Compositions for specific expression in multiple cells and uses thereof

Abstract

Provided herein are compositions and methods for making and using engineered at least two of different immune cells that each expresses a chimeric antigen receptor. Also provided herein are compositions and methods for using the nucleic acids and polypeptides disclosed herein for generating an adequate immune response against a diseased cell.

Description

WSGR Docket No. 56371-771.601COMPOSITIONS FOR SPECIFIC EXPRESSION IN MULTIPLE CELLS AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 746,644 filed on January 17, 2025 and U. S. Provisional Application No. 63 / 746,655 filed on January 17, 2025, each of which is incorporated herein in its entirety.SUMMARY

[0002] Provided herein is a composition comprising a nucleic acid encoding at least two chimeric fusion proteins (CFPs) comprising a first CFP and a second CFP, wherein the first CFP comprises (a) a first extracellular domain (ECD) comprising a first antigen-binding domain (ABD) and (b) a first transmembrane domain (TD) operatively linked to the first ECD; wherein the second CFP comprises (c) a second ECD comprising a second ABD and (d) a second TD operatively linked to the second ECD; wherein the first TD comprises a TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; wherein the second TD comprises a TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell; and wherein the first and second cells comprise any two of a natural killer (NK) cell, a monocyte, a T cell, or a B cell. In some embodiments, the nucleic acid comprises a first nucleic acid molecule comprising a sequence encoding the first CFP and a second nucleic acid molecule comprising a sequence encoding the second CFP. In some embodiments, the first nucleic acid molecule and the second nucleic acid molecule are encapsulated in an LNP. In some embodiments, the first nucleic acid molecule is encapsulated in a first LNP. In some embodiments, the second nucleic acid molecule is encapsulated in a second LNP. In some embodiments, the first or second LNP does not comprise a targeting moiety that specifically binds to a cell surface receptor. In some embodiments, first or second LNP comprises a targeting moiety that specifically binds to a cell surface receptor. In some embodiments, the first and second LNP comprise a targeting moiety that specifically binds to a cell surface receptor. In some embodiments, the first LNP comprises a targeting moiety that specifically binds to a first cell surface receptor and the second LNP comprises a targeting moiety that binds to a second cell surface receptor. In some embodiments, the first and second cell surface receptor are a same cell surface receptor. In some embodiments, the first and second cell surface receptor are different. In some embodiments, the first and second CFP are encoded by a same nucleic acid molecule. In some embodiments, the nucleic acid molecule is encapsulated in an LNP. In some embodiments, the LNP comprises a targeting moiety that specifically binds to a cell surface receptor. In some embodiments, the targetingWSGR Docket No. 56371-771.601moiety comprises an antibody, a VHH, a scFv, a DARPin, or an antigen binding fragment thereof. In some embodiments, the cell surface receptor is CD2, CD3, CD5, CD7, or CD8.

[0003] In some embodiments, the sequence encoding the first CFP and the sequence encoding the second CFP are coupled via an intermediate sequence that is configured to facilitate polycistronic expression of the first and second CFPs. In some embodiments, the first ABD or the second ABD is configured to bind a first antigen selected from the group consisting of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), HER2, CD30, or Folate Receptor alpha (FRa). In some embodiments, the first and second ABDs are a same ABD.

[0004] Also provided herein is a composition comprising a nucleic acid encoding at least three chimeric fusion proteins (CFPs) comprising a first CFP, a second CFP, and a third CFP, wherein the first CFP comprises (a) a first extracellular domain (ECD) comprising a first antigen-binding domain (ABD) and (b) a first transmembrane domain (TD) operatively linked to the first extracellular domain; wherein the second CFP comprises (c) a second ECD comprising a second ABD and (d) a second TD operatively linked to the second ECD; wherein the third CFP comprises (e) a third ECD comprising a third ABD and (f) a third TD operatively linked to the third ECD; wherein the first TD comprises a TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; wherein the second TD comprises a TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell; wherein the third TD comprises a TD from a third protein capable of multimerizing with a cell surface receptor expressed by a third cell such that the third CFP is expressed on a cell surface of the third cell; wherein the first; second; and third cells are different types of cells; and wherein the first, second, or third ABD is configured to bind at least one of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), HER2, CD30 or FRa. In some embodiments, the nucleic acid comprises two or more nucleic acid molecules. In some embodiments, the first, second, and third CFP is encoded by a same nucleic acid molecule. In some embodiments, two sequences encoding two of the at least three CFPs are coupled via an intermediate sequence that is configured to facilitate polycistronic expression of the two of the at least three CFPs. In some embodiments, the first, second, and third cells comprise any two of: a natural killer (NK) cell, a monocyte, a T cell, or a B cell. In some embodiments, the intermediate sequence: (1) comprises or encodes an internal ribosome entry site (IRES), or (2) encodes a ribosomal skipping site, or (3) a combination of (l)-(2). In some embodiments, the intermediate sequence comprises or encodes the IRES. In some embodiments,WSGR Docket No. 56371-771.601the intermediate sequence encodes the ribosomal skipping site. In some embodiments, the ribosomal skipping site comprises at least one of E2A F2A, T2A, or P2A. In some embodiments, the ribosomal skipping site comprises at least two copies of E2A F2A, T2A, or P2A. In some embodiments, the first cell or the second cell are a same cell type. In some embodiments, the first or second cell is aNK cell. In some embodiments, the first or second TD comprises a TD of: CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof. In some embodiments, the first or second TD comprises a TD of NKp44. In some embodiments, the first or second CFP further comprises a first intracellular domain (ICD). In some embodiments, the first or second ICD comprises an intracellular signaling domain of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3ζ, DAP 10, DAP 12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD137, or a combination thereof. In some embodiments, the first or second ICD comprises an ICD of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof. In some embodiments, the first or second ICD comprises an ICD of NKp44. In some embodiments, the first or second ECD further comprises an ECD of: CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof. In some embodiments, the first ECD further comprises an ECD of NKp44. In some embodiments, the first or second cell is a monocyte. In some embodiments, the first or second TD comprises a TD of: CD 16a, CD64, CD68, or CD89, or a combination thereof. In some embodiments, the first or second TD comprises a TD of CD89. In some embodiments, the first or second CFP further a second ICD. In some embodiments, the first or second ICD comprises an intracellular signaling domain of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3 DAP 10, DAP 12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD137, or a combination thereof. In some embodiments, the first or second ICD comprises an ICD of: CD 16a, CD64, CD68, or CD89, or a combination thereof. In some embodiments, the first or second ICD comprises an ICD of CD89. In some embodiments, the first or second ECD further comprises an ECD of: CD 16a, CD64, CD68, or CD89, or a combination thereof. In some embodiments, the first or second ECD further comprises an ECD of CD89. In some embodiments, the first or second cell is a T cell. In some embodiments, the first or second TD comprises a TD of: CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3s, CD36, CD3y, CD3 TCRa chain, TCRp chain, TCRy chain, or TCR6 chain, or a combination thereof. In some embodiments, the first or second TD comprises a TD of CD3s. In some embodiments, the first or second CFP further comprises a first or second ICD. In someWSGR Docket No. 56371-771.601embodiments, the first or second ICD comprises an intracellular signaling domain of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3ζ, DAP10, DAP12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD137, or a combination thereof. In some embodiments, the first or second ICD comprises an ICD of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3s, CD38, CD3y, CD3ζ, TCRa chain, TCRP chain, TCRy chain, or TCR6 chain, or a combination thereof. In some embodiments, the first or second ICD comprises an ICD of CD3s, CD36, or CD3y. In some embodiments, the first or second ECD further comprises an ECD of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3s, CD38, CD3y, CD3< TCRa chain, TCRP chain, TCRy chain, or TCR6 chain, or a combination thereof. In some embodiments, the first or second ECD comprises an ECD of CD3s, CD36, or CD3y. In some embodiments, the first or second ABD binds CD19. In some embodiments, the first or second ABD binds CD20. In some embodiments, the first or second ABD binds BCMA. In some embodiments, the first ABD binds CD 19 and the second ABD binds CD20. In some embodiments, the first ABD binds CD 19 and the second ABD binds BCMA. In some embodiments, the first ABD binds CD20 and the second ABD binds BCMA. In some embodiments, the first and second ABD binds CD 19. In some embodiments, the first and second ABD binds CD20. In some embodiments, the first and second ABD binds BCMA. In some embodiments, the first or second ABD binds CD 19, and the first or second ABD comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH and / or VL sequence having at least 80% sequence identity to any sequence set forth in Table 1 or Table 19. In some embodiments, the first or second ABD binds CD20, and wherein the first or second ABD comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH and / or VL sequence having at least 80% sequence identity to any sequence set forth in Table 3. In some embodiments, the first or second ABD binds BCMA, wherein the first or second ABD comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH and / or VL sequence having at least 80% sequence identity to any sequence set forth in Table 2. In some embodiments, the first or second ABD is configured to bind both BCMA and CD 19. In some embodiments, the first or second CFP comprises a sequence having at least 80% sequence identity to a sequence set forth in Table 19. In some embodiments, the first ABD binds HER2 and the second ABD binds TROP2. In some embodiments, the first ABD and the second ABD bind GPC3. In some embodiments, the composition further comprises a sequence encoding a third CFP, wherein the third CFP comprises a third ECD comprising a third ABD and a third TD operatively linked to the third ECD; and wherein the third TD comprises a TD from a third protein capable of multimerizing with a cell surface receptor expressed by a third cell such that the third CFP is expressed on a cell surface of the third cell. In some embodiments, the third cell is a NK cell, a T cell, a B cell, a monocyte, or a macrophage. In some embodiments, the first,WSGR Docket No. 56371-771.601second, or third CFP comprises a sequence having at least 80% sequence identity a sequence presented in Table 20.

[0005] Also provided herein is a composition comprising (a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD 19, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and (b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind CD20, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

[0006] Also provided herein is a composition comprising (a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD 19, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and (b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind BCMA, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

[0007] Also provided herein is a composition comprising (a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD20, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and (b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind BCMA, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

[0008] Also provided herein is a composition comprising (a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD 19 and BCMA, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and (b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, whereinWSGR Docket No. 56371-771.601the second ABD is configured to bind a second antigen selected from CD 19, BCMA, or CD20, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell. In some embodiments, the composition comprises a nucleic acid sequence having at least 80% sequence identity to any sequence presented in Table 12. In some embodiments, the composition comprises an unmodified nucleic acid. In some embodiments, the unmodified nucleic acid does not comprise a pseudouridine, 1-methyl-pseudouridine or 5-methoxyuridine. In some embodiments, a level of immune activation induced by the unmodified nucleic acid is substantially similar to a level of immune activation induced by a nucleic acid comprising one or more modifications, optionally wherein the one or more modifications comprise pseudouridine, 1-methyl-pseudouridine or 5-methoxyuridine. In some embodiments, the composition comprises RNA. In some embodiments, the composition comprises mRNA. In some embodiments, the composition further comprises an additional agent. In some embodiments, the additional agent is selected from the group consisting of (a) an engineered cell surface receptor or a sequence encoding the engineered cell surface receptor; (b) an engineered cytokine receptor or a sequence encoding the engineered cytokine receptor; (c) a sequence encoding a cytokine; (d) a checkpoint inhibitor or a sequence encoding a checkpoint inhibitor; and (e) any combination of (a)-(d). In some embodiments, the engineered cell surface receptor or the engineered cytokine receptor comprises a sequence having at least 80% sequence identity to any sequence set forth in Tables 7-11. In some embodiments, the cytokine is IL-12 or IL-15. In some embodiments, the checkpoint inhibitor comprises an anti-PD-1 antibody, an anti-TIGIT antibody, an anti-PDLl antibody, or any combination thereof.

[0009] Also provided herein is a pharmaceutical composition comprising (a) the composition of any one of the foregoing embodiments and (b) a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for systemic delivery or delivery by an intravenous route.

[0010] Also provided herein is a method of treating a disease or condition in a subject in need thereof, comprising administering the composition of any one of the foregoing embodiments or the pharmaceutical composition of any one of the foregoing embodiments. In some embodiments, the disease or condition comprises a neoplastic disease. In some embodiments, the neoplastic disease comprises cancer. In some embodiments, the disease or condition comprises autoimmunity.

[0011] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized,WSGR Docket No. 56371-771.601the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0012] 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF FIGURES

[0013] The features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and the disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0014] FIG. 1 shows schematic diagram of an exemplary screening assay set up for identifying immune receptors that exhibits dependency on coreceptors that are endogenous to NK cells for expression. This assay is designed to screen through immune receptors to determine whether their expression are dependent on the presence of a IT AM co-receptor as described elsewhere (e.g., Table 3) and then build chimeric fusion protein (CFP) for in vivo delivery. The screening and design of such CFPs are intended for preparing CFP mRNA constructs that can be delivered directly in vivo using a delivery vehicle (e.g., a suitable nanoparticle) and that can, by design, express in the intended cell (e.g., NK cell) in vivo. Such CFP constructs can be prepared for an “off the shelf’ product.

[0015] The schematic shows exemplary immune receptors, marked in the figure as immune receptor A, immune receptor B and immune receptor C, that are known by literature survey or bioinformatics to potentially pair with coreceptors, such as ITAM-domain containing coreceptors described here, are tested in HEK 293 cells. For each pair of receptor and coreceptor tested, HEK 293 cells are divided into two groups (i) control group (top right of the diagram, that is electroporated with the immune receptor construct but not with the coreceptor construct (vehicle), (ii) experimental group in which the immune receptor and the coreceptor are both electroporated. Each coreceptor construct can comprise a fluorescent tag, e.g., GFP as shown.WSGR Docket No. 56371-771.601Expression of both the immune receptor and the coreceptor are tested. The immune receptor that does not express in (i) and expressed in (ii) is selected as an NK cell specific receptor, and is further developed into a CFP by methods described herein.

[0016] FIG. 2A (Top) shows an exemplary myeloid cell-specific chimeric fusion protein (CFP) receptor design and expression in monocytes. Expression determined by flow cytometry. The CFP comprises TM domain of CD89 that oligomerize with CD89 receptor complex and integrates in the cell membrane of monocytes. FIG. 2A (Bottom) shows an exemplary myeloid and NK cell-specific CFP receptor design and expression in NK cells.

[0017] FIG. 2B shows an exemplary NK cell-specific CFP receptor design and expression in NK cells.

[0018] FIG. 3 shows graphical images of new designs for receptors tested for expression in primary NK cells and functional assay scheme. The new CFPs comprise an extracellular domain, a transmembrane (TM) domain from NKp30, NKp44, NKp46 TM, NKG2C, NKG2D or NK16 transmembrane domains with or without associated cytoplasmic and extracellular domains, and each construct comprises an extracellular antigen binding domain which may be a scFv or a SdB binder that can bind to a target antigen on a target cell. NKp30 intracellular domain can interact with associated adaptor proteins e.g., CD3z / FcsRy. NKp46 intracellular domain also can interact with associated adaptor proteins e.g., CD3z / FcsRy. CD16 intracellular domain can interact with associated adaptor proteins e.g., CD3z / FcsRy. The NKp44 intracellular domain can interact with associated adaptor proteins e.g., DAP12. The NKG2C or NKG2D intracellular domain can interact with associated adaptor proteins e.g., DAP 10.

[0019] FIG. 4A-4C shows construct design and data from the same experiment. In this case NK cell-specific CFP designs were as follows: N-terminal cytoplasmic domain (also designated as intracellular domain, ICD) and transmembrane (TM) domain of NKG2C or NKG2D, with or without the NKG2C or NKG2D extracellular domain respectively and with a short linker for the construct lacking the NKG2C or NKG2D extracellular domain and an scFv that can bind to the target at the C terminus. In the exemplary construct, the scFv is an anti-HER2 scFv, which binds to HER2. Expression results demonstrate poor expression of these constructs.

[0020] FIG. 5 shows graphical representations of the NKp30 CFPs from N-C terminal and demonstrates expression data for the CFP expression in NK cells detected by flow cytometry. Domain arrangements were flipped in these constructs as the scFV is in the N-terminal portion and the intracellular domain is in the C terminal ends compared to constructs described in FIGs 4A-4C.

[0021] FIG. 6A shows graphical representations of the NKp44 / 46 CFPs from N-C terminal and demonstrates expression data in NK cells detected by flow cytometry.WSGR Docket No. 56371-771.601

[0022] FIG. 6B shows graphical representations of the NKp44 / 46 CFPs from N-C terminal and demonstrates expression data in NK cells detected by flow.

[0023] FIG. 7 (Top panel) shows the cartoon structures of the CFPs as discussed before. Bottom panel shows data demonstrating tumor cell killing activity of NK cells expressing the different constructs as shown below.

[0024] FIG. 8 (Top panel) shows cartoon structures of CFPs with CD 16 structural domains including a TM domain, that is expressed in NK cells. FIG. 8 (Bottom panel) shows data demonstrating tumor cell killing activity by NK cells expressing TROP2-binding CD 16 TM binders as indicated, and compared to the first generation constructs having CD8TM-CD3z ICD domain structures.

[0025] FIG. 9 shows data on time course of cell lysis by NK cells expressing the indicated CFPs.

[0026] FIG. 10 shows data on cytokine generation by NK cells expressing the indicated CFP constructs in presence of the target antigen (TROP2+ cancer cell) or unstimulated.

[0027] FIG. 11A shows graphical representations of CFP constructs having the respective extracellular, transmembrane and intracellular domains as indicated. HER2 scFv, anti-HER2 scFV antigen binding domain; ectodomain, a portion of the extracellular domain from the same protein as the TM domain having about 20 aa.

[0028] FIG. 11B shows expression data of the indicated constructs in NK cells 24h after transfection, determined by flow cytometry.

[0029] FIG. 11C shows data on target cell killing (cytotoxicity) activity of NK cells expressing the indicated CFP constructs. Target cells are HER2+ cancer cells expressing luciferase. Level of significance indicated.

[0030] FIG. 11D shows NK-kappa B activation data in NK cells expressing the indicated CFP in presence or absence CFP stimulation by the target antigen (HER2+ cancer cell).

[0031] FIG. 12A shows a diagrammatic view of CFP designs for testing impact of the hinge domain on the CFP activation upon expression in NK cells. The CFPs either have no hinge, left, or have CD4 or CD8 hinge domains, monomer or dimer formats, or siglec4 hinge as indicated.

[0032] FIG. 12B shows data demonstrating that CD4 hinge improved Fey chain dependent expression in liver cell line Huh7 cells.

[0033] FIG. 12C shows data demonstrating inclusion of CD4 hinge improved Fey chain dependent expression in Huh7 cells over time as indicated by days after transfected.

[0034] FIG. 12D shows data demonstrating inclusion of CD4 hinge improved tumor specific killing activity.WSGR Docket No. 56371-771.601

[0035] FIG. 13 shows exemplary T cell-specific CFP receptors. Left, diagrammatic view of a natural T cell receptor complex. CFP designed for T cell specific expression to be integrated in the TCR complex is shown by an arrow, comprising a scFv targeting CD 19 (anti-CD19 scFv) and CD3e extracellular, transmembrane (TM) and intracellular domains. Middle panel shows CFP expression data. Expression was demonstrated in T cells only as determined by flow cytometry. On the right is shown results from cell killing assay by incubating T cells expressing the CFP and CD 19+ target cells, demonstrating significant cell death by the T cells expressing the CFP.

[0036] FIG. 14 depicts expression of the anti-GP75 CFP in tumors following the intravenous administration of the mRNA-LNP composition of the construct. The construct comprises a chimeric antigen receptor (CAR) polypeptide construct for in vivo delivery, the CAR comprising a cancer cell-specific extracellular antigen binding domain comprising an scFv that has antigen binding specificity to a target cancer antigen, e.g. TROP2 antigen. The extracellular antigen binding domain (e.g., comprising scFv) is operatively linked to a CD89 transmembrane domain (TM) and CD89 cytoplasmic (Cyto) domain. A chimeric protein such as exemplified in the figure is referred as anti-TROP2-CD89 CAR, (interchangeably indicated as anti-TROP2 chimeric fusion protein (CFP)) when the antigen binding domain is a TROP2 binding domain. The figure demonstrates a cross section of a cell membrane expressing the CAR polypeptide, where the CAR transmembrane domain associates with an endogenous FcR gamma chain that stabilizes its expression in the cell.

[0037] FIG. 15A depicts a non-limiting example nucleic acid construct to generate engineered myeloid cell and T cell that each expresses a CAR. FIG. 15B depicts a non-limiting example nucleic acid construct to generate engineered myeloid cell and NK cell that each expresses a CAR. FIG. 15C depicts a non-limiting example nucleic acid construct to generate engineered myeloid cell, T cell, and NK cell that each expresses a CAR. FIG. 15D depicts a non-limiting example nucleic acid construct design for expressing various engineered polypeptides as described herein.

[0038] FIG. 16 illustrates examples of the structural schematics of anti-folate receptor alpha (FRa) chimeric fusion proteins (CFPs). “Anti-FRa”: the FRa binding domain.

[0039] FIG. 17 illustrates examples of the structural schematics of the polynucleotides encoding the anti -FRa CFPs. “Anti-FRa”: the FRa binding domain; “5’ UTR”: the 5’ untranslated region; “3’ UTR”: the 3’ untranslated region. “ACD3s”: a portion of the CD3s full sequence, comprising a transmembrane domain of CD3s, an intracellular domain of CD3s, and at least a portion of the extracellular domain of CD3s. “ACD89”: a portion of the CD89 full sequence, comprising a transmembrane domain of CD89, an intracellular domain of CD89, and at least aWSGR Docket No. 56371-771.601portion of the extracellular domain of CD89. “ΔNKp44”: a portion of the NKp44 full sequence, comprising a transmembrane domain of NKp44, an intracellular domain of NKp44, and at least a portion of the extracellular domain of NKp44. “ΔCD19”: a portion of the CD19 full sequence, comprising a transmembrane domain of CD 19, an intracellular domain of CD 19, and at least a portion of the extracellular domain of CD 19.

[0040] FIG. 18 illustrates examples of the structural schematics of the polynucleotides encoding two anti-FRa CFPs, each of which has different preference in expression in specific cell types. The order of the CFP components in the schematics is not critical. For example, the first structural schematic showing 5’ UTR-Myeloid FRa CAR - T2A / IRES - T cell FRa CAR - 3’ UTR also implicates the structural of 5’ UTR - T cell FRa CAR - T2A / IRES - Myeloid FRa CAR - 3’ UTR. “5’ UTR”: the 5’ untranslated region; “3’ UTR”: the 3’ untranslated region. “T2A or IRES”: protein cleavage site such as T2A or an internal ribosome entry site (IRES) sequence. “Myeloid FRa CAR”: the anti-FRa CFP preferentially expressing on myeloid cells. “T cell FRa CAR”: the anti-FRa CFP preferentially expressing on T cells. “NK FRa CAR”: the anti-FRa CFP preferentially expressing on NK cells. “B cell FRa CAR”: the anti-FRa CFP preferentially expressing on B cells.

