AGAGTTGAGT GTTGTTCCAG TTTGGAACAA GAGTCCACTA 2941 TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG TCTATCAGGG CGATGGCCCA 3001 CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA GGTGCCGTAA AGCACTAAAT 3061 CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG GAAAGCCGGC GAACGTGGCG 3121 AGAAAGGAAG GGAAGAAAGC GAAAGGAGCG GGCGCTAAGG CGCT GGC A AGT GT AGCGGTC 3181 ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC CGCTACAGGG CGCGTACTAT 3241 GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG CGT AAGGAGA AAATACCGCA 3301 TCAGGCGCCA TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGATCG GTGCGGGCCT 3361 CTTCGCTATT ACGCCAGCTG GCGAAAGGGG GATGTGCTGC AAGGCGATTA AGTTGGGTAA 3421 CGCCAGGGTT TTCCCAGTCA CGACGTTGTA AAACGACGGC CAGTGAATTG ATCGAGATCG 3481 TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT CAGTGGAGAG GACTTTCACT 3541 GACTGACTGA CTGCGTCTCA ACCTCCTAGG GG AC ATT GAT TATTGACTAG TT ATT A AT AG 3601 TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG AGTTCCGCGT TACATAACTT 3661 ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC GCCCATTGAC GTCAATAATG 3721 ACGTATGTTC CC AT AGT A AC GCCAATAGGG ACTTTCCATT GACGTCAATG GGTGGAGTAT 3781 TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC ATATGCCAAG TACGCCCCCT 3841 ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG CCC AGT AC AT GACCTTATGG 3901 GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG CTATTACCAT GGTGATGCGG 3961 TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT CACGGGGATT TCCAAGTCTC 4021 CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA ATCAACGGGA CTTTCCAAAA 4081 TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA GGCGTGTACG GTGGGAGGTC 4141 TATATAAGCA GAGCTCGTTT AGTGAACCGG GTCTCTCTGG TTAGACCAGA TCTGAGCCTG 4201 GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT CAATAAAGCT TGCCTTGAGT 4261 GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT AACTAGAGAT CCCTCAGACC 4321 CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA ACAGGGACTT GAAAGCGAAA 4381 GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG CTGAAGCGCG CACGGCAAGA 4441 GGCGAGGGGC GGCGACTGGT GAGTACGCCA AAAATTTTGA CTAGCGGAGG CT AG A AGG AG 4501 AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA TT AG AT AA AT GGGAAAAAAT 4561 TCGGTTAAGG CCAGGGGGAA AGAAACAATA T A A ACT A A A A CATATAGTTA GGGCAAGCAG 4621 GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTT AG AG ACATCAGAAG GCTGTAGACA 4681 AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA GAAGAACTTA GATCATTATA 4741 TAATACAATA GCAGTCCTCT ATTGTGTGCA TCAAAGGATA GATGTAAAAG ACACCAAGGA 4801 AGCCTT AG AT A AG AT AG AGG AAGAGCAAAA CAAAAGTAAG AAAAAGGCACAGCAAGCGAT 4861 CTTCAGACCT GGAGGAGGCA GGAGGCGATA TGAGGGACAA TTGGAGAAGT G A ATT AT AT A 4921 AAT AT A A AGT AGTAAAAATT G A ACC ATT AG GAGTAGCACC CACCAAGGCA AAGAGAAGAG 4981 TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT GTTCCTTGGG TTCTTGGGAG 5041 CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC GGTACAGGCC AGACAATTAT 5101 TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC TATTGAGGCG CAACAGCATC 5161 TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC AAGAATCCTG GCTGTGGAAA 5221 GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG CTCTGGAAAA CTCATTTGCA 5281 CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC TCTGGAACAG ATTTGGAATA 5341 ACATGACCTG GATGGAGTGG GACAGAGAAA TTAACAATTA CACAAGCTTA ATACACTCCT 5401 TAATTGAAGA ATCGCAAAAC CAGCAAGAAA AGAATGAACA AG A ATT ATT G GAATT AG AT A 5461 AATGGGCAAG TTTGTGGAAT TGGTTTAACA T A AC A A ATT G GCTGTGGTAT ATAAAATTAT 5521 TCATAATGAT AGTAGGAGGC TTGGTAGGTT T A AG AAT AGT TTTTGCTGTA CTTTCTATAG 5581 TG AAT AG AGT TAGGCAGGGA TATTCACCAT TATCGTTTCA GACCCACCTC CCAATCCCGA 5641 GGGGACCACG CGTACAAATG GCAGTATTCA TCCACAATTT TAAAAGAAAA GGGGGGATTG 5701 GGGGGTACAG TGCAGGGGAA AGAATAGTAG AC AT AAT AGC AACAGACATA C A A ACT AA AG 5761 AATT AC A A A A ACAAATTACA A A A ATT C A A A ATTTTCGGGT TT ATT AC AGG GACAGCAGAA 5821 ATCCACTTTG GAAAGCTGAG CATCCGGCTC CGGTGCCCGT CAGTGGGCAG AGCGCACATC 5881 GCCCACAGTC CCCGAGAAGT TGGGGGGAGG GGTCGGCAAT TGAACCGGTG CCTAGAGAAG 5941 GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG CTCCGCCTTT TTCCCGAGGG

6061 TGCCGCCAGA ACACAGGTAA GTGCCGTGTG TGGTTCCCGC GGGCCTGGCC TCTTTACGGG 6121 TTATGGCCCT TGCGTGCCTT GAATTACTTC CACGCCCCTG GCTGCAGTAC GTGATTCTTG 6181 ATCCCGAGCT TCGGGTTGGA AGTGGGTGGG AGAGTTCGAG GCCTTGCGCT TAAGGAGCCC 6241 CTTCGCCTCG TGCTTGAGTT GAGGCCTGGC CTGGGCGCTG GGGCCGCCGC GTGCGAATCT 6301 GGTGGCACCT TCGCGCCTGT CTCGCTGCTT TCGATAAGTC TCTAGCCATT T AA A ATTTTT 6361 GATGACCTGC TGCGACGCTT TTTTTCTGGC AAGATAGTCT TGTAAATGCG GGCCAAGATC 6421 TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA CGGGGCCCGT GCGTCCCAGC 6481 GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC GAGAATCGGA CGGGGGTAGT 6541 CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC GCCGTGTATC GCCCCGCCCT 6601 GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC GGAAAGATGG CCGCTTCCCG 6661 GCCCTGCTGC AGGGAGCTCA AAATGGAGGA CGCGGCGCTC GGGAGAGCGG GCGGGTGAGT 6721 CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT CGCTTCATGT GACTCCACGG 6781 AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG CTTTTGGAGT ACGTCGTCTT 6841 TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA CACTGAGTGG GTGGAGACTG 6901 AAGTTAGGCC AGCTTGGCAC TTGATGTAAT TCTCCTTGGA ATTTGCCCTT TTTGAGTTTG 6961 GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG TTTTTTTCTT CCATTTCAGG 7021 TGTCGTGAAA ACTACCCCTC AGAGCCGCCA CCATGCTTCT CCTGGTGACA AGCCTTCTGC 7081 TCTGTGAGTT ACCACACCCA GCATTCCTCC TGATCCCAAG TCAGCCTCAT ACCAAACCAT 7141 CCGTTTTTGT CATGAAAAAT GGAACAAATG TCGCTTGTCT GGTGAAGGAA TTCTACCCCA 7201 AGGATATAAG AATAAATCTC GTGTCATCCA AGAAGATAAC AGAGTTTGAT CCTGCTATTG 7261 TCATCTCTCC CAGTGGGAAG TACAATGCTG TCAAGCTTGG T AA AT AT G AA GATT C A A ATT 7321 CAGTGACATG TTCAGTTCAA CACGACAATA AAACTGTGCA CTCCACTGAC TTTGAAGTGA 7381 AG AC AG ATT C TACAGATCAC GT A A A ACC A A AGGAAACTGA AAACACAAAG CAACCTTCAA 7441 AGAGCTGCCA TAAACCCAAA GCCATAGTTC AT ACCGAGAA GGTGAACATG ATGTCCCTCA 7501 CAGTGCTTGG GCTACGAATG CTGTTTGCAA AGACTGTTGC CGTCAATTTT CTCTTGACTG 7561 CC A AGTT ATT TTTCTTGGGG TCAGGCGCTA CTAACTTCAG CCTGCTGAAG CAGGCTGGAG 7621 ACGTGGAGGA GAACCCTGGA CCTATGCTAC TACTTGTGAC CTCACTATTG TTATGCGAAC 7681 TCCCTCATCC CGCATTCTTG CTGATTCCAG ACATTCAGAT GACTCAAACA ACTTCCAGCC 7741 TCTCCGCCTC ACTCGGCGAC CGCGTAACAA TAAGCTGTCG GGCCTCGCAA GAT ATT AGT A 7801 AGTACCTGAA TTGGTATCAG CAAAAACCCG ATGGTACAGT CAAGCTTCTG ATCTACCATA 7861 CCAGTCGTCT GCACAGCGGT GTCCCCAGCA GGTTCAGCGG CTCAGGATCT GGTACCGATT 7921 ATTCACTGAC GATTTCCAAC CTTGAGCAGG AGGACATCGC CACCTACTTC TGCCAGCAGG 7981 GTAATACTCT GCCGTACACA TTCGGGGGCG GTACCAAGCT CGAGATCACG GGTTCAACAA 8041 GCGGTTCTGG CAAGCCAGGC AGCGGCGAGG GG AGT AC A A A GGGGGAGGTG A AGTT GCAGG 8101 AAAGTGGCCC TGGATTGGTG GCCCCGAGCC AGAGTCTGTC TGTCACCTGC ACAGTTTCCG 8161 GAGTAAGTCT GCCT GATT AC GGAGTGTCCT GGATCAGACA GCCACCTCGA AAGGGCTTGG 8221 AGTGGCTTGG GGTCATTTGG GGCAGTGAAA CC AC AT ACT A CAACAGCGCT CTTAAGTCCA 8281 GGCTCACTAT CATCAAGGAC A ATT C A A AG A GCCAAGTATT CTTGAAAATG AATTCCCTGC 8341 AG ACT GAT G A CACCGCTATT T ATT ATT GCG CT AA AC ATT A TT ACT AT GG A GGTTCTTATG 8401 CCATGGACTA CTGGGGGCAG GGTACCTCTG TGACAGTGAG TTCAGCTGCA GCTGGAGGTG 8461 GAGGT AGCGG AGGCGGTGGT AGTGGAGGGG GTGGTTCTCT GG A AG AT AAA CAACTTGATG 8521 CAGATGTTTC CCCCAAGCCC ACTATTTTTC TTCCTTCAAT TGCTGAAACA AAGCTCCAGA 8581 AGGCTGGAAC ATACCTTTGT CTTCTTGAGA AATTTTTCCC TGATGTTATT AAGATACATT 8641 GGCAAGAAAA GAAGAGCAAC ACGATTCTGG GATCCCAGGA GGGGAACACC ATGAAGACTA 8701 ACGACACATA CATGAAATTT AGCTGGTTAA CGGTGCCAGA AAAGTCACTG GACAAAGAAC 8761 ACAGATGTAT CGTCAGACAT GAGAATAATA AAAACGGAGT T GAT C A AG A A ATTATCTTTC 8821 CTCCAATAAA GACAGATGTC ATCACAATGG ATCCCAAAGA CAATTGTTCA AAAGATGCAA 8881 ATGATACACT ACTGCTGCAG CTCACAAACA CCTCTGCATA TTACATGTAC CTCCTCCTGC 8941 TCCTCAAGAG TGTGGTCTAT TTTGCCATCA TCACCTGCTG TCTGCTTAGA AGAACGGCTT 9001 TCTGCTGCAA TGGAGAGAAA TCATAATGAG ATATCGAGCA TCTTACCGCC ATTTATACCC

9121 GGGGCAATCA TTTACATTTT TAGGGATATG T A ATT ACT AG TTCAGGTGTA TTGCCACAAG 9181 ACAAACATGT TAAGAAACTT TCCCGTTATT TACGCTCTGT TCCTGTTAAT CAACCTCTGG 9241 ATT AC A A A AT TTGTGAAAGA TT G ACT GAT A TTCTTAACTA TGTTGCTCCT TTTACGCTGT 9301 GTGGATATGC TGCTTTATAG CCTCTGTATC TAGCTATTGC TTCCCGTACG GCTTTCGTTT 9361 TCTCCTCCTT GTATAAATCC TGGTTGCTGT CTCTTTTAGA GGAGTTGTGG CCCGTTGTCC 9421 GTCAACGTGG CGTGGTGTGC TCTGTGTTTG CTGACGCAAC CCCCACTGGC TGGGGCATTG 9481 CCACCACCTG TCAACTCCTT TCTGGGACTT TCGCTTTCCC CCTCCCGATC GCCACGGCAG 9541 AACTCATCGC CGCCTGCCTT GCCCGCTGCT GGACAGGGGC TAGGTTGCTG GGCACTGATA 9601 ATTCCGTGGT GTTGTCAGTA CTGGTACCTT TAAGACCAAT GACTTACAAG GCAGCTGTAG 9661 ATCTTAGCCA CTTTTTAAAA GAAAAGGGGG GACTGGAAGG GCTAATTCAC TCCCAAAGAA 9721 GACAAGATCT GCTTTTTGCC TGTACTGGGT CTCTCTGGTT AGACCAGATC TGAGCCTGGG 9781 AGCTCTCTGG CTAACTAGGG AACCCACTGC TTAAGCCTCA ATAAAGCTTG CCTTGAGTGC 9841 TTCAA pLRPCU TRDC P2AW FMC63op TRGC1 (SEQ ID NO: 187)

1 GACATTGATT ATTGACTAGT TATTAATAGT AATCAATTAC GGGGTCATTA GTTCATAGCC 61 CATATATGGA GTTCCGCGTT ACATAACTTA CGGTAAATGG CCCGCCTGGC TGACCGCCCA 121 ACGACCCCCG CCCATTGACG TCAATAATGA CGTATGTTCC CATAGTAACG CCAATAGGGA 181 CTTTCCATTG ACGTCAATGG GTGGAGTATT TACGGTAAAC TGCCCACTTG GCAGTACATC 241 AAGTGTATCA TATGCCAAGT ACGCCCCCTA TTGACGTCAA TGACGGTAAA TGGCCCGCCT 301 GGCATTATGC CCAGTACATG ACCTTATGGG ACTTTCCTAC TTGGCAGTAC ATCTACGTAT 361 TAGTCATCGC T ATT ACC AT G GTGATGCGGT TTTGGCAGTA CATCAATGGG CGTGGATAGC 421 GGTTT G ACT C ACGGGGATTT CCAAGTCTCC ACCCCATTGA CGTCAATGGG AGTTTGTTTT 481 GGCACCAAAA TCAACGGGAC TTTCCAAAAT GTCGTAACAA CTCCGCCCCA TTGACGCAAA 541 TGGGCGGTAG GCGTGTACGG TGGGAGGTCT AT AT AAGC AG AGCTCGTTTA GTGAACCGGG 601 TCTCTCTGGT TAGACCAGAT CTGAGCCTGG GAGCTCTCTG GCTAACTAGG GAACCCACTG 661 CTTAAGCCTC AATAAAGCTT GCCTTGAGTG CTCAAAGTAG TGTGTGCCCG TCTGTTGTGT 721 GACTCTGGTA ACT AG AG AT C CCTCAGACCC TTTTAGTCAG TGTGGAAAAT CTCTAGCAGT 781 GGCGCCCGAA CAGGGACTTG AAAGCGAAAG TAAAGCCAGA GGAGATCTCT CGACGCAGGA 841 CTCGGCTTGC TGAAGCGCGC ACGGCAAGAG GCGAGGGGCG GCGACTGGTG AGTACGCCAA 901 AAATTTTGAC TAGCGGAGGC TAGAAGGAGA GAGTAGGGTG CGAGAGCGTC GGT ATT AAGC 961 GGGGGAGAAT TAGATAAATG GGAAAAAATT CGGTTAAGGC CAGGGGGAAA GA AAC A AT AT 1021 AAACTAAAAC AT AT AGTT AG GGCAAGCAGG GAGCTAGAAC GATTCGCAGT TAATCCTGGC 1081 CTTTTAGAGA CATCAGAAGG CTGTAGACAA ATACTGGGAC AGCTACAACC ATCCCTTCAG 1141 ACAGGATCAG AAGAACTTAG ATCATTATAT A AT AC A AT AG CAGTCCTCTA TTGTGTGCAT 1201 CAAAGGATAG ATGTAAAAGA CACCAAGGAA GCCTTAGATA AGATAGAGGA AGAGCAAAAC 1261 AAAAGTAAGA AAAAGGCACA GCAAGCGATC TTCAGACCTG GAGGAGGCAG GAGGCGATAT 1321 GAGGGACAAT TGGAGAAGTG A ATT AT AT A A AT AT A A AGT A GT A A A A ATT G AACCATTAGG 1381 AGTAGCACCC ACCAAGGCAA AGAGAAGAGT GGTGCAGAGA GAAAAAAGAGCAGTGGGAAT 1441 AGGAGCTTTG TTCCTTGGGT TCTTGGGAGC AGCAGGAAGC ACTATGGGCG CAGCGTCAAT 1501 GACGCTGACG GTACAGGCCA GACAATTATT GTCTGATATA GTGCAGCAGC AGAACAATTT 1561 GCTGAGGGCT ATTGAGGCGC AACAGCATCT GTTGCAACTC ACAGTCTGGG GCATCAAACA 1621 GCTCCAGGCA AGAATCCTGG CTGTGGAAAG ATACCTAAAG GATCAACAGC TCCTGGGGAT 1681 TTGGGGTTGC TCTGGAAAAC TCATTTGCAC CACTGCTGTG CCTTGGAATG CTAGTTGGAG 1741 TAATAAATCT CTGGAACAGA TTTGGAATAA CATGACCTGG ATGGAGTGGG ACAGAGAAAT 1801 TAACAATTAC ACAAGCTTAA TACACTCCTT AATTGAAGAA TCGCAAAACC AGCAAGAAAA 1861 GAATGAACAA GAATTATTGG AATT AG AT A A ATGGGCAAGT TTGTGGAATT GGTTT AAC AT 1921 AAC A A ATT GG CTGT GGT AT A T A A A ATT ATT CATAATGATA GTAGGAGGCT T GGT AGGTTT 1981 AAGAAT AGTT TTTGCTGTAC TTTCTATAGT GAATAGAGTT AGGCAGGGAT ATTCACCATT 2041 ATCGTTTCAG ACCCACCTCC CAATCCCGAG GGGACCACGC GTACAAATGG CAGTATTCAT 2101 CCACAATTTT AAAAGAAAAG GGGGGATTGG GGGGTACAGT GCAGGGGAAA GAATAGTAGA 2161 CATAATAGCA ACAGACATAC AAACTAAAGA ATT AC A A A A A CAAATTACAA A A ATT C A A A A 2221 TTTTCGGGTT TATTACAGGG ACAGCAGAAA TCCACTTTGG AAAGCTGAGC ATCCGGCTCC 2281 GGTGCCCGTC AGTGGGCAGA GCGCACATCG CCCACAGTCC CCGAGAAGTT GGGGGGAGGG 2341 GTCGGCAATT GAACCGGTGC CTAGAGAAGG TGGCGCGGGG TAAACTGGGA AAGTGATGTC 2401 GTGTACTGGC TCCGCCTTTT TCCCGAGGGT GGGGGAGAAC CGTATATAAG TGCAGTAGTC 2461 GCCGTGAACG TTCTTTTTCG CAACGGGTTT GCCGCCAGAA CACAGGTAAG TGCCGTGTGT 2521 GGTTCCCGCG GGCCTGGCCT CTTTACGGGT TATGGCCCTT GCGTGCCTTG AATTACTTCC 2581 ACGCCCCTGG CTGCAGTACG TGATTCTTGA TCCCGAGCTT CGGGTTGGAA GTGGGTGGGA 2641 GAGTTCGAGG CCTTGCGCTT AAGGAGCCCC TTCGCCTCGT GCTTGAGTTG AGGCCTGGCC 2701 TGGGCGCTGG GGCCGCCGCG TGCGAATCTG GTGGCACCTT CGCGCCTGTC TCGCTGCTTT

2821 AGATAGTCTT GTAAATGCGG GCCAAGATCT GCACACTGGT ATTTCGGTTT TTGGGGCCGC 2881 GGGCGGCGAC GGGGCCCGTG CGTCCCAGCG CACATGTTCG GCGAGGCGGG GCCTGCGAGC 2941 GCGGCCACCG AGAATCGGAC GGGGGTAGTC TCAAGCTGGC CGGCCTGCTC TGGTGCCTGG 3001 CCTCGCGCCG CCGTGTATCG CCCCGCCCTG GGCGGCAAGG CTGGCCCGGT CGGCACCAGT 3061 TGCGTGAGCG GAAAGATGGC CGCTTCCCGG CCCTGCTGCA GGGAGCTCAA AATGGAGGAC 3121 GCGGCGCTCG GGAGAGCGGG CGGGTGAGTC ACCCACACAA AGGAAAAGGG CCTTTCCGTC 3181 CTCAGCCGTC GCTTCATGTG ACTCCACGGA GTACCGGGCG CCGTCCAGGC ACCT CG ATT A 3241 GTTCTCGAGC TTTTGGAGTA CGTCGTCTTT AGGTTGGGGG GAGGGGTTTT ATGCGATGGA 3301 GTTTCCCCAC ACTGAGTGGG TGGAGACTGA AGTTAGGCCA GCTTGGCACT T GAT GT A ATT 3361 CTCCTTGGAA TTTGCCCTTT TTGAGTTTGG ATCTTGGTTC ATTCTCAAGC CTCAGACAGT

3481 CATGCTTCTC CTGGTGACAA GCCTTCTGCT CTGTGAGTTA CCACACCCAG CATTCCTCCT 3541 GATCCCAAGT CAGCCTCATA CCAAACCATC CGTTTTTGTC ATGAAAAATG GAACAAATGT 3601 CGCTTGTCTG GTGAAGGAAT TCTACCCCAA GG AT AT A AG A ATAAATCTCG TGTCATCCAA 3661 GAAGATAACA GAGTTTGATC CTGCTATTGT CATCTCTCCC AGTGGGAAGT ACAATGCTGT 3721 CAAGCTTGGT AAATATGAAG ATTCAAATTC AGTGACATGT TCAGTTCAAC ACGACAATAA 3781 AACTGTGCAC TCCACTGACT TTGAAGTGAA GACAGATTCT ACAGATCACG T A A A ACC A A A 3841 GGAAACTGAA AACACAAAGC AACCTTCAAA GAGCTGCCAT AAACCCAAAG CCATAGTTCA 3901 TACCGAGAAG GTGAACATGA TGTCCCTCAC AGTGCTTGGG CTACGAATGC TGTTTGCAAA 3961 GACTGTTGCC GTCAATTTTC TCTTGACTGC CAAGTTATTT TTCTTGGGGT CAGGCGCTAC 4021 TAACTTCAGC CTGCTGAAGC AGGCTGGAGA CGTGGAGGAG AACCCTGGAC CTATGCTACT 4081 ACTTGTGACC TCACTATTGT TATGCGAACT CCCTCATCCC GCATTCTTGC TGATTCCAGA 4141 CATTCAGATG ACTCAAACAA CTTCCAGCCT CTCCGCCTCA CTCGGCGACC GCGTAACAAT 4201 AAGCTGTCGG GCCTCGCAAG ATATTAGTAA GTACCTGAAT TGGTATCAGC AAAAACCCGA 4261 TGGTACAGTC AAGCTTCTGA TCTACCATAC CAGTCGTCTG CACAGCGGTG TCCCCAGCAG 4321 GTTCAGCGGC TCAGGATCTG GTACCGATTA TTCACTGACG ATTTCCAACC TTGAGCAGGA 4381 GGACATCGCC ACCTACTTCT GCCAGCAGGG TAATACTCTG CCGTACACAT TCGGGGGCGG 4441 TACCAAGCTC GAGATCACGG GTTCAACAAG CGGTTCTGGC AAGCCAGGCA GCGGCGAGGG 4501 GAGTACAAAG GGGGAGGTGA AGTTGCAGGA AAGTGGCCCT GGATTGGTGG CCCCGAGCCA 4561 GAGTCTGTCT GTCACCTGCA CAGTTTCCGG AGTAAGTCTG CCTGATTACG GAGTGTCCTG 4621 GATCAGACAG CCACCTCGAA AGGGCTTGGA GTGGCTTGGG GTCATTTGGG GCAGTGAAAC 4681 CACATACTAC AACAGCGCTC TTAAGTCCAG GCTCACTATC ATCAAGGACA ATT C A A AG AG 4741 CCAAGTATTC TTGAAAATGA ATTCCCTGCA GACTGATGAC ACCGCTATTT ATTATTGCGC 4801 TAAACATTAT TACTATGGAG GTTCTTATGC CATGGACTAC TGGGGGCAGG GTACCTCTGT 4861 GACAGTGAGT TCAGCTGCAG CTGGAGGTGG AGGT AGCGG A GGCGGTGGTA GTGGAGGGGG 4921 TGGTTCTCTG GAAGATAAAC AACTTGATGC AGATGTTTCC CCCAAGCCCA CTATTTTTCT 4981 TCCTTCAATT GCTGAAACAA AGCTCCAGAA GGCTGGAACA TACCTTTGTC TTCTTGAGAA 5041 ATTTTTCCCT GATGTT ATT A AGATACATTG GCAAGAAAAG AAGAGCAACA CGATTCTGGG 5101 ATCCCAGGAG GGGAACACCA TGAAGACTAA CGACACATAC ATGAAATTTA GCTGGTTAAC 5161 GGTGCCAGAA AAGTCACTGG ACAAAGAACA CAGATGTATC GTCAGACATG AG A AT A AT A A 5221 AAACGGAGTT GATCAAGAAA TTATCTTTCC TCCAATAAAG ACAGATGTCA TCACAATGGA 5281 TCCCAAAGAC AATTGTTCAA AAGATGCAAA T GAT AC ACT A CTGCTGCAGC TC AC A A AC AC 5341 CTCTGCATAT T AC AT GT ACC TCCTCCTGCT CCTCAAGAGT GTGGTCTATT TTGCCATCAT 5401 CACCTGCTGT CTGCTTAGAA GAACGGCTTT CTGCTGCAAT GGAGAGAAAT CATAATGAGA 5461 TATCGAGCAT CTTACCGCCA TTTATACCCA TATTTGTTCT GTTTTTCTTG ATTTGGGTAT 5521 ACATTTAAAT GTTAATAAAA CAAAATGGTG GGGCAATCAT TTACATTTTT AGGGATATGT 5581 AATTACTAGT TCAGGTGTAT TGCCACAAGA CAAACATGTT AAGAAACTTT CCCGTTATTT 5641 ACGCTCTGTT CCTGTTAATC AACCTCTGGA TT AC A A A ATT TGTGAAAGAT TGACTGATAT 5701 TCTTAACTAT GTTGCTCCTT TTACGCTGTG TGGATATGCT GCTTTATAGC CTCTGTATCT 5761 AGCTATTGCT TCCCGTACGG CTTTCGTTTT CTCCTCCTTG TATAAATCCT GGTTGCTGTC 5821 TCTTTTAGAG GAGTTGTGGC CCGTTGTCCG TCAACGTGGC GTGGTGTGCT CTGTGTTTGC 5881 TGACGCAACC CCCACTGGCT GGGGCATTGC CACCACCTGT CAACTCCTTT CTGGGACTTT 5941 CGCTTTCCCC CTCCCGATCG CCACGGCAGA ACTCATCGCC GCCTGCCTTG CCCGCTGCTG 6001 GACAGGGGCT AGGTTGCTGG GCACTGATAA TTCCGTGGTG TTGTCAGTAC TGGTACCTTT

6121 ACTGGAAGGG CTAATTCACT CCCAAAGAAG ACAAGATCTG CTTTTTGCCT GTACTGGGTC 6181 TCTCTGGTTA GACCAGATCT GAGCCTGGGA GCTCTCTGGC TAACTAGGGA ACCCACTGCT 6241 TAAGCCTCAA TAAAGCTTGC CTTGAGTGCT TCAAGTAGTG TGTGCCCGTC TGTTGTGTGA 6301 CTCTGGTAAC TAGAGATCCC TCAGACCCTT TTAGTCAGTG TGGAAAATCT CTAGCATGAT 6361 CATAATCAAG CCATATCACA TCTGTAGAGG TTTACTTGCT TTAAAAAACC TCCACACCTC 6421 CCCCTGAACC T G AA AC AT A A AATGAATGCA ATTGTTGTTG TTAACTTGTT TATTGCAGCT 6481 TATAATGGTT ACAAATAAAG CAATAGCATC ACAAATTTCA CAAATAAAGC ATTTTTTTCA 6541 CTGCATTCTA GTTGTGGTTT GT CCA A ACT C ATCAATGTAT CTTATCATGT CTGGATCTGC 6601 GTCGACACGA AGAGACGACT GACTGACTGA CTGGAAAGAG GAAGGGCTGG AAGAGGAAGG 6661 AGCTTGATCC AGATCCCGAT CTCGATCCAG ATCCGGATCG CAGCTTGGCG TAATCATGGT 6721 CAT AGCT GTT TCCTGTGTGA A ATT GTT AT C CGCTCACAAT TCCACACAAC ATACGAGCCG 6781 GAAGCATAAA GTGTAAAGCC TGGGGTGCCT AATGAGTGAG CTAACTCACA TTAATTGCGT 6841 TGCGCTCACT GCCCGCTTTC CAGTCGGGAA ACCTGTCGTG CCAGCTGCAT TAATGAATCG 6901 GCCAACGCGC GGGGAGAGGC GGTTTGCGTA TTGGGCGCTC TTCCGCTTCC TCGCTCACTG 6961 ACTCGCTGCG CTCGGTCGTT CGGCTGCGGC GAGCGGTATC AGCTCACTCA AAGGCGGTAA 7021 TACGGTTATC CACAGAATCA GGGGATAACG CAGGAAAGAA CATGTGAGCA AAAGGCCAGC 7081 AAAAGGCCAG GAACCGTAAA AAGGCCGCGT TGCTGGCGTT TTTCCATAGG CTCCGCCCCC 7141 CTGACGAGCA TCACAAAAAT CGACGCTCAA GTCAGAGGTG GCGAAACCCG ACAGGACTAT 7201 AA AG AT ACC A GGCGTTTCCC CCTGGAAGCT CCCTCGTGCG CTCTCCTGTT CCGACCCTGC 7261 CGCTTACCGG ATACCTGTCC GCCTTTCTCC CTTCGGGAAG CGTGGCGCTT TCTCATAGCT 7321 CACGCTGTAG GTATCTCAGT TCGGTGTAGG TCGTTCGCTC CAAGCTGGGC TGTGTGCACG 7381 AACCCCCCGT TCAGCCCGAC CGCTGCGCCT TATCCGGTAA CTATCGTCTT GAGTCCAACC 7441 CGGTAAGACA CGACTTATCG CCACTGGCAG CAGCCACTGG TAACAGGATT AGCAGAGCGA 7501 GGTATGTAGG CGGTGCTACA GAGTTCTTGA AGTGGTGGCC TAACTACGGC T AC ACT AG A A 7561 GAACAGTATT TGGTATCTGC GCTCTGCTGA AGCCAGTTAC CTTCGGAAAA AGAGTTGGTA