[0041] FIG. 19 illustrates examples of the structural schematics of the polynucleotides encoding three anti-FRa CFPs, each of which has different preference in expression in specific cell types. The order of the CFP components in the schematics is not critical. For example, the first structural schematic showing 5’ UTR- Myeloid FRa CAR-T2A / IRES-T cell FRa CAR -T2A / IRES - NK FRa CAR-3’ UTR also implicates the structural of (i) 5’ UTR- Myeloid FRa CAR - T2A / IRES - NK cell FRa CAR - T2A / IRES - T cell FRa CAR - 3’ UTR, (ii) 5’ UTR- T cell FRa CAR-T2A / IRES - NK FRa CAR - T2A / IRES-Myeloid FRa CAR - 3’ UTR, (iii) 5’ UTR- NK FRa CAR-T2A / IRES - T cell FRa CAR - T2A / IRES-Myeloid FRa CAR - 3’ UTR, (iv) 5’ UTR- NK FRa CAR-T2A / IRES - Myeloid FRa CAR - T2A / IRES- T cell FRa CAR - 3’ UTR, and (v) 5’ UTR- T cell FRa CAR - T2A / IRES - Myeloid FRa CAR - T2A / IRES- NK FRa CAR-3’ UTR. “5’ UTR”: the 5’ untranslated region; “3’ UTR”: the 3’ untranslated region. “T2A or IRES”: protein cleavage site such as T2A or an internal ribosome entry site (IRES) sequence. “Myeloid FRa CAR”: the anti-FRa CFP preferentially expressing on myeloid cells. “T cell FRa CAR”: the anti-FRa CFP preferentially expressing on T cells. “NK FRa CAR”: the anti-FRa CFP preferentially expressing on NK cells. “B cell FRa CAR”: the anti-FRa CFP preferentially expressing on B cells.

[0042] FIG. 20 illustrates an example of the structural schematic of the polynucleotide encoding anti-FRa CFP further comprises a sequence encoding enhancements such as immune response enhancers. For example, in this exemplary structure, the polynucleotide comprises aWSGR Docket No. 56371-771.601sequence encoding enhancement in addition to the sequence encoding three anti-FRa CFPs separated by T2A or IRES. Enhancements can be a protein able to enhance immune response, for example, dominant negative TGFβRII or a modified cytokine receptor.

[0043] FIG. 21 depicts two exemplary anti-CD20 CAR designs. Top comprising a 41BBζ domain and bottom comprising a CD3ε domain.

[0044] FIG. 22 depicts an exemplary LNP design for CD8 targeted delivery.

[0045] FIGs. 23A-23M depict results of a non-human primate study testing a two dose scheme (Day 0 and Day 3) of either CD3ε or 41BBζ constructs. FIG. 23A depicts the study design. FIG. 23B depicts frequency of B and T cells in the blood at the indicated time points in control animals. FIG. 23C depicts frequency of B and T cells in the blood at the indicated time points in animals receiving the CD3ε construct. FIG. 23D depicts frequency of B and T cells in the blood at the indicated time points in animals receiving the 41BBζ construct. FIG. 23E depicts B cell concentrations in blood. FIG. 23F depicts frequency of CD4 and CD8 T cells of control animals. FIG. 23G depicts frequency of CD4 and CD8 T cells of animals receiving the CD3ε construct. FIG. 23H depicts frequency of CD4 and CD8 T cells of animals receiving the 41BBζ construct. FIG. 231 depicts frequency of CAR expression. FIG. 23 J depicts frequency of B and T cells in blood and bone marrow. FIG. 23K depicts frequency of B and T cells in spleen and mesenteric lymph nodes. FIG. 23L depicts B cell concentration in the indicated tissues. Within each bar graph, the groups are vehicle, CD20-CD3e 0.75mg / kg, and CD20-41BBζ 0.75mg / kg, from left to right. FIG. 23M depicts B cell depletion normalized to control. Within each bar graph, the groups are CD20-CD3ε 0.75mg / kg and CD20-41BBζ 0.75mg / kg, from left to right.

[0046] FIGs. 24A-24J depict results of a non-human primate study testing a two dose scheme (Day 0 and Day 6) of either CD3ε or 41BBζ constructs. FIG. 24A depicts the study design. FIG. 24B depicts frequency of B and T cells in blood of animals receiving CD3ε constructs. FIG. 24C depicts frequency of B and T cells in blood of animals receiving 41BBζ constructs.FIG. 24D depicts results measuring B cell concentration in blood at indicated time points. FIG.24E depicts frequency of CD4 and CD8 T cells in blood of animals receiving CD3e constructs.FIG. 24F depicts frequency of CD4 and CD8 T cells in blood of animals receiving 41BBζ constructs. FIG. 24G depicts frequency of B and T cells in indicated tissues in vehicle or CD3ε groups. FIG. 24H depicts frequency of B and T cells in indicated tissues in 41BBζ constructs.FIG. 241 depicts concentration of B cells in indicated tissues. Within each bar graph, the groups are CD20-CD3e 0.75mg / kg and CD20-41BBζ 0.75mg / kg, from left to right. FIG. 24J depicts percentage of B cell depletion normalized to control groups. Within each bar graph, the groups are CD20-CD3ε 0.75mg / kg and CD20-41BBζ 0.75mg / kg, from left to right.WSGR Docket No. 56371-771.601

[0047] FIGs. 25A-25K depicts results of a non-human primate study testing a three dose scheme (Day 0, Day 3, and Day 6) of 41BBζ constructs at a dose of 0.25mg / kg or 0.5mg / kg. FIG. 25A depicts the study design. FIG. 25B depicts the frequency of B and T cells in blood of control animals. FIG. 25C depicts the frequency of B and T cells in blood of animals treated with 0.25 mg / kg. FIG. 25D depicts the frequency of B and T cells in blood of animals treated with 0.5 mg / kg. FIG. 25E depicts the concentration of B cells in the blood. FIG. 25F depicts the frequency of CD4 and CD8 T cells in blood of vehicle treated animals. FIG. 25G depicts frequency of CD4 and CD8 T cells in blood of animals treated with 0.25mg / kg. FIG. 25H depicts of CD4 and CD8 T cells in blood of animals treated with 0.5mg / kg. FIG. 251 depicts frequency of B and T cells in indicated tissues. FIG. 25 J depicts concentrations of B cells in indicated tissues. Within each bar graph, the groups are 0.25mg / kg and 0.5mg / kg, from left to right. FIG. 25K depicts B cell depletion normalized to control. Within each bar graph, the groups are 0.25mg / kg and 0.5mg / kg, from left to right.DETAILED DESCRIPTIONOverview

[0048] A major breakthrough has come across with the discovery of CAR-T cell and their potential use in immunotherapy. CAR-T cells are T lymphocytes expressing a chimeric antigen receptor which helps target the T cell to specific diseased cells such as cancer cells, and can induce cytotoxic responses intended to kill the target cancer cell or immunosuppression and / or tolerance depending on the intracellular domain employed and co-expressed immunosuppressive cytokines. However, several limitations along the way has slowed the progress on CAR-T cells and dampened its promise in clinical trials.

[0049] Revolutionary advancements in nucleic acid technology have encouraged the idea that recombinant polynucleic acid molecules such as CARs can be delivered locally or systemically in an organism in need thereof and induce an effect in the system caused by suitable expression of the sequence encoded by the recombinant polynucleic acid addressing a therapeutic need, and thereby bypassing the need for expensive and time-consuming generation of cells for administering. However, the current available therapeutics suffer from a wide range of disadvantages such as a lack of efficacy, applicability, efficiency, and specificity.

[0050] One overarching issue with such therapy, however, can comprise directing expression or activation of the recombinant polynucleic acid molecule, such as a CAR construct, in a specific cell or tissue type, for it to be most effective in bringing about the therapeutic effect and avoiding non-specific or harmful effects generated as a result of inadvertent expression of theWSGR Docket No. 56371-771.601polynucleic acid that has been delivered systemically or locally in a cell that was not the desired or intended cell for the purpose.

[0051] Additionally, understanding the limitations of CAR-T cells is the key to leveraging the technology and continue innovations towards better immunotherapy models. Specifically, in T cell malignancies, CAR-T cells appear to have faced a major problem. CAR-T cells and malignant T cells share surface antigen in most T cell lymphomas (TCL); therefore, CAR-T cells are subject to cytotoxicity in the same way as cancer cells. In some instances, the CAR-T products may be contaminated by malignant T cells. Additionally, T cell aplasia is a potential problem due to prolonged persistence of the CAR-T cells. Other limitations include the poor ability for CAR-T cells to penetrate into solid tumors and the potent tumor microenvironment which acts to downregulate their anti-tumor potential. CAR-T cell function is also negatively influenced by the immunosuppressive tumor microenvironment (TME) that leads to endogenous T cell inactivation and exhaustion. Accordingly, the current available therapeutics suffer from a lack of efficacy.

[0052] Cells from the innate immune defense repertoire are being recently tapped for their therapeutic potential. Among the early responders of immune defense system, NK cells, myeloid cells and certain lymphoid lineage cells are potent cytotoxic cells, and exhibit target-specific fast and efficient clearance of infective agents, pollutants, infected cells, dead or dying cells, and cells that undergo aberrant physiological changes. Particularly, natural killer (NK) cells, a type of granulocytes, play a vital role in innate immune response. These cells are responsible for the discrimination of target cells from healthy cells and are instrumental in cytolysis without triggering tissue damage. NK cells can lyse cells that exhibit surface markers associated with oncogenic transformation. In addition, NK cells are short-lived and therefore pose no long lasting issues encountered in other modes of cell therapy, for example, T cell therapy. Therefore, NK cells can be utilized as an excellent candidate in the development of in anticancer cell therapy. Similarly B cells and monocytes and a variety of T cells may likewise be considered. Targeting various immune cell types, such as NK cells, monocytes, and B cells can be the next frontier in immuno-oncology. However, the currently available technology does not provide efficient means to generate cell type specific immune responses.

[0053] The present disclosure also relates to targeting various immune cells for the purpose of immuno-oncology. For example, the present disclosure provides, in one aspect, chimeric fusion proteins (CFPs) that are encoded by one or more nucleic acid of the design disclosed herein, such that when a liquid formulation of a composition comprising the nucleic acids is administered to a subject, the nucleic acid, even if taken up by multitude of cells in vivo, will express the encoded engineered polypeptide in a certain cell type in vivo as is designed. TheWSGR Docket No. 56371-771.601polypeptide encoded by the nucleic acid may not express, may be degraded, or may not be functional in other cell types that are different from the certain cell type as allowed by the design of the polynucleic acids.

[0054] In one aspect, the CFPs disclosed herein can comprise a transmembrane domain (TD) that can specifically bind to or interact with a particular protein of one particular immune cell. The particular protein can facilitate the trafficking of the endogenous proteins of the particular immune cell to the plasma membrane or cell surface of the particular immune cell. Accordingly, a particular CFP with the TD that can bind to the particular protein can be trafficked to the plasma membrane or cell surface of the particular immune cell when it is expressed in the particular immune cell. Furthermore, the TD of the CFP may not interact or bind to a second protein (that may be expressed in an additional cell type different from the particular immune cell and can facilitate the trafficking of the proteins to the plasma membrane or cell surface of the additional cell type). Thus, the CFPs comprising the TD as described herein may only be expressed, activated, or trafficked to one specific immune cell type and but not the other cell types. Additionally, the ECD or ICD described herein can also facilitate the cell-specific expression, activation, or trafficking of the CFP. Accordingly, the specificity (such as the immune cell-specific therapeutic response) can be generated using the methods and compositions described herein, addressing this long-felt need. Additionally, the methods and compositions also allow engineering of different immune cell types and thus address the long-felt need of efficacious therapy.

[0055] In some cases, immune responses against a cancer cell may comprise recruitments of various different immune cell types to the TME. Thus, it can be hypothesized that directing multiple types of immune cells against one specific antigen of the cancer cell can increase the efficacy, efficiency, and specificity of the cancer therapy. The present disclosure, in one aspect, provides CFPs targeting the same antigens that are specifically expressed or activated in at least two cell types, thereby addressing the long-felt needs of increased efficacy, efficiency, and specificity of the cancer therapy.

[0056] Using specific cell types that are residing in vivo as therapeutic vehicles, and targeting individual cell types to express a therapeutic polynucleic acid when administered to a subject, can be a huge challenge for future drug development. For example, generating such engineered cells may be laborious: isolating or culturing the cells for engineering can be cost-prohibitive and technically challenging. Furthermore, maintaining and culturing the engineered cells can also be cost-prohibitive and technically challenging. Accordingly, the current available therapeutics suffer from a lack of applicability.WSGR Docket No. 56371-771.601

[0057] The present disclosure also addresses this long-felt need of applicability. In one aspect, the present disclosure provides the nucleic acid (such as those encoding the engineered polypeptides as disclosed herein) that can be delivered to the subjects for therapeutic effects. The disclosure, in one aspect, relates to methods and compositions comprising nucleic acids encoding one or more engineered polypeptides, the compositions comprising the nucleic acids are formulated for delivery to a subject in need thereof in various delivery methods, such that when exposed to a variety of cells in vivo, the nucleic acid is expressed in specific immune cells and not express in all cells in vivo. Accordingly, because the laborious and technical challenge aspects of engineering cells in in vitro is omitted, the present disclosure also addresses the long-felt needs of increased applicability in regards to the currently available technology.

[0058] Generation of different polypeptide molecules can traditionally require the uses of two separate nucleic acid molecules. However, the formulation of effective means to deliver the proper nucleic acid molecules to the proper target cells can also be technically challenging. For example, while the CFPs described herein allow for cell type-specific expression / activation / trafficking of the CFP, the target cells may need to be introduced with at least the proper nucleic acid in the first place. Thus, the current available therapeutics suffer from a lack of efficacy or efficiency.

[0059] The present disclosure, in one aspect, discloses the uses of a single polycistronic nucleic acid molecule that can encode at least two engineered polypeptides. The single nucleic molecules can comprise various sequence elements such that different nucleic acid sequences can be translated to encode the different engineered polypeptides either via post-transcriptional or post-translational means. Thus, in one aspect, the present disclosure provides means for expression / activation / trafficking of the CFP, addressing the long-felt needs of efficient or efficacious therapy.

[0060] The present disclosure, in one aspect, discloses CFPs that can specifically bind various antigens on the diseased cells (such as cancer cells) and direct immune responses against the cells. One such antigens can comprise Cluster of Differentiation 19 (CD 19). The human CD 19 antigen is a 95 kd transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily. CD 19 can be observed in cases of myeloid malignancies, including in 2% of AML cases (Wang et al., Exp. Hematol. Oncol. 2012 Nov 29; 1(1):36, which is incorporated herein by reference in its entirety). Rare cases of CD19-expressing myeloblastic leukemia (AML-M2) may lack any myeloid surface antigens. One model of lymphomagenesis involving CD 19 may be linked to the proto-oncogene c-Myc (Wang et al.). Upregulated CD19 expression and phosphorylation can be induced by constitutive c-Myc overexpression, further promoting and stabilizing c-Myc signaling — whose downstream effectors can include important cell cycleWSGR Docket No. 56371-771.601regulators like cyclin D2 — and enhancing lymphomagenesis (Wang et al.). Transgenic c-Myc mice have shown that CD 19 expression can also accelerates lymphomagenesis and can be associated with increased disease severity. On the other hand, c-myc transgenic mice with CD 19 deficiency, as compared to those expressing CD 19, can exhibit reduced malignancies and significantly higher (>80%) increase in survival and life spans, making CD 19 an attractive target for anti-cancer therapy (Wang et al.).

[0061] The present disclosure, in one aspect, discloses CFPs that can specifically bind CD20. CD20 is a surface protein that can specifically express in B cells with minimal occurrence in other tissues, making it an effective and specific target for therapy against B cell-derived malignancies, such as chronic lymphocytic leukemia (CLL) and various B cell-derived nonHodgkin lymphomas (B-NHL), including but not limited to follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL) (Dabkowska et al., Front. Immunol. 2024 Apr 4:15:1363102, which is incorporated herein by reference in its entirety). CD20-specific therapies can offer specific B cell targeting, minimizing impact on other cell types and making CD20 an attractive target for anti-cancer therapy. These therapies can efficiently deplete CD20-expressing B cells without hindering the replenishment of the B-cell compartment from early B cell precursors. CD20 can also be expressed in multiple subtypes of B cell precursor acute lymphoblastic leukemia (B-ALL) (Dabkowska et al.).

[0062] The present disclosure, in one aspect, discloses CFPs that can specifically bind CD30. CD30 can comprise a 120 kilodaltons (kD) transmembrane glycoprotein receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, with intracellular, trans-membrane and extracellular domains. CD30 can be expressed on a small subset of activated T and B lymphocytes, and a variety of lymphoid neoplasms, with the highest expression in classical Hodgkin lymphoma (HL) and anaplastic large cell lymphomas (ALCL) (van der Weyden et al., Blood Cancer J. 2017 Sep 8;7(9):e603., which is incorporated herein by reference in its entirety). An 88 kD form of soluble CD30 can also be detected in vivo in inflammatory states and CD30-positive hematologic malignancies, and is presumed to represent a cleavage byproduct of the extracellular portion of CD30 (van der Weyden et al.). CD30 can also expressed on a small subset of activated T and B lymphocytes, and a variety of lymphoid neoplasms. It has been demonstrated with variable expression and intensity in some cases, of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS); adult T-cell leukemia / lymphoma; cutaneous T-cell lymphoma (CTCL); extra-nodal NK-T-cell lymphoma; and a variety of B-cell non-HLs, including diffuse large B-cell lymphoma, particularly EBV-positive diffuse large B-cell lymphoma (van der Weyden et al.). Neoplastic mast cells in advanced systemic mastocytosis have also been shown to be CD30-positive. CD30 expression can also be detected in certainWSGR Docket No. 56371-771.601non-hematopoietic malignancies, including germ cell tumors and testicular embryonal carcinomas (van der Weyden et al.), making CD30 an attractive target for anti-cancer therapy.

[0063] The present disclosure, in one aspect, discloses CFPs that can specifically bind B-cell maturation antigen (BCMA). BMC A is a cell surface antigen that’s expressed in malignant plasma cells (PCs) in patients with multiple myeloma (MM) (Yu et al., J. Hematol. Oncol. 2020 Sep 17; 13(1): 125., which is incorporated herein by reference in its entirety). BCMA expression can be detected in various hematologic malignancies (Dogan et al., Blood Cancer J. 2020 Jun 30;10(6):73., which is incorporated herein by reference in its entirety). BCMA can comprise a 184 amino acid and 20.2-kDa type III transmembrane glycoprotein, with the extracellular N terminus containing a conserved motif of 6 cysteines. BCMA is a member of tumor necrosis factor (TNF) receptor (TNFR) superfamily. In some cases, BMCA can be detected on plasma cells, which are the cells that develop into multiple myeloma (Kleber et al., J. Clin. Med. 2021 Sep 10;10(18):4088., which is incorporated herein by reference in its entirety). BCMA can also be expressed at higher levels on tumor cells in patients with multiple myeloma, making BMCA an attractive target for anti-cancer therapy (Kleber et al.).

[0064] The present disclosure, in one aspect, discloses CFPs that can specifically bind Trophoblast cell surface antigen 2 (Trop-2). Trop-2 can comprise a 36-kDa cell surface glycoprotein. Trop2 can be upregulated in a variety of malignant tumors and participate in several oncogenic signaling pathways that lead to tumor development, invasion, and metastasis, but exhibits limited expression in normal human tissuesl3, making Trop-2 an attractive therapeutic target in cancer treatment (Zhou et al., NPJ. Precis. Oncol. 2024 Apr 23;8(1):94., which is incorporated herein by reference in its entirety).

[0065] The present disclosure, in one aspect, discloses CFPs that can specifically bind Glypican-3 (GPC3). GPC3 is a heparan sulfate proteoglycan (HSPG). There can comprise six glypican subtypes, namely, GPCs 1-6, with similar structures consisting of a 60-70 kDa protein connected to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, 14 conserved cysteine residues, and the last 50 residues at the carboxyl end modified by the heparan sulfate (HS) side-chain. GPC3 has been implicated in a variety of processes, including cell growth, differentiation, and migration. Specific expression of GPC3 in tumor cell has been observed, such as but not limited to hepatocellular carcinoma (HCC), squamous cell lung cancers, head and neck squamous cell cancers, and breast cancer, making it an attractive target for anti-cancer therapy (Feng et al., Front Oncol. 2022 Feb 16:12:824208.; and Moek et al., Am. J. Pathol. 2018 Sep;188(9):1973-1981., each of which is incorporated by reference in its entirety).

[0066] The present disclosure, in one aspect, discloses CFPs that can specifically bind PD-L1. The present disclosure, in one aspect, discloses CFPs that can specifically bind MIC-A / B. TheWSGR Docket No. 56371-771.601present disclosure, in one aspect, discloses CFPs that can specifically bind NKG2D. The present disclosure, in one aspect, discloses CFPs that can specifically bind EGFRvIII. The present disclosure, in one aspect, discloses CFPs that can specifically bind HER2. The present disclosure, in one aspect, discloses CFPs that can specifically bind mesothelin. The present disclosure, in one aspect, discloses CFPs that can specifically bind PSMA. The present disclosure, in one aspect, discloses CFPs that can specifically bind TIM3. The present disclosure, in one aspect, discloses CFPs that can specifically bind EGFR. Accordingly, the present disclosure provides engineered polypeptides that specifically bind various cancer antigens, addressing the long-felt needs of increased efficacy, specificity, and efficiency of anticancer therapy.

[0067] The present disclosure, in one aspect, also discloses various additional engineered polypeptides. These additional engineered polypeptides can increase the therapeutic efficacy or efficiency. In some cases, the present disclosure, in one aspect, additional engineered polypeptides comprising engineered cell surface receptors. In some cases, the engineered cell surface receptor can comprise a regulator of Transforming Growth Factor-β (TGF-β / TGF-b) signaling pathway.

[0068] TGF-b is a pleotropic immunosuppressive molecule secreted by many cell types that limits both the function and expansion of effector T cells. Clinical and pre-clinical data has suggested that tumor cells, stromal cells, and suppressive immune subsets including regulatory T cells secrete TGF-b, and many groups report that TGF-b inhibits effector T cell function and proliferation in the tumor microenvironment (TME) (Thomas et al. Cancer Cell, 8(5):369-380 (2005), Yang et al., Trends in Immunology, 31(6) (2010), and Pickup et al., Nat Rev Cancer, 13(11), 788-799 (2013), each of which is herein incorporated by reference in its entirety). The TGF-b signaling pathway begins with endogenous expression of two, dimeric, transmembrane Transforming Growth Factor- protein receptors: TGF-b Receptor Type I (TGF-b Rl) and TGF-b Receptor Type II (TGF-b R2). In T cells, TGF-b R2 is constitutively phosphorylated. Upon TGF-b ligand binding, two molecules each of TGF-b Rl and TGF-b R2 form a hetero-tetramer receptor complex that induces TGF-b R2 trans-phosphorylation of TGF-b at four key threonine sites between amino acids (aa) 185-205 of the TGF-RI protein (Heldin et al. Cold Spring Harb Perspect Biol. Aug 1:8(8) (2016), which is herein incorporated by reference in its entirety). Phosphorylated TGF-b Rl then initiates phosphorylation of a set of receptor regulated signal transducing proteins: SMAD2 and SMAD3. Both pSMAD2 and pSMAD3 form hetero- trimeric oligomers with pSMAD4. The resulting activated SMAD complex then enters the nucleus and docks at target transcription factor binding sites to induce expression of target genes that supportWSGR Docket No. 56371-771.601immunosuppression (Inman et al. Mol Cell, 10(2):283-294 (2002), which is herein incorporated by reference in its entirety).