7681 AGATTACGCG CAGAAAAAAA GGATCTCAAG AAGATCCTTT GATCTTTTCT ACGGGGTCTG 7741 ACGCTCAGTG GAACGAAAAC TCACGTTAAG GGATTTTGGT CATGAGATTA TCAAAAAGGA 7801 TCTTCACCTA GATCCTTTTA A ATT AAA A AT G A AGTTTT A A ATCAATCTAA AGT AT AT AT G 7861 AGTAAACTTG GTCTGACAGT TACCAATGCT TAATCAGTGA GGCACCTATC TCAGCGATCT 7921 GTCTATTTCG TTCATCCATA GTTGCCTGAC TCCCCGTCGT TGCTAGGTTA CTGTCATGAG 7981 CGGATACATA TTTGAATGTA TTT AG A A A A A TAAACAAAAG AGTTTGTAGA AACGCAAAAA 8041 GGCCATCCGT CAGGATGGCC TTCTGCTTAA TTTGATCGGT GGCAGTTTAT GGCGGGCGTC 8101 CTGCCCGCCA CCCTCCGGGC CGTTGCTTCG C A ACGTT C A A ATCCGCTCCC GGCGGATTTG 8161 TCCTACTCAG GAGAGCGTTC ACCGACAAAC AACAGATAAA ACGAAAGGCC CAGTCTTTCG 8221 ACTGAGCCTT TCGTTTTATT TGATGCCTGG CAGTTCCCTA CTCTCGCATG GGTTGCGGCC 8281 GCCCGGGCCG TCGACCAATT CTCATGTTTG ACAGCTTATC ATCGAATTTC TGCCATTCAT 8341 CCGCTTATTA TCACTTATTC AGGCGTAGCA ACCAGGCGTT TAAGGGCACC AATAACTGCC 8401 TT A A A A A A AT TACGCCCCGC CCTGCCACTC ATCGCAGTAC TGTTGTAATT C ATT AAGC AT 8461 TCTGCCGACA TGGAAGCCAT CACAAACGGC ATGATGAACC TGAATCGCCA GCGGCATCAG 8521 CACCTTGTCG CCTTGCGTAT AATATTTGCC CAT GGTGAAA ACGGGGGCGA AGAAGTTGTC 8581 CATATTGGCC ACGTTTAAAT CAAAACTGGT GAAACTCACC CAGGGATTGG CTGAGACGAA 8641 AAACATATTC TCAATAAACC CTTTAGGGAA ATAGGCCAGG TTTTCACCGT AACACGCCAC 8701 ATCTTGCGAA TATATGTGTA GAAACTGCCG GAAATCGTCG TGGTATTCAC TCCAGAGCGA 8761 TGAAAACGTT TCAGTTTGCT CATGGAAAAC GGTGTAACAA GGGTGAACAC TATCCCATAT 8821 CACCAGCTCA CCGTCTTTCA TTGCCATACG AAATTCCGGA TGAGCATTCA TCAGGCGGGC 8881 AAGAATGTGA ATAAAGGCCG GATAAAACTT GTGCTTATTT TTCTTTACGG TCTTTAAAAA 8941 GGCCGTAATA TCCAGCTGAA CGGTCTGGTT ATAGGTACAT TGAGCAACTG ACTGAAATGC 9001 CTCAAAATGT TCTTTACGAT GCCATTGGGA TATATCAACG GTGGTATATC CAGTGATTTT 9061 TTTCTCCATT TTAGCTTCCT TAGCTCCTGA AAATCTCGAT AACT C A A A A A ATACGCCCGG 9121 TAGTGATCTT ATTTCATTAT GGTGAAAGTT GGAACCTCTT ACGTGCCGAT CAACGTCTCA 9181 TTTTCGCCAA AAGTGACATT AACCT AT AAA AATAGGCGTA TCACGAGGCC AGCTTGGGAA 9241 ACCATAAGAC CGAGATAGAG TTGAGTGTTG TTCCAGTTTG GAACAAGAGT CC ACT ATT A A 9301 AGAACGTGGA CTCCAACGTC AAAGGGCGAA AAACCGTCTA TCAGGGCGAT GGCCCACTAC 9361 GTGAACCATC ACCCAAATCA AGTTTTTTGG GGTCGAGGTG CCGTAAAGCA CTAAATCGGA 9421 ACCCTAAAGG GAGCCCCCGA TTTAGAGCTT GACGGGGAAA GCCGGCGAAC GTGGCGAGAA 9481 AGGAAGGGAA GAAAGCGAAA GGAGCGGGCG CTAAGGCGCT GGCAAGTGTA GCGGTCACGC 9541 TGCGCGTAAC CACCACACCC GCCGCGCTTA ATGCGCCGCT ACAGGGCGCG TACTATGGTT 9601 GCTTTGACGT ATGCGGTGTG AAATACCGCA CAGATGCGTA AGGAGAAAAT ACCGCATCAG 9661 GCGCCATTCG CCATTCAGGC TGCGCAACTG TTGGGAAGGG CGATCGGTGC GGGCCTCTTC 9721 GCTATTACGC CAGCTGGCGA AAGGGGGATG TGCTGCAAGG CGATTAAGTT GGGTAACGCC 9781 AGGGTTTTCC CAGTCACGAC GTT GT AA AAC GACGGCCAGT GAATTGATCG AGATCGTGAT 9841 CCGGATCAAG ATCCAGATCG AATTGGAGGC TACAGTCAGT GGAGAGGACT TTCACTGACT 9901 GACTGACTGC GTCTCAACCT CCTAGGG pLCUS FMC63 TRDC P2AW TRGC1 (SEQ ID NO: 188)

1 TGATCATAAT CAAGCCATAT CACATCTGTA GAGGTTTACT TGCTTTAAAA AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTTATAAT GGTTACAAAT AAAGCAATAG CATC AC A A AT TTCACAAATA AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC AT GT CT GG AT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG ATCGCAGCTT GGTCTTCCGC 361 TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA 421 CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG

541 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 601 CCCGACAGGA CT AT AAA GAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 661 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 721 GCTTTCTCAT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 781 GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GT A ACT AT CG 841 TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG 901 GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA 961 CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG 1021 AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT 1081 TGTTTGCAAG CAGCAGATTA CGCGCAGAAA A A A AGG AT CT C A AG A AG AT C CTTTGATCTT 1141 TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG 1201 GTGAGGCACC TATCTCAGCG ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG 1261 TCGTTGCTAG GTT ACT GT C A TGAGCGGATA CAT ATTT G AA TGTATTTAGA AAAAT AAAC A 1321 AAAGAGTTTG TAGAAACGCA AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT 1381 CGGTGGCAGT TTATGGCGGG CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT 1441 TCAAATCCGC TCCCGGCGGA TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA 1501 TAAAACGAAA GGCCCAGTCT TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC 1561 CCTACTCTCG CATGGGTTGC GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT 1621 TATCATCGAA TTTCTGCCAT TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG 1681 CGTTTAAGGG CACCAATAAC TGCCTTAAAA AAATTACGCC CCGCCCTGCC ACTCATCGCA 1741 GTACTGTTGT A ATT C ATT A A GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG 1801 AACCTGAATC GCCAGCGGCA TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT 1861 GAAAACGGGG GCGAAGAAGT TGTCCATATT GGCCACGTTT A A AT C A A A AC TGGTGAAACT 1921 CACCCAGGGA TTGGCTGAGA CGAAAAACAT ATTCTCAATA AACCCTTTAG GGAAATAGGC 1981 CAGGTTTTCA CCGTAACACG CCACATCTTG CGAATATATG TGTAGAAACT GCCGGAAATC 2041 GTCGTGGTAT TCACTCCAGA GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA 2101 ACAAGGGTGA ACACTATCCC AT AT C ACC AG CTCACCGTCT TTCATTGCCA TACGAAATTC 2161 CGGATGAGCA TTCATCAGGC GGGCAAGAAT GTGAATAAAG GCCGGATAAA ACTTGTGCTT 2221 ATTTTTCTTT ACGGTCTTTA AAAAGGCCGT AATATCCAGC TGAACGGTCT GGTTATAGGT 2281 ACATTGAGCA ACTGACTGAA ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC 2341 AACGGTGGT A TATCCAGTGA TTTTTTTCTC CATTTTAGCT TCCTTAGCTC CTGAAAATCT 2401 CGATAACTCA AAAAATACGC CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC 2461 TCTTACGTGC CGATCAACGT CTCATTTTCG CCAAAAGTGA CATTAACCTA TAAAAATAGG 2521 CGTATCACGA GGCCAGCTTG GGAAACC AT A AGACCGAGAT AGAGTTGAGT GTTGTTCCAG 2581 TTTGGAACAA GAGTCCACTA TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG 2641 TCTATCAGGG CGATGGCCCA CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA 2701 GGTGCCGTAA AGCACTAAAT CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG 2761 GAAAGCCGGC GAACGTGGCG AGAAAGGAAG GGAAGAAAGCGAAAGGAGCGGGCGCTAAGG 2821 CGCTGGCAAG TGTAGCGGTC ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC 2881 CGCTACAGGG CGCGTACTAT GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG 2941 CGTAAGGAGA AAATACATCG TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT 3001 CAGTGGAGAG GACTTTCACT GACTGACTGA CTGCGTCTCA ACCTCCTAGG GGACATTGAT 3061 TATTGACTAG TTATTAATAG TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG 3121 AGTTCCGCGT T AC AT AACTT ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC 3181 GCCCATTGAC GTCAATAATG ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT 3241 GACGTCAATG GGTGGAGTAT TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC 3301 ATATGCCAAG TACGCCCCCT ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG 3361 CCCAGTACAT GACCTTATGG GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG 3421 CTATTACCAT GGTGATGCGG TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT 3481 CACGGGGATT TCCAAGTCTC CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA 3541 ATCAACGGGA CTTTCCAAAA TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA 3601 GGCGTGTACG GTGGGAGGTC TATATAAGCA GAGCTCGTTT AGTGAACCGG GTCTCTCTGG 3661 TTAGACCAGA TCTGAGCCTG GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT 3721 CAATAAAGCT TGCCTTGAGT GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT 3781 AACTAGAGAT CCCTCAGACC CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA 3841 ACAGGGACTT GAAAGCGAAA GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG 3901 CTGAAGCGCG CACGGCAAGA GGCGAGGGGC GGCGACTGGT GAGTACGCCA AAAATTTTGA 3961 CTAGCGGAGG CTAGAAGGAG AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA 4021 TT AG AT A A AT GGGAAAAAAT TCGGTTAAGG CCAGGGGGAA AG AA AC A AT A T A A ACT A A A A 4081 CATATAGTTA GGGCAAGCAG GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTTAGAG 4141 ACATCAGAAG GCTGTAGACA AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA 4201 GAAGAACTTA GATCATTATA T A AT AC AAT A GCAGTCCTCT ATTGTGTGCA TCAAAGGATA 4261 GATGTAAAAG ACACCAAGGA AGCCTTAGAT AAGATAGAGG AAGAGCAAAA CAAAAGTAAG 4321 AAAAAGGCAC AGCAAGCGAT CTTCAGACCT GGAGGAGGCA GGAGGCGAT A TGAGGGACAA 4381 TTGGAGAAGT G A ATT AT AT A AATATAAAGT AGT AAA A ATT GAACCATTAG GAGTAGCACC 4441 CACCAAGGCA AAGAGAAGAG TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT 4501 GTTCCTTGGG TTCTTGGGAG CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC 4561 GGTACAGGCC AGACAATTAT TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC 4621 TATTGAGGCG CAACAGCATC TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC 4681 AAGAATCCTG GCTGTGGAAA GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG 4741 CTCTGGAAAA CTCATTTGCA CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC 4801 TCTGGAACAG ATTTGGAATA ACATGACCTG GATGGAGTGG GACAGAGAAA TT A AC A ATT A 4861 CACAAGCTTA ATACACTCCT T A ATT G A AG A ATCGCAAAAC CAGCAAGAAA AGAATGAACA 4921 AGAATTATTG GAATTAGATA AATGGGCAAG TTTGTGGAAT TGGTTTAACA TAACAAATTG 4981 GCTGTGGTAT AT A A A ATT AT T CAT AAT GAT AGTAGGAGGC TTGGTAGGTT TAAGAATAGT 5041 TTTTGCTGTA CTTTCTATAG TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA 5101 GACCCACCTC CCAATCCCGA GGGGACCACG CGTACAAATG GC AGT ATT C A TCCACAATTT 5161 TAAAAGAAAA GGGGGGATTG GGGGGTACAG TGCAGGGGAA AGAATAGTAG ACATAATAGC 5221 AACAGACATA CAAACTAAAG A ATT AC A A A A AC A A ATT AC A AAAATTCAAA ATTTTCGGGT 5281 TT ATT ACAGG GACAGCAGAA ATCCACTTTG GA AAGCT GAG CATCCGGCTC CGGTGCCCGT 5341 CAGTGGGCAG AGCGCACATC GCCCACAGTC CCCGAGAAGT TGGGGGGAGG GGTCGGCAAT 5401 TGAACCGGTG CCT AG AG A AG GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG 5461 CTCCGCCTTT TTCCCGAGGG TGGGGGAGAA CCGTATATAA GTGCAGTAGT CGCCGTGAAC

5881 TGTAAATGCG GGCCAAGATC TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA 5941 CGGGGCCCGT GCGTCCCAGC GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC 6001 GAG A AT CGG A CGGGGGTAGT CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC 6061 GCCGTGTATC GCCCCGCCCT GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC 6121 GGAAAGATGG CCGCTTCCCG GCCCTGCTGC AGGGAGCTCA AAATGGAGGA CGCGGCGCTC 6181 GGGAGAGCGG GCGGGTGAGT CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT 6241 CGCTTCATGT GACTCCACGG AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG 6301 CTTTTGGAGT ACGTCGTCTT TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA 6361 CACTGAGTGG GTGGAGACTG AAGTTAGGCC AGCTTGGCAC TT GAT GT AAT TCTCCTTGGA 6421 ATTTGCCCTT TTTGAGTTTG GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG

6541 CCTGGTGACA AGCCTTCTGC TCTGTGAGTT ACCACACCCA GCATTCCTCC TGATCCCAGA 6601 CATCCAGATG ACACAGACTA CATCCTCCCT GTCTGCCTCT CTGGGAGACA GAGTCACCAT 6661 CAGTTGCAGG GCAAGTCAGG AC ATT AGT A A AT ATTT A A AT TGGTATCAGC AGAAACCAGA 6721 TGGAACTGTT AAACTCCTGA TCTACCATAC ATCAAGATTA CACTCAGGAG TCCCATCAAG 6781 GTTCAGTGGC AGTGGGTCTG GAACAGATTA TTCTCTCACC ATTAGCAACC TGGAGCAAGA 6841 AGATATTGCC ACTTACTTTT GCCAACAGGG TAATACGCTT CCGTACACGT TCGGAGGGGG 6901 GACTAAGTTG GAAATAACAG GCTCCACCTC TGGATCCGGC AAGCCCGGAT CTGGCGAGGG 6961 ATCCACCAAG GGCGAGGTGA AACTGCAGGA GTCAGGACCT GGCCTGGTGG CGCCCTCACA 7021 GAGCCTGTCC GTCACATGCA CTGTCTCAGG GGTCTCATTA CCCGACTATG GTGTAAGCTG 7081 GATTCGCCAG CCTCCACGAA AGGGTCTGGA GTGGCTGGGA GTAATATGGG GTAGTGAAAC 7141 CACATACTAT AATTCAGCTC TCAAATCCAG ACTGACCATC ATCAAGGACA ACTCCAAGAG 7201 CCAAGTTTTC TTAAAAATGA ACAGTCTGCA AACTGATGAC ACAGCCATTT ACTACTGTGC 7261 CAAAC ATT AT TACTACGGTG GTAGCTATGC TATGGACTAC TGGGGTCAAG GAACCTCAGT 7321 CACCGTCTCC TCAGCGGCCG CAGGTGGAGG AGGTTCTGGA GGTGGTGGAT CAGGTGGTGG 7381 AGGATCTTTA GAAAGTCAGC CTCATACCAA ACCATCCGTT TTTGTCATGA AAAATGGAAC 7441 AAATGTCGCT TGTCTGGTGA AGG A ATT CT A CCCCAAGGAT AT A AG AAT A A ATCTCGTGTC 7501 ATCCAAGAAG ATAACAGAGT TTGATCCTGC TATTGTCATC TCTCCCAGTG GGAAGTACAA 7561 TGCTGTCAAG CTTGGTAAAT ATGAAGATTC AAATTCAGTG ACATGTTCAG TTCAACACGA 7621 C A AT AAA ACT GTGCACTCCA CTGACTTTGA AGTGAAGACA GATTCTACAG ATCACGTAAA 7681 ACCAAAGGAA ACTGAAAACA CAAAGCAACC TTCAAAGAGC TGCCATAAAC CCAAAGCCAT 7741 AGTTCATACC GAGAAGGTGA ACATGATGTC CCTCACAGTG CTTGGGCTAC GAATGCTGTT 7801 TGCAAAGACT GTTGCCGTCA ATTTTCTCTT GACTGCCAAG TTATTTTTCT TGGGGTCAGG 7861 CGCT ACTA AC TTCAGCCTGC TGAAGCAGGC TGGAGACGTG GAGGAGAACC CTGGACCTAT 7921 GCTACTACTT GTGACCTCAC TATTGTTATG CGAACTCCCT CATCCCGCAT TCTTGCTGAT 7981 TCCAGATAAA CAACTTGATG CAGATGTTTC CCCCAAGCCC ACTATTTTTC TTCCTTCAAT 8041 TGCTGAAACA AAGCTCCAGA AGGCTGGAAC ATACCTTTGT CTTCTTGAGA AATTTTTCCC 8101 TGATGTTATT A AG AT AC ATT GGCAAGAAAA GAAGAGCAAC ACGATTCTGG GATCCCAGGA 8161 GGGGAACACC ATGAAGACTA ACGACACATA CAT G A A ATTT AGCTGGTTAA CGGTGCCAGA 8221 AAAGTCACTG GACAAAGAAC AC AG AT GT AT CGTCAGACAT GAGAATAATA AAAACGGAGT 8281 TGATCAAGAA ATTATCTTTC CTCCAATAAA GACAGATGTC ATCACAATGG ATCCCAAAGA 8341 C A ATT GTT C A A A AG AT GC AA ATGATACACT ACTGCTGCAG CTCACAAACA CCTCTGCATA 8401 TTACATGTAC CTCCTCCTGC TCCTCAAGAG TGTGGTCTAT TTTGCCATCA TCACCTGCTG 8461 TCTGCTTAGA AGAACGGCTT TCTGCTGCAA T GG AG AG AAA TC AT A AT GAG ATATCGAGCA

8581 T GTT AAT AAA ACAAAATGGT GGGGCAATCA TTTACATTTT TAGGGATATG TAATTACTAG 8641 TTC AGGTGT A TTGCCACAAG AC AA AC AT GT TAAGAAACTT TCCCGTTATT TACGCTCTGT 8701 TCCTGTTAAT CAACCTCTGG ATTACAAAAT TTGTGAAAGA TTGACTGATA TTCTTAACTA 8761 TGTTGCTCCT TTTACGCTGT GTGGATATGC TGCTTTATAG CCTCTGTATC TAGCTATTGC 8821 TTCCCGTACG GCTTTCGTTT TCTCCTCCTT GT AT A A AT CC TGGTTGCTGT CTCTTTTAGA 8881 GGAGTTGTGG CCCGTTGTCC GTCAACGTGG CGTGGTGTGC TCTGTGTTTG CTGACGCAAC 8941 CCCCACTGGC TGGGGCATTG CCACCACCTG TCAACTCCTT TCTGGGACTT TCGCTTTCCC 9001 CCTCCCGATC GCCACGGCAG AACTCATCGC CGCCTGCCTT GCCCGCTGCT GGACAGGGGC 9061 TAGGTTGCTG GGCACTGATA ATTCCGTGGT GTTGTCAGTA CTGGTACCTT TAAGACCAAT

9181 GCTAATTCAC TCCCAAAGAA GACAAGATCT GCTTTTTGCC TGTACTGGGT CTCTCTGGTT 9241 AGACCAGATC TGAGCCTGGG AGCTCTCTGG CTAACTAGGG AACCCACTGC TTAAGCCTCA 9301 ATAAAGCTTG CCTTGAGTGC TTCAAGTAGT GTGTGCCCGT CTGTTGTGTG ACTCTGGTAA 9361 CTAGAGATCC CTCAGACCCT TTTAGTCAGT GTGGAAAATC TCTAGCA pLCUS FMC63 TRDC P2AW FMC63op TRGC1 (SEQ ID NO:189)

1 CTCGCTGCGC TCGGTCGTTC GGCTGCGGCG AGCGGTATCA GCTCACTCAA AGGCGGTAAT 61 ACGGTTATCC ACAGAATCAG GGGATAACGC AGGAAAGAAC ATGTGAGCAA AAGGCCAGCA 121 AAAGGCCAGG AACCGTAAAA AGGCCGCGTT GCTGGCGTTT TTCCATAGGC TCCGCCCCCC 181 TGACGAGCAT CACAAAAATC GACGCTCAAG TCAGAGGTGG CGAAACCCGA CAGGACTATA 241 AAG AT ACC AG GCGTTTCCCC CTGGAAGCTC CCTCGTGCGC TCTCCTGTTC CGACCCTGCC 301 GCTTACCGGA TACCTGTCCG CCTTTCTCCC TTCGGGAAGC GTGGCGCTTT CTCATAGCTC 361 ACGCTGTAGG TATCTCAGTT CGGTGTAGGT CGTTCGCTCC AAGCTGGGCT GTGTGCACGA 421 ACCCCCCGTT CAGCCCGACC GCTGCGCCTT ATCCGGTAAC TATCGTCTTG AGTCCAACCC 481 GGTAAGACAC GACTTATCGC CACTGGCAGC AGCCACTGGT AACAGGATTA GCAGAGCGAG 541 GTATGTAGGC GGTGCTACAG AGTTCTTGAA GTGGTGGCCT AACTACGGCT ACACTAGAAG 601 AACAGTATTT GGTATCTGCG CTCTGCTGAA GCCAGTTACC TTCGGAAAAA GAGTTGGTAG

721 GATTACGCGC AGAAAAAAAG GATCTCAAGA AGATCCTTTG ATCTTTTCTA CGGGGTCTGA 781 CGCTCAGTGG AACGAAAACT CACGTTAAGG GATTTTGGTC ATGAGGTGAG GCACCTATCT 841 CAGCGATCTG TCTATTTCGT TCATCCATAG TTGCCTGACT CCCCGTCGTT GCTAGGTTAC 901 TGTCATGAGC GG AT AC AT AT TTGAATGTAT TT AG A AAA AT AAACAAAAGA GTTTGTAGAA 961 ACGCAAAAAG GCCATCCGTC AGGATGGCCT TCTGCTTAAT TTGATCGGTG GCAGTTTATG 1021 GCGGGCGTCC TGCCCGCCAC CCTCCGGGCC GTTGCTTCGC AACGTTCAAA TCCGCTCCCG 1081 GCGGATTTGT CCTACTCAGG AGAGCGTTCA CCGACAAACA ACAGATAAAA CGAAAGGCCC 1141 AGTCTTTCGA CTGAGCCTTT CGTTTTATTT GATGCCTGGC AGTTCCCTAC TCTCGCATGG 1201 GTTGCGGCCG CCCGGGCCGT CGACCAATTC TCATGTTTGA CAGCTTATCA TCGAATTTCT 1261 GCCATTCATC CGCTTATTAT CACTTATTCA GGCGTAGCAA CCAGGCGTTT AAGGGCACCA 1321 ATAACTGCCT T AAA A A A ATT ACGCCCCGCC CTGCCACTCA TCGCAGTACT GTTGTAATTC 1381 ATTAAGCATT CTGCCGACAT GGAAGCCATC ACAAACGGCA TGATGAACCT GAATCGCCAG 1441 CGGCATCAGC ACCTTGTCGC CTTGCGTATA ATATTTGCCC AT GGT G A A A A CGGGGGCGAA 1501 GAAGTTGTCC ATATTGGCCA CGTTTAAATC AAAACTGGTG AAACTCACCC AGGGATTGGC 1561 TGAGACGAAA AACATATTCT CAATAAACCC TTTAGGGAAA TAGGCCAGGT TTTCACCGTA 1621 ACACGCCACA TCTTGCGAAT ATATGTGTAG AAACTGCCGG AAATCGTCGT GGT ATT C ACT 1681 CCAGAGCGAT GAAAACGTTT CAGTTTGCTC ATGGAAAACG GTGTAACAAG GGTGAACACT 1741 ATCCCATATC ACCAGCTCAC CGTCTTTCAT TGCCATACGA AATTCCGGAT GAGCATTCAT 1801 CAGGCGGGCA AGAATGTGAA TAAAGGCCGG ATAAAACTTG TGCTTATTTT TCTTTACGGT 1861 CTTTAAAAAG GCCGTAATAT CCAGCTGAAC GGTCTGGTTA TAGGTACATT GAGCAACTGA 1921 CTGAAATGCC TCAAAATGTT CTTT ACGATG CCATTGGGAT ATATCAACGG TGGTATATCC 1981 AGTGATTTTT TTCTCCATTT TAGCTTCCTT AGCTCCTGAA AATCTCGATA ACTCAAAAAA 2041 TACGCCCGGT AGTGATCTTA TTTCATTATG GTGAAAGTTG GAACCTCTTA CGTGCCGATC 2101 AACGTCTCAT TTTCGCCAAA AGTGACATTA ACCTATAAAA ATAGGCGTAT CACGAGGCCA 2161 GCTTGGGAAA CCATAAGACC GAGATAGAGT TGAGTGTTGT TCCAGTTTGG AACAAGAGTC 2221 C ACT ATT AAA GAACGTGGAC TCCAACGTCA AAGGGCGAAA AACCGTCTAT CAGGGCGATG

2341 TAAATCGGAA CCCTAAAGGG AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG CCGGCGAACG 2401 TGGCGAGAAA GGAAGGGAAG AAAGCGAAAG GAGCGGGCGC TAAGGCGCTGGCAAGTGTAG 2461 CGGTCACGCT GCGCGTAACC ACCACACCCG CCGCGCTTAA TGCGCCGCTA CAGGGCGCGT 2521 ACTATGGTTG CTTTGACGTA TGCGGTGTGA AATACCGCAC AGATGCGTAA GGAGAAAATA 2581 CATCGTGATC CGGATCAAGA TCCAGATCGA ATTGGAGGCT ACAGTCAGTG GAGAGGACTT 2641 TCACTGACTG ACTGACTGCG TCTCAACCTC CTAGGGGACA TTGATTATTG ACTAGTTATT 2701 AATAGTAATC AATTACGGGG TCATTAGTTC ATAGCCCATA TATGGAGTTC CGCGTT AC AT 2761 AACTTACGGT AAATGGCCCG CCTGGCTGAC CGCCCAACGA CCCCCGCCCA TTGACGTCAA 2821 T AATGACGT A TGTTCCCATA GTAACGCCAA TAGGGACTTT CCATTGACGT CAATGGGTGG 2881 AGTATTTACG GTAAACTGCC CACTTGGCAG TACATCAAGT GTATCATATG CCAAGTACGC 2941 CCCCTATTGA CGTCAATGAC GGTAAATGGC CCGCCTGGCA TTATGCCCAG TACATGACCT 3001 TATGGGACTT TCCTACTTGG CAGTACATCT ACGT ATT AGT CATCGCTATT ACCATGGTGA 3061 TGCGGTTTTG GCAGTACATC AATGGGCGTG GATAGCGGTT TGACTCACGG GGATTTCCAA 3121 GTCTCCACCC CATTGACGTC AATGGGAGTT TGTTTTGGCA CCAAAATCAA CGGGACTTTC 3181 CAAAATGTCG TAACAACTCC GCCCCATTGA CGCAAATGGG CGGTAGGCGT GTACGGTGGG 3241 AGGTCTATAT AAGCAGAGCT CGTTTAGTGA ACCGGGTCTC TCTGGTTAGA CCAGATCTGA 3301 GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA A AGCTT GCCT 3361 TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG TTGTGTGACT CTGGTAACTA GAGATCCCTC 3421 AGACCCTTTT AGTCAGTGTG G AAA AT CT CT AGCAGTGGCG CCCGAACAGG GACTTGAAAG 3481 CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC GCAGGACTCG GCTTGCTGAA GCGCGCACGG 3541 CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA CGCCAAAAAT TTTGACTAGC GGAGGCTAGA 3601 AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA TTAAGCGGGG GAGAATTAGA TAAATGGGAA 3661 AAAATTCGGT TAAGGCCAGG GGGAAAGAAA C A AT AT A A AC T AAA AC AT AT AGTTAGGGCA 3721 AGCAGGGAGC TAGAACGATT CGCAGTTAAT CCTGGCCTTT T AG AG AC AT C AGAAGGCTGT 3781 AGACAAATAC TGGGACAGCT ACAACCATCC CTTCAGACAG GATCAGAAGA ACTTAGATCA 3841 TT AT AT A AT A CAATAGCAGT CCTCTATTGT GTGCATCAAA GGATAGATGT AAAAGACACC 3901 AAGGAAGCCT TAGATAAGAT AGAGGAAGAG CAAAACAAAA GTAAGAAAAAGGCACAGCAA 3961 GCGATCTTCA GACCTGGAGG AGGCAGGAGG CGATATGAGG GACAATTGGA GAAGTGAATT 4021 AT AT A A AT AT A AAGT AGT A A AAATTGAACC ATT AGG AGT A GCACCCACCA AGGCAAAGAG 4081 AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT GGGAATAGGA GCTTTGTTCC TTGGGTTCTT 4141 GGGAGCAGCA GGAAGCACTA TGGGCGCAGC GTCAATGACG CTGACGGTAC AGGCCAGACA 4201 ATTATTGTCT GATATAGTGC AGCAGCAGAA CAATTTGCTG AGGGCTATTG AGGCGCAACA 4261 GCATCTGTTG CAACTCACAG TCTGGGGCAT CAAACAGCTC CAGGCAAGAA TCCTGGCTGT 4321 GGAAAGATAC CTAAAGGATC AACAGCTCCT GGGGATTTGG GGTTGCTCTG GAAAACTCAT 4381 TTGCACCACT GCTGTGCCTT GGAATGCTAG TT GGAGT A AT AAATCTCTGG AACAGATTTG 4441 GAATAACATG ACCTGGATGG AGTGGGACAG AG A A ATT A AC AATTACACAA GCTTAATACA 4501 CTCCTTAATT GAAGAATCGC AAAACCAGCA AGAAAAGAAT GAACAAGAAT TATTGGAATT 4561 AGATAAATGG GCAAGTTTGT GGAATTGGTT TAACATAACA AATTGGCTGT GGTATATAAA 4621 ATTATTCATA ATGATAGTAG GAGGCTTGGT AGGTTTAAGA ATAGTTTTTG CTGTACTTTC 4681 T AT AGT G A AT AGAGTT AGGC AGGGATATTC ACCATTATCG TTTCAGACCC ACCTCCCAAT 4741 CCCGAGGGGA CCACGCGTAC AAATGGCAGT ATTCATCCAC AATTTTAAAA GAAAAGGGGG 4801 GATTGGGGGG TACAGTGCAG GGGAAAGAAT AGTAGACATA ATAGCAACAG AC AT AC A A AC 4861 TAAAGAATTA CAAAAACAAA TTACAAAAAT TCAAAATTTT CGGGTTTATT ACAGGGACAG 4921 CAGAAATCCA CTTTGGAAAG CTGAGCATCC GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC 4981 ACATCGCCCA CAGTCCCCGA GAAGTTGGGG GGAGGGGT CG GCAATTGAAC CGGTGCCTAG 5041 AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT GATGTCGTGT ACTGGCTCCG CCTTTTTCCC 5101 GAGGGTGGGG GAGAACCGTA TATAAGTGCA GTAGTCGCCG TGAACGTTCT TTTTCGCAAC 5161 GGGTTTGCCG CCAGAACACA GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT 5221 ACGGGTTATG GCCCTTGCGT GCCTTGAATT ACTTCCACGC CCCTGGCTGC AGTACGTGAT 5281 TCTTGATCCC GAGCTTCGGG TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG 5341 AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG 5401 AATCTGGTGG CACCTTCGCG CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG CCATTTAAAA

5521 AGATCTGCAC ACTGGTATTT CGGTTTTTGG GGCCGCGGGC GGCGACGGGG CCCGTGCGTC 5581 CCAGCGCACA TGTTCGGCGA GGCGGGGCCT GCGAGCGCGG CCACCGAGAA TCGGACGGGG 5641 GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT GCCTGGCCTC GCGCCGCCGT GTATCGCCCC 5701 GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC ACCAGTTGCG TGAGCGGAAA GATGGCCGCT 5761 TCCCGGCCCT GCTGCAGGGA GCTCAAAATG GAGGACGCGG CGCTCGGGAG AGCGGGCGGG 5821 TGAGTCACCC ACACAAAGGA AAAGGGCCTT TCCGTCCTCA GCCGTCGCTT CATGTGACTC 5881 CACGGAGTAC CGGGCGCCGT CCAGGCACCT CGATTAGTTC TCGAGCTTTT GGAGTACGTC 5941 GTCTTTAGGT TGGGGGGAGG GGTTTTATGC GATGGAGTTT CCCCACACTG AGTGGGTGGA 6001 GACTGAAGTT AGGCCAGCTT GGCACTTGAT GTAATTCTCC TTGGAATTTG CCCTTTTTGA

6121 TCAGGTGTCG TGAAAACTAC CCCTCTAGAG CCGCCACCAT GCTTCTCCTG GTGACAAGCC 6181 TTCTGCTCTG TGAGTTACCA CACCCAGCAT TCCTCCTGAT CCCAGACATC CAGATGACAC 6241 AG ACT AC AT C CTCCCTGTCT GCCTCTCTGG GAGACAGAGT CACCATCAGT TGCAGGGCAA 6301 GTCAGGACAT T AGT A A AT AT TTAAATTGGT ATCAGCAGAA ACCAGATGGA ACTGTTAAAC 6361 TCCTGATCTA CC AT AC AT C A AGATTACACT CAGGAGTCCC AT C A AGGTT C AGTGGCAGTG 6421 GGTCTGGAAC AG ATT ATT CT CTCACCATTA GCAACCTGGA GCAAGAAGAT ATTGCCACTT 6481 ACTTTTGCCA ACAGGGTAAT ACGCTTCCGT ACACGTTCGG AGGGGGGACT AAGTTGGAAA 6541 TAACAGGCTC CACCTCTGGA TCCGGCAAGC CCGGATCTGG CGAGGGATCC ACCAAGGGCG 6601 AGGTGAAACT GCAGGAGTCA GGACCTGGCC TGGTGGCGCC CTCACAGAGC CTGTCCGTCA 6661 CAT GC ACT GT CTCAGGGGTC TCATTACCCG ACTATGGTGT AAGCTGGATT CGCCAGCCTC 6721 CACGAAAGGG TCTGGAGTGG CTGGGAGTAA TATGGGGTAG TGAAACCACA TACTATAATT 6781 CAGCTCTCAA ATCCAGACTG ACCATCATCA AGGACAACTC CAAGAGCCAA GTTTTCTTAA 6841 AAATGAACAG T CT GCA A ACT GAT G AC AC AG CCATTTACTA CTGTGCCAAA CATTATTACT 6901 ACGGTGGTAG CTATGCTATG GACTACTGGG GTCAAGGAAC CTCAGTCACC GTCTCCTCAG 6961 CGGCCGCAGG TGGAGGAGGT TCTGGAGGTG GTGGATCAGG TGGTGGAGGA TCTTTAGAAA

7081 TGGTGAAGGA ATTCTACCCC AAGGATATAA GAATAAATCT CGTGTCATCC AAGAAGATAA 7141 CAGAGTTTGA TCCTGCTATT GTCATCTCTC CCAGTGGGAA GTACAATGCT GTCAAGCTTG 7201 GTAAATATGA AGATTCAAAT TCAGTGACAT GTTCAGTTCA ACACGACAAT AAAACTGTGC 7261 ACTCCACTGA CTTTGAAGTG AAGACAGATT CTACAGATCA CGTAAAACCA AAGGAAACTG 7321 AAAACACAAA GCAACCTTCA AAGAGCTGCC ATAAACCCAA AGCCATAGTT CATACCGAGA 7381 AGGTGAACAT GATGTCCCTC ACAGTGCTTG GGCTACGAAT GCTGTTTGCA AAGACTGTTG 7441 CCGTCAATTT TCTCTTGACT GCCAAGTTAT TTTTCTTGGG GTCAGGCGCT ACT A ACTT C A 7501 GCCTGCTGAA GCAGGCTGGA GACGTGGAGG AGAACCCTGG ACCTATGCTA CTACTTGTGA 7561 CCTCACTATT GTTATGCGAA CTCCCTCATC CCGCATTCTT GCTGATTCCA GACATTCAGA 7621 TGACTCAAAC AACTTCCAGC CTCTCCGCCT CACTCGGCGA CCGCGTAACA ATAAGCTGTC 7681 GGGCCTCGCA AGATATTAGT AAGTACCTGA ATTGGTATCA GCAAAAACCC GATGGTACAG 7741 TCAAGCTTCT GATCT ACC AT ACCAGTCGTC TGCACAGCGG TGTCCCCAGC AGGTTCAGCG 7801 GCTCAGGATC TGGTACCGAT TATTCACTGA CGATTTCCAA CCTTGAGCAa GAGGACATCG 7861 CCACCTACTT CTGCCAGCAG GGTAATACTC TGCCGTACAC ATTCGGGGGC GGTACCAAGC 7921 TCGAGATCAC GGGTTCAACA AGCGGTTCTG GCAAGCCAGG CAGCGGCGAG GGGAGTACAA 7981 AGGGGGAGGT GAAGTTGCAG GAAAGTGGCC CTGGATTGGT GGCCCCGAGC CAGAGTCTGT 8041 CTGTCACCTG CACAGTTTCC GGAGTAAGTC TGCCTGATTA CGGAGTGTCC TGGATCAGAC 8101 AGCCACCTCG AAAGGGCTTG GAGTGGCTTG GGGTCATTTG GGGCAGTGAA ACCACATACT 8161 ACAACAGCGC TCTTAAGTCC AGGCTCACTA TCATCAAGGA CAATTCAAAG AGCCAAGTAT 8221 T CTT G A A A AT GAATTCCCTG CAGACTGATG AC ACCGCT AT TTATTATTGC GCTAAACATT 8281 ATTACTATGG AGGTTCTTAT GCCATGGACT ACTGGGGGCA GGGTACCTCT GTGACAGTGA 8341 GTTCAGCTGC AGCTGGAGGT GGAGGTAGCG GAGGCGGTGG TAGTGGAGGG GGTGGTTCTC 8401 TGGAAGATAA AC A ACTT GAT GCAGATGTTT CCCCCAAGCC CACTATTTTT CTTCCTTCAA

8521 CTG AT GTT AT T AAG AT AC AT T GGCAAG AAA AGAAGAGCAA CACGATTCTG GGATCCCAGG 8581 AGGGGAACAC CATGAAGACT AACGACACAT ACATGAAATT TAGCTGGTTA ACGGTGCCAG 8641 AAAAGTCACT GGACAAAGAA CACAGATGTA TCGTCAGACA T GAG A AT A AT AAAAACGGAG 8701 TTGATCAAGA AATTATCTTT CCTCCAATAA AGACAGATGT CATCACAATG GATCCCAAAG 8761 ACAATTGTTC AAAAGATGCA A AT GAT AC AC TACTGCTGCA GCTCACAAAC ACCTCTGCAT 8821 ATT AC ATGT A CCTCCTCCTG CTCCTCAAGA GTGTGGTCTA TTTTGCCATC ATCACCTGCT 8881 GTCTGCTTAG AAGAACGGCT TTCTGCTGCA ATGGAGAGAA ATCATAATGA GATATCGAGC 8941 ATCTTACCGC CATTTATACC CATATTTGTT CTGTTTTTCT TGATTTGGGT ATACATTTAA 9001 AT GTT AAT A A AACAAAATGG TGGGGCAATC ATTTACATTT TTAGGGATAT GT AATT ACT A 9061 GTTCAGGTGT ATTGCCACAA GACAAACATG TT A AG A A ACT TTCCCGTTAT TTACGCTCTG 9121 TTCCTGTTAA TCAACCTCTG GATT AC A A A A TTTGTGAAAG ATT G ACT GAT ATTCTTAACT 9181 ATGTTGCTCC TTTTACGCTG TGTGGATATG CTGCTTTATA GCCTCTGTAT CTAGCTATTG 9241 CTTCCCGTAC GGCTTTCGTT TTCTCCTCCT TGTATAAATC CTGGTTGCTG TCTCTTTTAG 9301 AGGAGTTGTG GCCCGTTGTC CGTCAACGTG GCGTGGTGTG CTCTGTGTTT GCTGACGCAA 9361 CCCCCACTGG CTGGGGCATT GCCACCACCT GTCAACTCCT TTCTGGGACT TTCGCTTTCC 9421 CCCTCCCGAT CGCCACGGCA GAACTCATCG CCGCCTGCCT TGCCCGCTGC TGGACAGGGG 9481 CTAGGTTGCT GGGCACTGAT AATTCCGTGG TGTTGTCAGT ACTGGTACCT TTAAGACCAA 9541 TGACTTACAA GGCAGCTGTA GATCTTAGCC ACTTTTTAAA AGAAAAGGGG GGACTGGAAG

10021 TAGTTGTGGT TTGTCCAAAC TCATCAATGT ATCTTATCAT GTCTGGATCT GCGTCGACAC 10081 GAAGAGACGA CTGACTGACT G ACT GG A A AG AGGAAGGGCT GG A AG AGG A AGG AGCTT GAT 10141 CCAGATCCCG ATCTCGATCC AGATCCGGAT CGCAGCTTGG TCTTCCGCTT CCTCGCTCAC 10201 TGA pLRPC m971 TRDC T2AW m971op TRGC1 (SEQ ID NO: 190)

1 TG AT CAT AAT C AAGCCAT AT C AC AT CT GT A GAGGTTT ACT T GCTTT AAA A AACCTCCACA 61 CCTCCCCCTG AACCTGAAAC AT A A A AT G A A TGCAATTGTT GTTGTTAACT TGTTTATTGC 121 AGCTT AT AAT GGTT AC A A AT A A AGC AAT AG CAT C AC A A AT TT C AC A A AT A AAGCATTTTT 181 TTCACTGCAT TCTAGTTGTG GTTTGTCCAA ACTCATCAAT GTATCTTATC ATGTCTGGAT 241 CTGCGTCGAC ACGAAGAGAC GACTGACTGA CTGACTGGAA AGAGGAAGGG CTGGAAGAGG 301 AAGGAGCTTG ATCCAGATCC CGATCTCGAT CCAGATCCGG AT CGC AGCTT GGCGTAATCA 361 TGGTCATAGC TGTTTCCTGT GTGAAATTGT TATCCGCTCA CAATTCCACA CAACATACGA 421 GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT GCCTAATGAG TGAGCTAACT CACATTAATT 481 GCGTTGCGCT CACTGCCCGC TTTCCAGTCG GGAAACCTGT CGTGCCAGCT GCATTAATGA 541 ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG CGTATTGGGC GCTCTTCCGC TTCCTCGCTC 601 ACTGACTCGC TGCGCTCGGT CGTTCGGCTG CGGCGAGCGG TATCAGCTCA CTCAAAGGCG 661 GTAATACGGT TATCCACAGA ATCAGGGGAT AACGCAGGAA AGAACATGTG AGCAAAAGGC 721 CAGCAAAAGG CCAGGAACCG T AAAAAGGCC GCGTTGCTGG CGTTTTTCCA TAGGCTCCGC 781 CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA CCCGACAGGA 841 CT AT A A AG AT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC TGTTCCGACC 901 CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC GCTTTCTCAT 961 AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT GGGCTGTGTG 1021 CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG TCTTGAGTCC 1081 AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG GATTAGCAGA 1141 GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA CGGCTACACT 1201 AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG AAAAAGAGTT

1321 CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT TTCTACGGGG 1381 TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG ATTATCAAAA 1441 AGGATCTTCA CCTAGATCCT TTTAAATTAA AAATGAAGTT TTAAATCAAT CTAAAGTATA 1501 TATGAGTAAA CTTGGTCTGA CAGTTACCAA TGCTTAATCA GTGAGGCACC TATCTCAGCG 1561 ATCTGTCTAT TTCGTTCATC CATAGTTGCC TGACTCCCCG TCGTTGCTAG GTTACTGTCA 1621 TGAGCGGATA CATATTTGAA TGTATTTAGA AAAATAAACA AAAGAGTTTG TAGAAACGCA 1681 AAAAGGCCAT CCGTCAGGAT GGCCTTCTGC TTAATTTGAT CGGTGGCAGT TTATGGCGGG 1741 CGTCCTGCCC GCCACCCTCC GGGCCGTTGC TTCGCAACGT TCAAATCCGC TCCCGGCGGA 1801 TTTGTCCTAC TCAGGAGAGC GTTCACCGAC AAACAACAGA TAAAACGAAA GGCCCAGTCT 1861 TTCGACTGAG CCTTTCGTTT TATTTGATGC CTGGCAGTTC CCTACTCTCG CATGGGTTGC 1921 GGCCGCCCGG GCCGTCGACC AATTCTCATG TTTGACAGCT TATCATCGAA TTTCTGCCAT 1981 TCATCCGCTT ATTATCACTT ATTCAGGCGT AGCAACCAGG CGTTTAAGGG CACCAATAAC 2041 TGCCTTAAAA AAATTACGCC CCGCCCTGCC ACTCATCGCA GTACTGTTGT AATTCATTAA 2101 GCATTCTGCC GACATGGAAG CCATCACAAA CGGCATGATG AACCTGAATC GCCAGCGGCA 2161 TCAGCACCTT GTCGCCTTGC GT AT A AT ATT TGCCCATGGT GAAAACGGGG GCGAAGAAGT 2221 TGTCCATATT GGCCACGTTT AA AT C A A A AC TGGTGAAACT CACCCAGGGA TTGGCTGAGA 2281 CGAAAAACAT ATT CT C A AT A AACCCTTT AG GGAAATAGGC C AGGTTTT C A CCGTAACACG 2341 CCACATCTTG CGAATATATG TGTAGAAACT GCCGGAAATC GTCGTGGTAT TCACTCCAGA 2401 GCGATGAAAA CGTTTCAGTT TGCTCATGGA AAACGGTGTA ACAAGGGTGA ACACTATCCC 2461 ATATCACCAG CTCACCGTCT TTCATTGCCA TACGAAATTC CGGATGAGCA TTCATCAGGC 2521 GGGCAAGAAT GTGAATAAAG GCCGGATAAA ACTTGTGCTT ATTTTTCTTT ACGGTCTTTA 2581 AAAAGGCCGT A AT AT CC AGC TGAACGGTCT GGTTATAGGT ACATTGAGCA ACTGACTGAA 2641 ATGCCTCAAA ATGTTCTTTA CGATGCCATT GGGATATATC AACGGTGGTA TATCCAGTGA

2761 CCGGTAGTGA TCTTATTTCA TTATGGTGAA AGTTGGAACC TCTTACGTGC CGATCAACGT 2821 CTCATTTTCG CCAAAAGTGA CATTAACCTA TAAAAATAGG CGTATCACGA GGCCAGCTTG 2881 GGAAACC AT A AGACCGAGAT AGAGTTGAGT GTTGTTCCAG TTTGGAACAA GAGTCCACTA 2941 TTAAAGAACG TGGACTCCAA CGTCAAAGGG CGAAAAACCG TCTATCAGGG CGATGGCCCA 3001 CTACGTGAAC CATCACCCAA ATCAAGTTTT TTGGGGTCGA GGTGCCGTAA AGC ACT A A AT 3061 CGGAACCCTA AAGGGAGCCC CCGATTTAGA GCTTGACGGG GAAAGCCGGC GAACGTGGCG 3121 AGAAAGGAAG GGAAGAAAGC GAAAGGAGCG GGCGCTAAGG CGCTGGCAAGTGTAGCGGTC 3181 ACGCTGCGCG TAACCACCAC ACCCGCCGCG CTTAATGCGC CGCTACAGGG CGCGTACTAT 3241 GGTTGCTTTG ACGTATGCGG TGTGAAATAC CGCACAGATG CGTAAGGAGA AAATACCGCA 3301 TCAGGCGCCA TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGATCG GTGCGGGCCT 3361 CTTCGCTATT ACGCCAGCTG GCGAAAGGGG GATGTGCTGC AAGGCG ATT A AGTTGGGTAA 3421 CGCCAGGGTT TTCCCAGTCA CGACGTTGTA AAACGACGGC CAGTGAATTG ATCGAGATCG 3481 TGATCCGGAT CAAGATCCAG ATCGAATTGG AGGCTACAGT CAGTGGAGAG GACTTTCACT 3541 GACTGACTGA CTGCGTCTCA ACCTCCTAGG GGACATTGAT TATTGACTAG TT ATT A AT AG 3601 TAATCAATTA CGGGGTCATT AGTTCATAGC CCATATATGG AGTTCCGCGT TACATAACTT 3661 ACGGTAAATG GCCCGCCTGG CTGACCGCCC AACGACCCCC GCCCATTGAC GTCAATAATG 3721 ACGTATGTTC CCATAGTAAC GCCAATAGGG ACTTTCCATT GACGTCAATG GGTGGAGTAT 3781 TTACGGTAAA CTGCCCACTT GGCAGTACAT CAAGTGTATC ATATGCCAAG TACGCCCCCT 3841 ATTGACGTCA ATGACGGTAA ATGGCCCGCC TGGCATTATG CCCAGTACAT GACCTTATGG 3901 GACTTTCCTA CTTGGCAGTA CATCTACGTA TTAGTCATCG CTATTACCAT GGTGATGCGG 3961 TTTTGGCAGT ACATCAATGG GCGTGGATAG CGGTTTGACT CACGGGGATT TCCAAGTCTC 4021 CACCCCATTG ACGTCAATGG GAGTTTGTTT TGGCACCAAA ATCAACGGGA CTTTCCAAAA 4081 TGTCGTAACA ACTCCGCCCC ATTGACGCAA ATGGGCGGTA GGCGTGTACG GTGGGAGGTC 4141 T AT AT AAGC A GAGCTCGTTT AGTGAACCGG GTCTCTCTGG TTAGACCAGA TCTGAGCCTG 4201 GGAGCTCTCT GGCTAACTAG GGAACCCACT GCTTAAGCCT CAATAAAGCT TGCCTTGAGT 4261 GCTCAAAGTA GTGTGTGCCC GTCTGTTGTG TGACTCTGGT AACTAGAGAT CCCTCAGACC 4321 CTTTTAGTCA GTGTGGAAAA TCTCTAGCAG TGGCGCCCGA ACAGGGACTT GAAAGCGAAA 4381 GTAAAGCCAG AGGAGATCTC TCGACGCAGG ACTCGGCTTG CTGAAGCGCG CACGGCAAGA 4441 GGCGAGGGGC GGCGACTGGT GAGTACGCCA A A A ATTTT G A CTAGCGGAGG CT AG A AGG AG 4501 AGAGTAGGGT GCGAGAGCGT CGGTATTAAG CGGGGGAGAA TTAGATAAAT GGGAAAAAAT 4561 TCGGTTAAGG CCAGGGGGAA AGAAACAATA T A A ACT A A A A CATATAGTTA GGGCAAGCAG 4621 GGAGCTAGAA CGATTCGCAG TTAATCCTGG CCTTTT AG AG ACATCAGAAG GCTGTAGACA 4681 AATACTGGGA CAGCTACAAC CATCCCTTCA GACAGGATCA GAAGAACTTA GATCATTATA 4741 T AAT AC A AT A GCAGTCCTCT ATT GT GT GCA T C A A AGG AT A GAT GT AAA AG ACACCAAGGA 4801 AGCCTTAGAT AAGATAGAGG AAGAGCAAAA CAAAAGTAAG AAAAAGGCACAGCAAGCGAT 4861 CTTCAGACCT GGAGGAGGCA GGAGGCGATA TGAGGGACAA TTGGAGAAGT G A ATT AT AT A 4921 AAT AT A A AGT AGTAAAAATT G A ACC ATT AG GAGTAGCACC CACCAAGGCA AAGAGAAGAG 4981 TGGTGCAGAG AGAAAAAAGA GCAGTGGGAA TAGGAGCTTT GTTCCTTGGG TTCTTGGGAG 5041 CAGCAGGAAG CACTATGGGC GCAGCGTCAA TGACGCTGAC GGTACAGGCC AGACAATTAT 5101 TGTCTGATAT AGTGCAGCAG CAGAACAATT TGCTGAGGGC TATTGAGGCG CAACAGCATC 5161 TGTTGCAACT CACAGTCTGG GGCATCAAAC AGCTCCAGGC AAGAATCCTG GCTGTGGAAA 5221 GATACCTAAA GGATCAACAG CTCCTGGGGA TTTGGGGTTG CTCTGGAAAA CTCATTTGCA 5281 CCACTGCTGT GCCTTGGAAT GCTAGTTGGA GTAATAAATC TCTGGAACAG ATTTGGAATA 5341 ACATGACCTG GAT GG AGT GG GACAGAGAAA TT AAC A ATT A CACAAGCTTA ATACACTCCT 5401 TAATTGAAGA ATCGCAAAAC CAGCAAGAAA AGAATGAACA AG A ATT ATT G GAATT AG AT A 5461 AATGGGCAAG TTTGTGGAAT TGGTTTAACA T A AC A A ATT G GCTGTGGTAT ATAAAATTAT 5521 T CAT A ATG AT AGTAGGAGGC TTGGTAGGTT T A AG AAT AGT TTTTGCTGTA CTTTCTATAG 5581 TGAATAGAGT TAGGCAGGGA TATTCACCAT TATCGTTTCA GACCCACCTC CCAATCCCGA 5641 GGGGACCACG CGTACAAATG GCAGTATTCA TCCACAATTT T AAA AG A A A A GGGGGGATTG 5701 GGGGGTACAG TGCAGGGGAA AGAATAGTAG ACATAATAGC AACAGACATA CAAACTAAAG 5761 AATT AC A A A A ACAAATTACA A A A ATT C A A A ATTTTCGGGT TT ATT AC AGG GACAGCAGAA 5821 ATCCACTTTG G A A AGCT GAG CATCCGGCTC CGGTGCCCGT CAGTGGGCAG AGCGCACATC 5881 GCCCACAGTC CCCGAGAAGT TGGGGGGAGG GGTCGGCAAT TGAACCGGTG CCTAGAGAAG 5941 GTGGCGCGGG GTAAACTGGG AAAGTGATGT CGTGTACTGG CTCCGCCTTT TTCCCGAGGG