[0069] TGF-b blockade therapy for cancer has achieved some results but shows limited efficacy and side effects because these drugs are not selective and act on various types of cells throughout the body (see, for example, Böttinger et al., EMBO J. 1997 May 15;16(10):2621-33. and Li et al., Biomed Pharmacother. 2022 Apr: 148: 112754., each of which is herein incorporated by reference in its entirety). One solution is to use a dominant negative (DN) form of a TGF-b receptor (TGF-b R) specifically. Furthermore, the DN TGF-b R can also promote the proliferation and differentiation of T cells and increases the expression of T-bet, which in turn can promote the secretion of granzyme A, granzyme B, perforin and IFN-y secreted by T cells, and enhances the cytotoxicity and anti-tumor effects of the immune cells such as T cells (Li). Additionally, the DN TGF-b R can reduce the proportion of regulatory T cells (Tregs) in tumor tissue and spleen of tumor-bearing mice (Li et al).

[0070] The present disclosure, in one aspect, also discloses additional engineered polypeptides comprising various additional engineered cytokine receptors. Endogenous cytokine receptors present on the macrophages and monocytes can modulate immune responses. Macrophages can generally adopt either a pro-inflammatory (Ml) or an anti-inflammatory (M2) phenotype. A precise balance of M1 / M2 macrophages can be important in the body’s response to disease and injury, and various diseases include dysregulated M1 / M2 phenotypes. For example, macrophages in the TME may often be biased toward an M2 phenotype that safeguards the tumor, while Ml macrophages in atherosclerotic tissue typically promote plaque progression. Provided herein are methods and compositions for modulating existing macrophages or monocytes (e.g., distributing Ml macrophages to the TME). The engineered cytokine receptors provided herein can allow for the engineered regulations of the M1 / M2 phenotype.

[0071] The present disclosure, in one aspect, also discloses additional engineered polypeptides comprising Bi-specific T-cell engager (BiTE).

[0072] Provided herein, in one aspect, are compositions comprising a combination of at least two different engineered polypeptides. For example, the combination can at least comprise the combination of: CFP(s) + engineered cell surface receptor; CFP(s) + engineered cytokine receptor; CFP(s) + engineered cell surface receptor + engineered cytokine receptor; engineered cell surface receptor + engineered cytokine receptor; or at least two different CFPs; or at least one CFP and at least one BiTE. Accordingly, the present disclosure addresses the long-felt need of efficient and efficacious therapeutics.WSGR Docket No. 56371-771.601Compositions and engineered polypeptides

[0073] In an aspect, provided herein are compositions comprising a first nucleic acid encoding a chimeric fusion protein (CFP) as described herein, a second nucleic acid encoding an engineered cytokine receptor as described herein, or a third nucleic acid encoding an engineered cell surface receptor as described herein. In some cases, the composition may comprise the first nucleic acid. In some cases, the composition may comprise the second nucleic acid. In some cases, the composition may comprise the third nucleic acid. In some cases, the composition may comprise the first and second nucleic acids. In some cases, the composition may comprise the first and third nucleic acids. In some cases, the composition may comprise the first, second, and third nucleic acids. In an aspect, provided herein are compositions comprising a first engineered polypeptide comprising a chimeric fusion protein (CFP) as described herein, a second engineered polypeptide comprising an engineered cytokine receptor as described herein, or a third engineered polypeptide comprising an engineered cell surface receptor as described herein. In some cases, the composition may comprise the first engineered polypeptide. In some cases, the composition may comprise the second engineered polypeptide. In some cases, the composition may comprise the third engineered polypeptide. In some cases, the composition may comprise the first and second engineered polypeptides. In some cases, the composition may comprise the first and third engineered polypeptides. In some cases, the composition may comprise the first, second, and third engineered polypeptides. In an aspect, provided herein are composition comprising: (1) the first nucleic acid or the first engineered polypeptide; (2) the second nucleic acid or the second engineered polypeptide; or (3) the third nucleic acid or the third engineered polypeptide.. In some cases, the composition may (1). In some cases, the composition may comprise (2). In some cases, the composition may comprise (3). In some cases, the composition may comprise (1) and (2). In some cases, the composition may comprise (1) and (3). In some cases, the composition may comprise (1), (2), and (3).

[0074] In some embodiments, the compositions disclosed herein comprise one nucleic acid molecule. In some embodiments, the compositions disclosed herein comprise two nucleic acid molecules. In some embodiments, the compositions disclosed herein comprise one nucleic acid molecule encoding one, two, three, or more CFPs. In some embodiments, the compositions disclosed herein comprise a first nucleic acid molecule encoding a first CFP and a second nucleic acid molecule encoding a second CFP. In some embodiments, the compositions disclosed herein further comprise a third nucleic acid molecule encoding a third CFP. In some embodiments, the first, second, and third CFP is encoded by a same nucleic acid molecule. Chimeric fusion proteins (CFPs)WSGR Docket No. 56371-771.601

[0075] In an aspect, provided herein are compositions comprising a nucleic acid encoding a CFP as described herein. In some cases, provided herein are compositions comprising a CFP as described herein.

[0076] In some cases, a CFP may comprise a transmembrane domain (TD). In some cases, a CFP may comprise an extracellular domain (ECD). The ECD of a CFP may comprise an antigen-binding domain (ABD). In some cases, a CFP may comprise an intracellular domain (ICD).

[0077] In some cases, a TD of the CFP comprise a TD from a protein capable of multimerizing with a cell surface receptor expressed by a cell such that the CFP is specifically expressed on a cell surface of the cell.

[0078] A “ligand” can refer to a molecule which is capable of binding or forming a complex with another molecule, such as a receptor. A ligand can include, but is not limited to, a protein, a glycoprotein, a carbohydrate, a lipoprotein, a hormone, a fatty acid, a phospholipid, or any component that binds to a receptor. In some embodiments, a receptor has a specific ligand. In some embodiments, a receptor may have promiscuous binding to a ligand, in which case it can bind to several ligands that share at least a similarity in structural configuration, charge distribution or any other physicochemical characteristic. A ligand may be a biomolecule. A ligand may be an abiotic material. In the context of a CFP described herein, the ED or ABD may bind to a ligand, which is also designated as a target of the binding domain. In some embodiments, the target is an antigen expressed on a diseased cell, such as a cancer cell, which in this case is a target cell, in the sense that the target cell expresses on its cell surface a target antigen to which the extracellular antigen-binding domain of the CFP binds. Anti-(target) binding domain or anti-(target) binding extracellular domain or anti-(target) CFP are often interchangeably used with terms such as (target) binding domain or (target) binding extracellular domain or (target) CFP respectively in the disclosure. For example, Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), or CD30; expressed on cancer cells is an antigen (ligand) to which the anti-CD19, anti-CD20, anti -BCMA, anti-Trope-2, anti-GPC3, or anti-CD30 binding extracellular domain of a CFP binds, respectively; or alternatively stated as, anti-CD19, anti-CD20, anti-BCMA, anti-Trope-2, anti-GPC3, or anti-CD30 binding extracellular domain of a CFP binds, respectively.

[0079] In some cases, the TD of the CFP as described herein may facilitate cell surface expression of the CFP within a specific cell relative a non-specific cell. For example, in some cases, when the CFP is introduced into each of the specific cell and the non-specific cell, the detectable expression level of CFP present on the cell surface of the specific cell is at leastWSGR Docket No. 56371-771.601about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold higher than that of the non-specific cell. In some cases, when the CFP is introduced into each of the specific cell and the non-specific cell, the detectable expression level of CFP present within the specific cell is at most about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold higher than that of the non-specific cell. In some cases, the TD of the CFP as described herein may facilitate expression of the CFP within a specific cell relative a nonspecific cell. For example, in some cases, when the CFP is introduced into each of the specific cell and the non-specific cell, the detectable expression level of CFP present within the specific cell is at least about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold higher than that of the non-specific cell. In some cases, when the CFP is introduced into each of the specific cell and the non-specific cell, the detectable expression level of CFP present within the specific cell is at most about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold higher than that of the non-specific cell. In some cases, when the CFP is introduced into a population of the specific cells, at least about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more cells within the population can have detectable expression of the CFP or detectable expression of the CFP on the cell surface. In some cases, when the CFP is introduced into a population of the specific cells, at most about: 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 99.99% of cells within the population can have detectable expression of the CFP or detectable expression of the CFP on the cell surface. In some cases, when the CFP is introduced into each of populations of the specific cell and the non-specific cell, the detectable expression of the CFP present within the cells or on the cell surface of the cells of the population of the specific cells is at least about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold than that of the population of the non-specific cells, respectively. In some cases, when the CFP is introduced into each of populations of the specific cell and the non-specific cell, the detectable expression of the CFP present within the cells or on the cell surface of theWSGR Docket No. 56371-771.601cells of the population of the specific cells is at most about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold than that of the population of the non-specific cells, respectively. The CFP described herein may comprise an extracellular domain (ECD), an intracellular domain (ICD), or both ECD and ICD. In some cases, the ECD or ICD or a combination thereof of the CFP as described herein may also facilitate cell surface expression of the CFP within a specific cell relative a non-specific cell, similar to the TD of the CFP as described herein. The TD, ECD, or ICD may independently or synergistically facilitate cell surface expression of the CFP. Expression of the CFP (or any other proteins / polypeptides described herein) can be determined using fluorescence, immunochemistry, real-time polymerase chain reaction (RT-PCR), Fluorescence-activated cell sorting (FACS), or any derivatives thereof, or any combinations thereof.

[0080] In some case, the CFP may be specifically expressed in a cell. The term “specifically express” used herein include expression substantially, or preferentially in a specific cell type. In some case, the CFP may be specifically expressed in an immune cell. In some case, an immune cell may comprise a monocyte, macrophage, B cell, memory B cell, T cell (e.g., T helper cell, memory T cell, killer T cell), dendritic cell (DC), mast cell, natural killer (NK) cell, neutrophil, eosinophil, basophil, Kupfer cell, lymphocyte, histiocyte, alveolar macrophage, innate lymphoid cell, myeloid cell, or a combination thereof.

[0081] In some case, the CFP may be predominantly expressed in a cell. “Predominantly expressed” in a cell indicates cell-specific or selective expression of a gene or a construct. In the present context, a construct can be considered predominantly expressed e.g., in NK cells, where it is expressed in NK cells and not substantially expressed in the vast majority of other cell types, e.g., B cells, or dendritic cells, or epithelial cells or muscle cells. In another instance, “predominantly expressed” may not exclude expression in related cell types, e.g., NKT cells, or may allow, under circumstances, substantially low expression in some other cell types, as deemed acceptable by one of skill in the art. In some embodiments, the methods and compositions described here comprise polynucleic acid designs that are designed for expression in a cell type and not substantially express in another cell type. The desire or intention of the program to have a polynucleic acid express in a certain cell type may be such that the polynucleic acid expresses in a cell that can be detected reliably, at least over a period of time, for example, say for about 18 to 42 hours after introduction of the polynucleic acid, at a level of expression that can be determined by commonly known methods at disposal to one of ordinary skill in the art. Along the same lines, when a polynucleic acid is not substantially or predominantly expressed in a cell type, it may mean that the translated protein or polypeptideWSGR Docket No. 56371-771.601encoded by the polypeptide, generally understood as the entire polypeptide encoded by the sequence, is not within reliably detectable range by commonly known methods at disposal to one of ordinary skill in the art. It may even be transiently expressed and outside the window that is ordinarily perceived as a reliable protein expression from an exogenous nucleic acid sequence. In some case, the CFP may be predominantly expressed in an immune cell. In some case, an immune cell may comprise a monocyte, macrophage, B cell, memory B cell, T cell (e.g., T helper cell, memory T cell, killer T cell), dendritic cell (DC), mast cell, natural killer (NK) cell, neutrophil, eosinophil, basophil, Kupfer cell, lymphocyte, histiocyte, alveolar macrophage, innate lymphoid cell, myeloid cell, or a combination thereof.

[0082] Provided herein are compositions comprising a nucleic acid(s) that encodes at least two different CFPs (or the compositions may comprise the different CFPs). In some cases, each of the CFPs may be specifically expressed in one type of cell (or on the cell surface of one type of cell) as described herein. In some cases, the composition facilitate specific expression or cell surface expression of a CFP in at least each of: 2, 3, 4, 5, 6 or more different type of cells. In some cases, the composition facilitate specific expression or cell surface expression of a CFP in at most each of: 2, 3, 4, 5, or different type of cells. In some case, each of 2 different types of cells may specifically express a CFP or specifically express on CFP on its cell surface using the composition as described herein. In some case, each of 3 different types of cells may specifically express a CFP or specifically express on CFP on its cell surface using the composition as described herein. In some case, each of 4 different types of cells may specifically express a CFP or specifically express on CFP on its cell surface using the composition as described herein. In some cases, the different types of cells may comprise a monocyte, macrophage, B cell, memory B cell, T cell (e.g., T helper cell, memory T cell, killer T cell), dendritic cell (DC), mast cell, natural killer (NK) cell, neutrophil, eosinophil, basophil, Kupfer cell, lymphocyte, histiocyte, alveolar macrophage, innate lymphoid cell, or a combination thereof. In some cases, the different types of cells may comprise a T cell, a B cell, a NK cell, a monocyte, or a combination thereof.

[0083] In some embodiments, the nucleic acid comprises a first nucleic acid molecule comprising a sequence encoding the first CFP and a second nucleic acid molecule comprising a sequence encoding the second CFP. In some embodiments, the nucleic acid comprises two or more nucleic acid molecules. In some embodiments, the nucleic acid comprises two, three, four, five or more nucleic acid molecules. In some embodiments, the first ABD or the second ABD is configured to bind a first antigen selected from the group consisting of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), HER2, CD30, or Folate Receptor alpha (FRa).WSGR Docket No. 56371-771.601

[0084] In some case, each of a NK cell and a T cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a NK cell and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a NK cell and a monocyte may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a monocyte and a T cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a monocyte and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a T cell and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a NK cell, a monocyte, and a T cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a NK cell, a monocyte, and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a T cell, a NK cell, and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a T cell, a monocyte, and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein. In some case, each of a NK cell, a T cell, a monocyte, and a B cell may specifically express a CFP or specifically express a CFP on its cell surface using the composition as described herein.

[0085] In some case, a CFP may comprise a TD, ECD, ICD, a fragment thereof, a derivative thereof, or a combination that facilitate the specific expression or cell surface expression in a specific type of cell as described herein. A “fragment” can refer to a portion of a protein or nucleic acid. In some embodiments, a fragment retains at least 50%, 75%, or 80%, or 90%, 95%, or even 99% of the biological activity of a reference protein or nucleic acid. Unless otherwise indicated, a fragment contemplated in the descriptions herein are intended to be functionally relevant fragment of the protein or nucleic acid. In some case, a CFP may comprise a TD, ECD, ICD, a fragment thereof, a derivative thereof, or a combination that facilitate the specific expression or cell surface expression in a NK cell, T cell, B cell, or monocyte as described herein.

[0086] In some case, a CFP may comprise a TD, ECD, ICD, a fragment thereof, a derivative thereof, or a combination that facilitates the specific expression or cell surface expression in a NK cell. In some case, a TD that facilitates specific expression or cell surface expression of a CFP within a NK cell may comprise a TD or a fragment or derivative thereof of CD39, CD56,WSGR Docket No. 56371-771.601CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof. In some case, an ECD that facilitates specific expression or cell surface expression of a CFP within a NK cell may comprise a TD or a fragment or derivative thereof of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof. In some case, an ICD that facilitates specific expression or cell surface expression of a CFP within a NK cell may comprise a TD or a fragment or derivative thereof of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof. In some case, a CFP that is specifically expressed in a NK cell or a cell surface thereof may comprise: (1) a TD or a fragment or derivative thereof of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof; (2) a ECD or a fragment or derivative thereof of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof; (3) an ICD or a fragment or derivative thereof of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof; or a combination of (1-3).

[0087] In some case, a CFP may comprise a TD, ECD, ICD, a fragment thereof, a derivative thereof, or a combination that facilitates the specific expression or cell surface expression in a monocyte. In some case, a TD that facilitates specific expression or cell surface expression of a CFP within a monocyte may comprise a TD or a fragment or derivative thereof of CD 16a, CD64, CD68, or CD89, or a combination thereof. In some case, an ECD that facilitates specific expression or cell surface expression of a CFP within a monocyte may comprise a TD or a fragment or derivative thereof of CD 16a, CD64, CD68, or CD89, or a combination thereof. In some case, an ICD that facilitates specific expression or cell surface expression of a CFP within a monocyte may comprise a TD or a fragment or derivative thereof of CD 16a, CD64, CD68, or CD89, or a combination thereof. In some case, a CFP that is specifically expressed in a monocyte or a cell surface thereof may comprise: (1) a TD or a fragment or derivative thereof of CD 16a, CD64, CD68, or CD89, or a combination thereof; (2) a ECD or a fragment or derivative thereof of CD 16a, CD64, CD68, or CD89, or a combination thereof; (3) an ICD or a fragment or derivative thereof of CD 16a, CD64, CD68, or CD89, or a combination thereof; or a combination of (1-3).WSGR Docket No. 56371-771.601

[0088] In some case, a CFP may comprise a TD, ECD, ICD, a fragment thereof, a derivative thereof, or a combination that facilitates the specific expression or cell surface expression in a T cell. In some case, a TD that facilitates specific expression or cell surface expression of a CFP within a T cell may comprise a TD or a fragment or derivative thereof of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3s, CD36, CD3y, CD3< TCRa chain, TCRp chain, TCRy chain, or TCR6 chain, or a combination thereof. In some case, an ECD that facilitates specific expression or cell surface expression of a CFP within a T cell may comprise a TD or a fragment or derivative thereof of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3s, CD38, CD3y, CD3< TCRa chain, TCRP chain, TCRy chain, or TCR6 chain, or a combination thereof. In some case, an ICD that facilitates specific expression or cell surface expression of a CFP within a T cell may comprise a TD or a fragment or derivative thereof of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3s, CD36, CD3y, CD3 TCRa chain, TCRp chain, TCRy chain, or TCR6 chain, or a combination thereof. In some case, a CFP that is specifically expressed in a T cell or a cell surface thereof may comprise: (1) a TD or a fragment or derivative thereof of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3ε, CD3δ, CD3γ, CD3ζ, TCRα chain, TCRβ chain, TCRγ chain, or TCRδ chain, or a combination thereof; (2) a ECD or a fragment or derivative thereof of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3ε, CD3δ, CD3γ, CD3ζ, TCRα chain, TCRβ chain, TCRγ chain, or TCRδ chain, or a combination thereof; (3) an ICD or a fragment or derivative thereof of CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3ε, CD3δ, CD3γ, CD3ζ TCRα chain, TCRβ chain, TCRγ chain, or TCRδ chain, or a combination thereof; or a combination of (1-3).

[0089] In some case, a CFP may comprise a TD, ECD, ICD, a fragment thereof, a derivative thereof, or a combination that facilitates the specific expression or cell surface expression in a B cell. In some case, a TD that facilitates specific expression or cell surface expression of a CFP within a B cell may comprise a TD or a fragment or derivative thereof of CD 19, CD20, CD21, CD22, CD27, CD28, CD45, CD72, CD79a, CD79b, or CD81, or a combination thereof. In some case, an ECD that facilitates specific expression or cell surface expression of a CFP within a B cell may comprise a TD or a fragment or derivative thereof of CD 19, CD20, CD21, CD22, CD27, CD28, CD45, CD72, CD79a, CD79b, or CD81, or a combination thereof. In some case, an ICD that facilitates specific expression or cell surface expression of a CFP within a B cell may comprise a TD or a fragment or derivative thereof of CD 19, CD20, CD21, CD22, CD27, CD28, CD45, CD72, CD79a, CD79b, or CD81, or a combination thereof. In some case, a CFP that is specifically expressed in a B cell or a cell surface thereof may comprise: (1) a TD or a fragment or derivative thereof of CD 19, CD20, CD21, CD22, CD27, CD28, CD45, CD72, CD79a, CD79b, or CD81, or a combination thereof; (2) a ECD or a fragment or derivative thereof of CD 19, CD20, CD21, CD22, CD27, CD28, CD45, CD72, CD79a, CD79b, or CD81, orWSGR Docket No. 56371-771.601a combination thereof; (3) an ICD or a fragment or derivative thereof of CD 19, CD20, CD21, CD22, CD27, CD28, CD45, CD72, CD79a, CD79b, or CD81, or a combination thereof; or a combination of (1-3).

[0090] In some cases, the TD of the CFP may comprise a TD or a fragment or derivative thereof of: CD159a, CD159c, CD16a, CD19, CD20, CD21, CD22, CD27, CD28, CD3, CD314, CD335, CD336, CD337, CD39, CD3γ, CD3δ, CD3ε, CD3ζ, CD4, CD45, CD48, CD5, CD56, CD57, CD64, CD68, CD7, CD72, CD79a, CD79b, CD8, CD81, CD89, CD94, DAP10, DAP12, Ly49D, NKG2C, NKG2D, NKG2E, NKp30, NKp44, NKp46, TCRα chain, TCRβ chain, TCRγ chain, TCRδ chain, a portion thereof, a derivative thereof, or a combination thereof.

[0091] The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD 159a. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD 159c. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD 16a. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD 19. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD20. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD21. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD22. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD27. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD28. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD3. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD314. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD335. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD336. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD337. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD39. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD3γ. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD3δ. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD3ε. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD3ζ. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD4. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD45. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD48. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD5. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD56. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD57. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD64. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD68. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD7. The TD of the CFP may comprise a TD or a fragment or derivativeWSGR Docket No. 56371-771.601thereof of CD72. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD79a. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD79b. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD8. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD81. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD89. The TD of the CFP may comprise a TD or a fragment or derivative thereof of CD94. The TD of the CFP may comprise a TD or a fragment or derivative thereof of DAP 10. The TD of the CFP may comprise a TD or a fragment or derivative thereof of DAP 12. The TD of the CFP may comprise a TD or a fragment or derivative thereof of Ly49D. The TD of the CFP may comprise a TD or a fragment or derivative thereof of NKG2C. The TD of the CFP may comprise a TD or a fragment or derivative thereof of NKG2D. The TD of the CFP may comprise a TD or a fragment or derivative thereof of NKG2E. The TD of the CFP may comprise a TD or a fragment or derivative thereof of NKp30. The TD of the CFP may comprise a TD or a fragment or derivative thereof of NKp44. The TD of the CFP may comprise a TD or a fragment or derivative thereof of NKp46. The TD of the CFP may comprise a TD or a fragment or derivative thereof of TCRa chain. The TD of the CFP may comprise a TD or a fragment or derivative thereof of TCRP chain. The TD of the CFP may comprise a TD or a fragment or derivative thereof of TCRy chain. The TD of the CFP may comprise a TD or a fragment or derivative thereof of TCRδ chain.

[0092] In some embodiments, the ECD may further comprise an extracellular domain of a receptor, a hinge, a spacer and / or a linker, as described herein. In some embodiments, the ECD of the CFP is derived from the same receptor in which the ICD or TD or intracellular signaling domain is derived from. In some embodiments, the ECD comprises an extracellular domain of a scavenger receptor. In some embodiments, the ECD comprises an immunoglobulin domain. In some embodiments, the immunoglobulin domain comprises an ECD of an immunoglobulin or an immunoglobulin hinge region. In some embodiments, the ECD comprises a phagocytic engulfment domain. In some embodiments, the ECD comprises a structure capable of multimeric assembly. In some embodiments, the ECD comprises a scaffold for multimerization.