6061 TGCCGCCAGA ACACAGGTAA GTGCCGTGTG TGGTTCCCGC GGGCCTGGCC TCTTTACGGG 6121 TTATGGCCCT TGCGTGCCTT GAATTACTTC CACGCCCCTG GCTGCAGTAC GTGATTCTTG 6181 ATCCCGAGCT TCGGGTTGGA AGTGGGTGGG AGAGTTCGAG GCCTTGCGCT TAAGGAGCCC 6241 CTTCGCCTCG TGCTTGAGTT GAGGCCTGGC CTGGGCGCTG GGGCCGCCGC GTGCGAATCT 6301 GGTGGCACCT TCGCGCCTGT CTCGCTGCTT TCGATAAGTC TCTAGCCATT TAAAATTTTT 6361 GATGACCTGC TGCGACGCTT TTTTTCTGGC AAGATAGTCT TGTAAATGCG GGCCAAGATC 6421 TGCACACTGG TATTTCGGTT TTTGGGGCCG CGGGCGGCGA CGGGGCCCGT GCGTCCCAGC 6481 GCACATGTTC GGCGAGGCGG GGCCTGCGAG CGCGGCCACC GAGAATCGGA CGGGGGTAGT 6541 CTCAAGCTGG CCGGCCTGCT CTGGTGCCTG GCCTCGCGCC GCCGTGTATC GCCCCGCCCT 6601 GGGCGGCAAG GCTGGCCCGG TCGGCACCAG TTGCGTGAGC GGAAAGATGG CCGCTTCCCG 6661 GCCCTGCTGC AGGGAGCTCA AAATGGAGGA CGCGGCGCTC GGGAGAGCGG GCGGGTGAGT 6721 CACCCACACA AAGGAAAAGG GCCTTTCCGT CCTCAGCCGT CGCTTCATGT GACTCCACGG 6781 AGTACCGGGC GCCGTCCAGG CACCTCGATT AGTTCTCGAG CTTTTGGAGT ACGTCGTCTT 6841 TAGGTTGGGG GGAGGGGTTT TATGCGATGG AGTTTCCCCA CACTGAGTGG GTGGAGACTG 6901 AAGTTAGGCC AGCTTGGCAC TT GAT GT A AT TCTCCTTGGA ATTTGCCCTT TTTGAGTTTG 6961 GATCTTGGTT CATTCTCAAG CCTCAGACAG TGGTTCAAAG TTTTTTTCTT CCATTTCAGG 7021 TGTCGTGAAA ACTACCCCTC TGAGCCGCCA CCATGCTTCT GCTTGTGACG TCCCTCCTGC 7081 TTTGTGAACT CCCGCATCCT GCCTTCCTGC TCATCCCGCA GGTCCAACTT CAACAATCAG 7141 GACCAGGGCT CGTGAAGCCG TCCCAAACGC TTAGTCTCAC ATGCGCCATT AGTGGGGACT 7201 CCGTGAGTTC AAATTCCGCC GCCTGGAATT GGATTAGGCA AAGTCCATCT AGGGGTCTTG 7261 AGTGGCTCGG CCGCACTTAC TACAGATCCA AGTGGTATAA CGACTACGCA GTATCCGTAA 7321 AATCAAGAAT AACAATTAAT CCAGATACTT CTAAGAACCA ATTTAGTCTT CAACTGAACA 7381 GCGTGACCCC GGAGG AT AC A GCGGTGTATT ATTGTGCGCG AGAAGTTACC GGGGATCTGG 7441 AGGATGCTTT TGATATCTGG GGCCAAGGAA CAATGGTAAC CGTTAGTTCA GGAGGAGGGG 7501 GAAGTGATAT ACAAATGACA CAGAGCCCTA GTTCCCTTAG TGCCTCAGTT GGGGAT AGGG 7561 TAACAATCAC TTGCCGAGCA TCACAGACGA TATGGTCCTA TCTCAACTGG TATCAACAAC 7621 GCCCTGGCAA GGCACCCAAC CTGCTGATCT ACGCCGCTAG TAGTTTGCAA AGTGGGGTAC 7681 CTAGTAGATT CTCCGGCAGA GGTTCTGGCA CTGACTTTAC CTTGACAATC AGCAGCCTCC 7741 AAGCAGAAGA CTTCGCGACA TACTACTGTC AGCAAAGTTA CTCTATACCT CAGACGTTCG 7801 GTCAGGGGAC CAAGCTCGAG ATCAAGGCGG CCGCAGGTGG AGGAGGTTCT GGAGGTGGTG 7861 GATCAGGTGG TGGAGGATCT TTAGAAAGTC AGCCTCATAC CAAACCATCC GTTTTTGTCA 7921 TGAAAAATGG AACAAATGTC GCTTGTCTGG TGAAGGAATT CTACCCCAAG GATATAAGAA 7981 TAAATCTCGT GTCATCCAAG AAG AT A AC AG AGTTTGATCC TGCTATTGTC ATCTCTCCCA 8041 GTGGGAAGTA CAATGCTGTC AAGCTTGGTA AATATGAAGA TTCAAATTCA GTGACATGTT 8101 CAGTTCAACA CGACAATAAA ACTGTGCACT CCACTGACTT TGAAGTGAAG AC AG ATT CT A 8161 CAGATCACGT AAAACCAAAG GAAACTGAAA ACACAAAGCA ACCTTCAAAG AGCTGCCATA 8221 AACCCAAAGC CATAGTTCAT ACCGAGAAGG TGAACATGAT GTCCCTCACA GTGCTTGGGC 8281 TACGAATGCT GTTTGCAAAG ACTGTTGCCG TCAATTTTCT CTTGACTGCC AAGTTATTTT 8341 TCTTGGGGTC AGGCGAGGGC AGAGGAAGTC TGCTAACATG CGGTGACGTC GAGGAGAATC 8401 CTGGACCTAT GCTTCTCCTG GTGACAAGCC TTCTGCTCTG TGAGTTACCA CACCCAGCAT 8461 TCCTCCTGAT CCCACAGGTG CAGCTGCAGC AGAGCGGCCC CGGCCTGGTG AAGCCCAGCC 8521 AGACCCTGAG CCTGACCTGC GCTATCAGCG GCGACAGCGT TAGCAGCAAC AGCGCTGCTT 8581 GGAACTGGAT CAGACAGAGC CCCAGCAGAG GCCTGGAGTG GCTGGGCAGA ACCT ACT AT A 8641 GAAGCAAATG GTACAACGAT TACGCCGTGA GCGTGAAGAG CAGGATCACC ATCAACCCCG 8701 ACACCAGCAA GAATCAGTTC AGCCTGCAGC TCAATTCCGT CACCCCCGAG GACACCGCCG 8761 TGTACTACTG CGCCAGAGAG GTGACCGGCG ACCTCGAGGA CGCCTTCGAC ATTTGGGGAC 8821 AGGGCACCAT GGTTACCGTG TCTAGCGGTG GCGGAGGCAG CGACATCCAG ATGACCCAGT 8881 CCCCCAGCAG CCTGAGCGCC AGCGTGGGCG AC AG AGT G AC CATCACCTGC AGAGCCAGCC 8941 AGACCATCTG GAGCTACCTG AATTGGTACC AGCAGAGACC CGGAAAAGCC CCTAACCTCC 9001 TCATTTACGC TGCCAGCAGC CTGCAGAGCG GCGTGCCCAG CAGGTTCAGC GGAAGAGGCA 9061 GCGGAACCGA CTTCACCCTG ACCATTTCCT CTCTGCAGGC CGAGGACTTT GCCACCTATT 9121 ACTGCCAGCA GAGCTACAGC ATCCCCCAGA CCTTTGGCCA GGGCACAAAA CTGGAGATTA 9181 AGGCTGCAGC TGGAGGTGGA GGTAGCGGAG GCGGTGGTAG TGGAGGGGGT GGTTCTCTGG 9241 AAGATAAACA ACTTGATGCA GATGTTTCCC CCAAGCCCAC TATTTTTCTT CCTTCAATTG 9301 CTGAAACAAA GCTCCAGAAG GCTGGAACAT ACCTTTGTCT TCTTGAGAAA TTTTTCCCTG 9361 AT GTT ATT AA GATACATTGG CAAGAAAAGA AGAGCAACAC GATTCTGGGA TCCCAGGAGG 9421 GGAACACCAT GAAGACTAAC GACACATACA TGAAATTTAG CTGGTTAACG GTGCCAGAAA 9481 AGTCACTGGA CAAAGAACAC AGATGTATCG TCAGACATGA GAATAATAAA AACGGAGTTG 9541 ATCAAGAAAT TATCTTTCCT CCAATAAAGA C AG AT GT CAT CACAATGGAT CCCAAAGACA 9601 ATTGTTCAAA AGATGCAAAT GATACACTAC TGCTGCAGCT CACAAACACC TCTGCATATT 9661 ACATGTACCT CCTCCTGCTC CTCAAGAGTG TGGTCTATTT TGCCATCATC ACCTGCTGTC 9721 TGCTTAGAAG AACGGCTTTC TGCTGCAATG GAGAGAAATC ATAATGAGAT ATCGAGCATC 9781 TTACCGCCAT TTATACCCAT ATTTGTTCTG TTTTTCTTGA TTTGGGTATA CATTTAAATG

9901 CAGGTGTATT GCCACAAGAC AAACATGTTA AGAAACTTTC CCGTTATTTA CGCTCTGTTC 9961 CTGTT A AT C A ACCTCTGGAT T AC AAAATTT GTGAAAGATT G ACT GAT ATT CTT A ACT AT G 10021 TTGCTCCTTT TACGCTGTGT GGATATGCTG CTTTATAGCC TCTGTATCTA GCTATTGCTT 10081 CCCGTACGGC TTTCGTTTTC TCCTCCTTGT ATAAATCCTG GTTGCTGTCT CTTTTAGAGG 10141 AGTTGTGGCC CGTTGTCCGT CAACGTGGCG TGGTGTGCTC TGTGTTTGCT GACGCAACCC 10201 CCACTGGCTG GGGCATTGCC ACCACCTGTC AACTCCTTTC TGGGACTTTC GCTTTCCCCC 10261 TCCCGATCGC CACGGCAGAA CTCATCGCCG CCTGCCTTGC CCGCTGCTGG ACAGGGGCTA 10321 GGTTGCTGGG CACTGATAAT TCCGTGGTGT TGTCAGTACT GGTACCTTTA AGACCAATGA 10381 CTTACAAGGC AGCTGTAGAT CTTAGCCACT TTTTAAAAGA AAAGGGGGGA CTGGAAGGGC 10441 TAATTCACTC CCAAAGAAGA CAAGATCTGC TTTTTGCCTG TACTGGGTCT CTCTGGTTAG 10501 ACCAGATCTG AGCCTGGGAG CTCTCTGGCT AACTAGGGAA CCCACTGCTT AAGCCTCAAT 10561 AAAGCTTGCC TTGAGTGCTT CAA pLRPS TCR Y9G115 T2A 52cl5 (SEQ ID NO:191)

1 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 61 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA CTGGGAAAGT 121 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG GAGAACCGTA T AT A AGT GCA 181 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 241 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 301 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 361 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 421 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC

601 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 661 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 721 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 781 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 841 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 901 TCCGTCCTCA GCCGTCGCTT CAT GT GACT C CACGGAGTAC CGGGCGCCGT CCAGGCACCT 961 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 1021 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT

1141 GACAGTGGTT CAAAGTTTTT TTCTTCCATT TCAGGTGTCG TG AAA ACT AC CCCGGGATGC 1201 TACTACTTGT G ACCT C ACT A TTGTTATGCG AACTCCCTCA TCCCGCATTC TTGCTGATTC 1261 CAGCAGGACA CCTGGAGCAG CCTCAAATCT CTTCCACAAA GACTCTGTCT AAGACTGCTA 1321 GACTTGAGTG CGTCGTTAGC GGGATCACCA TCTCCGCAAC CTCCGTATAC TGGTACCGCG 1381 AACGGCCTGG AGAGGTGATT CAGTTTCTGG TAAGCATTTC TTACGATGGT ACCGTGCGTA 1441 AAGAAAGCGG GATCCCTTCA GGCAAGTTCG AAGTTGACCG CATCCCCGAG ACGTCAACTA 1501 GCACCCTCAC TATCCACAAC GTGGAGAAGC AGGACATCGC GACCTACTAT TGTGCCTTGT 1561 GGGAAGCGCA GCAGGAGCTG GGAAAAAAGA TTAAGGTGTT CGGGCCAGGG ACAAAGTTGA 1621 TT ATT ACCGA TAAGCAGCTC GATGCGGACG TGTCACCTAA ACCGACTATT TTCTTGCCAA 1681 GTATAGCCGA GACAAAGCTT CAGAAGGCAG GGACTTACTT ATGCCTGCTG GAGAAGTTTT 1741 TCCCTGACGT CATCAAGATT CACTGGGAAG AAAAGAAGAG CAACACTATC CTCGGATCCC 1801 AGGAGGGGAA TACAATGAAG ACCAATGATA CCT AT AT G A A GTTTTCTTGG CTGACTGTGC 1861 CCGAGAAGTC CCTTGATAAG GAACATAGAT GCATCGTGAG ACATGAGAAC AATAAAAACG 1921 GGGTGGATCA GGAAATCATT TTCCCCCCCA TTAAGACCGA CGTTATCACC ATGGATCCAA 1981 AGGATAATTG CTCTAAGGAC GCCAACGACA CTCTTCTGCT TCAGCTGACT AATACAAGCG 2041 Crr ACT AT AT GTACCTGCTC CTGCTTCTGA AAAGCGTGGT GTACTTCGCA ATCATTACTT 2101 GTTGCCTTCT GCGGAGAACT GCCTTCTGTT GTAACGGTGA AAAATCCGGG TCAGGCGAGG 2161 GCAGAGGAAG TCTGCTAACA TGCGGTGACG TCGAGGAGAA TCCTGGACCT ATGCAGAGAA 2221 TCAGCTCTCT GATCCACCTG AGCCTGTTCT GGGCAGGCGT GATGTCTGCC ATCGAGCTGG 2281 TGCCTGAGCA CCAGACCGTT CCAGTGAGCA TCGGCGTGCC TGCCACCCTG AGATGCAGCA 2341 TGAAGGGCGA GGCCATCGGC AACTATTACA TCAACTGGTA CAGAAAGACC CAGGGCAACA 2401 CCATGACCTT CATCT AC AG A GAGAAGGACA TCTACGGACC CGGCTTCAAG GACAACTTCC 2461 AGGGGGACAT TGACATCGCC AAGAACCTGG CTGTGCTGAA GATCCTGGCC CCTAGCGAGA 2521 GAGACGAGGG CAGCTACTAT TGCGCCTGCG ATGCACTGAA GAGAACCGAC ACCGATAAGC 2581 TGATCTTCGG CAAGGGAACC AGAGTGACCG TTGAGCCCAG AAGCCAGCCT CACACCAAGC 2641 CCAGCGTGTT CGTGATGAAG AACGGCACCA ACGTTGCCTG CCTGGTGAAG GAGTTCTACC 2701 CTAAGGACAT CAGAATCAAC CTGGTGTCCA GCAAGAAGAT CACCGAGTTC GACCCAGCCA 2761 TCGTGATCAG CCCAAGCGGA AAGTACAACG CCGTGAAACT GGGCAAGTAC GAGGACAGCA 2821 ACTCTGTGAC TTGCAGCGTG CAGCACGACA ACAAGACCGT TCACTCCACC GACTTCGAGG 2881 TGAAGACCGA CAGCACCGAT CACGTGAAGC CCAAGGAGAC CGAGAACACC AAACAGCCTA 2941 GCAAGAGCTG CCACAAGCCC AAAGCCATCG TGCACACCGA GAAGGTGAAC ATGATGAGCC 3001 TGACCGTGCT TGGACTCAGA ATGCTGTTCG CCAAGACCGT AGCCGTGAAC TTCCTGCTTA 3061 CCGCCAAGCT GTTCTTCCTG TAGATATCGA GCATCTTACC GCCATTTATA CCCATATTTG

3181 TCATTTACAT TTTT AGGGAT ATGTAATTAC TAGTTCAGGT GTATTGCCAC AAGACAAACA 3241 TGTTAAGAAA CTTTCCCGTT ATTTACGCTC TGTTCCTGTT AATCAACCTC TGGATTACAA 3301 AATTTGTGAA AGATTGACTG ATATTCTTAA CTATGTTGCT CCTTTTACGC TGTGTGGATA 3361 TGCTGCTTTA TAGCCTCTGT ATCTAGCTAT TGCTTCCCGT ACGGCTTTCG TTTTCTCCTC 3421 CTTGTATAAA TCCTGGTTGC TGTCTCTTTT AGAGGAGTTG TGGCCCGTTG TCCGTCAACG 3481 TGGCGTGGTG TGCTCTGTGT TTGCTGACGC AACCCCCACT GGCTGGGGCA TTGCCACCAC 3541 CTGTCAACTC CTTTCTGGGA CTTTCGCTTT CCCCCTCCCG ATCGCCACGG CAGAACTCAT 3601 CGCCGCCTGC CTTGCCCGCT GCTGGACAGG GGCTAGGTTG CTGGGCACTG ATAATTCCGT 3661 GGTGTTGTCA GTACTGGTAC CTTTAAGACC AATGACTTAC AAGGCAGCTG TAGATCTTAG

4081 CACTGCATTC TAGTTGTGGT TTGTCCAAAC TCATCAATGT ATCTTATCAT GTCTGGATCT 4141 GCGTCGACAC GAAGAGACGA CTGACTGACT GACTGGAAAG AGGAAGGGCT GGAAGAGGAA 4201 GGAGCTTGAT CCAGATCCCG ATCTCGATCC AGATCCGGAT CGCAGCTTGG TCTTCCGCTT 4261 CCTCGCTCAC TGACTCGCTG CGCTCGGTCG TTCGGCTGCG GCGAGCGGTA TCAGCTCACT 4321 CAAAGGCGGT AATACGGTTA TCCACAGAAT CAGGGGATAA CGCAGGAAAG AACATGTGAG 4381 CAAAAGGCCA GCAAAAGGCC AGGAACCGTA AAAAGGCCGC GTTGCTGGCG TTTTTCCATA 4441 GGCTCCGCCC CCCTGACGAG CATCACAAAA ATCGACGCTC AAGTCAGAGG TGGCGAAACC 4501 CGACAGGACT ATAAAG AT AC CAGGCGTTTC CCCCTGGAAG CTCCCTCGTG CGCTCTCCTG 4561 TTCCGACCCT GCCGCTTACC GGATACCTGT CCGCCTTTCT CCCTTCGGGA AGCGTGGCGC 4621 TTTCTCATAG CTCACGCTGT AGGTATCTCA GTTCGGTGTA GGTCGTTCGC TCCAAGCTGG 4681 GCTGTGTGCA CGAACCCCCC GTTCAGCCCG ACCGCTGCGC CTTATCCGGT AACTATCGTC 4741 TTGAGTCCAA CCCGGTAAGA CACGACTTAT CGCCACTGGC AGCAGCCACT GGTAACAGGA 4801 TTAGCAGAGC GAGGTATGTA GGCGGTGCTA CAGAGTTCTT GAAGTGGTGG CCTAACTACG 4861 GCTACACTAG A AG A AC AGT A TTTGGTATCT GCGCTCTGCT GAAGCCAGTT ACCTTCGGAA

4981 TTTGCAAGCA GCAGATTACG CGCAGAAAAA AAGGATCTCA AGAAGATCCT TTGATCTTTT 5041 CTACGGGGTC TGACGCTCAG TGGAACGAAA ACT C ACGTT A AGGGATTTTG GTCATGAGTT 5101 AATTAACTTG CGCCGTCCCG TCAAGTCAGC GTAATGCTCT GCCAGTGTTA CAACCAATTA 5161 ACC A ATT CT G ATT AG A A AAA CTCATCGAGC AT C AA AT G A A ACT GC A ATTT ATT C AC AT C A 5221 GGATTATCAA T ACC AT ATTT TTGAAAAAGC CGTTTCTGTA ATGAAGGAGA AAACTCACCG 5281 AGGCAGTTCC ATAGGATGGC AAGATCCTGG TATCGGTCTG CGATTCCGAC TCGTCCAACA 5341 TCAATACAAC CTATTAATTT CCCCTCGTCA A A A AT A AGGT TATCAAGTGA GAAATCACCA 5401 TGAGTGACGA CTGAATCCGG TGAGAATGGC AAAAGTTTAT GCATTTCTTT CCAGACTTGT 5461 TCAACAGGCC AGCCATTACG CTCGTCATCA AAATCACTCG CATCAACCAA ACCGTTATTC 5521 ATTCGTGATT GCGCCTGAGC AAGACGAAAT ACGCGATCGC TGTTAAAAGG AC A ATT AC A A 5581 ACAGGAATCG AATGCAACCG GCGCAGGAAC ACTGCCAGCG CATC A AC A AT ATTTTCACCT 5641 GAATCAGGAT ATTCTTCTAA TACCTGGAAT GCTGTTTTTC CGGGGATCGC AGTGGTGAGT 5701 AACCATGCAT CATCAGGAGT ACGGATAAAA TGCTTGATGG TCGGAAGAGG CATAAATTCC 5761 GTCAGCCAGT TTAGTCTGAC CATCTCATCT GTAACATCAT TGGCAACGCT ACCTTTGCCA 5821 TGTTTCAGAA ACAACTCTGG CGCATCGGGC TTCCCATACA AGCGATAGAT TGTCGCACCT 5881 GATTGCCCGA CATTATCGCG AGCCCATTTA TACCCATATA AATCAGCATC CATGTTGGAA 5941 TTTAATCGCG GCCTCGACGT TTCCCGTTGA ATATGGCTCA TAACACCCCT TGTATTACTG 6001 TTTATGTAAG CAGACAGTTT TATTGTTCAT GATGATATAT TTTTATCTTG TGCAATGTAA 6061 CATCAGAGAT TTTGAGACAC AACGTGGCTT TCCCCCCCCC CCCCATGACA TTAACCTATA 6121 AAAATAGGCG TATCACGAGG CCAGCTTGGG AAACCATAAG ACCGAGAT AG AGTTGAGTGT 6181 TGTTCCAGTT TGGAACAAGA GTCCACTATT AAAGAACGTG GACTCCAACG TCAAAGGGCG 6241 AAAAACCGTC TATCAGGGCG ATGGCCCACT ACGTGAACCA TCACCCAAAT CAAGTTTTTT 6301 GGGGTCGAGG TGCCGTAAAG CACTAAATCG GAACCCTAAA GGGAGCCCCC GATTTAGAGC 6361 TTGACGGGGA AAGCCGGCGA ACGTGGCGAG AAAGGAAGGGAAGAAAGCGAAAGGAGCGGG 6421 CGCTAAGGCG CTGGCAAGTG TAGCGGTCAC GCTGCGCGTA ACCACCACAC CCGCCGCGCT 6481 TAATGCGCCG CTACAGGGCG CGTACTATGG TTGCTTTGAC GTATGCGGTG TGAAATACCG 6541 CACAGATGCG TAAGGAGAAA ATACATCGTG ATCCGGATCA AGATCCAGAT CGAATTGGAG 6601 GCTACAGTCA GTGGAGAGGA CTTTCACTGA CTGACTGACT GCGTCTCAAC CTCCTAGGGG 6661 ACATTGATTA TTGACTAGTT ATTAATAGTA ATCAATTACG GGGTCATTAG TTCATAGCCC 6721 ATATATGGAG TTCCGCGTTA CAT A ACTT AC GGTAAATGGC CCGCCTGGCT GACCGCCCAA 6781 CGACCCCCGC CCATTGACGT C A AT A AT G AC GTATGTTCCC ATAGTAACGC CAATAGGGAC 6841 TTTCCATTGA CGTCAATGGG TGGAGTATTT ACGGTAAACT GCCCACTTGG CAGTACATCA 6901 AGTGTATCAT ATGCCAAGTA CGCCCCCTAT TGACGTCAAT GACGGTAAAT GGCCCGCCTG 6961 GCATTATGCC CAGTACATGA CCTTATGGGA CTTTCCTACT TGGCAGTACA TCTACGTATT 7021 AGT CAT CGCT ATT ACC ATGG TGATGCGGTT TTGGCAGTAC ATCAATGGGC GTGGATAGCG 7081 GTTTGACTCA CGGGGATTTC CAAGTCTCCA CCCCATTGAC GTCAATGGGA GTTTGTTTTG 7141 GCACCAAAAT CAACGGGACT TTCCAAAATG TCGTAACAAC TCCGCCCCAT TGACGCAAAT 7201 GGGCGGTAGG CGTGTACGGT GGGAGGTCTA TATAAGCAGA GCTCGTTTAG TGAACCGGGT 7261 CTCTCTGGTT AGACCAGATC TGAGCCTGGG AGCTCTCTGG CTAACTAGGG AACCCACTGC 7321 TTAAGCCTCA AT A A AGCTT G CCTTGAGTGC T C A A AGT AGT GTGTGCCCGT CTGTTGTGTG 7381 ACTCTGGTAA CTAGAGATCC CTCAGACCCT TTTAGTCAGT GTGGAAAATC TCTAGCAGTG 7441 GCGCCCGAAC AGGGACTTGA AAGCGAAAGT AAAGCCAGAG GAGATCTCTC GACGCAGGAC 7501 TCGGCTTGCT GAAGCGCGCA CGGCAAGAGG CGAGGGGCGG CGACTGGTGA GTACGCCAAA 7561 AATTTTGACT AGCGGAGGCT AGAAGGAGAG AGTAGGGTGC GAGAGCGTCG GTATTAAGCG 7621 GGGGAGAATT AGATAAATGG G A A A A A ATT C GGTTAAGGCC AGGGGGAAAG A A AC A AT AT A 7681 AACTAAAACA TATAGTTAGG GCAAGCAGGG AGCTAGAACG ATTCGCAGTT AATCCTGGCC 7741 TTTTAGAGAC ATCAGAAGGC TGTAGACAAA TACTGGGACA GCTACAACCA TCCCTTCAGA 7801 CAGGATCAGA AGAACTTAGA T C ATT AT AT A AT AC A AT AGC AGTCCTCTAT TGTGTGCATC 7861 AAAGGATAGA TGTAAAAGAC ACCAAGGAAG CCTTAGATAA GATAGAGGAA GAGCAAAACA 7921 AAAGTAAGAA AAAGGCACAG CAAGCGATCT TCAGACCTGG AGGAGGCAGG AGGCGATATG 7981 AGGGACAATT GGAGAAGTGA ATT AT AT AAA TATAAAGTAG T A A A A ATT G A ACCATTAGGA 8041 GTAGCACCCA CCAAGGCAAA GAGAAGAGTG GTGCAGAGAG AAAAAAGAGCAGTGGGAATA 8101 GGAGCTTTGT TCCTTGGGTT CTTGGGAGCA GCAGGAAGCA CTATGGGCGC AGCGTCAATG 8161 ACGCTGACGG TACAGGCCAG ACAATTATTG TCTGATATAG TGCAGCAGCA GAACAATTTG 8221 CTGAGGGCTA TTGAGGCGCA ACAGCATCTG TTGCAACTCA CAGTCTGGGG CATCAAACAG 8281 CTCCAGGCAA GAATCCTGGC TGTGGAAAGA TACCTAAAGG ATCAACAGCT CCTGGGGATT 8341 TGGGGTTGCT CTGGAAAACT CATTTGCACC ACTGCTGTGC CTTGGAATGC TAGTTGGAGT 8401 AATAAATCTC TGGAACAGAT TTGGAATAAC ATGACCTGGA TGGAGTGGGA CAGAGAAATT 8461 AACAATTACA CAAGCTTAAT ACACTCCTTA ATT G A AG AAT CGCAAAACCA GCAAGAAAAG 8521 AATGAACAAG AATTATTGGA ATT AG AT AAA TGGGCAAGTT TGTGGAATTG GTTTAACATA 8581 ACAAATTGGC TGTGGTATAT AAAATTATTC ATAATGATAG TAGGAGGCTT GGTAGGTTTA 8641 AGAATAGTTT TTGCTGTACT TTCTATAGTG AATAGAGTTA GGCAGGGATA TTCACCATTA 8701 TCGTTTCAGA CCCACCTCCC AATCCCGAGG GGACCACGCG TACAAATGGC AGT ATT CAT C 8761 CACAATTTTA AAAGAAAAGG GGGGATTGGG GGGTACAGTG CAGGGGAAAG AAT AGT AG AC 8821 ATAATAGCAA CAGACATACA AACTAAAGAA TTACAAAAAC AA ATT AC A A A AATTCAAAAT 8881 TTTCGGGTTT ATT AC AGGG A CAGCAGAAAT CCACTTTGGA AAGCTGAGCA TCC pLRPS TCR v9G 1 15 T2A 62d5 P2A FMC63s (SEQ ID NO:192)

1 GGCTCCGGTG CCCGTCAGTG GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG 61 GGAGGGGTCG GCAATTGAAC CGGTGCCTAG AGAAGGTGGC GCGGGGT AAA CTGGGAAAGT 121 GATGTCGTGT ACTGGCTCCG CCTTTTTCCC GAGGGTGGGG GAGAACCGTA TATAAGTGCA 181 GTAGTCGCCG TGAACGTTCT TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC 241 GTGTGTGGTT CCCGCGGGCC TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT 301 ACTTCCACGC CCCTGGCTGC AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG 361 GTGGGAGAGT TCGAGGCCTT GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC 421 CTGGCCTGGG CGCTGGGGCC GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC

601 GGCCGCGGGC GGCGACGGGG CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT 661 GCGAGCGCGG CCACCGAGAA TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT 721 GCCTGGCCTC GCGCCGCCGT GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC 781 ACCAGTTGCG TGAGCGGAAA GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG 841 GAGGACGCGG CGCTCGGGAG AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT 901 TCCGTCCTCA GCCGTCGCTT CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT 961 CGATTAGTTC TCGAGCTTTT GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC 1021 GATGGAGTTT CCCCACACTG AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT

1141 GACAGTGGTT CAAAGTTTTT TTCTTCCATT TCAGGTGTCG T G AA A ACT AC CCCGGGATGC 1201 TACTACTTGT GACCTCACTA TTGTTATGCG AACTCCCTCA TCCCGCATTC TTGCTGATTC 1261 CAGCAGGACA CCTGGAGCAG CCTCAAATCT CTTCCACAAA GACTCTGTCT AAGACTGCTA 1321 GACTTGAGTG CGTCGTTAGC GGGATCACCA TCTCCGCAAC CTCCGTATAC TGGTACCGCG 1381 AACGGCCTGG AGAGGTGATT CAGTTTCTGG TAAGCATTTC TTACGATGGT ACCGTGCGTA 1441 AAGAAAGCGG GATCCCTTCA GGCAAGTTCG AAGTTGACCG CATCCCCGAG ACGTCAACTA 1501 GCACCCTCAC TATCCACAAC GTGGAGAAGC AGGACATCGC GACCTACTAT TGTGCCTTGT 1561 GGGAAGCGCA GCAGGAGCTG GGAAAAAAGA TTAAGGTGTT CGGGCCAGGG ACAAAGTTGA 1621 TT ATT ACCGA TAAGCAGCTC GATGCGGACG TGTCACCTAA ACCGACTATT TTCTTGCCAA 1681 GTATAGCCGA GACAAAGCTT CAGAAGGCAG GGACTTACTT ATGCCTGCTG GAGAAGTTTT 1741 TCCCTGACGT CATCAAGATT CACTGGGAAG AAAAGAAGAG C AAC ACT AT C CTCGGATCCC 1801 AGGAGGGGAA TACAATGAAG ACCAATGATA CCTATATGAA GTTTTCTTGG CTGACTGTGC 1861 CCGAGAAGTC CCTTGATAAG GAACATAGAT GCATCGTGAG ACATGAGAAC AATAAAAACG 1921 GGGTGGATCA GGAAATCATT TTCCCCCCCA TTAAGACCGA CGTTATCACC ATGGATCCAA 1981 AGGATAATTG CTCTAAGGAC GCCAACGACA CTCTTCTGCT TCAGCTGACT AATACAAGCG 2041 CTTACTATAT GTACCTGCTC CTGCTTCTGA AAAGCGTGGT GTACTTCGCA ATCATTACTT 2101 GTTGCCTTCT GCGGAGAACT GCCTTCTGTT GTAACGGTGA AAAATCCGGG TCAGGCGAGG 2161 GCAGAGGAAG TCTGCTAACA TGCGGTGACG TCGAGGAGAA TCCTGGACCT ATGCAGAGAA 2221 TCAGCTCTCT GATCCACCTG AGCCTGTTCT GGGCAGGCGT GATGTCTGCC ATCGAGCTGG 2281 TGCCTGAGCA CCAGACCGTT CCAGTGAGCA TCGGCGTGCC TGCCACCCTG AGATGCAGCA 2341 TGAAGGGCGA GGCCATCGGC AACTATTACA T C A ACT GGT A CAGAAAGACC CAGGGCAACA 2401 CCATGACCTT CATCTACAGA GAGAAGGACA TCTACGGACC CGGCTTCAAG GACAACTTCC 2461 AGGGGGACAT TGACATCGCC AAGAACCTGG CTGTGCTGAA GATCCTGGCC CCTAGCGAGA 2521 GAGACGAGGG CAGCTACTAT TGCGCCTGCG ATGCACTGAA GAGAACCGAC ACCGATAAGC 2581 TGATCTTCGG CAAGGGAACC AGAGTGACCG TTGAGCCCAG AAGCCAGCCT CACACCAAGC 2641 CCAGCGTGTT CGTGATGAAG AACGGCACCA ACGTTGCCTG CCTGGTGAAG GAGTTCTACC 2701 CTAAGGACAT CAGAATCAAC CTGGTGTCCA GCAAGAAGAT CACCGAGTTC GACCCAGCCA 2761 TCGTGATCAG CCCAAGCGGA AAGTACAACG CCGTGAAACT GGGCAAGTAC GAGGACAGCA 2821 ACTCTGTGAC TTGCAGCGTG CAGCACGACA ACAAGACCGT TCACTCCACC GACTTCGAGG 2881 TGAAGACCGA CAGCACCGAT CACGTGAAGC CCAAGGAGAC CGAGAACACC AAACAGCCTA 2941 GCAAGAGCTG CCACAAGCCC AAAGCCATCG TGCAC ACCGA GAAGGTGAAC ATGATGAGCC 3001 TGACCGTGCT TGGACTCAGA ATGCTGTTCG CCAAGACCGT AGCCGTGAAC TTCCTGCTTA 3061 CCGCCAAGCT GTTCTTCCTG GGAAGTGGCG CTACTAACTT CAGCCTGCTG AAGCAGGCTG 3121 GAGACGTGGA GGAGAACCCT GGACCTATGC TTCTCCTGGT GACAAGCCTT CTGCTCTGTG 3181 AGTTACCACA CCCAGCATTC CTCCTGATCC CAGACATCCA GATGACACAG ACTACATCCT 3241 CCCTGTCTGC CTCTCTGGGA GACAGAGTCA CCATCAGTTG CAGGGCAAGT CAGGACATTA 3301 GTAAATATTT AAATTGGTAT CAGCAGAAAC CAGATGGAAC TGTTAAACTC CTGATCTACC 3361 ATACATCAAG ATTACACTCA GGAGTCCCAT CAAGGTTCAG TGGCAGTGGG TCTGGAACAG 3421 ATTATTCTCT CACCATTAGC AACCTGGAGC AAGAAGATAT TGCCACTTAC TTTTGCCAAC 3481 AGGGTAATAC GCTTCCGTAC ACGTTCGGAG GGGGGACTAA GTTGGAAATA ACAGGCTCCA 3541 CCTCTGGATC CGGCAAGCCC GGATCTGGCG AGGGATCCAC CAAGGGCGAG GTGAAACTGC 3601 AGGAGTCAGG ACCTGGCCTG GTGGCGCCCT CACAGAGCCT GTCCGTCACA TGCACTGTCT 3661 CAGGGGTCTC ATTACCCGAC TATGGTGTAA GCTGGATTCG CCAGCCTCCA CGAAAGGGTC 3721 TGGAGTGGCT GGG AGT A AT A TGGGGTAGTG A A ACC AC AT A CTATAATTCA GCTCTCAAAT 3781 CCAGACTGAC CATCATCAAG GACAACTCCA AGAGCCAAGT TTTCTTAAAA ATGAACAGTC 3841 TGCAAACTGA TGACACAGCC ATTTACTACT GTGCCAAACA TT ATT ACT AC GGTGGTAGCT 3901 ATGCTATGGA CTACTGGGGT CAAGGAACCT CAGTCACCGT CTCCTCAGCT GCCGCAGGTG 3961 GGGGAGGATC TGGAGGCGGT GGCAGTGGGG GTGGAGGCTC ACTGGAGGAT GGTAATGAAG 4021 AAATGGGTGG T ATT AC AC AG ACACCATATA AAGTCTCCAT CTCTGGAACC ACAGTAATAT 4081 TGACATGCCC TCAGTATCCT GGATCTGAAA TACT AT GGC A ACACAATGAT AAGAACATCG 4141 GCGGAGATGA GGATGATAAA AACATAGGCA GTGATGAGGA TCACCTGTCA CTGAAGGAAT 4201 TTTCAGAATT GGAGCAAAGT GGTT ATT ATG TCTGCTACCC CAGAGGAAGC AAACCAGAAG 4261 ATGCGAACTT TTATCTCTAC CTGAGGGCAA GAGTGTGTGA GAACTGCATG GAGATGGATG 4321 TGATGTCGGT GGCCACAATT GTCATAGTGG ACATCTGCAT CACTGGGGGC TTGCTGCTGC 4381 TGGTTTACTA CTGGAGCAAG AATAGAAAGG CCAAGGCCAA GCCTGTGACA CGAGGAGCGG 4441 GTGCTGGCGG CAGGCAAAGG GGACAAAACA AGGAGAGGCC ACCACCTGTT CCCAACCCAG 4501 ACTATGAGCC CATCCGGAAA GGCCAGCGGG ACCTGTATTC TGGCCTGAAT CAGAGACGCA 4561 TCTAAGATAT CGAGCATCTT ACCGCCATTT ATACCCATAT TTGTTCTGTT TTTCTTGATT 4621 TGGGTATACA TTTAAATGTT A AT AAA AC A A AATGGTGGGG CAATCATTTA CATTTTTAGG 4681 GAT AT GT A AT TACTAGTTCA GGTGTATTGC CACAAGACAA ACATGTTAAG AAACTTTCCC 4741 GTTATTTACG CTCTGTTCCT GTTAATCAAC CTCTGGATTA CAAAATTTGT GAAAGATTGA 4801 CTGATATTCT TAACTATGTT GCTCCTTTTA CGCTGTGTGG AT AT GCTGCT TTATAGCCTC 4861 TGTATCTAGC TATTGCTTCC CGTACGGCTT TCGTTTTCTC CTCCTTGTAT AAATCCTGGT 4921 TGCTGTCTCT TTTAGAGGAG TTGTGGCCCG TTGTCCGTCA ACGTGGCGTG GTGTGCTCTG 4981 TGTTTGCTGA CGCAACCCCC ACTGGCTGGG GCATTGCCAC CACCTGTCAA CTCCTTTCTG 5041 GGACTTTCGC TTTCCCCCTC CCGATCGCCA CGGCAGAACT CATCGCCGCC TGCCTTGCCC 5101 GCTGCTGGAC AGGGGCTAGG TTGCTGGGCA CT GAT A ATT C CGTGGTGTTG TCAGTACTGG 5161 TACCTTTAAG ACCAATGACT TACAAGGCAG CTGTAGATCT TAGCCACTTT TT A A A AG A A A 5221 AGGGGGGACT GGAAGGGCTA ATTCACTCCC AAAGAAGACA AGATCTGCTT TTTGCCTGTA 5281 CTGGGTCTCT CTGGTTAGAC CAGATCTGAG CCTGGGAGCT CT CTGGCT A A CTAGGGAACC 5341 CACTGCTTAA GCCTCAATAA AGCTTGCCTT GAGTGCTTCA ATGATCATAA TCAAGCCATA 5401 TCACATCTGT AGAGGTTTAC TTGCTTTAAA AAACCTCCAC ACCTCCCCCT GAACCTGAAA 5461 CAT AA AAT G A ATGCAATTGT TGTTGTTAAC TTGTTTATTG CAGCTTATAA TGGTTACAAA 5521 TAAAGCAATA GCATCACAAA TTTCACAAAT AAAGCATTTT TTTCACTGCA TTCTAGTTGT 5581 GGTTTGTCCA AACTC AT CAA TGTATCTTAT CATGTCTGGA TCTGCGTCGA CACGAAGAGA 5641 CGACTGACTG ACTGACTGGA AAGAGGAAGG GCTGGAAGAG GAAGGAGCTT GATCCAGATC 5701 CCGATCTCGA TCCAGATCCG GATCGCAGCT TGGTCTTCCG CTTCCTCGCT CACTGACTCG 5761 CTGCGCTCGG TCGTTCGGCT GCGGCGAGCG GTATCAGCTC ACTCAAAGGC GGTAATACGG 5821 TTATCCACAG AATCAGGGGA TAACGCAGGA AAGAACATGT GAGCAAAAGG CCAGCAAAAG 5881 GCCAGGAACC GTAAAAAGGC CGCGTTGCTG GCGTTTTTCC ATAGGCTCCG CCCCCCTGAC 5941 GAGCATCACA AAAATCGACG CTCAAGTCAG AGGTGGCGAA ACCCGACAGG ACT AT A A AG A 6001 TACCAGGCGT TTCCCCCTGG AAGCTCCCTC GTGCGCTCTC CTGTTCCGAC CCTGCCGCTT 6061 ACCGGATACC TGTCCGCCTT TCTCCCTTCG GGAAGCGTGG CGCTTTCTCA TAGCTCACGC 6121 TGTAGGTATC TCAGTTCGGT GTAGGTCGTT CGCTCCAAGC TGGGCTGTGT GCACGAACCC 6181 CCCGTTCAGC CCGACCGCTG CGCCTTATCC GGTAACTATC GTCTTGAGTC CAACCCGGTA 6241 AGACACGACT TATCGCCACT GGCAGCAGCC ACTGGTAACA GGATTAGCAG AGCGAGGTAT 6301 GTAGGCGGTG CTACAGAGTT CTTGAAGTGG TGGCCTAACT ACGGCTACAC TAGAAGAACA 6361 GTATTTGGTA TCTGCGCTCT GCTGAAGCCA GTTACCTTCG GAAAAAGAGT TGGTAGCTCT

6781 GGCAAGATCC TGGTATCGGT CTGCGATTCC GACTCGTCCA ACATCAATAC AACCTATTAA 6841 TTTCCCCTCG TCAAAAATAA GGTTATCAAG TGAGAAATCA CCATGAGTGA CGACTGAATC 6901 CGGTGAGAAT GGCAAAAGTT TATGCATTTC TTTCCAGACT TGTTCAACAG GCCAGCCATT 6961 ACGCTCGTCA T CAAAATC AC TCGCATCAAC CAAACCGTTA TTCATTCGTG ATTGCGCCTG 7021 AGCAAGACGA AATACGCGAT CGCTGTTAAA AGGACAATTA CAAACAGGAA TCGAATGCAA 7081 CCGGCGCAGG AACACTGCCA GCGCATCAAC AATATTTTCA CCTGAATCAG GATATTCTTC 7141 TAATACCTGG AATGCTGTTT TTCCGGGGAT CGCAGTGGTG AGTAACCATG CATCATCAGG 7201 AGTACGGATA AAATGCTTGA TGGTCGGAAG AGGCATAAAT TCCGTCAGCC AGTTTAGTCT 7261 GACCATCTCA TCTGTAACAT CATTGGCAAC GCTACCTTTG CCATGTTTCA GAAACAACTC 7321 TGGCGCATCG GGCTTCCCAT ACAAGCGATA GATTGTCGCA CCTGATTGCC CGACATTATC 7381 GCGAGCCCAT TTATACCCAT AT A A AT C AGC ATCCATGTTG GAATTTAATC GCGGCCTCGA 7441 CGTTTCCCGT TGAATATGGC TCATAACACC CCTTGTATTA CTGTTTATGT AAGCAGACAG 7501 TTTTATTGTT CATGATGATA TATTTTTATC TTGTGCAATG TAACATCAGA GATTTTGAGA 7561 CACAACGTGG CTTTCCCCCC CCCCCCCATG AC ATT AACCT AT A A A A AT AG GCGTATCACG 7621 AGGCCAGCTT GGGAAACCAT AAGACCGAGA TAGAGTTGAG TGTTGTTCCA GTTTGGAACA 7681 AGAGTCCACT ATTAAAGAAC GTGGACTCCA ACGTCAAAGG GCGAAAAACC GTCTATCAGG 7741 GCGATGGCCC ACTACGTGAA CCATCACCCA AATCAAGTTT TTTGGGGTCG AGGTGCCGTA 7801 AAGCACTAAA TCGGAACCCT AAAGGGAGCC CCCGATTTAG AGCTTGACGG GGAAAGCCGG 7861 CGAACGTGGC GAGAAAGGAA GGGAAGAAAG CG AAAGGAGCGGGCGCT AAGGCGCTGGC AA 7921 GTGTAGCGGT CACGCTGCGC GTAACCACCA CACCCGCCGC GCTTAATGCG CCGCTACAGG 7981 GCGCGTACTA TGGTTGCTTT GACGTATGCG GTGTGAAATA CCGCACAGAT GCGTAAGGAG 8041 AAA AT AC AT C GTGATCCGGA TCAAGATCCA GATCGAATTG GAGGCTACAG TCAGTGGAGA 8101 GGACTTTCAC TGACTGACTG ACTGCGTCTC AACCTCCTAG GGGACATTGA TTATTGACTA 8161 GTTATTAATA GTAATCAATT ACGGGGTCAT TAGTTCATAG CCCATATATG GAGTTCCGCG 8221 TT AC AT A ACT T ACGGT A A AT GGCCCGCCTG GCTGACCGCC CAACGACCCC CGCCCATTGA 8281 CGTCAATAAT GACGTATGTT CCCATAGTAA CGCCAATAGG GACTTTCCAT TGACGTCAAT 8341 GGGTGGAGTA TTT ACGGT A A ACTGCCCACT TGGCAGTACA TCAAGTGTAT CATATGCCAA 8401 GTACGCCCCC TATTGACGTC AATGACGGTA AATGGCCCGC CTGGCATTAT GCCCAGTACA 8461 TGACCTTATG GGACTTTCCT ACTTGGCAGT ACATCTACGT ATT AGT CATC GCTATTACCA 8521 TGGTGATGCG GTTTTGGCAG T AC AT C A AT G GGCGTGGATA GCGGTTTGAC TCACGGGGAT 8581 TTCCAAGTCT CCACCCCATT GACGTCAATG GGAGTTTGTT TTGGCACCAA AATCAACGGG 8641 ACTTTCCAAA ATGTCGTAAC AACTCCGCCC CATTGACGCA AATGGGCGGT AGGCGTGTAC 8701 GGTGGGAGGT CTATATAAGC AGAGCTCGTT TAGTGAACCG GGTCTCTCTG GTTAGACCAG 8761 ATCTGAGCCT GGGAGCTCTC TGGCTAACTA GGGAACCCAC TGCTTAAGCC TCAATAAAGC 8821 TTGCCTTGAG TGCTCAAAGT AGTGTGTGCC CGTCTGTTGT GTGACTCTGG T A ACT AG AG A 8881 TCCCTCAGAC CCTTTTAGTC AGTGTGGAAA ATCTCTAGCA GTGGCGCCCG AACAGGGACT 8941 TGAAAGCGAA AGTAAAGCCA GAGGAGATCT CTCGACGCAG GACTCGGCTT GCTGAAGCGC 9001 GCACGGCAAG AGGCGAGGGG CGGCGACTGG TGAGTACGCC A A A A ATTTT G ACTAGCGGAG 9061 GCTAGAAGGA GAGAGTAGGG TGCGAGAGCG TCGGTATTAA GCGGGGGAGA ATT AG AT AAA 9121 T GGG A A A A A A TTCGGTTAAG GCCAGGGGGA AAGAAACAAT AT A A ACT AAA AC AT AT AGTT 9181 AGGGCAAGCA GGGAGCTAGA ACGATTCGCA GTTAATCCTG GCCTTTTAGA GACATCAGAA 9241 GGCTGTAGAC AAATACTGGG ACAGCTACAA CCATCCCTTC AGACAGGATC AGAAGAACTT 9301 AGATCATTAT AT A AT AC A AT AGCAGTCCTC TATTGTGTGC AT C A A AGG AT AG AT GT AAA A 9361 GACACCAAGG AAGCCTTAGA TAAGATAGAG GAAGAGCAAA ACAAAAGTAAGAAAAAGGCA 9421 CAGCAAGCGA TCTTCAGACC TGGAGGAGGC AGGAGGCGAT AT G AGGG AC A ATT GG AG A AG 9481 TGAATTATAT AA AT AT A A AG TAGTAAAAAT TGAACCATTA GGAGTAGCAC CCACCAAGGC 9541 AAAGAGAAGA GTGGTGCAGA GAGAAAAAAG AGCAGTGGGA ATAGGAGCTT TGTTCCTTGG 9601 GTTCTTGGGA GCAGCAGGAA GCACTATGGG CGCAGCGTCA ATGACGCTGA CGGTACAGGC 9661 CAGACAATTA TTGTCTGATA TAGTGCAGCA GCAGAACAAT TTGCTGAGGG CTATTGAGGC 9721 GCAACAGCAT CTGTTGCAAC TCACAGTCTG GGGCATCAAA CAGCTCCAGG C A AG A AT CCT 9781 GGCTGTGGAA AGATACCTAA AGGATCAACA GCTCCTGGGG ATTTGGGGTT GCTCTGGAAA 9841 ACTCATTTGC ACCACTGCTG TGCCTTGGAA TGCTAGTTGG AGT A AT A A AT CTCTGGAACA 9901 GATTT GG A AT A AC AT G ACCT GGATGGAGTG GGACAGAGAA ATTAACAATT ACACAAGCTT 9961 AATACACTCC TTAATTGAAG AATCGCAAAA CCAGCAAGAA AAGAATGAAC A AG A ATT ATT 10021 GG A ATT AG AT A A AT GGGC A A GTTTGTGGAA TTGGTTTAAC AT A AC A A ATT GGCTGTGGTA 10081 TAT AAA ATT A TTCATAATGA TAGTAGGAGG CTTGGTAGGT TTAAGAATAG TTTTTGCTGT 10141 ACTTTCTATA GTGAATAGAG TTAGGCAGGG ATATTCACCA TTATCGTTTC AGACCCACCT 10201 CCCAATCCCG AGGGGACCAC GCGTACAAAT GGCAGTATTC ATCCACAATT TT A A A AG A A A 10261 AGGGGGGATT GGGGGGTACA GTGCAGGGGA AAGAATAGTA GACATAATAGCAACAGACAT 10321 AC A A ACT AAA G AATT AC A A A A AC A A ATT AC AAAAATTCAA AATTTTCGGG TTTATTACAG 10381 GGACAGCAGA AATCCACTTT GGAAAGCTGA GCATCC pLKaUS mTRAC(82-137) T2A mTRBC(123-173) P2A MHlCD3s (SEQ ID NO: 193)

541 TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC TCAAGTCAGA GGTGGCGAAA 601 CCCGACAGGA CT AT AAA GAT ACCAGGCGTT TCCCCCTGGA AGCTCCCTCG TGCGCTCTCC 661 TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT CTCCCTTCGG GAAGCGTGGC 721 GCTTTCTCAT AGCTCACGCT GTAGGTATCT CAGTTCGGTG TAGGTCGTTC GCTCCAAGCT 781 GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC GCCTTATCCG GTAACTATCG 841 TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG GCAGCAGCCA CTGGTAACAG 901 GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC TTGAAGTGGT GGCCTAACTA 961 CGGCTACACT AGAAGAACAG TATTTGGTAT CTGCGCTCTG CTGAAGCCAG TTACCTTCGG 1021 AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC GCTGGTAGCG GTGGTTTTTT 1081 TGTTTGCAAG CAGCAGATTA CGCGCAGAAA AAAAGGATCT CAAGAAGATC CTTTGATCTT 1141 TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT TAAGGGATTT TGGTCATGAG 1201 TT A ATT A ACT TGCGCCGTCC CGTCAAGTCA GCGTAATGCT CTGCCAGTGT TACAACCAAT 1261 TAACCAATTC T GATT AG AAA A ACT CAT CG A GCATCAAATG A A ACT GC AAT TTATTCACAT 1321 CAGGATTATC A AT ACC AT AT TTTTGAAAAA GCCGTTTCTG TAATGAAGGA GAAAACTCAC 1381 CGAGGCAGTT CCATAGGATG GCAAGATCCT GGTATCGGTC TGCGATTCCG ACTCGTCCAA 1441 CATCAATACA ACCT ATT AAT TTCCCCTCGT C AAA AAT A AG GTTATCAAGT GAG A A AT C AC 1501 CATGAGTGAC GACTGAATCC GGTGAGAATG GCAAAAGTTT ATGCATTTCT TTCCAGACTT 1561 GTTCAACAGG CCAGCC ATT A CGCTCGTCAT CAAAATCACT CGCATCAACC AAACCGTTAT 1621 TCATTCGTGA TTGCGCCTGA GCAAGACGAA ATACGCGATC GCTGTTAAAA GGACAATTAC 1681 AAACAGGAAT CGAATGCAAC CGGCGCAGGA ACACTGCCAG CGCATCAACA ATATTTTCAC 1741 CTGAATCAGG ATATTCTTCT AATACCTGGA ATGCTGTTTT TCCGGGGATC GCAGTGGTGA 1801 GTAACCATGC ATCATCAGGA GTACGGATAA AATGCTTGAT GGTCGGAAGA GGCATAAATT 1861 CCGTCAGCCA GTTTAGTCTG ACCATCTCAT CT GT A AC AT C ATTGGCAACG CTACCTTTGC 1921 CATGTTTCAG AAACAACTCT GGCGCATCGG GCTTCCCATA CAAGCGATAG ATTGTCGCAC 1981 CTGATTGCCC GACATTATCG CGAGCCCATT TATACCCATA TAAATCAGCA TCCATGTTGG 2041 AATTTAATCG CGGCCTCGAC GTTTCCCGTT GAATATGGCT CATAACACCC CTTGTATTAC 2101 TGTTTATGTA AGCAGACAGT TTTATTGTTC ATGATGATAT ATTTTTATCT TGTGCAATGT 2161 AACATCAGAG ATTTTGAGAC ACAACGTGGC TTTCCCCCCC CCCCATGACA TTAACCTATA 2221 AAAATAGGCG TATCACGAGG CCAGCTTGGG AAACCATAAG ACCGAGATAG AGTTGAGTGT 2281 TGTTCCAGTT TGGAACAAGA GTCCACTATT AAAGAACGTG GACTCCAACG TCAAAGGGCG 2341 AAAAACCGTC TATCAGGGCG ATGGCCCACT ACGTGAACCA TCACCCAAAT CAAGTTTTTT 2401 GGGGTCGAGG TGCCGTAAAG CACTAAATCG GAACCCTAAA GGGAGCCCCC GATTTAGAGC 2461 TTGACGGGGA AAGCCGGCGA ACGTGGCGAG AAAGGAAGGGAAGAAAGCGAAAGGAGCGGG 2521 CGCTAAGGCG CTGGCAAGTG TAGCGGTCAC GCTGCGCGTA ACCACCACAC CCGCCGCGCT 2581 TAATGCGCCG CTACAGGGCG CGTACTATGG TTGCTTTGAC GTATGCGGTG TGAAATACCG 2641 CACAGATGCG TAAGGAGAAA ATACATCGTG ATCCGGATCA AGATCCAGAT CGAATTGGAG 2701 GCTACAGTCA GTGGAGAGGA CTTTCACTGA CTGACTGACT GCGTCTCAAC CTCCTAGGGG 2761 ACATTGATTA TTGACTAGTT ATTAATAGTA ATCAATTACG GGGTCATTAG TTCATAGCCC 2821 ATATATGGAG TTCCGCGTTA CAT A ACTT AC GGTAAATGGC CCGCCTGGCT GACCGCCCAA 2881 CGACCCCCGC CCATTGACGT C A AT A AT G AC GTATGTTCCC ATAGTAACGC CAATAGGGAC 2941 TTTCCATTGA CGTCAATGGG TGGAGTATTT ACGGTAAACT GCCCACTTGG CAGTACATCA 3001 AGTGTATCAT ATGCCAAGTA CGCCCCCTAT TGACGTCAAT GACGGTAAAT GGCCCGCCTG 3061 GCATTATGCC CAGTACATGA CCTTATGGGA CTTTCCTACT TGGCAGTACA TCTACGTATT 3121 AGT CAT CGCT ATT ACC ATGG TGATGCGGTT TTGGCAGTAC ATCAATGGGC GTGGATAGCG 3181 GTTTGACTCA CGGGGATTTC CAAGTCTCCA CCCCATTGAC GTCAATGGGA GTTTGTTTTG 3241 GCACCAAAAT CAACGGGACT TTCCAAAATG TCGTAACAAC TCCGCCCCAT TGACGCAAAT 3301 GGGCGGTAGG CGTGTACGGT GGGAGGTCTA TATAAGCAGA GCTCGTTTAG TGAACCGGGT 3361 CTCTCTGGTT AGACCAGATC TGAGCCTGGG AGCTCTCTGG CTAACTAGGG AACCCACTGC 3421 TTAAGCCTCA AT A A AGCTT G CCTTGAGTGC T C A A AGT AGT GTGTGCCCGT CTGTTGTGTG 3481 ACTCTGGTAA CTAGAGATCC CTCAGACCCT TTTAGTCAGT GTGGAAAATC TCTAGCAGTG 3541 GCGCCCGAAC AGGGACTTGA AAGCGAAAGT AAAGCCAGAG GAGATCTCTC GACGCAGGAC 3601 TCGGCTTGCT GAAGCGCGCA CGGCAAGAGG CGAGGGGCGG CGACTGGTGA GTACGCCAAA 3661 AATTTTGACT AGCGGAGGCT AGAAGGAGAG AGTAGGGTGC GAGAGCGTCG GTATTAAGCG 3721 GGGGAGAATT AGATAAATGG G A A A A A ATT C GGTTAAGGCC AGGGGGAAAG A A AC A AT AT A 3781 AACTAAAACA TATAGTTAGG GCAAGCAGGG AGCTAGAACG ATTCGCAGTT AATCCTGGCC 3841 TTTTAGAGAC ATCAGAAGGC TGTAGACAAA TACTGGGACA GCTACAACCA TCCCTTCAGA 3901 CAGGATCAGA AG A ACTT AG A TC ATT AT AT A AT AC A AT AGC AGTCCTCTAT TGTGTGCATC 3961 AAAGGATAGA TGTAAAAGAC ACCAAGGAAG CCTTAGATAA GATAGAGGAA GAGCAAAACA 4021 AAAGTAAGAA AAAGGCACAG CAAGCGATCT TCAGACCTGG AGGAGGCAGG AGGCGATATG 4081 AGGGACAATT GGAGAAGTGA ATT AT AT AAA T AT A A AGT AG T A A A A ATT G A ACCATTAGGA 4141 GTAGCACCCA CCAAGGCAAA GAGAAGAGTG GTGCAGAGAG AAAAAAGAGCAGTGGGAATA 4201 GGAGCTTTGT TCCTTGGGTT CTTGGGAGCA GCAGGAAGCA CTATGGGCGC AGCGTCAATG 4261 ACGCTGACGG TACAGGCCAG ACAATTATTG TCTGATATAG TGCAGCAGCA GAACAATTTG 4321 CTGAGGGCTA TTGAGGCGCA ACAGCATCTG TTGCAACTCA CAGTCTGGGG CATC A A AC AG 4381 CTCCAGGCAA GAATCCTGGC TGTGGAAAGA TACCTAAAGG ATCAACAGCT CCTGGGGATT 4441 TGGGGTTGCT CTGGAAAACT CATTTGCACC ACTGCTGTGC CTTGGAATGC TAGTTGGAGT 4501 AATAAATCTC TGGAACAGAT TTGGAATAAC ATGACCTGGA TGGAGTGGGA CAGAGAAATT 4561 AACAATTACA CAAGCTTAAT ACACTCCTTA ATT G A AG AAT CGCAAAACCA GCAAGAAAAG 4621 AATGAACAAG AATTATTGGA ATT AG AT AAA TGGGCAAGTT TGTGGAATTG GTTTAACATA 4681 ACAAATTGGC TGTGGTATAT AAAATTATTC ATAATGATAG TAGGAGGCTT GGTAGGTTTA 4741 AGAATAGTTT TTGCTGTACT TTCTATAGTG AATAGAGTTA GGCAGGGATA TTCACCATTA 4801 TCGTTTCAGA CCCACCTCCC AATCCCGAGG GGACCACGCG TACAAATGGC AGT ATT CAT C 4861 CACAATTTTA AAAGAAAAGG GGGGATTGGG GGGTACAGTG CAGGGGAAAG AATAGTAGAC 4921 ATAATAGCAA CAGACATACA AACTAAAGAA TTACAAAAAC AA ATT AC A A A AATTCAAAAT 4981 TTTCGGGTTT ATTACAGGGA CAGCAGAAAT CCACTTTGGA AAGCTGAGCA TCCGGCTCCG 5041 GTGCCCGTCA GTGGGCAGAG CGCACATCGC CCACAGTCCC CGAGAAGTTG GGGGGAGGGG 5101 TCGGCAATTG AACCGGTGCC TAGAGAAGGT GGCGCGGGGT A A ACT GGG A A AGTGATGTCG 5161 TGTACTGGCT CCGCCTTTTT CCCGAGGGTG GGGGAGAACC GTATATAAGT GCAGTAGTCG 5221 CCGTGAACGT TCTTTTTCGC AACGGGTTTG CCGCCAGAAC ACAGGTAAGT GCCGTGTGTG 5281 GTTCCCGCGG GCCTGGCCTC TTTACGGGTT ATGGCCCTTG CGTGCCTTGA ATTACTTCCA 5341 CGCCCCTGGC TGCAGTACGT GATTCTTGAT CCCGAGCTTC GGGTTGGAAG TGGGTGGGAG 5401 AGTTCGAGGC CTTGCGCTTA AGGAGCCCCT TCGCCTCGTG CTTGAGTTGA GGCCTGGCCT 5461 GGGCGCTGGG GCCGCCGCGT GCGAATCTGG TGGCACCTTC GCGCCTGTCT CGCTGCTTTC 5521 GATAAGTCTC TAGCCATTTA AAATTTTTGA TGACCTGCTG CGACGCTTTT TTTCTGGCAA 5581 GAT AGTCTTG TAAATGCGGG CCAAGATCTG CACACTGGTA TTTCGGTTTT TGGGGCCGCG 5641 GGCGGCGACG GGGCCCGTGC GTCCCAGCGC ACATGTTCGG CGAGGCGGGG CCTGCGAGCG 5701 CGGCCACCGA GAATCGGACG GGGGTAGTCT CAAGCTGGCC GGCCTGCTCT GGTGCCTGGC 5761 CTCGCGCCGC CGTGTATCGC CCCGCCCTGG GCGGCAAGGC TGGCCCGGTC GGCACCAGTT 5821 GCGTGAGCGG AAAGATGGCC GCTTCCCGGC CCTGCTGCAG GGAGCTCAAA ATGGAGGACG 5881 CGGCGCTCGG GAGAGCGGGC GGGTGAGTCA CCCACACAAA GGAAAAGGGC CTTTCCGTCC 5941 TCAGCCGTCG CTTCATGTGA CTCCACGGAG TACCGGGCGC CGTCCAGGCA CCTCGATTAG 6001 TTCTCGAGCT TTTGGAGTAC GTCGTCTTTA GGTTGGGGGG AGGGGTTTTA TGCGATGGAG 6061 TTTCCCCACA CTGAGTGGGT GG AG ACT G A A GTTAGGCCAG CTTGGCACTT GATGTAATTC 6121 TCCTTGGAAT TTGCCCTTTT TGAGTTTGGA TCTTGGTTCA TTCTCAAGCC TCAGACAGTG