[0093] The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD 159a. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD 159c. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD 16a. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD 19. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD20. The ECD or a fragmentWSGR Docket No. 56371-771.601or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD21. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD22. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD27. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD28. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD3. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD314. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD335. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD336. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD337. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD39. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD3γ. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD3δ. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD3ε. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD3ζ. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD4. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD45. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD48. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD5. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD56. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD57. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD64. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD68. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD7. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD72. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD79a. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD79b. The ECD or a fragment or derivative thereof of theWSGR Docket No. 56371-771.601CFP may comprise a ECD or a fragment or derivative thereof of CD8. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD81. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD89. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of CD94. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of DAP10. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of DAP12. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of Ly49D. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of NKG2C. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of NKG2D. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of NKG2E. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of NKp30. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of NKp44. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of NKp46. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of TCRα chain. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of TCRβ chain. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of TCRγ chain. The ECD or a fragment or derivative thereof of the CFP may comprise a ECD or a fragment or derivative thereof of TCRδ chain.

[0094] In some cases, the extracellular antigen binding domain comprises a receptor domain, antibody domain, wherein the antibody domain comprises a functional antibody fragment, a single chain variable fragment (scFv), a Fab, a single-domain antibody (sdAb), a nanobody, a VHdomain, a VLdomain, a VNAR domain, a VHHdomain, a bispecific antibody, a diabody, or a functional fragment or a combination thereof. In some embodiments, the extracellular antigen binding domain comprises a ligand, an extracellular domain of a receptor or an adaptor. In some embodiments, the extracellular antigen binding domain comprises a single extracellular antigen binding domain that is specific for a single antigen. In some embodiments, the extracellular antigen binding domain comprises at least two extracellular antigen binding domains, wherein each of the at least two extracellular antigen binding domains is specific for a different antigen. In some cases, the extracellular domain further comprises an extracellular domain of a receptor, a hinge, a spacer and / or a linker. In some embodiments, the extracellular domain comprises anWSGR Docket No. 56371-771.601extracellular domain of a scavenger receptor. In some embodiments, the extracellular domain comprises an immunoglobulin domain. In some embodiments, the immunoglobulin domain comprises an extracellular domain of an immunoglobulin or an immunoglobulin hinge region. In some embodiments, the extracellular domain further a hinge domain from CD8, wherein the hinge domain is operatively linked to the transmembrane domain. In some aspects, the extracellular domain comprises a hinge domain from CD8, CD28 or Siglec4, wherein the hinge domain is operatively linked to the transmembrane domain.

[0095] The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD 159a. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD 159c. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD 16a. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD 19. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD20. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD21. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD22. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD27. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD28. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD3. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD314. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD335. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD336. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD337. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD39. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD3γ. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD3δ. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD3ε. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD3ζ. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD4. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD45.WSGR Docket No. 56371-771.601The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD48. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD5. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD56. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD57. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD64. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD68. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD7. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD72. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD79a. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD79b. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD8. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD81. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD89. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of CD94. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of DAP10. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of DAP12. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of Ly49D. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of NKG2C. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of NKG2D. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of NKG2E. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of NKp30. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of NKp44. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of NKp46. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of TCRα chain. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of TCRβ chain. The ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of TCRγ chain. TheWSGR Docket No. 56371-771.601ICD or a fragment or derivative thereof of the CFP may comprise an ICD or a fragment or derivative thereof of TCRδ chain.

[0096] In some cases, the ICD of the CFP or the CFP further comprises an intracellular signaling domain. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3ζ, DAP10, DAP12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD 137, or a portion thereof, or a derivative thereof, or a combination thereof. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of Fc receptor g subunit. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of FcαR. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of FcεR. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of CD40. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of CD3ζ. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of DAP 10. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of DAP12. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of 2B4. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of NTB-A. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of CRACC. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of 41BB. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of 0X40. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of CRTAM. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of CD28. In some cases, the intracellular signaling domain may comprise an intracellular signaling domain or a fragment or derivative thereof of CD137.

[0097] In some cases, the ABD of the CFP as described herein may specifically bind to an antigen. An “antigen” can comprise a molecule capable of stimulating an immune response. Antigens recognized by T cells, whether helper T lymphocytes (T helper (TH) cells) or cytotoxic T lymphocytes (CTLs), are not recognized as intact proteins, but rather as small peptides that associate with MHC proteins (such as class I or class II MHC proteins) on the surface of cells.WSGR Docket No. 56371-771.601During the course of a naturally occurring immune response, antigens that are recognized in association with class II MHC molecules on antigen presenting cells (APCs) are acquired from outside the cell, internalized, and processed into small peptides that associate with the class II MHC molecules. In some cases, the antigen can comprise an antigen on a diseased cell. In some cases, the antigen can comprise an antigen on a neoplastic cell. The term “major histocompatibility complex (MHC),” “MHC molecule,” or “MHC protein” refers to a protein capable of binding an antigenic peptide and present the antigenic peptide to T lymphocytes. Such antigenic peptides can represent T cell epitopes. The human MHC is also called the HLA complex. Thus, the terms “human leukocyte antigen (HLA),” “HLA molecule” or “HLA protein” are used interchangeably with the terms “major histocompatibility complex (MHC),” “MHC molecule,” and “MHC protein.” HLA proteins can be classified as HLA class I or HLA class II. The structures of the proteins of the two HLA classes are very similar; however, they have very different functions. Class I HLA proteins are present on the surface of almost all cells of the body, including most tumor cells. Class I HLA proteins are loaded with antigens that usually originate from endogenous proteins or from pathogens present inside cells, and are then presented to naive or cytotoxic T-lymphocytes (CTLs). HLA class II proteins are present on antigen presenting cells (APCs), including but not limited to dendritic cells, B cells, and macrophages. They mainly present peptides which are processed from external antigen sources, e.g. outside of cells, to helper T cells.

[0098] In the HLA class II system, phagocytes such as macrophages and immature dendritic cells can take up entities by phagocytosis into phagosomes - though B cells exhibit the more general endocytosis into endosomes - which fuse with lysosomes whose acidic enzymes cleave the uptaken protein into many different peptides. Autophagy is another source of HLA class II peptides. The most studied subclass II HLA genes are: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1.

[0099] Presentation of peptides by HLA class II molecules to CD4+ helper T cells can lead to immune responses to foreign antigens. Once activated, CD4+ T cells can promote B cell differentiation and antibody production, as well as CD8+ T cell (CTL) responses. CD4+ T cells can also secrete cytokines and chemokines that activate and induce differentiation of other immune cells. HLA class II molecules are typically heterodimers of a-and P-chains that interact to form a peptide-binding groove that is more open than class I peptide-binding grooves.

[0100] HLA alleles are typically expressed in codominant fashion. For example, each person carries 2 alleles of each of the 3 class I genes, (HLA- A, HLA-B and HLA-C) and so can express six different types of class II HLA. In the class II HLA locus, each person inherits a pair of HLA-DP genes (DPA1 and DPB1, which encode a and P chains), HLA-DQ (DQA1 and DQB1,WSGR Docket No. 56371-771.601for a and P chains), one gene HLA-DRa (DRA1), and one or more genes HLA-DRP (DRB1 and DRB3, -4 or-5). HLA-DRB1, for example, has more than nearly 400 known alleles. That means that one heterozygous individual can inherit six or eight functioning class II HL A alleles: three or more from each parent. Thus, the HLA genes are highly polymorphic; many different alleles exist in the different individuals inside a population. Genes encoding HLA proteins have many possible variations, allowing each person’s immune system to react to a wide range of foreign invaders. Some HLA genes have hundreds of identified versions (alleles), each of which is given a particular number. In some embodiments, the class I HLA alleles are HLA-A*02:01, HLA-B* 14:02, HLA-A*23:01, HLA-E*01:01 (non-classical). In some embodiments, class II HLA alleles are HLA-DRB*01:01, HLA-DRB*01:02, HLA-DRB* 11:01, HLA-DRB*15:01, and HLA-DRB *07:01.

[0101] In some cases, the antigen can comprise an antigen on a cancer cell. In some cases, an antigen may comprise an epitope. The term “epitope” can refer to any protein determinant, such as a sequence or structure or amino acid residues, capable of binding to an antibody or binding fragment thereof, a T cell or B cell receptor, and / or an antibody-like molecule. Epitopic determinants typically consist of chemically active surface groups of molecules such as amino acids or sugar side chains and generally have specific three dimensional structural characteristics as well as specific charge characteristics. A “T cell epitope” can refer to peptide or peptide-MHC complex recognized by a T cell receptor.

[0102] “Specific binding” between two molecules may refer to the binding affinity between the two molecules is substantially higher than the binding affinities of any of the two molecules with any other different molecule. In some cases, the binding affinity between two molecules that are specific binding partners may have a KD of at most about: 10-6molar (M), 10-7M, 10-8M, 10-9M, 10-10M, 10-11M, 10-12M, 10-13M, 10-14M, or 10-15M. In some cases, the binding affinity between two molecules that are specific binding partners may have a KDof at least about: 10-6molar (M), 10-7M, 10-8M, 10-9M, 10-10M, 10-11M, 10-12M, 10-13M, 10-14M, or 10-15M. In some cases, the binding affinity between two molecules that are specific binding partners may be at least about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, or 10000-fold higher than that of two molecules that are not specific binding partners. In some cases, the binding affinity between two molecules that are specific binding partners may be at most about: 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 100 %, 150 %, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,WSGR Docket No. 56371-771.601100-fold, 1000-fold, or 10000-fold higher than that of two molecules that are not specific binding partners.

[0103] Provided herein are CFP that can specifically bind to an antigen present on a cancer cell. In some cases, the ABD of the CFP as disclosed herein may specifically bind at least or any one of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), PD-L1, MIC-A / B, NKG2D, EGFRvIII, EGFR, HER2, mesothelin, PSMA, TIM3, or CD30.

[0104] In some cases, the ABD of the CFP as disclosed herein may specifically bind CD 19. In some cases, the ABD of the CFP as disclosed herein may specifically bind CD20. In some cases, the ABD of the CFP as disclosed herein may specifically bind BCMA. In some cases, the ABD of the CFP as disclosed herein may specifically bind Trop-2. In some cases, the ABD of the CFP as disclosed herein may specifically bind GPC3. In some cases, the ABD of the CFP as disclosed herein may specifically bind CD30. In some cases, the ABD of the CFP as disclosed herein may specifically bind PD-L1. In some cases, the ABD of the CFP as disclosed herein may specifically bind MIC-A / B. In some cases, the ABD of the CFP as disclosed herein may specifically bind NKG2D. In some cases, the ABD of the CFP as disclosed herein may specifically bind EGFRvIII. In some cases, the ABD of the CFP as disclosed herein may specifically bind HER2. In some cases, the ABD of the CFP as disclosed herein may specifically bind mesothelin. In some cases, the ABD of the CFP as disclosed herein may specifically bind PSMA. In some cases, the ABD of the CFP as disclosed herein may specifically bind TIM3. In some cases, the ABD of the CFP as disclosed herein may specifically bind EGFR.

[0105] In some cases, the ABD of the CFP as disclosed herein may predominantly bind CD 19. In some cases, the ABD of the CFP as disclosed herein may predominantly bind CD20. In some cases, the ABD of the CFP as disclosed herein may predominantly bind BCMA. In some cases, the ABD of the CFP as disclosed herein may predominantly bind Trop-2. In some cases, the ABD of the CFP as disclosed herein may predominantly bind GPC3. In some cases, the ABD of the CFP as disclosed herein may predominantly bind CD30. In some cases, the ABD of the CFP as disclosed herein may predominantly bind PD-L1. In some cases, the ABD of the CFP as disclosed herein may predominantly bind MIC-A / B. In some cases, the ABD of the CFP as disclosed herein may predominantly bind NKG2D. In some cases, the ABD of the CFP as disclosed herein may predominantly bind EGFRvIII. In some cases, the ABD of the CFP as disclosed herein may predominantly bind HER2. In some cases, the ABD of the CFP as disclosed herein may predominantly bind mesothelin. In some cases, the ABD of the CFP as disclosed herein may predominantly bind PSMA. In some cases, the ABD of the CFP as disclosed herein may predominantly bind TIM3. In some cases, the ABD of the CFP asWSGR Docket No. 56371-771.601disclosed herein may predominantly bind EGFR. In some cases, the ABD of the CFP as disclosed herein may predominantly bind folate receptor alpha.

[0106] In some cases, the first or second ABD binds CD 19. In some embodiments, the first or second ABD binds CD20. In some embodiments, the first or second ABD binds BCMA. In some embodiments, the first ABD binds CD 19 and the second ABD binds CD20. In some embodiments, the first ABD binds CD 19 and the second ABD binds BCMA. In some embodiments, the first ABD binds CD20 and the second ABD binds BCMA. In some embodiments, the first and second ABD binds CD 19. In some embodiments, the first and second ABD binds CD20. In some embodiments, the first and second ABD binds BCMA. In some embodiments, the first or second ABD is configured to bind both BCMA and CD 19. In some embodiments, the first or second CFP comprises a sequence having at least 60%, 70%, 80% 85%, 90%, 95%, 99% or 100% sequence identity to any one sequence set forth in Table 19. In some embodiments, the first ABD binds HER2 and the second ABD binds TROP2. In some embodiments, the first ABD and the second ABD bind GPC3.

[0107] In some embodiments, the composition further comprises a sequence encoding a third CFP, wherein the third CFP comprises a third ECD comprising a third ABD and a third TD operatively linked to the third ECD; and wherein the third TD comprises a TD from a third protein capable of multimerizing with a cell surface receptor expressed by a third cell such that the third CFP is expressed on a cell surface of the third cell. In some embodiments, the third cell is a NK cell, a T cell, a B cell, a monocyte, or a macrophage. In some embodiments, the first, second, or third CFP comprises a sequence having at least 60%, 70%, 80% 85%, 90%, 95%, 99% or 100% sequence identity to a sequence presented in Table 20.

[0108] Also provided herein is a composition comprising a first nucleic acid sequence encoding a first CFP. In some embodiments, the first CFP comprises a first ECD. In some embodiments, the first ECD comprises a first ABD. In some embodiments, the first ABD is configured to bind CD 19. In some embodiments, the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell. In some embodiments, the composition comprises a second nucleic acid sequence encoding a second CFP. In some embodiments, the second CFP comprises a second ECD. In some embodiments, the second ECD comprises a second ABD. In some embodimetns, the second ABD is configured to bind CD20. In some embodiments, the second CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.WSGR Docket No. 56371-771.601

[0109] Also provided herein is a composition comprising a first nucleic acid sequence encoding a first CFP. In some embodiments, the first CFP comprises a first ECD. In some embodiments, the first ECD comprises a first ABD. In some embodiments, the first ABD is configured to bind CD 19. In some embodiments, the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell. In some embodiments, the composition comprises a second nucleic acid sequence encoding a second CFP. In some embodiments, the second CFP comprises a second ECD. In some embodiments, the second ECD comprises a second ABD. In some embodimetns, the second ABD is configured to bind BCMA. In some embodiments, the second CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

[0110] Also provided herein is a composition comprising a first nucleic acid sequence encoding a first CFP. In some embodiments, the first CFP comprises a first ECD. In some embodiments, the first ECD comprises a first ABD. In some embodiments, the first ABD is configured to bind CD20. In some embodiments, the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell. In some embodiments, the composition comprises a second nucleic acid sequence encoding a second CFP. In some embodiments, the second CFP comprises a second ECD. In some embodiments, the second ECD comprises a second ABD. In some embodimetns, the second ABD is configured to bind BCMA. In some embodiments, the second CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell

[0111] In some cases, the ABD of the CFP described herein may comprise complementarity determining (CDR) regions as described herein; an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) as described herein; an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) as described herein; an ABD that does not comprise CDRs / VH / VL sequences, or a combination thereof. In some instances, the antibodies and antigen-binding fragments disclosed herein comprise complementarity determining regions (CDRs; synonymous with “hypervariable region” or “HVR”), CDRs are known in the art to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. The CDRs ofWSGR Docket No. 56371-771.601the ABDs disclosed herein can comprise three CDRs in the heavy chain variable region (HCDR1 / CDR-H1, HCDR2 / CDR-H2, HCDR3 / CDR-H3). CDRs can also comprise three CDRs in the light chain variable region (LCDR1 / CDR-L1, LCDR2 / CDR-L2, LCDR3 / CDR-L3).

[0112] In some instances, the ABDs disclosed herein comprise further framework regions (FRs). FRs are known in the art to refer to the non-CDR portions of the variable regions of the heavy or light chains. In general, there are four FRs in the full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in the full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

[0113] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol.262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho” numbering scheme); and Whitelegg NR and Rees AR, “WAM: an improved algorithm for modelling antibodies on the WEB,” Protein Eng. 2000 Dec;13(12):819-24 (“AbM” numbering scheme. In certain embodiments, the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.

[0114] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

[0115] The term “antibody” refers to a class of proteins that are generally known as immunoglobulins, including, but not limited to IgGl, IgG2, IgG3, and IgG4), IgA (including IgAl and IgA2), IgD, IgE, IgM, and IgY, The term “antibody” includes, but is not limited to, fullWSGR Docket No. 56371-771.601length antibodies, single-chain antibodies, single domain antibodies (sdAb) and antigen-binding fragments thereof. Antigen-binding antibody fragments include, but are not limited to, Fab, Fab’ and F(ab’)2, Fd (consisting of VH and CHI), single-chain variable fragment (scFv), single-chain antibodies, disulfide-linked variable fragment (dsFv) and fragments comprising a VL and / or a VH domain. Antibodies can be from any animal origin. Antigen-binding antibody fragments, including single-chain antibodies, can comprise variable region(s) alone or in combination with tone or more of a hinge region, a CHI domain, a CH2 domain, and a CH3 domain. Also included are any combinations of variable region(s) and hinge region, CHI, CH2, and CH3 domains. Antibodies can be monoclonal, polyclonal, chimeric, humanized, and human monoclonal and polyclonal antibodies which, e.g., specifically bind an HLA-associated polypeptide or an HLA-peptide complex.

[0116] In some cases, an ABD of a CFP described herein can specifically bind CD30. In some cases, an ABD that can specifically bind the CD30 can comprise a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 4. In some cases, an ABD that can specifically bind the CD30 can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 4. In some cases, an ABD that can specifically bind the CD30 can comprise a sequence that has 100% sequence identity to a sequence listed in Table 4.

[0117] In some cases, an ABD that can specifically bind the CD30 comprises: (1) (a) a heavy chain complementarity determining region 1 (HCDR1) sequence listed in Table 4, (b) a HCDR2 sequence listed in Table 4, (c) a HCDR3 sequence listed in Table 4, (d) a light chain complementarity determining region 1 (LCDR1) sequence listed in Table 4, (e) a LCDR2 sequence listed in Table 4, and (f) a LCDR3 sequence listed in Table 4; (2) an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) sequence listed in Table 4 and / or an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) listed in Table 4; (3) a HCDR1 of a VH sequence listed in Table 4, a HCDR2 of a VH sequence listed in Table 4, a HCDR3 of a VH sequence listed in Table 4, a LCDR1 of a VL sequence listed in Table 4, a LCDR2 of a VL sequence listed in Table 4, or a LCDR3 of a VL sequence listed in Table 4; (4) any combination of (l)-(3).

[0118] In some cases, an ABD that can specifically bind the CD30 comprises an ABD of: ADCETRIS™, Anti-CD30, anti-CD30 Ki-3, anti-CD30 Ki-4, anti-CD30-A12, anti-CD30-A2,WSGR Docket No. 56371-771.601anti-CD30-A3, anti-CD30-A4, anti-CD30-A9, anti-CD30-Ber-H2, anti-CD30-CL2, anti-CD30-HeFi-1, anti-CD30-T13, anti-CD30-T14-A, anti-CD30-T14-B, anti-CD30-T24, anti-CD30-T25, anti-CD30-T427, anti-CD30-T6, Anti-human CD30 10C2, Anti-human CD30 12B1, Antihuman CD30 13H1, Anti-human CD30 15B8, Anti-human CD30 8D10, brentuximab, brentuximab vedotin, cAClO-Val-Cit-MMAE, iratumumab, itezocabtagene autoleucel, MDX-060, SGN-35, TT-11, or a combination thereof.

[0119] In some cases, an ABD of a CFP described herein can specifically bind CD 19. some cases, an ABD that can specifically bind the CD 19 can comprise a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 1. In some cases, an ABD that can specifically bind the CD 19 can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 1. In some cases, an ABD that can specifically bind the CD 19 can comprise a sequence that has 100% sequence identity to a sequence listed in Table 1.

[0120] In some cases, an ABD that can specifically bind the CD19 comprises: (1) (a) a heavy chain complementarity determining region 1 (HCDR1) sequence listed in Table 1, (b) a HCDR2 sequence listed in Table 1, (c) a HCDR3 sequence listed in Table 1, (d) a light chain complementarity determining region 1 (LCDR1) sequence listed in Table 1, (e) a LCDR2 sequence listed in Table 1, and (f) a LCDR3 sequence listed in Table 1; (2) an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) sequence listed in Table 1 and / or an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) listed in Table 1; (3) a HCDR1 of a VH sequence listed in Table 1, a HCDR2 of a VH sequence listed in Table 1, a HCDR3 of a VH sequence listed in Table 1, a LCDR1 of a VL sequence listed in Table 1, a LCDR2 of a VL sequence listed in Table 1, or a LCDR3 of a VL sequence listed in Table 1; (4) any combination of (l)-(3).