6241 ATGCTTCTCC TGGTGACAAG CCTTCTGCTC TGTGAGTTAC CACACCCAGC ATTCCTCCTG 6301 ATCCCCGCCA CCTACCCCAG TTCAGACGTT CCCTGTGATG CCACGTTGAC TGAGAAAAGC 6361 TTTGAAACAG ATATGAACCT AAACTTTCAA AACCTGTCAG TT AT GGG ACT CCGAATCCTC 6421 CTGCTGAAAG TAGCCGGATT TAACCTGCTC ATGACGCTGA GGCTGTGGTC CAGTGGCAGC 6481 GGCGAGGGCA GAGGAAGTCT GCTAACATGC GGTGACGTCG AGGAGAATCC TGGACCTGGT 6541 CGAGCAGACT GTGGTATTAC CTCAGCATCC TATCAACAAG GAGTCTTGTC TGCCACCATC 6601 CTCTATGAGA TCCTGCTAGG GAAAGCCACC CTGTATGCTG TGCTTGTCAG TACACTGGTG 6661 GTGATGGCTA TGGTCAAAAG A A AG A ATT C A GGGTCAGGCG CTACTAACTT CAGCCTGCTG 6721 AAGCAGGCTG GAGACGTGGA GGAGAACCCT GGACCTATGC TACTACTTGT GACCTCACTA 6781 TTGTTATGCG AACTCCCTCA TCCCGCATTC TTGCTGATTC CAGAAGTTCA GCTGGTAGAG 6841 TCCGGTGGCG GGCTGGTACA GCCAGGGGGA TCTCTCCGTC TCTCATGTGC TGCCAGTGGG 6901 GGAGATTGGT CCGCTAACTT TATGTACTGG TATCGTCAAG CACCTGGGAA ACAACGCGAG 6961 CTGGTTGCAC GGATCTCTGG ACGAGGGGT A GTGGATTACG TGGAAAGTGT GAAAGGACGA 7021 TTCACAATTT CCAGGGACAA TTCTAAAAAC ACCCTTTATT TGCAAATGAA TAGTCTGAGA 7081 GCAGAAGACA CAGCCGTATA TTATTGTGCA GTCGCATCCT ATTGGGGGCA GGGGACTCTT 7141 GTCACAGTCT CGAGTGCTGC CGCAGGAGGC GGTGGCAGTG GTGGGGGAGG ATCTGGCGGA 7201 GGAGGTAGCC TCGAGGATGG TAATGAAGAA ATGGGTGGTA TT AC AC AG AC ACCATATAAA 7261 GTCTCCATCT CTGGAACCAC AGTAATATTG ACATGCCCTC AGTATCCTGG ATCTGAAATA 7321 CTATGGCAAC ACAATGAcAA AAACATAGGC GGaGATGAGG ATGATAAgAA CATAGGCAGT 7381 GATGAGGATC ACCTGTCACT GAAGGAATTT TCAGAATTGG AGCAAAGTGG TTATTATGTC 7441 TGCTACCCCA GAGGAAGCAA ACCAGAAGAT GCGAACTTTT ATCTCTACCT GAGGGCAAGA 7501 GTGTGTGAGA ACTGCATGGA GATGGATGTG ATGTCGGTGG CCACAATTGT CATAGTGGAC 7561 AT CT GC AT C A CTGGGGGCTT GCTGCTGCTG GTTTACTACT GGAGCAAGAA TAGAAAGGCC 7621 AAGGCCAAGC CTGTGACACG AGGAGCGGGT GCTGGCGGCA GGCAAAGGGG ACAAAACAAG 7681 GAGAGGCCAC CACCTGTTCC CAACCCAGAC TATGAGCCCA TCCGGAAAGG CCAGCGGGAC 7741 CTGTATTCTG GCCTGAATCA GAGACGCATC T A AG AT AT CG AGCATCTTAC CGCCATTTAT 7801 ACCCATATTT GTTCTGTTTT TCTTGATTTG GGT AT AC ATT TAAATGTTAA T AAA AC A A A A 7861 TGGTGGGGCA ATCATTTACA TTTTTAGGGA TATGTAATTA CTAGTTCAGG TGTATTGCCA 7921 CAAGACAAAC ATGTTAAGAA ACTTTCCCGT TATTTACGCT CTGTTCCTGT TAATCAACCT 7981 CTGGATTACA AAATTTGTGA AAGATTGACT GATATTCTTA ACTATGTTGC TCCTTTTACG 8041 CTGTGTGGAT ATGCTGCTTT AT AGCCTCT G TATCTAGCTA TTGCTTCCCG TACGGCTTTC 8101 GTTTTCTCCT CCTTGTATAA ATCCTGGTTG CTGTCTCTTT TAGAGGAGTT GTGGCCCGTT 8161 GTCCGTCAAC GTGGCGTGGT GTGCTCTGTG TTTGCTGACG CAACCCCCAC TGGCTGGGGC 8221 ATTGCCACCA CCTGTCAACT CCTTTCTGGG ACTTTCGCTT TCCCCCTCCC GATCGCCACG 8281 GCAGAACTCA TCGCCGCCTG CCTTGCCCGC TGCTGGACAG GGGCTAGGTT GCTGGGCACT 8341 GATAATTCCG TGGTGTTGTC AGTACTGGTA CCTTTAAGAC C A AT G ACTT A CAAGGCAGCT 8401 GTAGATCTTA GCCACTTTTT AAAAGAAAAG GGGGGACTGG AAGGGCTAAT TCACTCCCAA 8461 AGAAGACAAG ATCTGCTTTT TGCCTGTACT GGGTCTCTCT GGTTAGACCA GATCTGAGCC 8521 TGGGAGCTCT CTGGCTAACT AGGGAACCCA CTGCTT A AGC CTCAAT AAAG CTTGCCTTGA 8581 GTGCTTCAAG TAGTGTGTGC CCGTCTGTTG TGTGACTCTG GTAACTAGAG ATCCCTCAGA 8641 CCCTTTTAGT CAGTGTGGAA AATCTCTAGC A pLKaUS MHlmTRAC(2-137) P2A MHlmTRBC(2-173) (SEQ ID NO: 194)

1 CTCGCTGCGC TCGGTCGTTC GGCTGCGGCG AGCGGTATCA GCT C ACT C A A AGGCGGTAAT 61 ACGGTTATCC ACAGAATCAG GGGATAACGC AGGAAAGAAC ATGTGAGCAA AAGGCCAGCA 121 AAAGGCCAGG AACCGTAAAA AGGCCGCGTT GCTGGCGTTT TTCCATAGGC TCCGCCCCCC 181 TGACGAGCAT CACAAAAATC GACGCTCAAG TCAGAGGTGG CGAAACCCGA CAGGACTATA 241 AAGATACCAG GCGTTTCCCC CTGGAAGCTC CCTCGTGCGC TCTCCTGTTC CGACCCTGCC 301 GCTTACCGGA TACCTGTCCG CCTTTCTCCC TTCGGGAAGC GTGGCGCTTT CTCATAGCTC 361 ACGCTGTAGG TATCTCAGTT CGGTGTAGGT CGTTCGCTCC AAGCTGGGCT GTGTGCACGA 421 ACCCCCCGTT CAGCCCGACC GCTGCGCCTT ATCCGGTAAC TATCGTCTTG AGTCCAACCC 481 GGT A AG AC AC GACTTATCGC CACTGGCAGC AGCCACTGGT AACAGGATTA GCAGAGCGAG 541 GTATGTAGGC GGTGCTACAG AGTTCTTGAA GTGGTGGCCT AACTACGGCT ACACTAGAAG 601 AACAGTATTT GGTATCTGCG CTCTGCTGAA GCCAGTTACC TTCGGAAAAA GAGTTGGTAG

721 GATTACGCGC AGAAAAAAAG GATCTCAAGA AGATCCTTTG ATCTTTTCTA CGGGGTCTGA 781 CGCTCAGTGG AACGAAAACT CACGTTAAGG GATTTTGGTC ATGAGTTAAT TAACTTGCGC 841 CGTCCCGTCA AGTCAGCGTA ATGCTCTGCC AGTGTTACAA CCA ATT A ACC AATTCTGATT 901 AGAAAAACTC ATCGAGCATC A A AT G A AACT GCAATTTATT CACATCAGGA TTATCAATAC 961 CATATTTTTG AAAAAGCCGT TTCTGTAATG AAGGAGAAAA CTCACCGAGG CAGTTCCATA 1021 GGATGGCAAG ATCCTGGTAT CGGTCTGCGA TTCCGACTCG TCCAACATCA ATACAACCTA 1081 TTAATTTCCC CTCGTCAAAA AT AAGGTT AT CAAGTGAGAA ATCACCATGA GTGACGACTG 1141 AATCCGGTGA GAATGGCAAA AGTTTATGCA TTTCTTTCCA GACTTGTTCA ACAGGCCAGC 1201 CATTACGCTC GTCATCAAAA TCACTCGCAT CAACCAAACC GTTATTCATT CGTGATTGCG 1261 CCTGAGCAAG ACGAAAT ACG CGATCGCTGT TAAAAGGACA ATT AC A A AC A GGAATCGAAT 1321 GCAACCGGCG CAGGAACACT GCCAGCGCAT CAACAATATT TTCACCTGAA TCAGGATATT

1441 CAGGAGTACG GAT AAAATGC TTGATGGTCG GAAGAGGCAT AAATTCCGTC AGCCAGTTTA 1501 GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC TTTGCCATGT TTCAGAAACA 1561 ACTCTGGCGC ATCGGGCTTC CCATACAAGC GAT AG ATT GT CGCACCTGAT TGCCCGACAT 1621 TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT GTTGGAATTT AATCGCGGCC 1681 TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT ATTACTGTTT ATGTAAGCAG 1741 AC AGTTTT AT TGTTCATGAT GATATATTTT TATCTTGTGC A AT GT A AC AT CAGAGATTTT 1801 GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA ACCTATAAAA ATAGGCGTAT 1861 CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT TGAGTGTTGT TCCAGTTTGG 1921 AACAAGAGTC CACTATTAAA GAACGTGGAC TCCAACGTCA AAGGGCGAAA AACCGTCTAT 1981 CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA GTTTTTTGGG GTCGAGGTGC 2041 CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG 2101 CCGGCGAACG TGGCGAGAAA GGAAGGGAAG AAAGCGAAAG GAGCGGGCGCTAAGGCGCTG 2161 GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG CCGCGCTTAA TGCGCCGCTA 2221 CAGGGCGCGT ACTATGGTTG CTTTGACGTA TGCGGTGTGA AATACCGCAC AGATGCGTAA 2281 GGAGAAAATA CATCGTGATC CGGATCAAGA TCCAGATCGA ATTGGAGGCT ACAGTCAGTG 2341 GAGAGGACTT T CACT G ACT G ACTGACTGCG TCTCAACCTC CTAGGGGACA TTGATTATTG 2401 ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC ATAGCCCATA TATGGAGTTC 2461 CGCGTT AC AT AACTT ACGGT AAATGGCCCG CCTGGCTGAC CGCCCAACGA CCCCCGCCCA 2521 TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA TAGGGACTTT CCATTGACGT 2581 CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG TACATCAAGT GTATCATATG 2641 CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC CCGCCTGGCA TTATGCCCAG 2701 TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT ACGTATTAGT CATCGCTATT 2761 ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG GATAGCGGTT TGACTCACGG 2821 GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT TGTTTTGGCA CCAAAATCAA 2881 CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA CGCAAATGGG CGGTAGGCGT 2941 GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTT AGTGA ACCGGGTCTC TCTGGTTAGA 3001 CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA 3061 AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG TTGTGTGACT CTGGTAACTA 3121 GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT AGCAGTGGCG CCCGAACAGG 3181 GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC GCAGGACTCG GCTTGCTGAA 3241 GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA CGCCAAAAAT TTTGACTAGC 3301 GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA TTAAGCGGGG GAGAATTAGA 3361 TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA C A AT AT A A AC TAAAACATAT 3421 AGTTAGGGCA AGCAGGGAGC T AGAACG ATT CGCAGTTAAT CCTGGCCTTT TAGAGACATC 3481 AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC CTTCAGACAG GATCAGAAGA 3541 ACTTAGATCA TT AT AT A AT A CAATAGCAGT CCTCTATTGT GTGCATCAAA GGATAGATGT 3601 AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG CAAAACAAAAGTAAGAAAAA 3661 GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG CGATATGAGG GACAATTGGA 3721 GAAGTGAATT AT AT AAAT AT A A AGT AGT A A AAATTGAACC ATT AGG AGT A GCACCCACCA 3781 AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT GGGAATAGGA GCTTTGTTCC 3841 TTGGGTTCTT GGGAGCAGCA GGAAGCACTA TGGGCGCAGC GTCAATGACG CTGACGGTAC 3901 AGGCCAGACA ATTATTGTCT GATATAGTGC AGCAGCAGAA CAATTTGCTG AGGGCTATTG 3961 AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT CAAACAGCTC CAGGCAAGAA 4021 TCCTGGCTGT GG A A AG AT AC CTAAAGGATC AACAGCTCCT GGGGATTTGG GGTTGCTCTG 4081 GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG TTGGAGTAAT AAATCTCTGG 4141 AACAGATTTG GAATAACATG ACCTGGATGG AGTGGGACAG AG A A ATT AAC A ATT AC AC A A 4201 GCTT AATAC A CTCCTTAATT GAAGAATCGC AAAACCAGCA AGAAAAGAAT GAACAAGAAT 4261 TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT T AAC AT AAC A AATTGGCTGT 4321 GGT AT AT A A A ATTATTCATA ATGATAGTAG GAGGCTTGGT AGGTTTAAGA ATAGTTTTTG 4381 CTGTACTTTC TATAGTGAAT AGAGTTAGGC AGGGATATTC ACCATTATCG TTTCAGACCC 4441 ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT ATTCATCCAC AATTTTAAAA 4501 GAAAAGGGGG GATT GGGGGG TACAGTGCAG GGGAAAGAAT AGT AG AC AT A AT AGC A AC AG 4561 AC AT AC A A AC T A A AG A ATT A CAAAAACAAA TTACAAAAAT TCAAAATTTT CGGGTTTATT 4621 ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC GGCTCCGGTG CCCGTCAGTG 4681 GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG GGAGGGGTCG GCAATTGAAC 4741 CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT GATGTCGTGT ACTGGCTCCG 4801 CCTTTTTCCC GAGGGTGGGG GAGAACCGT A T AT A AGT GCA GTAGTCGCCG TGAACGTTCT 4861 TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC 4921 TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT ACTTCCACGC CCCTGGCTGC 4981 AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT 5041 GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC 5101 GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG

5821 TTCTTCCATT TCAGGTGTCG TGAAAACTAC CCCATGCCGC CACCATGCTT CTCCTGGTGA 5881 CAAGCCTTCT GCTCTGTGAG TTACCACACC CAGCATTCCT CCTGATCCCA GAAGTTCAGC 5941 TGGTAGAGTC CGGTGGCGGG CTGGTACAGC CAGGGGGATC TCTCCGTCTC TCATGTGCTG 6001 CCAGTGGGGG AGATTGGTCC GCT A ACTTT A T GT ACT GGT A TCGTCAAGCA CCTGGGAAAC 6061 AACGCGAGCT GGTTGCACGG ATCTCTGGAC GAGGGGTAGT GGATTACGTG GAAAGTGTGA 6121 AAGGACGATT CACAATTTCC AGGGACAATT CTAAAAACAC CCTTTATTTG CAAATGAAT A 6181 GTCTGAGAGC AGAAGACACA GCCGTATATT ATTGTGCAGT CGCATCCTAT TGGGGGCAGG 6241 GGACTCTTGT CACAGTCTCG AGTATTCAGA ACCCTGAGCC TGCCGTGTAT CAACTGAAGG 6301 ACCCTAGAAG CCAGGACAGC ACCCTGTGCC TGTTCACCGA CTTCGACAGC CAGATCAACG 6361 TGCCCAAGAC CAT GG A A AGC GGCACCTTCA TCACCGATAA GACTGTGCTG GACATGAAGG 6421 CCATGGACAG CAAGAGCAAC GGCGCCATTG CATGGTCCAA TC AG ACC AGC TTTACCTGCC 6481 AAGACATCTT CAAAGAGACA AACGCCACCT ACCCCAGTTC AGACGTTCCC TGTGATGCCA 6541 CGTTGACTGA GAAAAGCTTT GAAACAGATA TGAACCTAAA CTTTCAAAAC CTGTCAGTTA 6601 TGGGACTCCG AATCCTCCTG CTGAAAGTAG CCGGATTTAA CCTGCTCATG ACGCTGAGGC 6661 TGTGGTCCAG TGGCAGCGGC GCT ACT A ACT TCAGCCTGCT GAAGCAGGCT GGAGACGTGG 6721 AGGAGAACCC TGGACCTATG CTACTACTTG TGACCTCACT ATTGTTATGC GAACTCCCTC 6781 ATCCCGCATT CTTGCTGATT CCAGAGGTGC AACTTGTGGA A AGT GGGGG A GGTCTCGTTC 6841 AACCTGGTGG CAGCCTTAGA CTGAGCTGCG CAGCTTCAGG AGGTGACTGG AGTGCAAATT 6901 TCATGTATTG GTACAGACAG GCTCCAGGAA AGCAGCGAGA ACTTGTAGCC AGAATTAGCG 6961 GTAGGGGAGT TGTCGACTAT GTCGAGTCAG TTAAGGGTAG GTTTACCATC AGTCGAGATA 7021 ACAGCAAGAA TACATTGTAC CTCCAGATGA ACTCACTTCG GGCTGAGGAT ACTGCAGTGT 7081 ACTACTGCGC TGTTGCTAGT TACTGGGGAC A AGGT AC ATT GGTAACTGTT AGTTCAGATC 7141 TGAGAAATGT GACTCCACCC AAGGTCTCCT TGTTTGAGCC ATCAAAAGCA GAGATTGCAA 7201 ACAAACAAAA GGCTACCCTC GTGTGCTTGG CCAGGGGCTT CTTCCCTGAC CACGTGGAGC 7261 TGAGCTGGTG GGTGAATGGC AAGGAGGTCC ACAGTGGGGT CAGCACGGAC CCaCAGGCCT 7321 ACAAGGAGAG C A ATT AT AGC TACTGCCTGA GCAGCCGCCT GAGGGTCTCT GCTACCTTCT 7381 GGCACAATCC TCGCAACCAC TTCCGCTGCC AAGTGCAGTT CCATGGGCTT TCAGAGGAGG 7441 ACAAGTGGCC AGAGGGCTCA CCCAAACCTG TCACACAGAA CATCAGTGCA GAGGCCTGGG 7501 GTCGAGCAGA CTGTGGTATT ACCTCAGCAT CCTATCAACA AGGAGTCTTG TCTGCCACCA 7561 TCCTCTATGA GATCCTGCTA GGGAAAGCCA CCCTGTATGC TGTGCTTGTC AGTACACTGG 7621 TGGTGATGGC TATGGTCAAA AGAAAGAATT CATGAGATAT CGAGCATCTT ACCGCCATTT 7681 ATACCCATAT TTGTTCTGTT TTTCTTGATT TGGGTATACA TTT AAATGTT AAT AAA AC A A

7801 CACAAGACAA ACATGTTAAG AAACTTTCCC GTTATTTACG CTCTGTTCCT GTTAATCAAC 7861 CTCT GG ATT A CAAAATTTGT GAAAGATTGA CTGATATTCT TAACTATGTT GCTCCTTTTA 7921 CGCTGTGTGG ATATGCTGCT TTATAGCCTC TGTATCTAGC TATTGCTTCC CGTACGGCTT 7981 TCGTTTTCTC CTCCTTGTAT AAATCCTGGT TGCTGTCTCT TTTAGAGGAG TTGTGGCCCG 8041 TTGTCCGTCA ACGTGGCGTG GTGTGCTCTG TGTTTGCTGA CGCAACCCCC ACTGGCTGGG 8101 GCATTGCCAC CACCTGTCAA CTCCTTTCTG GGACTTTCGC TTTCCCCCTC CCGATCGCCA 8161 CGGCAGAACT CATCGCCGCC TGCCTTGCCC GCTGCTGGAC AGGGGCTAGG TTGCTGGGCA 8221 CTGATAATTC CGTGGTGTTG TCAGTACTGG TACCTTTAAG ACCAATGACT TACAAGGCAG 8281 CTGTAGATCT TAGCCACTTT TT A A A AG A A A AGGGGGGACT GG A AGGGCT A ATTCACTCCC 8341 AAAGAAGACA AGATCTGCTT TTTGCCTGTA CTGGGTCTCT CTGGTTAGAC CAGATCTGAG 8401 CCTGGGAGCT CTCTGGCTAA CTAGGGAACC CACTGCTTAA GCCTCAATAA AGCTTGCCTT 8461 GAGTGCTTCA AGTAGTGTGT GCCCGTCTGT TGTGTGACTC TGGTAACTAG AGATCCCTCA 8521 GACCCTTTTA GTCAGTGTGG AAAATCTCTA GCATGATCAT AATCAAGCCA TATCACATCT 8581 GTAGAGGTTT ACTTGCTTTA AAAAACCTCC ACACCTCCCC CTGAACCTGA A AC AT A A A AT 8641 GAATGCAATT GTTGTTGTTA ACTTGTTTAT TGCAGCTTAT AATGGTT AC A A AT A A AGC A A

8761 CAAACTCATC AATGTATCTT ATCATGTCTG GATCTGCGTC GACACGAAGA GACGACTGAC 8821 TGACTGACTG GAAAGAGGAA GGGCTGGAAG AGGAAGGAGC TTGATCCAGA TCCCGATCTC 8881 GATCCAGATC CGGATCGCAG CTTGGTCTTC CGCTTCCTCG CTCACTGA pLKaUS mTRAC(2-137) T2A mTRBC(2-173) P2AMHlCD3e (SEQ ID NO: 195)

1 CTCGCTGCGC TCGGTCGTTC GGCTGCGGCG AGCGGTATCA GCTCACTCAA AGGCGGTAAT 61 ACGGTTATCC ACAGAATCAG GGGATAACGC AGGAAAGAAC ATGTGAGCAA AAGGCCAGCA 121 AAAGGCCAGG AACCGTAAAA AGGCCGCGTT GCTGGCGTTT TTCCATAGGC TCCGCCCCCC 181 TGACGAGCAT CACAAAAATC GACGCTCAAG TCAGAGGTGG CGAAACCCGA CAGGACTATA 241 AAGATACCAG GCGTTTCCCC CTGGAAGCTC CCTCGTGCGC TCTCCTGTTC CGACCCTGCC 301 GCTTACCGGA TACCTGTCCG CCTTTCTCCC TTCGGGAAGC GTGGCGCTTT CTCATAGCTC 361 ACGCTGTAGG TATCTCAGTT CGGTGTAGGT CGTTCGCTCC AAGCTGGGCT GTGTGCACGA 421 ACCCCCCGTT CAGCCCGACC GCTGCGCCTT ATCCGGTAAC TATCGTCTTG AGTCCAACCC 481 GGT A AG AC AC GACTTATCGC CACTGGCAGC AGCCACTGGT AACAGGATTA GCAGAGCGAG 541 GTATGTAGGC GGTGCTACAG AGTTCTTGAA GTGGTGGCCT AACTACGGCT ACACTAGAAG 601 AACAGTATTT GGTATCTGCG CTCTGCTGAA GCCAGTTACC TTCGGAAAAA GAGTTGGTAG