[0121] In some cases, an ABD that can specifically bind the CD 19 comprises an ABD of: 1D3-28Z, 4G7_H1.227_L1.99, acmucabtagene autoleucel, ADCT-402, AMG103, anbalcabtagene autoleucel, ant679_766_A02, ant679_766_B02, ant679_766_Cll, ant679_766_E07, ant679_766_G05, ant679_766_Gl 1, ant679_766_H01, Anti-CD19, anti-CD19-14H5, anti-CD19-14H5-DG, anti-CD19-14H5-LG, anti-CD19-14H5-YG, anti-CD19-15D1, anti-CD19-15D7, anti-CD19-16C9, anti-CD19-lA7, anti-CD19-lCl 1, anti-CD19-lH4, anti-CD19-25Cl, anti-CD19-2Bll, anti-CD19-2D10, anti-CD19-3B4, anti-CD19-3C3, anti-WSGR Docket No. 56371-771.601CD19-3C6, anti-CD 19-3D4, anti-CD19-3E5, anti-CD19-3Fl 1, anti-CD19-4G7, anti-CD19-5C11, anti-CD 19-5C4, anti-CD19-5D4, anti-CD19-6Cl 1, anti-CD19-6C2, anti-CD19-6F7, anti-CD19-7E12, anti-CD 19-9G7, anti-CD 19- Antibody #1, anti-CD19-Antibody #2, anti-CD19-B4, anti-CD19-B4 VH0 / VK0, anti-CD19-B4 VHvl / VKvl, anti-CD19-B4 VHvll / VKvll, anti-CD19-B4 VHv2 / VKv2, anti-CD19-B4 VHv3 / VKv3, anti-CD19-B4 VHv34 / VKv34, anti-CD19-B4 VHv4 / VKv4, anti-CD 19-B4 VHv5 / VKv4, anti-CD 19-B4 VHv6 / VKv4, anti-CD 19-B43, anti-CD 19-BLY3, anti-CD 19-cAl 9, anti-CD 19-FMC63, anti-CD19-GB4vl. O, anti-CD19-GB4v2.0, anti-CD19-GN901vl.0, anti-CD19-GN901vl.l, anti-CD 19-hAl 9, anti-CD19-HB12a, anti-CD19-HB12B, anti-CD19-HB12B-9M / 36, anti-CD19-HB12B-9M / 3649, anti-CD19-HB12B-9M / 364987, anti-CD19-HB12B-J4, anti-CD 19-HD37, anti-CD 19-SRB-37, anti-CD19-SRB-85, anti-CD81-hu5A6, ARI-0001, AUTO-1, Autologous T cells transduced with FMC63 scFv-28Z CAR (FMC63 scFv-CD28-CD247 (CD3Z), KTE-C19, PG13-CD19-H3, FMC63 CD28z, Axi-cel), Autologous T cells transduced with FMC63 scFv-8A-F9Z CAR (FMC63 scFv-CD8A-TNFRSF9-CD247 (CD3Z), CART 19, CTL019, tisagenlecleucel-T), Autologous T cells transduced with FMC63 scFv-G4h-28-F9Z-TpERt CAR (FMC63 scFv-IGHG4 hinge-CD28-TNFRSF9-CD247 (CD3Z)-TEApep-EGFRt, JCAR017, JCAR-017), Autologous T cells transduced with SJ25C1 scFv-28Z CAR (SJ25C1 scFv-CD28-CD247 (CD3Z), JCAR015, JCAR-015), axicabtagene ciloleucel, azercabtagene zapreleucel, belacabnagene franleucel, BITE MT-103, blinatumomab, BLINCYTO®, brexucabtagene autoleucel, BREYANZI™, bscCD19xCD3, budoprutug, CAT-41BBZ CAR T cells, CD19-4-1BBL, CD19CAT-41BBZ CAR T cells, CD19-TAC01, cemacabtagene ansegedleucel, coltuximab, coltuximab ravtansine, CRC01, CTX-110, dalucabtagene autoleucel, denintuzumab, denintuzumab mafodotin, duvortuxizumab, emfizatamab, englumafusp alfa, evoncabtagene pazurgedleucel, GNC 038, GNC038, GNC-038, hBU12(2.4)-hXR32-MP3 Ml.2, hBU12-491, huAnti-B4, inaticabtagene autoleucel, inebilizumab, inebilizumab-cdon, INI-64052781, JWCAR-029, KTE-C19, KTE-XI 9, KYMRIAH™, lisocabtagene maraleucel, loncastuximab, loncastuximab tesirine, loncastuximab tesirine-lpyl, MB-CART2019.1, MEDI-538, MEDI-551, MGD011, MONIUVI®, MOR-00208, MOR208, MOR-208, MT 103, obecabtagene autoleucel, obexelimab, Oncolysin B, anti-B4 blocked ricin immunotoxin, PBCAR-0191, plixacabtagene autoleucel, prizloncabtagene autoleucel, rapcabtagene autoleucel, RB4vl.2, RB4vl.2-SG-3249, relmacabtagene autoleucel, RES192M1.2, RG 6076, RG6076, RO7227166, RO-7227166, SAR3419, SGN-19A, SGN-CD19A, TACO 1 -CD 19, TAC-921, tafasitamab, tafasitamab-cxix, taplitumomab paptox, TBI-1501, tebrocabtagene autoleucel, TECARTUS™, TG1801, TG-1801, tinocabtagene autoleucel, tisagenlecleucel, unconjugated: huBU12, UPLIZNA®, vadacabtagene leraleucel, var-cel, vamimcabtagene autoleucel, XENP-5574, XmAb®5574, XmAb®5871,WSGR Docket No. 56371-771.601XmAb5574, XmAb-5574, XmAb5871, Xmab-CD19, XMP-5574, YESCARTA®, zamtocabtagene autoleucel, zeripatamig, ZYNLONTA™, or a combination thereof.

[0122] In some cases, an ABD of a CFP described herein can specifically bind CD20. In some cases, an ABD that can specifically bind the CD20 can comprise a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 3. In some cases, an ABD that can specifically bind the CD20 can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 3. In some cases, an ABD that can specifically bind the CD20 can comprise a sequence that has 100% sequence identity to a sequence listed in Table 3.

[0123] In some cases, an ABD that can specifically bind the CD20 comprises: (1) (a) a heavy chain complementarity determining region 1 (HCDR1) sequence listed in Table 3, (b) a HCDR2 sequence listed in Table 3, (c) a HCDR3 sequence listed in Table 3, (d) a light chain complementarity determining region 1 (LCDR1) sequence listed in Table 3, (e) a LCDR2 sequence listed in Table 3, and (f) a LCDR3 sequence listed in Table 3; (2) an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) sequence listed in Table 3 and / or an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) listed in Table 3; (3) a HCDR1 of a VH sequence listed in Table 3, a HCDR2 of a VH sequence listed in Table 3, a HCDR3 of a VH sequence listed in Table 3, a LCDR1 of a VL sequence listed in Table 3, a LCDR2 of a VL sequence listed in Table 3, or a LCDR3 of a VL sequence listed in Table 3; (4) any combination of (l)-(3).

[0124] In some cases, an ABD that can specifically bind the CD20 comprises an ABD of: 2H7, 10E3-17FGL, 10E3-17GSP, 10E3-17N, 10F2-13FGL, 10F2-13GSP, 10F2-13N, 2B7-7FGL, 2B7-7GSP, 2B7-7N, 2C11-4FGL, 2C11-4N, 3B9-10FGL, 3H7-6FGL, 3H7-6N, 5H2-17FGL, 5H2-17GSP, 5H2-17N, 6B9-4FGL, 6B9-4GSP, 6B9-4N, 6F6-1FGL, 6F6-1GSP, 6F6-1N, 7E1-13FGL, 7E1-13N, 8G6-5FGL, 8G6-5GSP, 8G6-5N, 9C11-14FGL, 9C11-14GSP, 9C11-14N, 9C3-8N, 9D4-7FGL, 9D4-7N, 9E4-20GSP, 9E4-20N, 9H4-12FGL, 9H4-12GSP, 9H4-12N, afutuzumab, AME-133v, amulirafusp alfa, anti-CD20, anti-CD20 1H4, Anti-CD20 odronextamab, anti-CD20-lF5, anti-CD20-2H7, anti-CD20-ml, anti-CD20-ml0, anti-CD20-M110B, anti-CD20-Ml 10C, anti-CD20-Ml 10G, anti-CD20-Ml 1 IB, anti-CD20-Ml 1 ID, anti-CD20-M112D, anti-CD20-Ml 12H, anti-CD20-M12H, anti-CD20-m2, anti-CD20-M210H, anti-CD20-M212E, anti-CD20-M24E, anti-CD20-M25F, anti-CD20-M27G, anti-CD20-M28C, anti-WSGR Docket No. 56371-771.601CD20-m7, anti-CD20-m9, anti-humCD20, ARZERRA®, B1R1, BCD- 132, BEXXAR®, blontuvetmab, BRIUMVI™, BTCT4465A, C2B8_H1.202_L1.113, C2B8 H1L1, CAR RN 894777-94-7, CD20-11B8, CD20-2C6, CD20-7D8, CD20-TCB (2:1), COLUMVI™, divozilimab, epcoritamab, epcoritamab-bysp, epitumomab, EPKINLY™, eramkafusp alfa, FBTA05 (anti-CD20 x anti-CD3E), lymphomun, GA101, GAZYVA®, GAZYVARO®, GEN3013, glofitamab, glofitamab-gxbm, hA20, HB-9645, HS006, HuMax-CD20®, ibritumomab tiuxetan, IDEC-C2B8, IGM 2323, IGM2323, IGM-2323, IGN002, IGN-002, IMM 0306, IMM0306, IMM-0306, IMMU-106, imvotamab, In-111 Zevalin, KESIMPTA®, LFB-R603, LUNSUMIO™, LY2469298, MABTHERA® (EU), MB-CART2019.1, mosunetuzumab, mosunetuzumab-axgb, obinutuzumab, ocaratuzumab, ocrelizumab, OCREVUS™, odronextamab, ofatumumab, plamotamab, prizloncabtagene autoleucel, REGN1979, REGN-1979, RG-6026, RG7159, RG-7828, ripertamab, RITUXAN® (US, Canada and Japan), rituximab, RO5072759, R07030816, SCT-400, technetium (99mTc) nofetumomab merpentan, TG-1101, TGTX-1101, tinocabtagene autoleucel, tositumomab, ublituximab, ublituximab-xiiy, veltuzumab, VERLUMA®, XmAb-13676, Y-90 Zevalin, zamtocabtagene autoleucel, ZEVALIN®, zuberitamab, or a combination thereof.

[0125] In some cases, an ABD of a CFP described herein can specifically bind BCMA. In some cases, an ABD that can specifically bind the BCMA can comprise a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 2. In some cases, an ABD that can specifically bind the BCMA can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 2. In some cases, an ABD that can specifically bind the BCMA can comprise a sequence that has 100% sequence identity to a sequence listed in Table 2.

[0126] In some cases, an ABD that can specifically bind the BCMA comprises: (1) (a) a heavy chain complementarity determining region 1 (HCDR1) sequence listed in Table 2, (b) a HCDR2 sequence listed in Table 2, (c) a HCDR3 sequence listed in Table 2, (d) a light chain complementarity determining region 1 (LCDR1) sequence listed in Table 2, (e) a LCDR2 sequence listed in Table 2, and (f) a LCDR3 sequence listed in Table 2; (2) an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) sequence listed in Table 2 and / or an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) listed in Table 2; (3) a HCDR1 of a VH sequence listed in Table 2, aWSGR Docket No. 56371-771.601HCDR2 of a VH sequence listed in Table 2, a HCDR3 of a VH sequence listed in Table 2, a LCDR1 of a VL sequence listed in Table 2, a LCDR2 of a VL sequence listed in Table 2, or a LCDR3 of a VL sequence listed in Table 2; (4) any combination of (l)-(3).

[0127] In some cases, an ABD that can specifically bind the BCMA comprises an ABD of: 2857916, ABBV 383, ABBV383, ABBV-383, ABECMA™, ALLO 715, ALLO715, ALLO-715, alnuctamab, AMG420, AMG-420, AMG-701, anitocabtagene autoleucel, Autologous T cells transduced with Cl 1D5.3 scFv-8A-F9Z CAR (Cl 1D5.3 scFv-CD8A-TNFRSF9-CD247 (CD3Z), bb2121, bb-2121), BCMA HLE-BiTE, belantamab, belantamab mafodotin, belantamab mafodotin-blm, BI-836909, BLENREP, BMS-986352, CARVYKTI™, CC-93269, CC-99712, cesnicabtagene autoleucel, ciltacabtagene autoleucel, CT-053, CT103A, CT-103A, CTX-120, durcabtagene autoleucel, elranatamab, elranatamab-bcmm, ELREXFIO™, EM-901, equecabtagene autoleucel, etentamig, FCARH-143, GSK2857916, HPN 217, HPN217, HPN-217, idecabtagene vicleucel, ispectamab debotansine, ispectamab tazide, J6M0, J6M0-mcMMAF, JCARH-125, JNJ-64007957, JNJ-68284528, LCAR-B38M, linvoseltamab, motacabtagene lurevgedleucel, nendocabtagene onogedleucel, orvacabtagene autoleucel, pacanalotamab, pavurutamab, PF-06863135, PF-3135, podentamig, REGN 5458, REGN5458, REGN-5458, ribrecabtagene autoleucel, SP8893, SP-8893, SP8919, teclistamab, teclistamab-cqyv, TECVAYLI™, TNB 383B, TNB383B, TNB-383B, trovocabtagene autoleucel, vonsetamig, zevorcabtagene autoleucel, J22.9-xi Fab, BCBM127, BCBM128, BCBM69, BCBM125, BCBM126, BCBM129, BCMB118, BCBM124, BCBM119, BCBM120, BCBM130, BCBM131, BCBM176, BCBM123, BCBM180, BCBM179, BCBM181, BCBM182, BCBM177, BCBM184, BCBM183, BCBM185, BCBM178, BCBM187, BCBM186, BCBM188, BCBM121, BCBM122, anti-BCMA UniAb, BCMA-1, BCMA-2, BCMA-3, BCMA-4, BCMA-5, BCMA-6, BCMA-7, BCMA-8, BCMA-9, BCMA-10, BCMA-11, BCMA-12, BCMA-13, BCMA-14, BCMA-15, BCMA-16, BCMA-17, BCMA-18, BCMA-19, BCMA-20, BCMA-21, BCMA-22, BCMA-23, BCMA-24, BCMA-25, BCMA-26, BCMA-27, BCMA-28, BCMA-29, BCMA-30, BCMA-31, BCMA-32, BCMA-33, BCMA-34, BCMA-35, BCMA-36, BCMA-37, BCMA-38, BCMA-39, BCMA-40, BCMA-41, BCMA-42, BCMA-43, BCMA-44, BCMA-45, BCMA-46, BCMA-47, BCMA-48, BCMA-49, BCMA-50, BCMA-51, BCMA-52, BCMA-53, BCMA-54, BCMA-55, BCMA-56, BCMA-57, BCMA-58, BCMA-59, BCMA-60, BCMA-61, BCMA-62, BCMA-63, BCMA-64, BCMA-65, BCMA-66, BCMA-67, BCMA-68, BCMA-69, BCMA-70, BCMA-71, BCMA-72, BCMA-73, BCMA-74, BCMA-75, BCMA-76, BCMA-77, BCMA-78, BCMA-79, BCMA-80, BCMA-81, BCMA-82, BCMA-83, BCMA-84, BCMA-85, BCMA-86, BCMA-87, BCMA-88, BCMA-89, BCMA-90, BCMA-91, BCMA-92, BCMA-93, BCMA-94, BCMA-95, BCMA-96, BCMA-97, BCMA-98, BCMA-WSGR Docket No. 56371-771.60199, BCMA-100, BCMA-101, BCMA-102, BCMA-103, BCMA-104, BCMA-105, BCMA-106, BCMA-107, BCMA-108, A7D12.2, C12A3.2, C13F12.1, chC12A3.2, chCHD5.3 A, chCHD5.3 C, C11D5.3 A, C11D5.3 B, C11D5.3 C, muCA8, huCA8 JOMO, huCA8 J0M1, huCA8 J0M2, huCA8 J1M0, huCA8 JIMI, huCA8 J1M2, huCA8 J2M0, huCA8 J2M1, huCA8 J2M2, huCA8 J3M0, huCA8 J3M1, huCA8 J3M2, huCA8 J4M0, huCA8 J4M1, huCA8 J4M2, huCA8 J5M0, huCA8 J5M1, huCA8 J5M2, huCA8 J6M1, huCA8 J6M2, huCA8 J7M0, huCA8 J7M1, huCA8 J7M2, huCA8 J8M0, huCA8 J8M1, huCA8 J8M2, huCA8 J9M0, huCA8 J9M1, huCA8 J9M2, muS307118GO3, chS307118GO3, S322110D07, S332121F02, S332126E04, S335115GO1, S335122F05, S336105A07, huS307118G03 H0L0, huS307118G03 H0L1, huS307118G03 H1L0, huS307118G03 H1L1, huS307118G03 H2L0, huS307118G03 H2L1, huS307118G03 H3L0, huS307118G03 H3L1, huS307118G03 H4L0, huS307118G03 H4L1, huS307118G03 H5L0, huS307118G03 H5L1, ET140-192, ET140-197, ET140-180, ET140-172, ET140-157, ET140-153, ET140-201, ET140-167, ET140-163, ET140-207, ET140-165, ET140-188, ET140-196, ET140-204, ET140-190, ET140-187, ET140-174, anti-BCMA-15B2WT, anti-BCMA-15B2GL, anti-BCMA-109, anti-BCMA-L15, anti-BCMA-M02, anti-BCMA-N22, anti-BCMA-P10, anti-BCMA 269A37346, anti-BCMA 269A37348, anti-BCMA 269A37917, anti-BCMA 269A37355, anti-BCMA 269A37915, anti-BCMA 269A37936, anti-BCMA 269A37953, anti-BCMA 269A37965, anti-BCMA 269A37972, anti-BCMA 269A37353, anti-BCMA 269A37948, anti-BCMA 269B005, anti-BCMA 269B023, anti-BCMA 269B024, anti-BCMA 269B028, anti-BCMA 269B030, anti-BCMA 269B038, anti-BCMA 269B059, anti-BCMA 269B069, anti-BCMA 269B074, anti-BCMA 269B076, anti-BCMA 269B079, anti-BCMA 269B083, anti-BCMA 269B085, anti-BCMA 269B093, anti-BCMA 269B094, anti-BCMA 269B104, anti-BCMA 269B109, anti-BCMA 269B110, anti-BCMA 269B113, anti-BCMA 269B126, anti-BCMA 269B129, anti-BCMA 269B131, anti-BCMA 269B135, anti-BCMA 269B136, anti-BCMA 269B139, Anti-BCMA PF-3135, or a combination thereof.

[0128] In some cases, an ABD of a CFP described herein can specifically bind Trop-2. In some cases, an ABD that can specifically bind the Trop-2 can comprise a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 6. In some cases, an ABD that can specifically bind the Trop-2 can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 6. In some cases, an ABD that can specifically bind the Trop-2 can comprise a sequence that has 100% sequence identity to a sequence listed in Table 6.WSGR Docket No. 56371-771.601

[0129] In some cases, an ABD that can specifically bind the Trop-2 comprises: (1) (a) a heavy chain complementarity determining region 1 (HCDR1) sequence listed in Table 6, (b) a HCDR2 sequence listed in Table 6, (c) a HCDR3 sequence listed in Table 6, (d) a light chain complementarity determining region 1 (LCDR1) sequence listed in Table 6, (e) a LCDR2 sequence listed in Table 6, and (f) a LCDR3 sequence listed in Table 6; (2) an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) sequence listed in Table 6 and / or an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) listed in Table 6; (3) a HCDR1 of a VH sequence listed in Table 6, a HCDR2 of a VH sequence listed in Table 6, a HCDR3 of a VH sequence listed in Table 6, a LCDR1 of a VL sequence listed in Table 6, a LCDR2 of a VL sequence listed in Table 6, or a LCDR3 of a VL sequence listed in Table 6; (4) any combination of (l)-(3).

[0130] In some cases, an ABD of a CFP described herein can specifically bind GPC. In some cases, an ABD that can specifically bind the GPC can comprise a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 5. In some cases, an ABD that can specifically bind the GPC can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 5. In some cases, an ABD that can specifically bind the GPC can comprise a sequence that has 100% sequence identity to a sequence listed in Table 5.

[0131] In some cases, an ABD that can specifically bind the GPC comprises: (1) (a) a heavy chain complementarity determining region 1 (HCDR1) sequence listed in Table 5, (b) a HCDR2 sequence listed in Table 5, (c) a HCDR3 sequence listed in Table 5, (d) a light chain complementarity determining region 1 (LCDR1) sequence listed in Table 5, (e) a LCDR2 sequence listed in Table 5, and (f) a LCDR3 sequence listed in Table 5; (2) an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a heavy chain variable region (VH) sequence listed in Table 5 and / or an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% sequence identity to a light chain variable region (VL) listed in Table 5; (3) a HCDR1 of a VH sequence listed in Table 5, a HCDR2 of a VH sequence listed in Table 5, a HCDR3 of a VH sequence listed in Table 5, a LCDR1 of a VL sequence listed in Table 5, a LCDR2 of a VL sequence listed in Table 5, or a LCDR3 of a VL sequence listed in Table 5; (4) any combination of (l)-(3).WSGR Docket No. 56371-771.601

[0132] In some cases, an ABD that can comprise any ABD that can bind to the antigen described herein, such as those described in: Manso et al., Front Immunol. 2023 May 5:14:1129323.; Manso et al., Nucleic Acids Res. 2022 Jan 7;50(Dl): D1262-D1272; and Lima et al., Nucleic Acids Res. 2020 Jan 8;48(D1): D261-D264., each of which is herein incorporated by reference in its entirety.

[0133] In some cases, the CFP may have at least about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 1000, 2000 or more amino acids. In some cases, the CFP may have at most about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 1000, or 2000 amino acids.

[0134] In some cases, the TD of the CFP may have at least about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167,WSGR Docket No. 56371-771.601168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 1000, or more amino acids. In some cases, the TD of the CFP may have at most about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, or 1000 amino acids.

[0135] In some cases, the ECD of the CFP may have at least about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 1000, or more amino acids. In some cases, the ECD of the CFP may have at most about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,WSGR Docket No. 56371-771.601188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, or 1000 amino acids.

[0136] In some cases, the ICD of the CFP may have at least about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 1000, or more amino acids. In some cases, the ICD of the CFP may have at most about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, or 1000 amino acids.

[0137] In some cases, the intracellular signaling domain of the CFP may have at least about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500,WSGR Docket No. 56371-771.6011000, or more amino acids. In some cases, the intracellular signaling domain of the CFP may have at most about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, or 1000 amino acids.

[0138] In some cases, the ABD of the CFP may have at least about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 1000, or more amino acids. In some cases, the ABD of the CFP may have at most about: 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, 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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, or 1000 amino acids.WSGR Docket No. 56371-771.601Exemplary ABD

[0139] In some cases, the ABD of a CFP described herein can comprise any antigen binder as described in any of Tables 1-6. When listing or disclosing one particular binder or type of sequence, the particular binder or type of sequence may be used an a non-limiting and apply to other binders with similar protein domain organization, binding site structure, bind sequence arrangement, or constituent, as described in Tables 1-6 and elsewhere in this disclosure.

[0140] In some cases, the ABD of an antigen binder may comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCD3 (see for example, CD19 binder #1). When referring to a particular CDR sequence listed in Tables 1-6, the CDR sequence can comprise a sequence that has: (1) at least: 1, 2, 3, 4 or more mutations relative to that particular CDR sequence; (2) a sequence that has at most: 1, 2, 3, or 4 more mutations relative that particular CDR sequence; (3) a sequence that has 100% sequence identity to that particular CDR sequence; (4) any combinations of (l)-(3).

[0141] In some cases, the ABD of an antigen binder may comprise VH and VL (see for example, CD19 binder #1). When referring to a particular VH (or VL) sequence listed in Tables 1-6, the VH (or VL) sequence can comprise a sequence that has: (1) at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to that particular VH (or VL) sequence; (2) a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to VH (or VL) sequence; (3) a sequence that has 100% sequence identity to VH (or VL) sequence; (4) any combinations of (l)-(3). In some cases, the ABD of an antigen binder may not comprise a VH sequence but not a VL sequence (or vice versa; see for example, BCMA binder #10). In some cases, the ABD of an antigen binder may not comprise HCDR sequences but not LCDR sequences (or vice versa; see for example, BCMA binder #10). In some cases, the ABD of an antigen binder may not comprise VH, VL, or CDR sequences (see for example, BCMA binder #13).