1441 CAGGAGTACG GATAAAATGC TTGATGGTCG GAAGAGGCAT AAATTCCGTC AGCCAGTTTA 1501 GTCTGACCAT CTCATCTGTA ACATCATTGG CAACGCTACC TTTGCCATGT TTCAGAAACA 1561 ACTCTGGCGC ATCGGGCTTC CC AT AC A AGC GAT AG ATT GT CGCACCTGAT TGCCCGACAT 1621 TATCGCGAGC CCATTTATAC CCATATAAAT CAGCATCCAT GTTGGAATTT AATCGCGGCC 1681 TCGACGTTTC CCGTTGAATA TGGCTCATAA CACCCCTTGT ATTACTGTTT ATGTAAGCAG 1741 AC AGTTTT AT TGTTCATGAT GATATATTTT TATCTTGTGC A AT GT A AC AT CAGAGATTTT 1801 GAGACACAAC GTGGCTTTCC CCCCCCCCCC CATGACATTA ACCTATAAAA ATAGGCGTAT 1861 CACGAGGCCA GCTTGGGAAA CCATAAGACC GAG AT AG AGT TGAGTGTTGT TCCAGTTTGG 1921 AACAAGAGTC CACTATTAAA GAACGTGGAC TCCAACGTCA AAGGGCGAAA AACCGTCTAT 1981 CAGGGCGATG GCCCACTACG TGAACCATCA CCCAAATCAA GTTTTTTGGG GTCGAGGTGC 2041 CGTAAAGCAC TAAATCGGAA CCCTAAAGGG AGCCCCCGAT TTAGAGCTTG ACGGGGAAAG 2101 CCGGCGAACG TGGCGAGAAA GGAAGGGAAG AAAGCGAAAG GAGCGGGCGCTAAGGCGCTG 2161 GCAAGTGTAG CGGTCACGCT GCGCGTAACC ACCACACCCG CCGCGCTTAA TGCGCCGCTA 2221 CAGGGCGCGT ACTATGGTTG CTTTGACGTA TGCGGTGTGA AATACCGCAC AGATGCGTAA 2281 GGAGAAAATA CATCGTGATC CGGATCAAGA TCCAGATCGA ATTGGAGGCT ACAGTCAGTG 2341 GAGAGGACTT T CACT G ACT G ACTGACTGCG TCTCAACCTC CTAGGGGACA TTGATTATTG 2401 ACTAGTTATT AATAGTAATC AATTACGGGG TCATTAGTTC ATAGCCCATA TATGGAGTTC 2461 CGCGTTACAT AACTTACGGT AAATGGCCCG CCTGGCTGAC CGCCCAACGA CCCCCGCCCA 2521 TTGACGTCAA TAATGACGTA TGTTCCCATA GTAACGCCAA T AGGG ACTTT CCATTGACGT 2581 CAATGGGTGG AGTATTTACG GTAAACTGCC CACTTGGCAG TACATCAAGT GTATCATATG 2641 CCAAGTACGC CCCCTATTGA CGTCAATGAC GGTAAATGGC CCGCCTGGCA TTATGCCCAG 2701 TACATGACCT TATGGGACTT TCCTACTTGG CAGTACATCT ACGTATTAGT CATCGCTATT 2761 ACCATGGTGA TGCGGTTTTG GCAGTACATC AATGGGCGTG GATAGCGGTT TGACTCACGG 2821 GGATTTCCAA GTCTCCACCC CATTGACGTC AATGGGAGTT TGTTTTGGCA CCA A A AT C A A 2881 CGGGACTTTC CAAAATGTCG TAACAACTCC GCCCCATTGA CGCAAATGGG CGGTAGGCGT 2941 GTACGGTGGG AGGTCTATAT AAGCAGAGCT CGTTT AGTGA ACCGGGTCTC TCTGGTTAGA 3001 CCAGATCTGA GCCTGGGAGC TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA 3061 AAGCTTGCCT TGAGTGCTCA AAGTAGTGTG TGCCCGTCTG TTGTGTGACT CTGGTAACTA 3121 GAGATCCCTC AGACCCTTTT AGTCAGTGTG GAAAATCTCT AGCAGTGGCG CCCGAACAGG 3181 GACTTGAAAG CGAAAGTAAA GCCAGAGGAG ATCTCTCGAC GCAGGACTCG GCTTGCTGAA 3241 GCGCGCACGG CAAGAGGCGA GGGGCGGCGA CTGGTGAGTA CGCCAAAAAT TTTGACTAGC 3301 GGAGGCTAGA AGGAGAGAGT AGGGTGCGAG AGCGTCGGTA TTAAGCGGGG GAGAATTAGA 3361 TAAATGGGAA AAAATTCGGT TAAGGCCAGG GGGAAAGAAA C A AT AT A A AC TAAAACATAT 3421 AGTTAGGGCA AGCAGGGAGC T AGAACG ATT CGCAGTTAAT CCTGGCCTTT T AG AG AC AT C 3481 AGAAGGCTGT AGACAAATAC TGGGACAGCT ACAACCATCC CTTCAGACAG GATCAGAAGA 3541 ACTTAGATCA TT AT AT A AT A CAATAGCAGT CCTCTATTGT GTGCATCAAA GGATAGATGT 3601 AAAAGACACC AAGGAAGCCT TAGATAAGAT AGAGGAAGAG CAAAACAAAAGTAAGAAAAA 3661 GGCACAGCAA GCGATCTTCA GACCTGGAGG AGGCAGGAGG CGATATGAGG GACAATTGGA 3721 G A AGTGA ATT AT AT AAAT AT A A AGT AGT A A AAATTGAACC ATT AGG AGT A GCACCCACCA 3781 AGGCAAAGAG AAGAGTGGTG CAGAGAGAAA AAAGAGCAGT GGGAATAGGA GCTTTGTTCC 3841 TTGGGTTCTT GGGAGCAGCA GGAAGCACTA TGGGCGCAGC GTCAATGACG CTGACGGTAC 3901 AGGCCAGACA ATTATTGTCT GATATAGTGC AGCAGCAGAA CAATTTGCTG AGGGCTATTG 3961 AGGCGCAACA GCATCTGTTG CAACTCACAG TCTGGGGCAT CAAACAGCTC CAGGCAAGAA 4021 TCCTGGCTGT GG A A AG AT AC CTAAAGGATC AACAGCTCCT GGGGATTTGG GGTTGCTCTG 4081 GAAAACTCAT TTGCACCACT GCTGTGCCTT GGAATGCTAG TTGGAGTAAT AAATCTCTGG 4141 AACAGATTTG GAATAACATG ACCTGGATGG AGT GGG AC AG AG A A ATT AAC A ATT AC AC A A 4201 GCTT AATAC A CTCCTTAATT GAAGAATCGC AAAACCAGCA AGAAAAGAAT GAACAAGAAT 4261 TATTGGAATT AGATAAATGG GCAAGTTTGT GGAATTGGTT T AAC AT AAC A AATTGGCTGT 4321 GGT AT AT A A A ATTATTCATA ATGATAGTAG GAGGCTTGGT AGGTTTAAGA ATAGTTTTTG 4381 CTGT ACTTT C TAT AGTGA AT AGAGTTAGGC AGGGATATTC ACCATTATCG TTTCAGACCC 4441 ACCTCCCAAT CCCGAGGGGA CCACGCGTAC AAATGGCAGT ATTCATCCAC AATTTTAAAA 4501 GAAAAGGGGG GATT GGGGGG TACAGTGCAG GGGAAAGAAT AGT AG AC AT A AT AGC A AC AG 4561 AC AT AC A A AC T A A AG A ATT A CAAAAACAAA TTACAAAAAT TCAAAATTTT CGGGTTTATT 4621 ACAGGGACAG CAGAAATCCA CTTTGGAAAG CTGAGCATCC GGCTCCGGTG CCCGTCAGTG 4681 GGCAGAGCGC ACATCGCCCA CAGTCCCCGA GAAGTTGGGG GGAGGGGTCG GCAATTGAAC 4741 CGGTGCCTAG AGAAGGTGGC GCGGGGTAAA CTGGGAAAGT GATGTCGTGT ACTGGCTCCG 4801 CCTTTTTCCC GAGGGTGGGG GAGAACCGT A T AT A AGT GCA GTAGTCGCCG TGAACGTTCT 4861 TTTTCGCAAC GGGTTTGCCG CCAGAACACA GGTAAGTGCC GTGTGTGGTT CCCGCGGGCC 4921 TGGCCTCTTT ACGGGTTATG GCCCTTGCGT GCCTTGAATT ACTTCCACGC CCCTGGCTGC 4981 AGTACGTGAT TCTTGATCCC GAGCTTCGGG TTGGAAGTGG GTGGGAGAGT TCGAGGCCTT 5041 GCGCTTAAGG AGCCCCTTCG CCTCGTGCTT GAGTTGAGGC CTGGCCTGGG CGCTGGGGCC 5101 GCCGCGTGCG AATCTGGTGG CACCTTCGCG CCTGTCTCGC TGCTTTCGAT AAGTCTCTAG

5221 ATGCGGGCCA AGATCTGCAC ACTGGTATTT CGGTTTTTGG GGCCGCGGGC GGCGACGGGG 5281 CCCGTGCGTC CCAGCGCACA TGTTCGGCGA GGCGGGGCCT GCGAGCGCGG CCACCGAGAA 5341 TCGGACGGGG GTAGTCTCAA GCTGGCCGGC CTGCTCTGGT GCCTGGCCTC GCGCCGCCGT 5401 GTATCGCCCC GCCCTGGGCG GCAAGGCTGG CCCGGTCGGC ACCAGTTGCG TGAGCGGAAA 5461 GATGGCCGCT TCCCGGCCCT GCTGCAGGGA GCTCAAAATG GAGGACGCGG CGCTCGGGAG 5521 AGCGGGCGGG TGAGTCACCC ACACAAAGGA AAAGGGCCTT TCCGTCCTCA GCCGTCGCTT 5581 CATGTGACTC CACGGAGTAC CGGGCGCCGT CCAGGCACCT CGATT AGTTC TCGAGCTTTT 5641 GGAGTACGTC GTCTTTAGGT TGGGGGGAGG GGTTTTATGC GATGGAGTTT CCCCACACTG 5701 AGTGGGTGGA GACTGAAGTT AGGCCAGCTT GGCACTTGAT GTAATTCTCC TTGGAATTTG

5821 TTCTTCCATT TCAGGTGTCG TGAAAACTAC CCCATGCCGC CACCATGCTT CTCCTGGTGA 5881 CAAGCCTTCT GCTCTGTGAG TTACCACACC CAGCATTCCT CCTGATCCCA ATTCAGAACC 5941 CTGAGCCTGC CGTGTATCAA CTGAAGGACC CTAGAAGCCA GGACAGCACC CTGTGCCTGT 6001 TCACCGACTT CGACAGCCAG ATCAACGTGC CCAAGACCAT GGAAAGCGGC ACCTTCATCA 6061 CCGATAAGAC TGTGCTGGAC ATGAAGGCCA TGGACAGCAA GAGCAACGGC GCCATTGCAT 6121 GGTCCAATCA GACCAGCTTT ACCTGCCAAG ACATCTTCAA AGAGACAAAC GCCACCTACC 6181 CC AGTTC AG A CGTTCCCTGT GATGCCACGT TGACTGAGAA AAGCTTTGAA AC AG AT AT G A 6241 ACCTAAACTT TCAAAACCTG TCAGTTATGG GACTCCGAAT CCTCCTGCTG AAAGTAGCCG 6301 GATTTAACCT GCTCATGACG CTGAGGCTGT GGTCCAGTGG CAGCGGCGAG GGCAGAGGAA 6361 GTCTGCTAAC ATGCGGTGAC GTCGAGGAGA ATCCTGGACC TATGCTACTA CTTGTGACCT 6421 CACTATTGTT ATGCGAACTC CCTCATCCCG CATTCTTGCT GATTCCAGAT CTGAGAAATG 6481 TGACTCCACC CAAGGTCTCC TTGTTTGAGC CATCAAAAGC AGAGATTGCA AACAAACAAA 6541 AGGCTACCCT CGTGTGCTTG GCCAGGGGCT TCTTCCCTGA CCACGTGGAG CTGAGCTGGT 6601 GGGTGAATGG CAAGGAGGTC CACAGTGGGG TCAGCACGGA CCCaCAGGCC TACAAGGAGA 6661 GCAATTATAG CTACTGCCTG AGCAGCCGCC TGAGGGTCTC TGCTACCTTC TGGCACAATC 6721 CTCGCAACCA CTTCCGCTGC CAAGTGCAGT TCCATGGGCT TTCAGAGGAG GACAAGTGGC 6781 CAGAGGGCTC ACCCAAACCT GTCACACAGA ACATCAGTGC AGAGGCCTGG GGTCGAGCAG 6841 ACTGTGGTAT TACCTCAGCA TCCTATCAAC AAGGAGTCTT GTCTGCCACC ATCCTCTATG 6901 AGATCCTGCT AGGGAAAGCC ACCCTGTATG CTGTGCTTGT CAGTACACTG GTGGTGATGG 6961 CTATGGTCAA AAGAAAGAAT TCAGGATCTG GT GCT ACT A A CTTCAGCCTG CTGAAGCAGG 7021 CTGGAGACGT GGAGGAGAAC CCTGGACCTA TGCTCCTGCT TGTGACGTCC CTCCTGCTTT 7081 GTGAACTCCC GCATCCTGCC TTCCTGCTCA TCCCTGAAGT TCAGCTGGTA GAGTCCGGTG 7141 GCGGGCTGGT ACAGCCAGGG GGATCTCTCC GTCTCTCATG TGCTGCCAGT GGGGGAGATT 7201 GGTCCGCTAA CTTTATGTAC TGGTATCGTC AAGCACCTGG GAAACAACGC GAGCTGGTTG 7261 CACGGATCTC TGGACGAGGG GTAGTGGATT ACGTGGAAAG TGTGAAAGGA CG ATT C AC AA 7321 TTTCCAGGGA CAATTCTAAA AACACCCTTT ATTTGCAAAT GAATAGTCTG AGAGCAGAAG 7381 ACACAGCCGT AT ATT ATT GT GCAGTCGCAT CCTATTGGGG GCAGGGGACT CTTGTCACAG 7441 TCTCGAGTGC TGCCGCAGGA GGCGGTGGCA GTGGTGGGGG AGGATCTGGC GGAGGAGGTA 7501 GCCTCGAGGA CGGAAACGAG GAGATGGGGG GAATCACTCA AACCCCTTAC AAGGTGTCTA 7561 TTTCCGGCAC TACCGTGATT CTTACCTGTC CACAATACCC AGGCAGCGAT ATTCTCTGGC 7621 AGCATAACGA CAAAAATATC GGAGGAGACG AAGACGACAA GAATATCGGG TCGGACGAAG 7681 ACCATCTCAG CCTTAAAGAG TTCAGCGAGC TTGAACAGAG CGGCTACTAC GTTTGTTATC 7741 CACGAGGGTC TAAGCCTGAG GACGCAAATT TCTACCTGTA TCTCAGAGCT AGGGTTTGCG 7801 AAAATTGTAT GGAAATGGAC GTTATGAGTG TCGCTACGAT CGTGATTGTT GATATTTGTA 7861 TTACAGGAGG GCTGCTTTTG CTCGTCTATT ATTGGTCTAA AAACCGGAAA GCT A A AGC A A 7921 AACCCGTAAC GAGGGGCGCT GGAGCAGGAG GAAGACAGAG AGGCCAGAATAAAGAACGTC 7981 CTCCCCCAGT GCCAAATCCC GATTACGAAC C A ATT AG A A A GGGACAAAGA GATTTGTACA 8041 GCGGACTCAA CCAACGGAGA ATTTGAGATA TCGAGCATCT TACCGCCATT TATACCCATA 8101 TTTGTTCTGT TTTTCTTGAT TTGGGTATAC ATTTAAATGT T A AT A A A AC A AAATGGTGGG

8221 AACATGTTAA GAAACTTTCC CGTTATTTAC GCTCTGTTCC TGTTAATCAA CCTCTGGATT 8281 ACAAAATTTG TGAAAGATTG ACTGATATTC TTAACTATGT TGCTCCTTTT ACGCTGTGTG 8341 GATATGCTGC TTTATAGCCT CT GT AT CT AG CTATTGCTTC CCGTACGGCT TTCGTTTTCT 8401 CCTCCTTGTA TAAATCCTGG TTGCTGTCTC TTTTAGAGGA GTTGTGGCCC GTTGTCCGTC 8461 AACGTGGCGT GGTGTGCTCT GTGTTTGCTG ACGCAACCCC CACTGGCTGG GGCATTGCCA 8521 CCACCTGTCA ACTCCTTTCT GGGACTTTCG CTTTCCCCCT CCCGATCGCC ACGGCAGAAC 8581 TCATCGCCGC CTGCCTTGCC CGCTGCTGGA CAGGGGCTAG GTTGCTGGGC ACTGATAATT 8641 CCGTGGTGTT GTCAGTACTG GT ACCTTT A A GACCAATGAC TTACAAGGCA GCTGTAGATC 8701 TTAGCCACTT TTT A A A AG A A AAGGGGGGAC TGGAAGGGCT AATTCACTCC CAAAGAAGAC 8761 AAGATCTGCT TTTTGCCTGT ACTGGGTCTC TCTGGTTAGA CCAGATCTGA GCCTGGGAGC 8821 TCTCTGGCTA ACTAGGGAAC CCACTGCTTA AGCCTCAATA AAGCTTGCCT TGAGTGCTTC 8881 AAGTAGTGTG TGCCCGTCTG TTGTGTGACT CTGGTAACTA GAGATCCCTC AGACCCTTTT 8941 AGTCAGTGTG GAAAATCTCT AGCATGATCA TAATCAAGCC ATATCACATC TGTAGAGGTT 9001 TACTTGCTTT AAAAAACCTC CACACCTCCC CCTGAACCTG AA AC AT A A A A TGAATGCAAT 9061 TGTTGTTGTT AACTTGTTTA TTGCAGCTTA TAATGGTTAC AAATAAAGCA ATAGCATCAC

9181 CAATGTATCT TATCATGTCT GGATCTGCGT CGACACGAAG AGACGACTGA CTGACTGACT 9241 GGAAAGAGGA AGGGCTGGAA GAGGAAGGAG CTTGATCCAG ATCCCGATCT CGATCCAGAT 9301 CCGGATCGCA GCTTGGTCTT CCGCTTCCTC GCTCACTGA Anti-MSLN-CD3 epsilon (SEQ ID NO 198)

MLLLVTSLLLCELPHPAFLUPEVQLVESGGGLVGPGGSLRLSCAASGGDWSANFMYWYRQAPGKQRELVARISGRGW

DYVESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVASYWGQGTLVTVSSAAAGGGGSGGGGSGGGGSLEDGN

EEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPE

DANFYLYLRARVCENC EMDVMSVATIViVDlC!TGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVP

NPDYEPIRKGQRDLYSGLIMQRRi

Anti-CD 19-CD3 epsilon (SEQ ID NO 199)

MLLLVTSLLLCELPHPAFLL!PDIQMTQTTSSLSASLGDRVT!SCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSR

FSGSGSGTDYSLTISMLEQEDiATYFCQ.QGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQ.ESGPGLVAPSQ.SLS

VTCTVSGVSLPDYGVSW!RQPPRKGLEWLGViWGSETTYYNSALKSRLTi!KDNSKSQVFLKMNSLQTDDTAIYYCAKHY

YYGGSYAMDYWGQGTSVTVSSAAAGGGGSGGGGSGGGGSLEDGNEEMGGiTQTPYKVSiSGTTVILTCPQYPGSEIL

WQHMDKNiGGDEDDKNiGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDAMFYLYLRARVCENCMEMDVMSVATIVIV

DIGTGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPMPDYEP!RKGQRDLYSGLNQRRi

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A recombinant nucleic acid comprising

(a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising

(i) a TCR subunit comprising

(1) at least a portion of a TCR extracellular domain, and

(2) a transmembrane domain, and

(ii) an antibody comprising an antigen binding domain; and

(b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain, or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

2. A recombinant nucleic acid comprising

(a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising

(i) a TCR subunit comprising

(1) at least a portion of a TCR extracellular domain,

(2) a transmembrane domain, and

(ii) a binding ligand or a fragment thereof that is capable of binding to an antibody or fragment thereof; and

(b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain, or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

3. The recombinant nucleic acid of claim 1 or claim 2, wherein the TCR subunit further comprises an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta.

4. The recombinant nucleic acid of any one of claims 1-3, wherein the TCR constant domain is a TCR delta constant domain.

5. The recombinant nucleic acid of claim 4, wherein the TCR delta constant domain comprises SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

6. The recombinant nucleic acid of any one of claims 3-5, wherein the intracellular domain is an intracellular domain of TCR gamma.

7. The recombinant nucleic acid of any one of claims 3-5, wherein the sequence encoding the TCR delta constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR delta constant domain.

8. The recombinant nucleic acid of claim 7, wherein the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP.

9. The recombinant nucleic acid of claim 7, wherein the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR delta constant domain via a linker.

10. The recombinant nucleic acid of any one of claims 1-3, wherein the TCR constant domain is a TCR gamma constant domain.

11. The recombinant nucleic acid of claim 10, wherein the TCR gamma constant domain comprises SEQ ID NO:21 or SEQ ID NO:155, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

12. The recombinant nucleic acid of claim 10 or 11, wherein the intracellular domain is an intracellular domain of TCR delta.

13. The recombinant nucleic acid of any one of claims 8-12, wherein the sequence encoding the TCR gamma constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR gamma constant domain.

14. The recombinant nucleic acid of claim 13, wherein the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP.

15. The recombinant nucleic acid of claim 13, wherein the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR gamma constant domain via a linker.

16. The recombinant nucleic acid of any one of claims 1-3, wherein the recombinant nucleic acid comprises a sequence encoding a TCR gamma constant domain and a TCR delta constant domain.

17. The recombinant nucleic acid of claim 16, wherein the TCR gamma constant domain comprises SEQ ID NO:21 or SEQ ID NO:155, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

18. The recombinant nucleic acid of claim 16 or 17, wherein the sequence encoding the TCR gamma constant domain further encodes a TCR gamma variable domain, thereby encoding a full TCR gamma domain.

19. The recombinant nucleic acid of claim 18, wherein the full TCR gamma domain is gamma 9 or gamma 4.

20. The recombinant nucleic acid of claim 18 or 19, wherein the full TCR gamma domain comprises SEQ ID NO:255, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

21. The recombinant nucleic acid of any one of claims 16-20, wherein the TCR delta constant domain comprises SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:243 or SEQ ID NO:265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

22. The recombinant nucleic acid of any one of claims 16-21, wherein the sequence encoding the TCR delta constant domain further encodes a TCR delta variable domain, thereby encoding a full TCR delta domain.

23. The recombinant nucleic acid of claim 22, wherein the full TCR delta domain is delta 2 or delta 1.

24. The recombinant nucleic acid of claim 22 or 23, wherein the full TCR delta constant domain comprises SEQ ID NO:256, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

25. The recombinant nucleic acid of any one of claims 16-24, wherein the intracellular signaling domain is CD3 epsilon, CD3 gamma, or CD3 delta.

26. The recombinant nucleic acid of any one of claims 16-25, wherein the intracellular signaling domain is CD3 epsilon.

27. The recombinant nucleic acid of any one of claims 1-26, further comprising at least one leader sequence and at least one linker.

28. The recombinant nucleic acid of claim 27, further comprising a portion of a TCR alpha constant domain, a portion of a TCR beta domain, or both.

29. The recombinant nucleic acid of claim 1, wherein the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRGC gene sequence.

30. The recombinant nucleic acid of claim 1, wherein the sequence comprises, from 5’-3’, a first leader sequence, a TRDC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker sequence, and a TRGC gene sequence.

31. The recombinant nucleic acid of claim 1, wherein the sequence comprises, from 5’-3’, a first leader sequence, an antigen binding domain sequence, a first linker sequence, a TRDC gene sequence, a cleavable linker, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, and a TRGC gene sequence.

32. The recombinant nucleic acid of claim 1, wherein the sequence comprises, from 5’-3’, a first leader sequence, a TRDC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRGC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence.

33. The recombinant nucleic acid of claim 1, wherein the sequence comprises, from 5’-3’, a first leader sequence, a first antigen binding domain sequence, a first linker sequence, a TRDC gene sequence or fragment thereof, a TRAC gene sequence or fragment thereof, a cleavable linker sequence, a second leader sequence, a second antigen binding domain sequence, a second linker sequence, a TRGC gene sequence or fragment thereof, and a TRBC gene sequence or fragment thereof.

34. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO: 1.

35. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:2.

36. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:3.

37. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:4.

38. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:5.

39. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO: 242.

40. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO: 244.

41. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO:245.

42. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO: 246.

43. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO:248.

44. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO:250.

45. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO:252.

46. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO:257.

47. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO: 263.

48. The recombinant nucleic acid of any one of claims 1-33, wherein the sequence encodes a sequence of SEQ ID NO: 264.

49. The recombinant nucleic acid of claim 1, wherein the binding ligand is capable of binding an Fc domain of the antibody.

50. The recombinant nucleic acid of claim 1, wherein the binding ligand is capable of selectively binding an IgGl antibody.

51. The recombinant nucleic acid of claim 1, wherein the binding ligand is capable of specifically binding an IgG4 antibody.

52. The recombinant nucleic acid of claim 1, wherein the antibody or fragment thereof binds to a cell surface antigen.

53. The recombinant nucleic acid of claim 1, wherein the antibody or fragment thereof is murine, human or humanized.

54. The recombinant nucleic acid of claim 1, wherein the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell.

55. The recombinant nucleic acid of claim 1, wherein the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer.

56. The recombinant nucleic acid of claim 1, wherein the binding ligand does not comprise an antibody or fragment thereof.

57. The recombinant nucleic acid of claim 56, wherein the binding ligand comprises a CD16 polypeptide or fragment thereof.

58. The recombinant nucleic acid of claim 56, wherein the binding ligand comprises a CD16- binding polypeptide.

59. The recombinant nucleic acid of claim 1, wherein the binding ligand is human or humanized.

60. The recombinant nucleic acid of claim 1, further comprising a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand.

61. The recombinant nucleic acid of claim 60, wherein the antibody or fragment thereof is capable of being secreted from a cell.

62. A recombinant nucleic acid comprising

(a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising

(i) a TCR subunit comprising

(1) at least a portion of a TCR extracellular domain, and

(2) a transmembrane domain, and

(ii) an antigen binding domain comprising a ligand or a fragment thereof that binds to a receptor or polypeptide expressed on a surface of a cell; and

(b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain or a TCR delta constant domain; or a sequence encoding a TCR gamma constant domain and a TCR delta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

63. The recombinant nucleic acid of claim 62, wherein the TCR subunit further comprises an intracellular domain of TCR alpha, TCR beta, TCR gamma, or TCR delta or an intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon, CD3 gamma, or CD3 delta.

64. The recombinant nucleic acid of any one of claims 1-63, further comprising at least a partial sequence encoding a TCR alpha constant domain, a TCR beta constant domain, or a partial sequence of both a TCR alpha constant domain and a TCR beta constant domain.

65. The recombinant nucleic acid of claim 62, wherein the antigen binding domain comprises a ligand.

66. The recombinant nucleic acid of claim 62, wherein the ligand binds to the receptor of a cell.

67. The recombinant nucleic acid of claim 62, wherein the ligand binds to the polypeptide expressed on a surface of a cell.

68. The recombinant nucleic acid of claim 62, wherein the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide.

69. The recombinant nucleic acid of claim 62, wherein the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein.

70. The recombinant nucleic acid of claim 69, wherein the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof.

71. The recombinant nucleic acid of claim 62, wherein the antigen binding domain comprises a monomer, a dimer, a turner, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer.

72. The recombinant nucleic acid of claim 71, wherein the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof.

73. The recombinant nucleic acid of claim 62, wherein the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer.

74. The recombinant nucleic acid of claim 73, wherein the ligand or fragment thereof is a monomer or a dimer.

75. The recombinant nucleic acid of claim 62, wherein the antigen binding domain does not comprise an antibody or fragment thereof.

76. The recombinant nucleic acid of claim 62, wherein the antigen binding domain does not comprise a variable region.

77. The recombinant nucleic acid of claim 62, wherein the antigen binding domain does not comprise a CDR.

78. The recombinant nucleic acid of claim 62, wherein the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof.

79. The recombinant nucleic acid of any one of claims 1-78, wherein the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell.

80. The recombinant nucleic acid of any one of claims 1-79, wherein the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell.

81. The recombinant nucleic acid of any one of claims 1-80, wherein the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within a same nucleic acid molecule.

82. The recombinant nucleic acid of any one of claims 1-81, wherein the encoded TFP and the encoded TCR constant domains are operatively linked by a first linker sequence.

83. The recombinant nucleic acid of claim 82, wherein the first linker comprises a protease cleavage site.

84. The recombinant nucleic acid of claim 83, wherein the protease cleavage site is a 2A, e g., a T2A or a P2A cleavage site.

85. The recombinant nucleic acid of any one of claims 1-84, wherein the sequence encoding the TFP and the sequence encoding the TCR constant domain are contained within different nucleic acid molecules.

86. The recombinant nucleic acid of any one of claims 1-85, wherein the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof of the TFP are operatively linked by a second linker sequence.

87. The recombinant nucleic acid of claim 86, wherein the second linker sequence comprises (G4S)_n, wherein n=l to 4.

88. The recombinant nucleic acid of any one of claims 1-87, wherein the transmembrane domain is a TCR transmembrane domain from CD3 epsilon, CD3 gamma, CD3 delta, TCR alpha, TCR beta, TCR delta, or TCR gamma.

89. The recombinant nucleic acid of any one of claims 3-61 and 63-88, wherein the intracellular domain is derived from only CD3 epsilon, only CD3 gamma, only CD3 delta, only TCR alpha, TCR beta, TCR gamma, or TCR delta.

90. The recombinant nucleic acid of any one of claims 1-89, wherein the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, wherein at least two of (i), (ii), and (iii) are from the same TCR subunit.

91. The recombinant nucleic acid of any one of claims 1-90, wherein the TCR extracellular domain comprises an extracellular domain or portion thereof of a protein selected from the group consisting of a TCR gamma chain, a TCR delta chain, a CD3 epsilon TCR subunit, a CD3 gamma TCR subunit, a CD3 delta TCR subunit, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

92. The recombinant nucleic acid of claim 91, wherein the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain of a TCR gamma chain or a TCR delta chain.

93. The recombinant nucleic acid of claim 92, wherein the TCR extracellular domain comprises the extracellular portion of a constant domain of a TCR gamma chain or a TCR delta chain, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

94. The recombinant nucleic acid of claim 92 or 93, wherein the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a delta constant domain, or a fragment thereof.

95. The recombinant nucleic acid of claim 94, wherein the delta constant domain has the sequence of SEQ ID NO:20, SEQ ID NO:22, SEQ ID N0 243 or SEQ ID N0 265, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

96. The recombinant nucleic acid of claim 92 or 93, wherein the TCR subunit comprising (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a gamma constant domain.

97. The recombinant nucleic acid of claim 96, wherein the gamma constant domain has the sequence of SEQ ID NO:21 or SEQ ID NO: 155, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

98. The recombinant nucleic acid of any one of claims 94-97, wherein the extracellular domain of the TFP does not comprise the variable domain of a gamma chain or a delta chain.

99. The recombinant nucleic acid of any one of claims 3-61 and 63-88, wherein the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto.

100. The recombinant nucleic acid of claim 99, wherein the TCR subunit of the TFP comprises the extracellular, transmembrane and intracellular domain of CD3 epsilon.

101. The recombinant nucleic acid of claim 100, wherein the TCR subunit of CD3 epsilon comprises the sequence of SEQ ID NO:258, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

102. The recombinant nucleic acid of any one of claims 1-101, wherein the TFP, the TCR gamma constant domain, the TCR delta constant domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide.

103. The recombinant nucleic acid of any one of claims 1-102, wherein

(a) the TCR constant domain is a TCR gamma constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR delta, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof;

(b) the TCR constant domain is a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of TCR gamma, CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or

(c) the TCR constant domain is a TCR gamma constant domain and a TCR delta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

104. The recombinant nucleic acid of any one of claims 1-103, wherein the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP.

105. The recombinant nucleic acid of any one of claims 1, 3-61 and 85-104, wherein the antibody is an antibody fragment.

106. The recombinant nucleic acid of claim 105, wherein the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain.

107. The recombinant nucleic acid of any one of claims 1, 3-61 and 85-106, wherein an antigen binding domain is selected from a group consisting of an anti-CDl 9 binding domain, an anti-B-cell maturation antigen (BCMA) binding domain, an anti-mesothelin (MSLN) binding domain, an anti-CD20 binding domain, an anti-CD70 binding domain, an anti-79b binding domain, an anti-HER2 binding domain, an anti-PMSA binding domain, an anti-MUC16 binding domain, an anti-CD22 binding domain, an anti-PD-Ll binding domain, an anti BAFF or BAFF receptor binding domain, an anti-Nectin-4 binding domain, an anti-TROP-2 binding domain, an anti-GPC3 binding domain, and an anti-ROR-1 binding domain.

108. The recombinant nucleic acid of claim 107, wherein the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:60, a CDR2 of SEQ ID NO:61, and a CDR3 of SEQ ID NO:62.

109. The recombinant nucleic acid of claim 107, wherein the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:63, a CDR2 of SEQ ID NO:64, and a CDR3 of SEQ ID NO:65.