[0142] As disclosed herein, any combination of the TD, ECD, ICD, intracellular signaling domain, hinge, spacer, ABD, linkers, additional polypeptide sequences; or the sequences thereof, of a CFP, can comprise those as described herein. In some cases, the methods for assaying the expression or functional characteristics of the CFPs are disclosed elsewhere in this disclosure, such as in Examples 1-7. In some cases, the expression or functional characteristics resulting the inclusion or exclusion of a domain or sequence can also be assayed using the methods disclosed elsewhere in this disclosure, such as Examples 5-6. Accordingly, provided herein are CFPs having the domain(s), sequence(s), or any combinations thereof using theWSGR Docket No. 56371-771.601disclosure provide herein. Any particular CFP of those described herein can be identified using the disclosure and examples as described herein.Engineered cytokine receptors

[0143] Provided herein are modified cytokine receptors. In some embodiments, the modified cytokine receptor comprises an extracellular binding domain of a first cytokine receptor and an intracellular signaling domain of a second cytokine receptor, wherein the modified cytokine receptor comprising the extracellular binding domain of the first cytokine receptor and the intracellular signaling domain of the second cytokine receptor does not exist naturally. In some embodiments, the first cytokine receptor is a proinflammatory cytokine receptor. In some embodiments, the first cytokine receptor is an anti-inflammatory cytokine receptor. In some embodiments, the second cytokine receptor is a proinflammatory cytokine receptor. In some embodiments, the second cytokine receptor is an anti-inflammatory cytokine receptor. In some embodiments, the first cytokine receptor is a proinflammatory cytokine receptor and the second cytokine receptor is an anti-inflammatory cytokine receptor. In some embodiments, the first cytokine receptor is an anti-inflammatory cytokine receptor and the second cytokine receptor is a proinflammatory cytokine receptor. In some embodiments, the anti-inflammatory cytokine receptor is selected from the group consisting of an IL10RA, TGFβRII, TGFβRI, IFNGR1, and IL17RA. In some embodiments, the proinflammatory cytokine receptor is selected from the group consisting of IFNλR1, IFNAR1, IFNAR2, IL10RA, CD30, IL28R, TREM2, MerTK, and CSF3R. In some embodiments, the intracellular domain is derived from a receptor selected from the group consisting of TGF-βRI, TGF-βRII, PDGFR, CD4, CD8, CD28, CD127, CD132, CD3z, 4-IBB, 0X40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, IL-5R, IL-7R, IL-7Ra, and BTLA. In some embodiments, the intracellular domain is from CD40. In some embodiments, the intracellular domain is from MyD88. In some embodiments, the first cytokine receptor is associated with an Ml phenotype. In some embodiments, the first cytokine receptor is associated with an M2 phenotype. In some embodiments, the second cytokine receptor is associated with an Ml phenotype. In some embodiments, the second cytokine receptor is associated with an M2 phenotype.

[0144] In some cases, the engineered cytokine receptor may comprise an ECD. The ECD may comprise an ABD. The ABD or ECD of an engineered cytokine receptor may bind a cytokine. The ABD or ECD of an engineered cytokine receptor may bind a pro-inflammatory cytokine. The ABD or ECD of an engineered cytokine receptor may bind an anti-inflammatory cytokine. In some cases, the engineered cytokine receptor may comprise an ICD. The ICD may comprise an intracellular signaling domain.WSGR Docket No. 56371-771.601

[0145] In some embodiments, a cell expressing any one of the CFP constructs described herein is engineered to express a modified cytokine receptor disclosed herein. In some embodiments, a cell expressing any one of the modified cytokine receptors described herein is engineered to express any one of the CFP constructs disclosed herein. In some embodiments, one or more nucleic acids encoding (1) any one of the CFP constructs described herein and (2) a modified cytokine receptor disclosed herein are expressed in a cell.

[0146] Exemplary cytokine receptor domain sequences are provided in Tables 7-10. In some embodiments, the modified cytokine receptor comprises one or more of the sequences selected from the sequences provided in Tables 7-10. In some embodiments, the modified cytokine receptor comprises one or more sequences having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to one or more sequences selected from the sequences provided in Tables 7-10. In some embodiments, cytokine receptor domains are operably linked by a GSS linker sequence. In some embodiments, the modified cytokine receptor comprises a P2A cleavage site. In some embodiments, the P2A cleavage site comprises a sequence having at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to ATNFSLLKQAGDVEENPGP (SEQ ID NO: 520).

[0147] In some embodiments, a cell expressing any one of the CFP constructs described herein is engineered to express a modified cytokine receptor disclosed herein. In some embodiments, a cell expressing any one of the modified cytokine receptors described herein is engineered to express any one of the CFP constructs disclosed herein. In some embodiments, one or more nucleic acids encoding (1) any one of the CFP constructs described herein and (2) a modified cytokine receptor disclosed herein are expressed in a cell.

[0148] The engineered cell surface receptor may also comprise those that are described in International Patent Application Nos. PCT / EP2023 / 087043 and PCT / US2023 / 026348, each of which is herein incorporated by reference in its entirety.Engineered cell surface receptors

[0149] Provided herein, are engineered cell surface receptors. A ’’cell surface receptor” refers to a receptor that is present on a cell surface of a cell. A “receptor” can comprise a chemical structure composed of a polypeptide, which transduces a signal, such as a polypeptide that transduces an extracellular signal to a cell. A receptor can serve to transmit information in a cell, a cell formation or an organism. A receptor can comprise at least one receptor unit and can contain two or more receptor units, where each receptor unit comprises a protein molecule, e.g.,WSGR Docket No. 56371-771.601a glycoprotein molecule. A receptor can contain a structure that binds to a ligand and can form a complex with the ligand. Signaling information can be transmitted by a conformational change of the receptor following binding with the ligand on the surface of a cell.

[0150] In some cases, the engineered receptors disclosed herein can modulate an immune signaling pathway. In some cases, the engineered receptors disclosed herein can inhibit an immune signaling pathway. In some cases, the engineered receptor can modulate TGF-beta (TGF-b) signaling pathway. In some cases, an engineered receptor can inhibit TGF-beta signaling pathway. In some cases, the engineered receptor may comprise a dominant negative form of the TGF-beta signaling pathway. In some case, an engineered receptor may inhibit a type 1 TGF-beta receptor-mediated signaling pathway, type 2 TGF-beta receptor-mediated signaling pathway, type 3 TGF-beta receptor-mediated signaling pathway, type 4 TGF-beta receptor-mediated signaling pathway, or a combination thereof. In some case, an engineered receptor may inhibit a type 1 TGF-beta receptor-mediated signaling pathway. In some case, an engineered receptor may inhibit a type 2 TGF-beta receptor-mediated signaling pathway. In some case, an engineered receptor may inhibit a type 3 TGF-beta receptor-mediated signaling pathway. In some case, an engineered receptor may inhibit a type 4 TGF-beta receptor-mediated signaling pathway.

[0151] In some cases, the engineered receptor may comprise a dominant negative form of the TGF-beta receptor (DN TGF-b R). In some cases, the engineered receptor may comprise a dominant negative form of the type 1 TGF-beta receptor (TGF-b Rl), type 2 TGF-beta receptor (TGF-b R2), type 3 TGF-beta receptor (TGF-b R3), type 4 TGF-beta receptor (TGF-b R4), or a combination thereof. In some cases, the engineered receptor may comprise a dominant negative form of the type 1 TGF-beta receptor. In some cases, the engineered receptor may comprise a dominant negative form of the type 2 TGF-beta receptor. In some cases, the engineered receptor may comprise a dominant negative form of the type 3 TGF-beta receptor. In some cases, the engineered receptor may comprise a dominant negative form of the type 4 TGF-beta receptor. A type 2 TGF-beta receptor may comprise ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, ALK7, or a combination thereof. A type 2 TGF-beta receptor may comprise TGFPR2, BMPR2, ACVR2A, ACVR2B, AMHR2, or a combination thereof. A type 3 TGF-beta receptor may comprise TGFPR3.

[0152] In some cases, the engineered cell surface receptor may comprise a truncation or mutation that results in an inhibition of the signaling pathway. In some cases, the truncation or mutation of a TGF-b R can suppress or reduce phosphorylation such that it results in a nonfunctional TGF-b signaling pathway. In some cases, the DN TGF-beta may lack one or more amino acid residues responsible for signaling and phosphorylation and results in a non-WSGR Docket No. 56371-771.601functional signaling pathway as compared to the wild-type receptor. In some cases, the DN TGF-b R may be truncated before the threonine N-terminal to the intracellular domain. In some embodiments, the DN TGF-b R may not have an intracellular domain. In some cases, the DN TGF-b R may be modified to replace the intracellular domain with an exogenous sequence that does not include amino acid residues involved in phosphorylation signaling. In some cases, the DN TGF-b R is truncated or mutated to reduce phosphorylation activity as compared to the WT TGF-b R. In some cases, the DN TGF-b R is truncated or mutated to have lower phosphorylation signaling molecules from interacting with pSMAD molecules, as compared to that of the WT TGF-b R. In some cases, the DN TGF-b R can be engineered to remove or mutate the amino acids involved in phosphorylation signaling of the intracellular domain of the WT TGF-b R.

[0153] Provided herein are DN TGF-b R2. In some cases, WT TGF-b R2 (the sequence is depicted in SEQ ID NO: 433) can comprise a signal peptide (amino acids 1-22), an extracellular domain (amino acids 33-170), a transmembrane domain (amino acids 171-201) and an intracellular domain (amino acids 202-567). In some cases, the engineered cell surface receptor may comprise a truncation or mutation that results in an inhibition of the signaling pathway. In some cases, the truncation or mutation of a TGF-b R2 can suppress or reduce phosphorylation such that it results in a non-functional TGF-b signaling pathway. In some cases, the DN TGF-beta may lack one or more amino acid residues responsible for signaling and phosphorylation and results in a non-functional signaling pathway as compared to the wild-type receptor. In some cases, the DN TGF-b R2 may be truncated before the threonine N-terminal to the intracellular domain. In some cases, the DN TGF-b R2 may not have an intracellular domain. In some cases, the DN TGF-b R2 may be modified to replace the intracellular domain with an exogenous sequence that does not include amino acid residues involved in phosphorylation signaling. In some cases, the DN TGF-b R2 is truncated or mutated to reduce phosphorylation activity as compared to the WT TGF-b R2. In some cases, the DN TGF-b R2 is truncated or mutated to have lower phosphorylation signaling molecules from interacting with pSMAD molecules, as compared to that of the WT TGF-b R2. In some cases, the DN TGF-b R2 can be engineered to remove or mutate the amino acids involved in phosphorylation signaling of the intracellular domain of the WT TGF-b R2. In some cases, an engineered TGF-b R (deriving from a first type of TGF-b R) may be engineered to interact with another engineered or WT TGF-b R (deriving from a second type of TGF-b R), wherein the first and second TGF-Rs are different types of TGF-b R. Such engineering may facilitate the inhibition of the first (or second or both) TGF-b signaling pathways.WSGR Docket No. 56371-771.601

[0154] In some cases, the DN TGF-b R2 may have a WT TGF-b R2 extracellular ligand binding domain couple to one or more heterologous polypeptide sequences. In some cases, the extracellular domain of the DN TGF-b R2 may be engineered to specifically bind to the target TGF-b molecule in order to initiate oligomerization of the complex of DN TGF-b R2 with a non-WT TGF-b R2. In some cases, the binding of DN TGF-b R2 to all TGF-b R (TGF-b Rl-R4). In some cases, the DN TGF-b R2 may be engineered to bind TGF-b Rl, TGF-b R2, TGF-b R3 and / or TGF-b R4. In some cases, the DN TGF-b R2 binds TGF-b 1.

[0155] In some cases, the DN TGF-b R2 comprises an extracellular ligand-binding domain fused to a TD. In some cases, the TD is a heterologous transmembrane domain or a fragment thereof; or the TD of WT TGF-b R2 or a fragment thereof. The TD of the DN TGF-b R2 can comprise a hydrophobic alpha helix that spans at least a portion of the membrane and assists in anchoring the DN TGF-b R2 to the membrane and facilitates dimerization of the DN TGF-b R2 construct. The TD of the DN TGF-b R2 may be designed such that after TGF-b binding, no intracellular signal is transmitted in the cell via the DN TGF-b R2 to WT or engineered TGF-b Rl. In some cases, the DN TGF-b R2 may comprises a heterologous extracellular ligand binding domain. In some cases, the TD of DN TGF-b R2 may interact with wild-type or engineered TGF-b Rl. In some cases, the TD of DN TGF-b R2 may inhibit the pSMAD signal transduction. In some cases, the TD of the DN TGF-b R2 may also stimulate beneficial cytokine expression and signaling while suppressing pSMAD signal transduction. In some cases, the TD of the DN TGF-b R2 may be derived from any another polypeptide expressed in an immune cell or precursor cell thereof, having a TD, including any TDs disclosed herein. In some cases, the TD may be derived from a polypeptide that is either naturally or not naturally expressed in a T cell. In some cases, the DN TGF-b R2 may have a TD or a fragment of TGF-b Rl, TGF-b R2, PDGFR, CD4, CD8, CD28, CD127, CD132, CD3z, 4-IBB, 0X40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, IL-5, IL-7, IL-7Ra, BTLA or a combination thereof. In some cases, the TD of the TGF-b R2 may have a WT or mutant IL-7Ra TD. In some cases, the TD of the TGF-b R2 may have a WT IL-7Ra TD having an amino acid insertion of “CPT.”

[0156] In some cases, the engineered cell surface receptor may not have an ICD or a truncated ICD. In some cases, the ECD of the DN TGF-b R2 may have a ECD or a fragment of TGF-b Rl, TGF-b R2, PDGFR, CD4, CD8, CD28, CD127, CD132, CD3z, 4-IBB, 0X40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, IL-5, IL-7, IL-7Ra, BTLA, or a combination thereof. In some cases, the DN TGF-b R2 can comprise an ECD, a TD, and an ICD intracellular domain.

[0157] In some cases, the cell surface receptor can comprise a sequence that has at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or more sequence identity to a sequence listed in Table 11. In some cases, theWSGR Docket No. 56371-771.601engineered cytokine receptor can comprise a sequence that has at most about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% sequence identity to a sequence listed in Table 11. In some cases, the engineered cell surface receptor can comprise a sequence that has 100% sequence identity to a sequence listed in Table 11.

[0158] In some cases, the engineered cell surface receptor may comprise a signal peptide as described herein. The TGF-b R2 may comprise a N-terminal signal peptide. In some cases, the engineered cell surface receptor may comprise a heterologous signal peptide. The ECD of a DN TGF-b R2 may be coupled to a leader or a signal peptide that directs the nascent protein into the endoplasmic reticulum and subsequent translocation to the cell surface. The signal peptide may comprise Colony Stimulating Factor 2 Receptor Alpha subunit (CSF2Ra) signal peptide.

[0159] Exemplary sequences of the engineered cell surface receptor is disclosed elsewhere in this disclosure.

[0160] The engineered cell surface receptor may also comprise those that are described in International Patent Application No. PCT / US2020 / 070157; Böttinger et al., EMBO J. 1997 May 15;16(10):2621-33.; and Li et al., Biomed Pharmacother. 2022 Apr: 148: 112754., each of which is herein incorporated by reference in its entirety.BiTE

[0161] Provided herein, are BiTEs. In some embodiments, an “engager” can bind to a target antigen on a cell or a diseased cell with a target binder domain, located for example, at one end of the protein; and is capable of binding to an effector cell such as an immune effector cell. The effector cell can comprise myeloid cell. The effector cell can comprise T cell. The effector cell can comprise NK cell, monocyte, T cell, B cell, or a combination thereof. A BiTE can comprise at least two engager moieties (such as ABDs, fragments or derivatives thereof) that each can specifically bind to one target antigen. In some cases, the BiTE can specifically bind at least two target antigens.

[0162] In some embodiments, the first engager moiety of the BiTE may specifically bind a first antigen (Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), PD-L1, MIC-A / B, NKG2D, EGFRvIII, HER2, mesothelin, PSMA, TIM3, or CD30) on a diseased or a cancer cell, and wherein the second engager moiety of the BiTE may specifically bind a surface molecule on a T cell (such as CD3 or CD3 epsilon). Thus, the BiTE can couple the diseased or cancer cell to a cytotoxic T cell such that the cytotoxic T cell can exert cytotoxic activity on the coupled diseased or cancer cell.WSGR Docket No. 56371-771.601

[0163] The engager moiety of the BiTE can comprise any ABD as described herein. In some embodiment, an engager moiety described herein may be an antigen -binding fragment (Fab), a single-chain variable fragment (scFv), a nanobody, a VHdomain, a VLdomain, a single domain antibody (sdAb), a VNAR domain, and a VHHdomain, a bispecific antibody, a diabody, or a functional fragment of any thereof.

[0164] In some embodiments, the BiTE described herein may comprise a first engager moiety. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind at least or any one of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), PD-L1, MIC-A / B, NKG2D, EGFRvIII, HER2, mesothelin, PSMA, TIM3. or CD30. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind CD19. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind CD20. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind BCMA. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind Trop-2. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind GPC3. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind CD30. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind PD-L1. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind MIC-A / B. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind NKG2D. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind EGFRvIII. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind HER2. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind mesothelin. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind PSMA. In some cases, the first engager moiety of the BiTE as disclosed herein may specifically bind TIM3. In some embodiments, the BiTE described herein may comprise a second engager moiety. The second engager moiety of the BiTE may specifically bind CD3γ, CD3δ, CD3ε, CD3ζ, or a combination thereof. The second engager moiety of the BiTE may specifically bind CD3γ. The second engager moiety of the BiTE may specifically bind CD3δ. The second engager moiety of the BiTE may specifically bind CD3ε. The second engager moiety of the BiTE may specifically bind CD3ζ

[0165] The linker of the BiTE may comprise a XTEN linker. The XTEN linker may be configured to block the engager moiety from specifically bind to its target antigen. The BiTE may further comprise a nuclease cleavage such that the XTEN linker portion of the BiTE can be removed from the BiTE upon nuclease cleavage. In some cases, when the BiTE is exposedWSGR Docket No. 56371-771.601within the TME or contact a diseased or cancer cell, the TME or diseased cell or cancer cell may comprise or release a nuclease that can cleave the nuclease cleavage site so that the engager moiety can specifically bind the target antigen of the diseased or cancer cell as described herein. The configuration of the XTEN linker or any portion of BiTE described herein or the nuclease cleavage site can comprise those described in Cattaruzza et al., Nat Cancer. 2023 Apr;4(4):485-501, which is incorporated by reference herein in its entirety.

[0166] In some cases, the XTEN may have at least 12 amino acids, 24 amino acids, 36 amino acids or at most about 3000 amino acid residues. The XTEN linker may comprise glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues. The G, A, S, T, E, or P residues of the XTEN linker may constitute more than about: 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total amino acid residues of the XTEN. In some cases, the XTEN sequence may be substantially non-repetitive such that (i) the XTEN sequence may contain no three contiguous amino acids that are identical unless the amino acids are serine, (ii) at least about 80%, or about 90%, or about 95% of the XTEN sequence may comprise or consist of nonoverlapping sequence motifs, (iii) each of the sequence motifs many comprise about 9 to about 14 amino acid residues, wherein any two contiguous amino acid residues does not occur more than twice in each of the sequence motifs; (iv) the XTEN sequence may have a subsequence score of less than 10; or (v) a combination of (i)-(iv). In some cases, the XTEN sequence may have greater than 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or greater than 99% random coil formation as determined by GOR algorithm. In some cases, the XTEN sequence may have less than 2%, or 3%, or 4%, or 5% alpha helices. In some cases, the XTEN sequence may have less than 2%, or 3%, or 4%, or 5% beta-sheets as determined by Chou-Fasman algorithm. In some cases, the XTEN sequence may not have a predicted T-cell epitope when analyzed by TEPITOPE algorithm, wherein the TEPITOPE algorithm prediction for epitopes within the XTEN sequence is based on a score of - 8, or -9, or -10. In some cases, the XTEN may comprise a sequence having at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or 100% sequence identity to a sequence selected from the group consisting of the sequences set forth in Table 14-1 to Table 14-15 below:WSGR Docket No. 56371-771.601Table 14-1 to 14-15: Exemplary XTEN linkerTable 14-1XTFVXi M i > MX v <\p: x? I H > MM x x 5 P PM AS < M I* s i si <xi I F \!> '"XI -? I ' I PM 4 H XIX >sF XM AM S 1 1 1 1 A M X X I IX # six sM r x I [ M ■*(rV -M'i S n U M HN-i I XH \J ’Al ■ -4 * i i SPA'S XX I i i A A < I i* I A XsyMX t':-'''-. I A<>( < X i'< < XP( A’M A* iXM'J ’ S SS M A MNXl AX XI \H’ MsSFI Vt H A fs lSl s'l' sSsXPi iv-A PXi s X A >i-AX s XSih M Ss M A<W ' M hi PX4 sSp | h'M h <?-. Hi!:v hiM^M IhiP H M'SiWWs ^iAXI M ' { ^ P ’S S M. M 'Fi AM x X J PI UWyArhH b. KH FsFisS X FISsi 4’ \ i si A? i is >\i r x i M PA I IX A A1M M, V I ps A X: i PM c six *, x> \ \ i FPS, I sth ssl P X FM iM I p4 s7 X 1 I'PsIX rS XF i XI X 4: X sF XS > X? fx H UfTSM 'i PPI %(. W s- I " Fl I PM i A %F( M HP I X M I I A V A F'si < H XF I ( A h l? PM i A X A A Xi s A I Pi M?A > M i> X I SI - V i'IS < M F X I M Hi I IX <> F M < M’ I X i I > I MTMH XTPI'SHPMTS'M 'FM X H XPh I X? A? x ’ MA i M bxXh^Kf fXPKtH iAS n N S^ Shf lxV PM S A XA A M x XTI'IHisF h | A | > MA I H X>'S M SI m p| ^ih. XJ F X Pii. M A A \L' AKA XH - A H FM-X. X X4IX A M S X I PI Xis A A Si S< X 11'1 h< AS sXI sM?<!• ',’h H PM i A XIXAPXS APHU I MS I! FM (»S X|S AMI Psi Ms XIX A A s X I PPM sP b l Xll PM S A X'A A M S X i l’l M«I\A I' X ISMM ' P* AM > PM (A XA A X 1 1 PM MS X _ _(A Si PP.xi < A XPs A S 11 PM i As MX s I h 1 1 PSI «, sS XIX A M: PsPMS A A A S A PMX A X IX AP XMMM M; M A S A< IM G'X MMXI 'M * M’M?M’I M I I (AM S X I PS Sl AXAPP X HAM ( A A M '^ x i S! s^piA M I PSH sS XP l(All PSI i xh X A A X I I PSo t A XA A X 11 Psi < XPi A M i FA (sx X A A " A I PM'f, S X PMM' XiA-Pi x' > M 1 - X TM x X T PI MASAI P X INAM IMA M S X I P! F X l SirA iPx Asi S X I PhA P’(A M I PM s A XM < I M s X I Pi M AS4 > sP Xi < xF I M I I « *sP Xs, xp I M I M < M'M >sP I S 11 I%M A >1 \ X I P! Si PS A S M FA s PX XPAXI A I'i ' M(S X t PI M AX,si F X IM PS ilSASI SSA PI Xi 'lX fSI P X I S4 AI MS A s! s x A'l M fF A I x i F I'M i > S XI'S A SI "> 'X I Fl M AX <sp M, SIM s i? 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XX i F'"-s s X M ssp4; Ss I PS4 < X M < SIS <sS I Fix Xx M A I AS <sspx XM 4 A * AM XMM I As 11fMX M IX < M » I XxxXI’X <ss I pMsX 14(MSfI>SVPS SsIX AMP* <sxPx XS T(. T< AX, XxPXn ' A: ’ Pi shxFx SPAS' Al Ax HSPS X AM?T» fTP* s SX sT X sSMX > WPxi;XTi <sF| sssps X’STl > T (AS; SSI’S; I sS II -Sf'X 1 1 FlfSI A XSVAM’SX I FSi; X A APS A ISsSh I SSSMh? X AX A SXs'A?SFi I X Ph,fI sh A?MX A Fl HIfT XSSSXi i < 4 X Is XSlX A SM l sSlX; SXPh MX M A i AX sWFP- XS Ml s lx six s I IS $si; I XisMAX »XX Mi,S< s X 11 - S A >s M’s Xs I i « AX » X MS I XX ■' i sxFI FIX sM > I XMAIX ssS I Psi < X I ( < M'X < I IS <'M < I XsSsPi « XSI X A xs I < PAS s, SSP( » F Sslt,sPWSGR Docket No. 56371-771.601Table 14-2x^FS.WFI XSBI.'Xi s l>: 4 I A < Xi > > S{'-X\A < XX > l>\4 X A \A i '-, x$\. I x>- ' i > XA V 4 F < xx XA > XX {i’Xt. 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X' *A >A t A A V JX XSA A? M AAF h 4A i' xs >Xhi xx i SSVx IM VAi, ' XA S i xl XhA A XA A xAViJ xx 3 SAixFV xPvA XA < SF xi xAxM XAA xAS-hi xh AXA i x Fxl < f S A ix Ki xAxi h XA A K5 V5V A XA Ax ' AF Shx XxAhA xI x As A X Af(xH'i XA; l X Xxh iX l xM XWX < A x J xS S X^ xA 'A S x ^ A Shx XxA A AX M A XSA > X. xl XA<;; F. l SA i A<? A Sh x XXA A x'US xhx XxA iS l xS V<xh? XA x A-S Xl’Ss? xA s^ xASF' i: M sI XA ATxxT V xA iM / FxTA SAX X XA ITXT A XA X XXA A'FM xFAAT XA sXlSK i I AM < 1 X A J I X f A: x41 x XxA i'x i M x^M < i XIX5x I x| V’M A X A 1 1 X, A x» <x X’xA < S xAx i A XX’ X A sxl XX W xA ASf| X|’x< si xx? XI'S A ’ Sx I XI SA i A A X I A x<. iX XxA «x Fx | ' I U’xS I XI’XFA'ii s Xxl XS AM s iAA iShi sI PS; M w AxI X(>xxA iOA <xxl St sxxA iAA <xx| xs Ax| A i: 4 Asxxl XAxx < sX iA 'Sxl xi iXX i << iA >' xA iAX^X A| Si AH I XM SA II XXS sXX xAxM i j441 A sxx? XF < XSI S t< i A sXxJ XF tSSI i. iF i A sSF 'S?l I’SI V 1XS$ si x A X sXx4 »\F X4 yl xA shWSGR Docket No. 56371-771.601Table 14-3’‘.iiGsw W M.'G’Sts Site'M 'SS M V A Vs xt S-AMPM M xSS i ii I’T 'W {‘-j? P$i yy‘^ y ( AX 4 siX ' i X M <4 " IS s4 A Xi s'xi M > ■>'< ■■< si $”>4 G < V-s, --.s.4 jj A $ Si f Al sXi s’ si i’Xi M A Xi 1'1'w '" i sVl Gi siVi xlVAxSi Al M S! Si X4 il xl St st x( sl y A xi sM xt. Sxi SS. XX ( ii sIVxt sV I’xi M AG i GSVx 4 st si F G 'G AM iSxi G GAI < si 8 Pt s XS 8* s ' IMS xt A G s ' '-<ps s< sXXS s''xi H ' I xlX ii '- ■> xs tXl S S AG X( AG 4.( sH A( > G; I’M M Wxx M -Al V A. M G i’x| M A'S* M < <4 i’-y M s xM < S X A '* sXX< >x| M AS < <xxt si's <1 xx<. Sxt xs AM'I < V A> X tXM PX <| xx M '. y. 4 Ap v <x|’i x i | M G M X ’-G Pi XS tPH ix I I PM S AA A AF V »SI* I x Is’ S 4 s I X 21 Pxl *' sX \IV I ” 14 SA* V S’* xs s*X sxS? \ SS S IX A! 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PS s S x i l I’xS * 'x xsx xl’ M sM’ IM I M M V S S’--” t s^ vx," M I i’Xi 4 < X XH ' s M x X S FS M six < SS S’A S 'x?,x| I SX S’ X I M < M I SX s’xi'Af s xl' S S I A 4 < F x| x X. t i'i Xi six 8 l x I S I’M S s'x XlX > s 'x l i l‘x| 4 sX X X (Xi’ Xi iM’ l -s i s i S s I X i I I’X’ 4sx X M I x l i '< X| < v MX M H S X I l”l V sSX s 2 X S I I’X; 4,sx MX. | M \ \ * PW sIX s M S’ X W AS I S’S s s 21 S'"xi 4 < X Xix M X s s S’ M 4 s'- X |X S X' -■ X I S’S x4sSX s I xl 'x ’s I S’S Xi >4 X. X*’ M. Xi” 'x 41 S 4. S X X 1 4'4 Xi sSX sXl p X i 'xt s\. S 1 1’4 s I M -X X S 1’4 Xi 'SX? X 4 S i’M 4 s'; XS‘4 s ' X 11 I’X' If'x MXf' 'x S I PSS GX XSX s I X 11 F’xl 4sx XM.: x I s S'M (,x X S'x; S X s S PSS s s'x XS’S S xP \( sXFI X M I t. F x 1 FPM iS-X XPi GM 'X XT PI G -< S F ’s'* M Al M’s s7 V x s. IPS ’xt s Pi A' F’ X I G -G TlxfI >1 V PS XS sH < i v S I’M s sx ’i A ' S xs y X | G X< GX sxIMF sXP s S ' I Msxl”s4 AP M I I _ S AS’ M sxS’l x i S'S H I M:x M S’S xs tIX s Sx | S S’M S t” V’ _MM Sts S sVG XS sXSI 4 '( si's AM M AX* S sS sSX si MX 'S SMXGM M MHG:* I’M xs sxSF G M’i sHxM A ' M s! FpGG AS AS M i VS M s VS 4 'S ips s'xXpG, AM S st AX s VS Xs sW sS spS sS SIX s* A -4 4 A| ^4; I xSX it AXi iX xt i I Xpl si xAS Al xi MX| XS exM 4 s( 8*X <xx|'Xs. xXs 4 aS > SX tXX' Xi / -. Si i < spt, sX'xi M A'xl S s4 si’S 8 SSI S( i'xXi 4, s( > Fl sXXt M -SsS 41< S’! As si A I’Xl M; X'x< 'I SIX s 4 < V4 sx| ss >| M'i )i >xx4 <xi >>s < M >44 VI Xi 8 Xi 4 Ays >iX <| xM <xx| Xi -xxS i t< >iX <yt < t il PM xl sxSi s-xl 48 Vi 8 A si SSS iXM M sXSS i' st tiX,-MVl I’M xS tXM si xPi si tXM sM M A i 4 s4.s i’X* x< 'XX( iX4 si si |A| M sX'xi sXM x< SM 4 ><.1’4 s'X< <4 <1 VI 'X4 sXx< M it 'I pxi X4 iXx 4 > M 4 iXS4 <iX si MVS Xi’S t sXM sXi M s’xi S AM 'FS <1 XM < Xi GyM siX >i xM ' M. Gi PM ‘>4. Sys 8 VI S4 » VI I si ip’, sXXF -Si AM i,< v st <p( si tXX4 sX* X. GS48-4 si PS? Si, W sM'i sSSi V s' XX( > S 'xl'4 <( s'XXi.x| M sXi * ''xX4 <pt AM S4 i’A> 4 s4 ip4 A4 >s <i i’ xi x<4 'XXi s'xi S sXXi six -I X'xWSGR Docket No. 56371-771.601Table 14-4Xsnim* M'& I M SSWMXMXMX?’ '-, M I MX? -> M XI X? X.? S > x I M M'sM? X > X? SpSMl s x I X IS MS. vM \SSS? S <s s I I' XM X i M xlS <ss|M X 'M M i Mi S s X? '’ X I xi >x*, PM l x? ''A l 'I XMlS SI P X I SMS# MM s I sS? X I > P< SMs K s | X? SM SS M MMMI SS XPMM '’ X I SMS? I IS,s| P X I s? s?? P M 's s i» xs \ W ’S A i M f’M U PM i s: > PM » <\ x?s < i -< $ i px? i, < x MS. s xv?*M, \?u x?s <s\?"\ x s i M i MIS < i sx? M I Six, M P X i $i >s? I PM I si > X I?*? MS<s > P Si >lP I s | i ' 4 M > I?’X< M?? M? X ^M’x X S < < _ j i i lS; XSjS M XX M < X|S <? Si S X I?’? M.'X. ' X? i P'M $ |*Sj M,\ XP _..x xi i? ' <> M I X M PM M S XPMM P X I XMX?? PMXP XMXP I S '??? ^? s^ i x? XMPM M P M M S PMS I Sl SpM > I X IS P' i x? 'IPxi < t M'S, I s I p? MM s? S I M P? St » o X '|X sSl P X I St P>l?!’< > ’ S- s \ l pl s<. SMSP X? < MM X U H. f st? ^' ) < X MSf? si s \ I P? M <?s,? M: Sj I < MXls >? s n PS? < *s MS xsP Xi. XP I s 1 1 M < s 1 1 IS I i s X Ps I s? I Psi i -s xn > I s? s X I:;<i sMPM i M S X? Pi Si?Pt * I s I I Ps? M" MS M S I ' Psi 5 P' MX > 3 s? s X I P: '■>< 'Pif? M??s ' M x 'siS N' I'M M f * M’M\P XMsP l x; i IhMt s i I* <x< M X xXMS. VM Ps M 'X I M S? X <?, N 1 Px? M s XPM I S M px| i s x?\ M?‘ M ^ <>. I?\ »AP X< SIM M M? MP X: i P-IP i S '? I I! I M l I’M Ms XiS,p.<?<?(,?< X P x< Ms ' P X I si? S» ' 'M I M x x? PI M PS; Sp X I MSP I s X? I M I S? s X? PI s( P'S P'P X< is*' " s i? H 'M’ Xi V? s |?? <; x? M l?'? M <, SP SMSP ' x D I M SP SMSP; X i? I Ms? xx? X? s?\sJS <x I si MM > i Si’M i XPXM? Ss I XIS <s I Si 'si 'st j I X? S? s I X? xi’xi5XIS s I sps< >1 ss ' SIX. ' \? i?"s? I (X X IS? I X? x X I Pi -P, - ’M I xl sX I?*? st < S? p X I s<, M 1?s < I M / ' X 1 P, Si I\ M svs X C PI SM?\» I s? | PSI MS XP M I SI s X I PI sMPM! S I s PSI MX XIS s I sPs<,| w ’ MS <’ K'M si S '■; I XIS s I XP M P sS? X I’M I S? ' PM l > S XIS > SP Xi > SPI M i l l ' s 1 1 P-^ I MS X IS 'MPS Xs. I M 1 Ml*MS M I 'Si s X 11 > MS MS? PsitX? < " PS MM. I PM, X 11 j s|X 'XX? PM > X 11 ' s'S;X's|X, I 's x | M s|S < XS XM, X P xTt iMV sr P XsT XPMX'I', MT X I SPi Il'S.-SPM P SXT XM, TM \ x T PI Ms|S JT^TI PM MS X IS. s M Psi M ■■> X IS. xxpx X x? M i < P< xx PM > X I t >, S'X;XX|X > sM I MS i I s I Pl s I Ps XSpM t xPM s? XX I Xis <? XPXM l Sx: MS s I Si X x? PI M > PI Pxl P \ I XM X? HX d X I?'?’ S' i iX X is,, X | xl \?‘V M SIX 'S I XI xpxs * X P< ‘ X I?»? X4 A sx? S sSP Xt S'’ I X? | i | S' X X? PI M > PM l x M PM M ' MX 'SP XM -" P < S I M I X? X ■>??>? xM 'S < Xl P X? XMM 5? S <xx I P'S > X I?. iSPi s \ s|S M ss lM sIX 'i \ ■>! PSI X M fX? X sX l M xPX< > I \vs! | sP xM l xx I XPMX I xs I X? X? S <? S PPM PXM M MXPM SSPM - S I MXPM I PMXS,? \xxM ’MM‘ X< >xP " M? | Ms, P SMSP I M I I M I X? S Pss M X SP?& MP. M I S M PS MX M XM? M? PS? IS 'X XI MS P X? XM M I'x-MXi ' XX? P MM '' IS 'X? P X I SM M? MM X? IMJ SI M S PXM Xl? M, X x< M?’XM S ' X sl I X 1 1 PM I x M Px| PMX XMS| P X I Xi 1 1 P M <? X? |! M??s < x XMS? P X? SM? I MMs M' X xj s M PSM l s i pxl PMX X< ' s |? >s I IS > S SMM P X I Xi M PM 'Si P X I M > 1 1 l'" P < I s| P,x | >? IS. M Msi< X M P I S 1 1 IS < I -■>. P S I S' IS > XM M P X i M i l I PM sX' P X t M! M pxs s i x '” psi ISSX M ' X X? I px? IS s St Psi?SM P I M l IS < M P X? sM M PM <x? i' X. M < 1 1 Al> \>?’ X? ss<? | pM >x? p \ I xMvI p->< I X 1'1 PSI Pi; S MsSI P X I M; 1 1 px?SM. X s I PI X M IS I >? I Ps|? Ssx Xi?P. P X I Si5? | PS I 'Si i XM P I X I P IS M s M IMS IS > S X? < X>. X X??'? s I?? S < X? " X? st ' I '?»M x? > Xsl?’? S? I PM MM’ S 1 s» 1 1 1 PM iM > X'M P I M I IS MM I 3M I IS 'S. Xt M P X C M > 1 1 3' si PM < XM 3‘ I X?!PM? x l? ”sl PM -' M P'I P X I Xi. '? ''xi M s l? pX ' lx x Xi. X! P X ' SI M I P'rf<? x}"?< ^? P iMG? s? i px? PMS XM ' -M? px?? X x M M X 1 1 PX” *’M x M H X?. PSI S X sS M M X?? I PM IS Ps XM 3 S| Pxl Si '" M SMSi ' X x P C x j? |X,? s |? px| pMx XM I 'M I P xl PMS XM I S? I?’X* 'S P' X? »Xl $' X I XM M?XM < M < s x> l> s? ’? S A ’?’ X? M < I I ’x?fX» I’ X I X? M I I’M ' X? p i I ->i. M PXi; x? p t? ■><.?! pXi I X? Px > x? S XM’M P M XM M P'M'>i XX P| X I P M l s l l PM? S,x XMXl P X I sM i l PXMXi X M P l x l l PM I x l? Psi PMX X ISMxsxi MX? I X? XMM I XM? M x M X? S< « XMS i XMxs? s, - XM ' X? s X I s? xM X MM I X ' M P'.I T xs 'X? T X’S< s'M T M ilsTI X X? i x Xx? M xM \sl M'x \s< > Tx| x X't'M s< s KM 7 X7 SM si I XM I -M i X x? i s X X X?; X? Xi. '-I ' 'f I I X? i I X'l -J X I Si x? < M M M | '> S' Xi > S I X I M 'M I SI M M -MM '-M SM Xi M s M \Xj < -X X xMx l I X I M < SI I Xi sM | X I S’M xl I X M i x 1 1 XM s x X xi >s I XS ' M I s i I X? M x| s X I s' XM \< > | x i ' XM 3 >s X si< S| I X I M x I I XMS? XM'M i s I I XMs? XMs? i s?? \?? x? ^? ^,?? XM l xl s X I. M XM XM I X* X X I M S« < XMM I X P-'MXi I V x'l x i X X I M XI?XM l xl x X I M 'sM Xi <x.| I XVXMSI I X< M I X I xi x? | Xi M S 1 1 X M Ms XX? P'? V x.: x?? xt <xs s\ I p?. p?? XM? si K X i M M < x S M l Xi Ml I M I x, S M l x, MXS I MS XMXI XMX? I ' l l XM I < M XM MX X xMS P XMM I S I S Xi ' S? \t » s| i x l i SM | s | i X x| I s X M <x? X< X? I x ' l XMXi I X I M x?? X< < I S I? i X? I Ps X S<; i s’ X X I x| SM Xi >xl I X 1 st x? | X< S I s X ' M xi X? < I xi s X I s? X?5XMsl PX 1 x» X? I XM I SI X X I X3 SM XMM I \ | > M >. I XM l '. M X XI MX W O M I Xsi M x X i.I.'s ' XI.si I x 1 1 X,« A? XISX > I s i I Xi 'S?? x I Xi jsi: X? M M s \ I si XM XM ' X? X X I S 'WSGR Docket No. 56371-771.601Table 14-5j % <, isi’Xsassn'xi, M,x| F x? xfsxS F \<.v: X: Xf5xi F X»5xF J X F xiS\F F M V-,’ i,x X'xi >! ^ x X, XS Vi Xi, Xi S X F X4 < X’ i XifSF F X F Xi, XS F XS s F xs x x F xs Si s Xi, i xF x ' xF xi, Xi <xtvX? xf sM 1 Xsi x;* F’S? is\ w ^v'svr* HX ^ XF S VH ^ >* X F F *SW WH H i o | x p »'V M <^ FS ' F SF x X i F’F xi '<’i, S >1 X X B"i \ < <xF F’ X FNf F F'X s 5 x 11 t’SF Fsi XF^ M \ X? F’F xif1 x F F F’XF i?X SF'f * F % F I t’SF i s I x XPi xF F’ X F xGxF HXi hH F’xF i < xXF*< xf S' x F xi, xF i h AF PV ViM * FX, F > F s F’xF F i,x X F’i, M r x ' Xs," X S SX S S’ X F X* <xF F FX < f x F F F’M F -"> XFS ^F F’ XAXF >"> F F FX X$,'>?’ F F \ F F F S s F M S WF -S<, FX < F x F F F^F F sx XFX s sF F’ X F '■«, XF F s"< s F?< x V F F*F sf iF’i' sXF S’ V F Xi s ^S F F^ ' 'F S> \ F '< xS S SX s ' M x M F’F xi xX < XF’ \F > '>", 5 F F F F < F XF X \ F F’F \i, SX >xS' M, i XF’ F x F s F F< F ■> F F F’SF <.!\ \;'-< x x F FS xi d’’ s F X! F F’XF f,x SFXfF X F F F’X: i; S XFX, XF’ \ F < " JF’FM F i f, F \ F F F’xF * <x XFX, F xF x X F F’F xs.r’i < M< M -.xS’ S x F F F (, > S* \» <\F’i x F: F < < F x F F x V F'F M, SX < F '-> F '" ’-. F ’X x« dX ' F x F F F’F" ' i «X X f^x” M xF’ F X F F ' < < F V x X F F*F ->« < F’s; F X x F v'xF i <x XF'x,xF F’ 's F X< <x| F FX <x|’ Xf,xF’ t "< F F F t, I SF x M F’F M -F’U M F FSU < x \F* < F \F F* X F \^ xF F F’X ' xF X F x< <•>) F >-, F F‘ X F^s < XF F FX <xFF> X« > MXF '-s F < £, F \F x X F F’F xGF1i J i X? F> X F XF S -> F F FX < M F’ X? ^,^ i FX.^F’ XF ’XFS' X n F <,xF>XX <xFyF '-' F i F F sxF< X< 'X;> F x F F F F F > F XF x \ F FfF xi, FX <xF " x: x «..-j * f>v F xH '»v,,:x > F 'x F F F’SF $ »x ^Fx ^xF4XF, XF’ F ' F F F i * > F‘ V <xF*'A F F F < >">? XG > F* F x F F F? < F x F F F‘"> F < X F*X > F xF x X F F’F X^F^ - f xF x X F F‘F F M»R F M F F'^F X ix XF^ j F x F F FsxF F iX XF'V FSF F?x£ Jf> X^; F xF S X tF^F MfF xF x X F?.. JxxGF’ FF X? 