110. The recombinant nucleic acid of claim 107, wherein the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:66, a CDR2 of SEQ ID NO:67, and a CDR3 of SEQ ID NO:68.

111. The recombinant nucleic acid of claim 107, wherein the anti-MSLN binding domain comprises a sequence with at least about 80% sequence identity to a sequence of SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:71.

112. The recombinant nucleic acid of claim 107, wherein the anti-CD19 binding domain comprises a light chain CDR1 of SEQ ID NO:73, a CDR2 of SEQ ID NO:75, and a CDR3 of SEQ ID NO: 77

113. The recombinant nucleic acid of claim 107, wherein the anti-CD 19 binding domain comprises a heavy chain CDR1 of SEQ ID NO:79, a CDR2 of SEQ ID NO:81, and a CDR3 of SEQ ID NO: 83

114. The recombinant nucleic acid of claim 107, wherein the anti-CD19 binding domain comprises a light chain variable region having at least about 80% sequence identity to a sequence of SEQ ID NO:85 and/or a heavy chain variable region having at least about 80% sequence identity to a sequence of SEQ ID NO: 87.

115. The recombinant nucleic acid of any one of claims 1-114, further comprising a sequence encoding a TCR alpha transmembrane domain.

116. The recombinant nucleic acid of any one of claims 1-114, further comprising a sequence encoding a TCR beta transmembrane domain.

117. The recombinant nucleic acid of any one of claims 1-114, further comprising a sequence encoding a TCR alpha transmembrane domain and a sequence encoding a TCR beta transmembrane domain.

118. A recombinant nucleic acid comprising

(a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising (i) a TCR subunit comprising (1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and

(2) a murine TCR alpha or murine TCR beta transmembrane domain, and

(ii) an antibody or fragment thereof comprising an antigen binding domain; and (b) a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antibody are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

119. A recombinant nucleic acid comprising

(a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising

(i) a TCR subunit comprising

(1) at least a portion of a murine TCR alpha or murine TCR beta extracellular domain, and

(2) a murine TCR alpha or murine TCR beta transmembrane domain, and

(b) a sequence encoding a TCR constant domain(s), wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the binding ligand or fragment thereof are operatively linked, and wherein the TFP functionally incorporates into TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

120. The recombinant nucleic acid of claim 118 or 119, wherein the TCR subunit comprises an intracellular domain of murine TCR alpha or murine TCR beta.

121. The recombinant nucleic acid of any one of claims 118 or 120, wherein the TCR constant domain is a TCR alpha constant domain

122. The recombinant nucleic acid of claim 121, wherein the TCR alpha constant domain comprises SEQ ID NO:17, SEQ ID NO: 142, SEQ ID NO:143, SEQ ID NO:146, or SEQ ID NO:207, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

123. The recombinant nucleic acid of claim 121, wherein the TCR alpha constant domain comprises a murine TCR alpha constant domain.

124. The recombinant nucleic acid of claim 123, wherein the murine TCR alpha constant domain comprises amino acids 2-137 of the murine TCR alpha constant domain.

125. The recombinant nucleic acid of claim 124, wherein the murine TCR alpha constant domain comprises amino acids 2-137 of SEQ ID NO: 146.

126. The recombinant nucleic acid of claim 124, wherein the murine TCR alpha constant domain comprises a sequence of SEQ ID NO:207.

127. The recombinant nucleic acid of claim 123, wherein the murine TCR alpha constant domain comprises amino acids 82-137 of SEQ ID NO: 146.

128. The recombinant nucleic acid of claim 127, wherein the murine TCR alpha constant domain comprises a sequence of SEQ ID NO: 17.

129. The recombinant nucleic acid of any one of claims 122-128, wherein the intracellular domain is an intracellular domain of TCR beta.

130. The recombinant nucleic acid of any one of claims 121-129, wherein the sequence encoding the TCR alpha constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR alpha constant domain.

131. The recombinant nucleic acid of claim 130, wherein the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP.

132. The recombinant nucleic acid of claim 130, wherein the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR alpha constant domain via a linker.

133. The recombinant nucleic acid of any one of claims 118-120, wherein the TCR constant domain is a TCR beta constant domain.

134. The recombinant nucleic acid of claim 133, wherein the TCR beta constant domain comprises SEQ ID NO: 18, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 152, or SEQ ID NO:209, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

135. The recombinant nucleic acid of claim 134, wherein TCR beta constant domain comprises a murine TCR beta constant domain.

136. The recombinant nucleic acid of claim 134, wherein murine TCR beta constant domain comprises amino acids 2-173 of the murine TCR beta constant domain.

137. The recombinant nucleic acid of claim 134, wherein murine TCR beta constant domain comprises amino acids 2-173 of SEQ ID NO: 152.

138. The recombinant nucleic acid of claim 134, wherein murine TCR beta constant domain comprises SEQ ID NO:209.

139. The recombinant nucleic acid of claim 134, wherein the TCR beta constant domain comprises amino acids 123-173 of SEQ ID NO: 152.

140. The recombinant nucleic acid of claim 134, wherein the TCR beta constant domain comprises SEQ ID NO: 18.

141. The recombinant nucleic acid of any one of claims 133-140, wherein the intracellular domain is an intracellular domain of TCR alpha.

142. The recombinant nucleic acid of any one of claims 118-141, wherein the sequence encoding the TCR beta constant domain further encodes a second antigen binding domain or ligand binding domain that is operatively linked to the sequence encoding the TCR beta constant domain.

143. The recombinant nucleic acid of claim 142, wherein the second antigen binding domain or ligand binding domain is the same or different as the antigen binding domain or ligand binding domain of the TFP.

144. The recombinant nucleic acid of claim 142, wherein the second antigen binding domain or ligand binding domain is operatively linked to the sequence encoding the TCR beta constant domain via a linker.

145. The recombinant nucleic acid of any one of claims 118-120, wherein the recombinant nucleic acid comprise sequence encoding a TCR alpha constant domain and a TCR beta constant domain.

146. The recombinant nucleic acid of claim 145, wherein the TCR alpha constant domain comprises SEQ ID NO: 17, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, or SEQ ID NO:207, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

147. The recombinant nucleic acid of claim 145 or 146, wherein the TCR beta constant domain comprises SEQ ID NO 18, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:152, or SEQ ID NO:209, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

148. The recombinant nucleic acid of any one of claims 118-147, wherein the intracellular signaling domain is CD3 epsilon, CD3 gamma, or CD3 delta.

149. The recombinant nucleic acid of any one of claims 118-147, wherein the intracellular signaling domain is CD3 epsilon.

150. The recombinant nucleic acid of claim 145, wherein the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence.

151. The recombinant nucleic acid of claim 145, wherein the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, and a TRBC gene sequence.

152. The recombinant nucleic acid of claim 145, wherein the sequence comprises, from 5’ to 3’, a first leader sequence, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker, and a TRBC gene sequence.

153. The recombinant nucleic acid of claim 145, wherein the sequence comprises, from 5’ to 3’, a first leader sequence, an antigen binding domain sequence, a linker, a TRAC gene sequence, a cleavable linker sequence, a second leader sequence, an antigen binding domain sequence, a linker, and a TRBC gene sequence.

154. The recombinant nucleic acid of claim 145, wherein the sequence comprises, from 5’-3’, a first leader sequence, a TRAC gene sequence, a first cleavable linker sequence, a second leader sequence, a TRBC gene sequence, a second cleavable linker sequence, a third leader sequence, an antigen binding domain sequence, a linker sequence, and a CD3 epsilon gene sequence.

155. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO: 10.

156. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:204.

157. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO 206.

158. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:210.

159. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:211.

160. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:217.

161. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:218.

162. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:219.

163. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:220.

164. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:259.

165. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:261.

166. The recombinant nucleic acid of any one of claims 115-154, wherein the sequence encodes the polypeptide as set forth in SEQ ID NO:262.

167. The recombinant nucleic acid of any one of claims 115-166, further comprising at least one leader sequence and at least one linker.

168. The recombinant nucleic acid of any one of claims 119-167, wherein the binding ligand is capable of binding an Fc domain of the antibody.

169. The recombinant nucleic acid of any one of claims 119-167, wherein the binding ligand is capable of selectively binding an IgGl antibody.

170. The recombinant nucleic acid of any one of claims 119-167, wherein the binding ligand is capable of specifically binding an IgG4 antibody.

171. The recombinant nucleic acid of any one of claims 118 and 120-170, wherein the antibody or fragment thereof binds to a cell surface antigen.

172. The recombinant nucleic acid of any one of claims 118 and 120-170, wherein the antibody or fragment thereof is murine, human or humanized

173. The recombinant nucleic acid of any one of claims 118 and 120-170, wherein the antibody or fragment thereof binds to a cell surface antigen on the surface of a tumor cell.

174. The recombinant nucleic acid of any one of claims 119-167, wherein the binding ligand comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer.

175. The recombinant nucleic acid of any one of claims 119-167, wherein the binding ligand does not comprise an antibody or fragment thereof.

176. The recombinant nucleic acid of claim 175, wherein the binding ligand comprises a CD16 polypeptide or fragment thereof.

177. The recombinant nucleic acid of claim 175, wherein the binding ligand comprises a CD 16-binding polypeptide.

178. The recombinant nucleic acid of any one of claims 119-167, wherein the binding ligand is human or humanized.

179. The recombinant nucleic acid of any one of claims 119-167, further comprising a nucleic acid sequence encoding an antibody or fragment thereof capable of being bound by the binding ligand.

180. The recombinant nucleic acid of any one of claims 118 and 120-170, wherein the antibody or fragment thereof is capable of being secreted from a cell.

181. A recombinant nucleic acid comprising

(a) a sequence encoding a T cell receptor (TCR) fusion protein (TFP) comprising

(i) a TCR subunit comprising

(2) a murine TCR alpha or murine TCR beta transmembrane domain, and

(b) a sequence encoding a TCR constant domain, wherein the TCR constant domain is a murine TCR alpha constant domain or a murine TCR beta constant domain; or a sequence encoding a murine TCR alpha constant domain and a murine TCR beta constant domain; wherein the TCR subunit and the antigen binding domain are operatively linked, and wherein the TFP functionally incorporates into a TCR complex when expressed in a modified T cell comprising a functional disruption of an endogenous TCR.

182. The recombinant nucleic acid of claim 181, wherein the TCR subunit comprises an intracellular domain of murine TCR alpha or murine TCR beta.

183. The recombinant nucleic acid of any one of claims 118-182, wherein the extracellular domain comprises the extracellular portion of a TCR alpha constant domain or TCR beta constant domain, or a fragment thereof.

184. The recombinant nucleic acid of any one of claims 118-183, further comprising at least a partial sequence encoding a TCR gamma constant domain, a TCR delta constant domain, or a partial sequence of both a TCR gamma constant domain and a TCR delta constant domain.

185. The recombinant nucleic acid of any one of claims 181-184, wherein the antigen binding domain comprises a ligand.

186. The recombinant nucleic acid of claim 185, wherein the ligand binds to the receptor of a cell.

187. The recombinant nucleic acid of claim 185, wherein the ligand binds to the polypeptide expressed on a surface of a cell.

188. The recombinant nucleic acid of claim 185, wherein the receptor or polypeptide expressed on a surface of a cell comprises a stress response receptor or polypeptide.

189. The recombinant nucleic acid of claim 185, wherein the receptor or polypeptide expressed on a surface of a cell is an MHC class I-related glycoprotein.

190. The recombinant nucleic acid of claim 189, wherein the MHC class I-related glycoprotein is selected from the group consisting of MICA, MICB, RAET1E, RAET1G, ULBP1, ULBP2, ULBP3, ULBP4 and combinations thereof.

191. The recombinant nucleic acid of claim 185, wherein the antigen binding domain comprises a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer.

192. The recombinant nucleic acid of claim 191, wherein the antigen binding domain comprises a monomer or a dimer of the ligand or fragment thereof.

193. The recombinant nucleic acid of claim 185, wherein the ligand or fragment thereof is a monomer, a dimer, a trimer, a tetramer, a pentamer, a hexamer, a heptamer, an octomer, a nonamer, or a decamer.

194. The recombinant nucleic acid of claim 193, wherein the ligand or fragment thereof is a monomer or a dimer.

195. The recombinant nucleic acid of claim 185, wherein the antigen binding domain does not comprise an antibody or fragment thereof.

196. The recombinant nucleic acid of claim 185, wherein the antigen binding domain does not comprise a variable region.

197. The recombinant nucleic acid of claim 185, wherein the antigen binding domain does not comprise a CDR.

198. The recombinant nucleic acid of claim 185, wherein the ligand or fragment thereof is a Natural Killer Group 2D (NKG2D) ligand or a fragment thereof.

199. The recombinant nucleic acid of any one of claims 118-198, wherein the TCR constant domain incorporates into a functional TCR complex when expressed in a T cell.

200. The recombinant nucleic acid of any one of claims 199, wherein the TCR constant domain incorporates into a same functional TCR complex as the functional TCR complex that incorporates the TFP when expressed in a T cell.

201. The recombinant nucleic acid of any one of claims 118-200, wherein the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within a same nucleic acid molecule.

202. The recombinant nucleic acid of any one of claims 118-200, wherein the TFP and the TCR constant domains are operatively linked by a first linker sequence.

203. The recombinant nucleic acid molecule of claim 202, wherein the first linker comprises a protease cleavage site.

204. The recombinant nucleic acid molecule of claim 203, wherein the protease cleavage site is a 2 A, e.g., a T2A or a P2A cleavage site.

205. The recombinant nucleic acid of any one of claims 118-200, wherein the sequence encoding the TFP and the sequence encoding the TCR constant domain(s) are contained within different nucleic acid molecules.

206. The recombinant nucleic acid of any one of claims 118-205, wherein the TCR subunit and the antibody domain, the antigen binding domain or the binding ligand or fragment thereof of the TFP are operatively linked by a second linker sequence.

207. The recombinant nucleic acid of claim 206, wherein the second linker sequence comprises (G4S) , wherein n=l to 4.

208. The recombinant nucleic acid of any one of claims 118-207, wherein the transmembrane domain is a TCR transmembrane domain from TCR alpha or TCR beta, e g., murine TCR alpha or TCR beta.

209. The recombinant nucleic acid of any one of claims 118-207, wherein the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain, of TCR alpha or TCR beta.

210. The recombinant nucleic acid of any one of claims 118-207, wherein the TCR extracellular domain comprises the extracellular portion of a constant domain TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

211. The recombinant nucleic acid of any one of claims 118-207, wherein the TCR subunit comprises a transmembrane domain comprising a transmembrane domain of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

212. The recombinant nucleic acid of any one of claims 118-207, wherein the TCR subunit comprises a TCR intracellular domain of a TCR alpha chain or a TCR beta chain, e.g., a murine TCR alpha chain or a TCR beta chain, or an amino acid sequence having at least one modification thereto.

213. The recombinant nucleic acid of any one of claims 118-207, wherein the TCR subunit comprises (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises an alpha constant domain.

214. The recombinant nucleic acid of claim 213, wherein the alpha constant domain has the sequence of SEQ ID NO: 17, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 146, or SEQ ID NO:207 functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications, e.g., amino acids 2-137 of SEQ ID NO: 146.

215. The recombinant nucleic acid of any one of claims 118-207, wherein the encoded TCR comprising (i) at least a portion of a TCR extracellular domain, (ii) a TCR transmembrane domain, and (iii) a TCR intracellular domain is or comprises a beta constant domain.

216. The recombinant nucleic acid of claim 215, wherein the beta constant domain has the sequence of SEQ ID NO:18, SEQ ID O:148, SEQ ID NO:149, SEQ ID NO:152, or SEQ ID NO:209, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications, e.g., amino acids 2-173 of SEQ ID NO: 152.

217. The recombinant nucleic acid of claim 215 or 216, wherein the extracellular domain of the TCR subunit does not comprise the variable domain of an alpha chain or a beta chain.

218. The recombinant nucleic acid of any one of claims 1-217, wherein the TCR subunit comprises a TCR intracellular domain comprising a stimulatory domain of a protein selected from an intracellular signaling domain of CD3 epsilon, CD3 gamma or CD3 delta, or an amino acid sequence having at least one modification thereto.

219. The recombinant nucleic acid of claim 218, wherein the TCR subunit of the TFP comprises the extracellular, transmembrane and intracellular domain of CD3 epsilon.

220. The recombinant nucleic acid of claim 218 or 219, wherein the TCR subunit of CD3 epsilon comprises the sequence of SEQ ID NO:258, functional fragments thereof, or amino acid sequences thereof having at least one but not more than 20 modifications.

221. The recombinant nucleic acid of any one of claims 1-220, wherein the TFP, the TCR alpha constant domain, the TCR beta domain, and any combination thereof is capable of functionally interacting with an endogenous TCR complex and/or at least one endogenous TCR polypeptide.

222. The recombinant nucleic acid of any one of claims 1-221, wherein

(a) the TCR constant domain is a TCR alpha constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof;

(b) the TCR constant domain is a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof; or

(c) the TCR constant domain is a TCR alpha constant domain and a TCR beta constant domain and the TFP functionally integrates into a TCR complex comprising an endogenous subunit of CD3 epsilon, CD3 gamma, CD3 delta, or a combination thereof.

223. The recombinant nucleic acid of any one of claims 220-222, wherein the at least one but not more than 20 modifications thereto comprise a modification of an amino acid that mediates cell signaling or a modification of an amino acid that is phosphorylated in response to a ligand binding to the TFP.

224. The recombinant nucleic acid of any one of claims 118 and 120-180, wherein the antibody is an antibody fragment.

225. The recombinant nucleic acid of claim 224, wherein the antibody fragment is a scFv, a single domain antibody domain, a VH domain or a VL domain.

226. The recombinant nucleic acid of any one of claims 118 and 120-180, wherein an antigen binding domain is selected from a group consisting of an anti-CD 19 binding domain, an anti-B-cell maturation antigen (BCMA) binding domain, an anti-mesothelin (MSLN) binding domain, an anti-CD20 binding domain, an anti-CD70 binding domain, an anti- 79b binding domain, an anti-FlER2 binding domain, an anti-PMSA binding domain, an anti-MUC16 binding domain, an anti-CD22 binding domain, an anti-PD-Ll binding domain, an anti BAFF or BAFF receptor binding domain, an anti-Nectin-4 binding domain, an anti-TROP-2 binding domain, an anti-GPC3 binding domain, and an anti- ROR-1 binding domain.

227. Fhe recombinant nucleic acid of claim 226, wherein the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:60, a CDR2 of SEQ ID NO:61, and a CDR3 of SEQ ID NO:62.

228. The recombinant nucleic acid of claim 226, wherein the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:63, a CDR2 of SEQ ID NO:64, and a CDR3 of SEQ ID NO:65.

229. The recombinant nucleic acid of claim 226, wherein the anti-MSLN binding domain comprises a CDR1 of SEQ ID NO:66, a CDR2 of SEQ ID NO:67, and a CDR3 of SEQ ID NO:68.

230. The recombinant nucleic acid of claim 226, wherein the anti-MSLN binding domain comprises a sequence with at least about 80% sequence identity to a sequence of SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:71.

231. The recombinant nucleic acid of claim 226, wherein the anti-CD 19 binding domain comprises a light chain CDR1 of SEQ ID NO:73, a CDR2 of SEQ ID NO:75, and a CDR3 of SEQ ID NO: 77

232. The recombinant nucleic acid of claim 226, wherein the anti-CD 19 binding domain comprises a heavy chain CDR1 of SEQ ID NO:79, a CDR2 of SEQ ID NO:81, and a CDR3 of SEQ ID NO: 83.

233. The recombinant nucleic acid of claim 226, wherein the anti-CD 19 binding domain comprises a light chain variable region with at least about 80% sequence identity to a sequence of SEQ ID NO:85 and/or a heavy chain variable region with at least about 80% sequence identity to a sequence of SEQ ID NO:87.

234. The recombinant nucleic acid of any one of the preceding claims, wherein the nucleic acid is selected from the group consisting of a DNA and an RNA

235. The recombinant nucleic acid of any one of the preceding claims, wherein the nucleic acid is an mRNA.

236. The recombinant nucleic acid of any one of the preceding claims, wherein the nucleic acid is a circRNA.

237. The recombinant nucleic acid of any one of the preceding claims, wherein the recombinant nucleic acid comprises a nucleic acid analog, wherein the nucleic acid analog is not in an encoding sequence of the recombinant nucleic acid.

238. The recombinant nucleic acid of claim 237, wherein the nucleic analog is selected from the group consisting of 2’-0-methyl, 2’-0-methoxyethyl (2’-0-M0E), 2’-0-aminopropyl, 2’-deoxy, T-deoxy-2’-fluoro, 2’-0-aminopropyl (2’-0-AP), 2'-0-dimethylaminoethyl (2’- O-DMAOE), 2’-0-dimethylaminopropyl (2’-0-DMAP), T-O- dimethylaminoethyloxyethyl (2’-0-DMAE0E), 2’-0-N-methylacetamido (2’-0-NMA) modified, a locked nucleic acid (LNA), an ethylene nucleic acid (ENA), a peptide nucleic acid (PNA), a l’,5’- anhydrohexitol nucleic acid (HNA), a morpholino, a methylphosphonate nucleotide, a thiolphosphonate nucleotide, and a 2’-fluoro N3-P5’- phosphoramidite.

239. The recombinant nucleic acid of any one of the preceding claims, further comprising a leader sequence.

240. The recombinant nucleic acid of any one of the preceding claims, further comprising a promoter sequence.

241. The recombinant nucleic acid of any one of the preceding claims, further comprising a sequence encoding a poly(A) tail.

242. The recombinant nucleic acid of any one of the preceding claims, further comprising a 3’EITR sequence.

243. The recombinant nucleic acid of any one of the preceding claims, wherein the nucleic acid is an isolated nucleic acid or a non-naturally occurring nucleic acid.

244. The recombinant nucleic acid molecule of any one of the preceding claims, wherein the nucleic acid is an in vitro transcribed nucleic acid.

245. A vector comprising the recombinant nucleic acid of any one of the preceding claims.

246. The vector of claim 245, wherein the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, an adeno-associated viral vector (AAV), a Rous sarcoma viral (RSV) vector, or a retrovirus vector.

247. The vector of claim 245 or 246, wherein the vector is an AAV6 vector.

248. The vector of any one of claims 245-247, further comprising a promoter.

249. The vector of any one of claims 245-248, wherein the vector is an in vitro transcribed vector.

250. A modified T cell comprising the recombinant nucleic acid of any one of claims 1-244, or the vector of any one of claims 245-249, wherein the modified T cell comprises a functional disruption of an endogenous TCR.

251. A modified T cell comprising the sequence encoding the TFP of the nucleic acid of any one of claims 1-244 or a TFP encoded by the sequence of the nucleic acid of any one of claims 1-244 encoding the TFP, wherein the modified T cell comprises a functional disruption of an endogenous TCR.

252. A modified allogenic T cell comprising the sequence encoding the TFP of any one of claims 1-244 or a TFP encoded by the sequence of the nucleic acid of any one of claims 1-244 encoding the TFP.

253. The modified T cell of any one of claims 250-252, wherein the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR gamma constant domain, a TCR delta constant domain or a TCR gamma constant domain and a TCR delta constant domain.

254. The modified T cell of any one of claims 250-253, wherein the T cell further comprises a heterologous sequence encoding a TCR constant domain, wherein the TCR constant domain is a TCR alpha constant domain, a TCR beta constant domain or a TCR alpha constant domain and a TCR beta constant domain.

255. The modified T cell of claim 254, wherein the TCR constant domain, e g., the TCR alpha constant domain, the TCR beta constant domain or the TCR alpha constant domain and the TCR beta constant domain, is a murine TCR constant domain, e.g., a murine TCR alpha constant domain, a murine TCR beta constant domain or a murine TCR alpha constant domain and a murine TCR beta constant domain.

256. The modified T cell of any one of claims 250-255, wherein the endogenous TCR that is functionally disrupted is an endogenous TCR alpha chain, an endogenous TCR beta chain, or an endogenous TCR alpha chain and an endogenous TCR beta chain.

257. The modified T cell of any one of claims 250-256, wherein the endogenous TCR that is functionally disrupted has reduced binding to MHC -peptide complex compared to that of an unmodified control T cell.

258. The modified T cell of any one of claims 250-257, wherein the functional disruption is a disruption of a gene encoding the endogenous TCR.

259. The modified T cell of claim 258, wherein the disruption of a gene encoding the endogenous TCR is a removal of a sequence of the gene encoding the endogenous TCR from the genome of a T cell.

260. The modified T cell of any one of claims 250-259, wherein the T cell is a human T cell selected from CD4 cells, CD8 cells, naive T-cells, memory stem T-cells, central memory T- cells, double negative T-cells, effector memory T-cells, effector T-cells, ThO cells, TcO cells, Thl cells, Tel cells, Th2 cells, Tc2 cells, Thl7 cells, Th22 cells, alpha/beta T cells, gamma/delta T cells, natural killer (NK) cells, natural killer T ( KT) cells, hematopoietic stem cells and pluripotent stem cells.

261. The modified T cell of any one of claims 250-260, wherein the T cell is a CD8+ or CD4+ T cell.

262. The modified T cell of any one of claims 250-261, wherein the T cell is an allogenic T cell.

263. The modified T cell of any one of claims 250-262, further comprising a nucleic acid encoding an inhibitory molecule that comprises a first polypeptide comprising at least a portion of an inhibitory molecule, associated with a second polypeptide comprising a positive signal from an intracellular signaling domain.

264. The modified T cell of claim 263, wherein the inhibitory molecule comprises the first polypeptide comprising at least a portion of PD1 and the second polypeptide comprising a costimulatory domain and primary signaling domain.

265. A pharmaceutical composition comprising:

(a) the modified T cells of any one of claims 250-264; and

(b) a pharmaceutically acceptable carrier.

266. A method of producing the modified T cell of any one of claims 250-264, the method comprising

(a) disrupting an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain; thereby producing a T cell containing a functional disruption of an endogenous TCR gene; and

(b) transducing the T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid of any one of claims 1-244, or the vector of any one of claims 245-249.

267. The method of claim 266, wherein disrupting comprises transducing the T cell with a nuclease protein or a nucleic acid sequence encoding a nuclease protein that targets the endogenous gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain.

268. A method of producing the modified T cell of any one of claims 250-264, the method comprising transducing a T cell containing a functional disruption of an endogenous TCR gene with the recombinant nucleic acid of any one of claims 1-244, or the vector of any one of claims 245-249.

269. The method of claim 268, wherein the T cell containing a functional disruption of an endogenous TCR gene is a T cell containing a functional disruption of an endogenous TCR gene encoding a TCR alpha chain, a TCR beta chain, or a TCR alpha chain and a TCR beta chain.

270. The method of any one of claims 266-269, wherein the T cell is a human T cell.

271. The method of any one of claims 266-270, wherein the T cell containing a functional disruption of an endogenous TCR gene has reduced binding to MHC -peptide complex compared to that of an unmodified control T cell.

272. The method of any one of claims 267-271, wherein the nuclease is a meganuclease, a zinc-finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a CRISPR/Cas nuclease, or a megaTAL nuclease.

273. The method of any one of claims 266-272, wherein the sequence comprised by the recombinant nucleic acid or the vector is inserted into the endogenous TCR subunit gene at the cleavage site, and wherein the insertion of the sequence into the endogenous TCR subunit gene functionally disrupts the endogenous TCR subunit.

274. The method of any one of claims 267-271, wherein the nuclease is a meganuclease.

275. The method of claim 274, wherein the meganuclease comprises a first subunit and a second subunit, wherein the first subunit binds to a first recognition half-site of the recognition sequence, and wherein the second subunit binds to a second recognition half site of the recognition sequence.

276. The method of claim 275, wherein the meganuclease is a single-chain meganuclease comprising a linker, wherein the linker covalently joins the first subunit and the second subunit.

277. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 265.

278. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the method of any one of claims 266-276; and (b) a pharmaceutically acceptable carrier.

279. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) a modified T cell produced according to the method of any one of claims 266-276; and (b) a pharmaceutically acceptable carrier.

280. The method of any one of claims 277-279, wherein the modified T cell is an allogeneic T cell.

281. The method of any one of claims 277-280, wherein less cytokines are released in the subject compared a subject administered an effective amount of an unmodified control T cell.

282. The method of any one of claims 277-281, wherein less cytokines are released in the subject compared a subject administered an effective amount of a modified T cell comprising the recombinant nucleic acid of any one of claims 1-244, or the vector of any one of claims 245-249.

283. The method of any one of claims 277-282, wherein the method comprises administering the pharmaceutical composition in combination with an agent that increases the efficacy of the pharmaceutical composition.

284. The method of any one of claims 277-283, wherein the method comprises administering the pharmaceutical composition in combination with an agent that ameliorates one or more side effects associated with the pharmaceutical composition.

285. The method of any one of claims 277-284, wherein the cancer is a solid cancer, a lymphoma or a leukemia.

286. The method of any one of claims 277-285, wherein the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, cervical cancer, brain cancer, liver cancer, pancreatic cancer, kidney and stomach cancer.

287. The method of any one of claims 277-286, wherein less cytokines are released in the subject compared to a subject administered an effective amount of an autologous T cell expressing the TFP of claims 1-244.

288. The method of any one of claims 277-287, wherein the method does not induce graft versus host disease.

289. The method of any one of claims 277-288, wherein the subject has a reduced risk of developing graft versus host disease compared to a subject administered an effective amount of an autologous T cell expressing the TFP of claims 1-244.

290. The recombinant nucleic acid of any one of claims 1-244, the vector of any one of claims 245-249, the modified T cell of any one of claims 250-264, or the pharmaceutical composition of claim 265, for use as a medicament or in the preparation of a medicament.