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FX X< »1X < XF!M i-r F x F F F X > F xF x X F I’F XX > FX F5X F xF; XF F F\; X x F F F’xF i ^xXF^ > XF F VF xi iX ' FXX, F xF x X F F'F xGFX < rx H f xF F iX X FX s F xF \ \ X Fx \i fFX 7 x TF t’xF i iX XPS?f x F i F’X < -X \; X, XF r X i XF 'X' F FX ' xi’ Xt iXF5,F x F F * s ' xF x x, sX Xi sF'X > F x F F F^F i <x XF’i5X F p X< sxFs* X F F F i < F x F i i, S X FX s F XF' x A F x<? FX < F X F F F’XF i iX VX F> X F V,x5 F FX i XF I* X F xi,\F F FX < F xF X X F F’F -<i. FX, F xF X X? FX Xi sFX, F M x X F F'F x<, FX F x F i F'x* x <-< Xi’ i i - F x F F F’xi i,x SFX -.xF’ Xi 'xi’ F x F F ’ GXF'- X* < XF’ F x H F i < XF x X F F'F ->«<?» <\F’ Xi -xF F x F F i i i sxF' Xi, X?’ F xF F F o F xF x x F F'i XX, FX >\F F’ X F xt sXF F FXsF x F 5 F’xF s >< SFX ixF F‘ X F -X > Xi i F iX <v' 'Xi <xF’ F \ F F i i, F x< x X F F"< Xi sF’i < F xF x X F F’F X?sFXsXi F’ X F xi, XF F FX > F X F F F’xF >i I X X^; F-' I F F’XF « ' x X. FS sXF’ Xi >"> F' F x F F F i - F X F F? XF » < S XF’i - F x F F'F’x; 4 -X XFX < XF? X I S« < xF F x,xF’ Xi 'XF' F x i F F i s F xF x X F F’F xisiX <? x F ’ F’X? 4 sX xFX,xF’ Xi sxi'F S ' 4 F i s F xF x X F i >;;^7^7xiFX < XF S’ X F <-'* -XF- F R x’’ Xi -"-F5' F x F F S i i F \F x X FPF xt > FX S' X F xi <xF F?s < F x F F F'xF i < -■> X; X, x < x x i FS xi > FXfF xF x X F F’F xs, s FX > X F i F’X? I sx X FX; F x F F F ‘ M i,x x F’i >\F S’ x F Si,x i F F F'X < XF’ Xi > xF’ F x F 1 s i?? x F F F’X.. i < X XF'X >xi FXX F xf < SF' F fV < XF’ XfSXF F X C F F f, F x X F FSF F i 'S xFX i F xS ■> X F F'F ^, FS X ’ Xf i’ i ’- F F » t < F x F F F’xi i.x SFX, F xF x x? F'F xi < F*i xF F’ X F x i i -SI C FX, F XF X F F'F Xf SX <xF F’ X F x(,xF F FX, F x F F F’xF « <x XFX F X F; F",x f, X ’s FX, F S F F F' F xs S <x XFX <xF’ Xi,xi’; x F F S S < XS’ Xi,xi ’ F x i F f <., F xi x X F S'F Xf,iX,; x ’ F FSx’ i < x s F x F i F’xF i ' x XS\ < SF’ XF i XF’ ’ X F > F « >,< F‘ X< < X?’F x F F F i.,xF”si < xF» F x r F F < > F XF X X F F’F " F^ <?f <xF F’ F X F xi, X S FX, S XF X X F F’F xi, SX,xS’ Xf >x?’ S x S F F f. F x F F F’XF i <’- XFX. F xF X X S F’F X4,?’s,xS i j F’ X F xi sXF F FX,,\F’ Xi i XF’ F X ’ F F i > F X I F ’’XF i < x X FX i ’ XF "- X 1 F’F xf, FX; F xF x X F F’s X< <? X / x S S' Xi <xF’' X F I S i, F x | i ',’ xx X FX <xF!Xi JXS’ F X F F F i, 'F' Xf <xF’F x F S S i > F xF \ X F F'F xi iSS. i xS S’ X F xi "-F F SX, F '- F S >’xi S sX X ’X<xF S’ X S V, XS S FX s S XF x X S <’F V JSX F X S i s’Xi $s■> XF' i i x i XF S X F F'F XX sF'f, F XF< 'x X * F’F 'si, FSfF X F F F’xF i, X XF’X <vX ’? F’XF 11 x XF X,xF F’ X F Xt; SF F FS > F xF x X F i’F xf,> X,; X F ' F’x, i ^’xi’f, XF? X F xs,xi FX, xi’ Xf < M’ F x F F F i > F xF \ X F F’'F"x F i;’X sxS' Xi ’Xi’ F S s F f <, I x > S i’SF S sx XFS,xi F’ X F xs s xi F FX s xi F' X F x<,xf F F'X,xF F’ X F xi?\ F F FX, F xF x x F F'F x<, FX F > F x X F F’F xf sFH s, > ' F F’xF i? S X FX, F x F F F’xF i sx XFS > SF F’ X FsF XF F ' ’i s F x F F F’XF « x\ XF’f < F xi x X F F'F xi SX <\?’,x?» F x F F S i,", F’ Xi < XF’ F S " F F i(F x S i F’x F i sX XF'x;xi’ X< iXf’' F x F F F 4 i XF" X F XF ' i,xPXi,svF’l S F F F n F x F F F’xF i,x XF’i FSF’ Xux. F’ C x n S i < rsS S X F f'F Xi ^xF F’ X F xi sSF FFX, F x F F F’XF i; X \SX i X F S F’x- (, x XS’i;F xF x X F ’S Xi sFX F xi F F’X' i <x X X, S x F S F’XF i,xWSGR Docket No. 56371-771.601Table 14-6VS. M i'A I -J -'^ I AjS? St Ap i s I M IX' M i ilM ' 'Mpt, '( MvM'MiM'hH i u Psi SA AP S« -M’h H Ud's U PM i A SA AP St A ’I si i $ < xp v APTS? 1 1 < < HII PM i A x p< >xi p s'i'st AI TPt >xp st AP3 STI > t r ~< s'! i i‘i M < X P S Xt A* I A rd P S i xt i ll - x S i <’i St PS AP Si XI s S IP! vP’S ’ d P S lStAi I Pi x xi P 'M M AI MX dxl > \! xdi” d xl xS l Pl XdA dx i l I Pxl i Is SA d X P>> i d S Pi d '-d x S l Pl SGA sp St 'MM V ll! bhH PXl M$ S! XiSl P S! M >si dS AP M AP I M I A d s' I psl t A SA d S l i pxi { A SA MAt ApM H < ASP St 'Xp I X! I I t AP XX di’h!!! u? "<i x S I Pl st Pt pd P S F p?XJ I Pt d M X S I P! st > PisF ’i X! x t l P' SMA dx ' l pxi t'SSAdM x X H’i si A Ap St AM M i M dS"x S I!‘i st <pi isl x S l P.1 MsPb lM l PM I A SA AI I’ Sl Si Ai! Pt Is!! t,s SPiAPSt APISH I < PM \ V Is! xi <lx h h pxl X A s Pt d si * Pxl t n X Pt A* P S I stfx! I Pt A* P S I xi I I Is r xl x \ l \ M<ltAl P S I si Ai l A AP StA,' M I S t i s$ x l lPi SAsX Al P I ' St Al I Pt > C'x I PPSI * A %!\, jitix I p! st >pt;| "d x \ I pi st O d x 1 i Psi tssAd ' sPP S I Xt A I I, A i l x I PM t A X, N AP SI Adlx l l! P eP MAPI Ii M d lXi t l i l’I Xi dS AI P U< K( Xi ', A <xP St AP I x! j i i, <xp M <sP I S I C i t! i xl x S i Pc \i PS; si PA I xi. A,. I A d X 11 Px I t A MX d X ' l PXM A SA APP i M A A < Ap M < X<’I S<' I I t l x l;' PM i > -, S lX >! -< ' x X I VI ",« P>«I'" P s \ I PS st P’i j'A s< X! ISi ' s H Px! i d 'tPti Si x ’! P< xi PS AP XtiX ’ xH i t P-* I I *xx' sfs X A d M s % IP! x i P*t <xp v <xp? s n i <.fi x 11 pxt t >s sis ' i si x x; PI X» < PU i 't 11 PM t AAP« A! P S I stsx I dS sXl P M xi sxI I A < S! p x l xi ed IVi d xI X X I P! Si dS Ap V sXd K i m ' I x?x w<;; S st <pi5S' P S l xt AI ' pi> I si S i d’! xt<pt> I M s s l p S^A JSP SASPI S i! I d! MS P< I t A Sld d Sl S S i PI M <pt d S >! Psi Ax sPS d s ’ Px * A S< S d s H PS' s <x sPi A P S ' Xi s! Pi < S \ S < sS i iX XP’ i ' X x X IP! Xs sP< < Ixl X X f<xXt sIS i; X l I ps i 'X SPt dXl X S! A M< Pt> X X S IP St iA iXi P S i xt 'd S IX ' XI I px' t A XA d SI x t d’I XI 'SS 'XP S X sSId x S S I t iXpAt 'XPI x I I I t s l s d PSI AsSPtAl P S I xt 'S! I^^I PA ' XX AC I A d x I I Pv t;x x 's,x! p x ' St s si I issxP Xt i XP HP mix \ X I;xPSs sixsx> P X I st > x! I pt sS s I P S ' st <x! I pt >! x x X I PS st <ps >! si x \ I d xt ' s d px! t > X SPt >sP St -xp ' x I i! t > i I x! S XTPI Xt PS AST I PS! i n SPi d'd P X FAX; Sf I A - "< P S< iSPT S A I I PF Px! t A XP t d s I pxl Ax S A XI P X i Si Ai S pi d x' x s i d st <! X > s 1 1 Pxl t > -> Xpt >sP St xp X I I I I I d 'd X S I PI st PX x I V S S I PI S< dX d s 1 1 '<x! i A XA,f-d P S I St A! T Pt A! P S I Xt Al I I ptfI s I PPxi i X SIX 1 1 si S X i PI xt XX ssP St Apd X I! H d x I S Psi i A Sid h i! Psi t < s s!x xs* Si AP I M I i t AP X« AP I x 1 1 1 1 d X 1 1 Pxl i '< SIXs'd P S I si Al I A > SP St r-<4i I s u i t I SI S S: PI ",i n M PA I X? Al I Pt > SI PA I At Al F pi ' I Si AS I PI St sPt, C Si x / S I I PI si 'X d -■> I '' PSI I A XIS d s i S >d C ' S Adi P S I S< A< I I IS Sp \t AiX sSi P S (Xt Ai I IS d si S t I 'X St i IX d s 1 1 PM'i 'S MX i ' Si X X I p' si S d PS' t A XPi > I X I ' P"d t A SIX A<> X< Apt S'! I 1 1 d "d I is; I 'S ’ 'A ' I Si x s 1 Pi s« dX i -d P s I St A<i I Pi d s -■> S I Pl SisA x' PS i stAi IPt i ' X I I px! i A ’MS d S l l PM i A SPt Ai p s i xtAl l A d s ' HAi I t Al Six i I Sd I PM t S X IS AP st Aid S I i 1 1 i I X 11 PM t >sAPt < I MA S I i'i '?» > Pt I "s X S C Pi si A d S I Psi t A Six d S I P"d < A Xi’s, AP Xi -d’ I X 11 I i AP Si AP I S I I I i J I X I I P I M tAMMM PS i si Al IA >sp Si "'P i x p l t d s d Psi i A SIS Ai'IXt >sP'' X M I t!sp xt > sFl S 11 I i d si S S I Pl St PSss. P X I St sSi I P? A! P S I Si, -d FIXsI s 1 1 P?d t AAIX AP X t API 's! > l i,sP St M'M! I G i Si S X I P* st <lS (Xl S' S 1 st -'-S' dS > si P S ' xi A,' i X d x i I s S Pi Xi, 'A A! P S S< <si I IX A, I p s I St Al Pt i I S' x s i A " P sl\ A S' X X i Pi M sPt;, I Xi X \ I pi Xt iis d xl X v Pi M dS A< P Xt AP i S ' i I t d "d i PX4t sS S d ■> I S' x X I Pi St i pi ' I X d pxl i 'X MS ' I 11 PS I iss XPi ' I -d X S I PI St PS, I'x 11 ^d t A XPi d Si S X I PI St; P I t Al’ Xi A<’ i"> d'i t I x l ' pXl i A S pi Al i’ S I St Al I IS, "d i PSI t A M’t > X' >xS I xt Al I tx d xl i PSI AX Mxd X'l i psi AS MS AP St ApI XF l I t M"d x S TPI si SS d 'd '' PS! t A SA Al P,s I xi 'Xi i 'Xd x! X s Pi Si <'X d X ' X s i’i xi <ix d x! X s I Pi Xi < Pi > i x l ' >xXl't > I X sis 'X’ l’S I M AI I PI AP SI API s!! i t i i xi x t ' SS -d 'Pt i i x d'i’xi i <s S IX d s ' ' Px! I < A SIS Ai’ Si <-dd x! * A dXpx x ' Pi S« 'A d xvI pxi i >x SA <! S >5pxl t>s Six xP St AP i s I i t d sl X S i i‘1 st > IX >'■>!’ SM ~ t d S ' I t> M i >t MX l td M’S S ’' A d M i! M! t > S M’t > ' s i I PSI AS MS > MxSt sp i ed i I I > XP Stdxn S I! I i x F s< '-, M Pl St > ISP-d i' X I St > XI d’S, F s F I P'd t A SPt s I Xi's Mid s t ' A < ' X M px i >x X A d xl x S” Pi si '1sth-!<$ s4, A{-d> s < JM’ I x I I i, I s 1 1 t'xi i > s MX 'X' p s I st Al I Pt > ' 'S i I Pxl i A MX >sp Si API x? I I t d" I i! PM t <x M'M'd'‘ St >s X I s l l i t sp M AP I s M I t xp v AP I x M;i d "s < X I Pi st <pi Ai P S I A A! I pi >! sl s, S IPi si X i i si x S lPl xt >iX i-d’ M Ai’ l <i l ” t d x I l pxi t x Six AS PS 1 st si i PA sl i pWSGR Docket No. 56371-771.601Table 14-7XTFT*XHAA« Xs,i< Sx < A UWWS X S i S * >->'’ Wl -3 H i. x * P> bMSMi! X. n-’ T*. ( xS* H A S t A 'A X V I PS xs. AT, nS S’ X? x* -x< S S’S. -*- " Xs nF S X ' S 5 * A xS X X S S’S M AT s * ’A x ’A S'S ' * (S’s, A S P' S * \ \h A S”A '> x!? X,’ X Txs S S F* ” xS x. S’S MS’s,. <> V « Ai A s i i S i'A *. M XST nS’ X* nS’ S X S S s < s!!'--• ■ (A XMtM <> 1 Ti ns?f > ■> s s’ x FS< ns? Pi ns’ M, n*’i xi n < A xs x s, p s*s x<,p$ A X A FXS < » -; stx nF x<, X:’TX P n *, ~ F X< ’ ’ X I i < M \ X PS “ M’A S’ A ’ {* x S i s i i\ b’ ’ S’! > S Xi, P < MS S’ X? x< nS ' S’*, n! S' X S AM ' SX A xS x X! PS x< (ST! i xi 'MM S'S xi AX A -A - PxS s n X S’s A x S S S’>,’ *, n ’AX, nS S’ X S x? ns IfX A x A A< A i n MX A xS M: S’; xs < SX nF xs nF S X P S S MS' Xi AP S 'X S S S S A M S ’'< A « X XSX A A X ’M ''S xj.n nS’ X’. MS’ S x! * S M M * S’ A M x \ST 'XJ S’ X r-x A; M’S A M 'MA PS XS N 'Xi S’ X I x» 'Xr S S’S -A 'M,, S PS & Ax n. P x Stx- S Sx n i S' X S S»S-A S SX A X S S S’x,' I n X X S xS -M S S’S xssSX, ' < A I S’X* i n 'A5*, A x ■ S SA S M XSX A XS x x s n V AX A-AXT.,'A:?•,'** ASS S’ X S xA A P SX A 'x S S P’A i A XSX ns S’ X S x* - A S SX A X ’ S px;4. x XST A A X X S S5S ".*5SX < S XS x V S'S x* < SX, -A S' X S x< p---' ' S'* S x S * SA* s >"- s SX > S x S S S'x' * < X XS5* < ' XS X X ' S'S x ASS, X S S S’ A AX XSX A X S SXXS * >x xs5* > A S' < ' xs. A S*AX > XAX A X S A ^ XS X X S S^ xS, SS ” A A ’PS xMVx'S N n H n x S * \M <h^ X S A,x’ ’ X A A X X S P S XASS A XS X X ' S’S SAS’* A X S S S’XS AX -U’A S X A SA A, X XS*s >'A '' S I XA-A A5* S X S S S * A X^ \ \ { S'S X* < FS >'sS S’ X S AsXS S S'Ax* S' \. M A S SX S x, x X S I’S A SX A xAx \ S PS XASX Ai’ XAxSA x S S S S A X S S S" A S x xn S xS X X S S'S A < S> A S -A S SAS S x X PA ’ x S S S’X S * x M’S S xS X X S S'S M < S^ S s S S S'x* * - XSX. A5A A5S x S S S < xs’ X< <xs»; x * S * S A X S’S xs sSX < XS V X i P < XS S’S > -> S' X S XS A s A < X S S S’X* i, A >i * -> -> ’ S’S xs >sX < X1A -Sr* Px PS S A xP A 'Xp? s S A T XK' ^’SS <;x xK,,p s$ -sp S XT S S s,xS' V - MAA'S S S S 'P X x n sA XAW A, M S M >-, S S AS X S S 'AS S x A 'A S S'xS * X vA’ *A x* x S SX xS* M A'* S S>:S ’ s s ’ xS x % S S’S x( sS'* < XS’ M AS*; X ' S S S A X S S S' -■>' *? X \SX A XS x V S'S xt > S5s sSS S' X S xi > XS " S'*. A \< S x X S S’S x*. * A s S xS x X ' '5S xs -Sx. ^P5X*. A< S5S x 'A * * A x ' ' S’ A *. > X X PA A -n S xAxS S SVxS’ VMxS’ S X J * * S x S S SA’ S X X Sx,x> S' X S A A S S'* < X' '' X S x* < „ T PA^XS x \TPS >* *PX A > S x nps XAFX? xT Sz’ x s AA’P A XS npS xs >h XS XT ^ < X S SX A xS X \ S A ^<SX,? X' x WS xs >*X < x i * S’x* * >x5A> S A xs x X S’S x* AX. <x P ' x< < x'P P A A x S' S PS? *, sX ’P’AxS’ *> AAM -i A S S A xS " s V S'S xMSX s PX P S?•%< P?x XSX ~ ’ A S Px S ( AAMX!'-A' -S( > XP S '-- S S S A S X SI. AS "*> < A M XA, S S’S XX iSX A X S S S’x S G’$\S*X A -sS x x S S’S x*, Sx A x T S S’x' *. > x X S’S?x* S’ V y. A 'S’S > XS’ \S,, XS’S x * S A S SS X V S'S X*. < S’S - A ” X S XS > X* S sx <x> ’ X S X* <x> * sx A xS X S S’S X *Ssx A " A x X S S’S x< iSX A x S ’ S’XS *., -< XSS »xS S’ s P xx x* ’ S’*,,xs S’ x * x*5xS S S’*, s S x* x X S S’S xi sS’s si x x ' S’S xs, Sx <xS S' X S ’-,* sxP S!S x"» s *’* xs Ax X ’ XAXSS' -A S S; X ' XS, X ’ ’A S S « S S S; S’SS *' ' > X S’* > XS S' X S M > XS ' SX <xS’ X*. < XS’ S X S S S 4 A XS x X S ’’S N*. SX. xS’ -V. sSS’ S x S S S S A -A 5 S'XS S x X SX;\S S’ X S -A; XS S S'O A’ XX A’ S x S S S i S \ X ’A S X M \, A’ XS S’ S X S - S *. i’-< S’ XX i -A’ S x S S S A S PA S *’XS Ax XS’x P< S’ X ' V > XS S S5* AS' XM xS’ S x A S A S < x s s’s "p. <sx A ">: s S”A < <x xs5?'sxs”A < X ’; x: s s s, ’ xs x s s*s xs -s5* <x, s’ x s ns ' sx A x ' s S’xs s x sx ' X5xs >-'-S’ S x s ' s n s x s s S’M S -- X X, A X X S?’> xs "'* < S X* X X S'S X* < SX A -X? S Px, *,sAA’*' A x P S S’SS X XS\sxS S’ X S xs, x; S S’* < V xS x x t PS x*;S’< » S x: x x P S'., xs A’* < V ~A S ”xs * 'X XS’s A X? s S’xS Ax X SX x?’ X< <x*’ S x ' S S s. xS5X* <--S5-A S ' < * x S ’ S5x> * < x X Sx X, FA S A A-A S ST ns S’,\ S 'A ns S S’s A ’A ", X S S’S \s AT ns’ X* X / S x S S S s ' S X’ x x P S’S Xi A‘ s A x ' S,’xS s, SX XS5*, A x S S S’XS < n X S’*. n” X*. nS ' S x S i s sxS’ X*,xf' S -A S 5 A ' A x x S " S x<?S’s. r-,p xs A, S’Px r S ’ *, S X S S S’x’ (, XT’s. "-S > X s x< S ST < A5X* < A’: X S S S s,x(’ \s, -A’ S x S S S x, s \ i ’ Px! S x X A A X S S’ x! (S’s >! x! x X S >'« "* -SX nA’ A PA’ S x S S, ~ S x S <’x! *., \ XSX n''’ Xs nf’’' x '' * ' SA ^ PS S‘ A < n ’ / T \f‘ xs xr <i s ~ M S S’ A *. x x 'T A xA Px* *s$ XS5*, (XS S’ X, 'A ns S SX AA5s( ^< P S x S i - S - S X- M S’S A sSX nA S’ T S xn -A ( ST, x5' X*sX'’ S -A S S < ( S X S S’* M AX ( S xSI APMsT *' A XSn X ’ S’S ’A (S’X PA' XP ASS' S XA ’ S? nS" X* nS’ S -A i ’ * A " A X X * S’S M AT nS S’ X? ’A < SS P PT MXTS p\S S n X pi < TXTS K’ < n X A AMTS pM(\ P? np Xs,xP''x',S! * M< AS p<p $ XS5* s Xi -■> \ s S’S M, AT 1 S -A X< X S S’S x< Ax#> P M S;< ' *. n-’ X* *’<-' S x! * *s-n ’>«sx'’ S -fP S'M M XS X V P? '-A A’AM P X S XM'-A SHA A (ST ' S 'A S PSS *,fx X“’* A M S xi A'* ( S x S S’xM >’MAX A ’A S S' (S *. < X X *T < S \* \ \ M'S »* < SX > -' Xs,, S', x ', ' * ' xs x X ' *>, xj v^ M x S S PSS S < M SX nP XS ' A*S x S S S i A '" x X S S'' -A 'X < A '' X S XM-" S ST S x S S S’ x’ i s x xsx n' S' x? ’-<* <ss r sx ('A P ■* ' M (X* - p* A xs x x - ps x*,sx r -A X X P S’S x*. 'P*5' n s *'< A i X XST ' s X! \ '< i S'S -A (ST SA' XS 'xS’ S x! * S *■ A X! * P A! X TiT S' X S xs S ’T. S X.* X X S PS X*' AX 'XS P X'S A nS S p*S, I "> S S S’-A s A VT A *- x X S S'S -M 'S’* <-4’ X* <x S’ S 'A S * *. nFXi XS’ S X S S S % 'S’ X* A’ S X ' S S i;S 'A x X S ’! A n. -A S’ X S xS -'S S ’i A '-S x X! '' x SWSGR Docket No. 56371-771.601Table 14-8MMsxs vddMsissivM U 1’1 X’ dVXi I’ M x<.xl s'xi < Msi’G I ' l l 'Mb x \A iU ' i’M bMh bl I SX ' i xi x U"i xc dV d |”> i x* >' h’cd 'iJ! i’M i x M" Ki I’ Mxhxl T h M> V WTI I ’ Mxl x x7h xi 'i’s KS' -> V|’I xS shMxi x \Th ’-*. K s d" U A'M '- I S U<! » b »*M < U'M i M U h' X -X h -' < i’ '--S K S x * }>\ i,\ UM I Ml I’" I s!x V<shmU'M»IxM U d M - U h xs dM<d " Vxs5'ti I N MM x x i h ^< R > H U n>Kth< h H >'M i UKM Ih Wi '* I M S x' x M i’s xs A.x ’ M.x M M l I f < h! l JU ’M i't: ^f-iH! < 'T' b!? ' U hl "> U >1 x.lVd' M. X|< $ •l l’ ^ M < ') H<t ’h i I px i <x MX > I >5 XA: h M VS 'xl > I M;x " |X s A I I’M I »S X IW l( h"l 'K UdM x h h xi >\, M> M -d’i x i l ' s i x i i IXH A Vx.x’!> U Mfy i ix. i ' 1 1 r-d of. J x \ \ i ri xs >h "i n JM. M: K si m xt i n <: M u: u V.ni KHXHH M’s. hi K iS” x< A'Xi’ M x|< M S s > -. ' \s, -> U x 1 1 i s > i V -< X ' i’i xs. >n dM S WI 'M1! > hH S’x' <. Mi’s, h i ' '»xs ><. x u -d’ hH i h: > H r>b 6 sn. M I’ U ^. M ' IX» M IK I X’ S XI duxi m i ^i OM m: xs ixl: H) i x| X X I S*' xl dX hi -d! '' xi. SX IX- x M ‘K.h. AH iXB x ' X< xi x X I IX M >n.h X '-, | h M, I X M |’x| i <x x h -"ds\t xh’ V I ' h ’ V I I’M t, X XhfM S’ V xS ” I X.xl'M < M M S U' I A. R xt n.’ x, i’x< Si MM si? < { ^ d I X I l x V i’S d < SX > S \S X M S"' 'd dX ' I ld ' ■AX'M 'M R.xi i 'W M M x f i ' i. xl x V I'i x<?h H M U | h dM H", J xU - x MX#x; I’ \ ' -d, x| MX M> U "'IM x " I * ' i d > ’> I ’d X’ dX.xi I’ M -d; Xi HX h d W MX -X* S' \ | x< ’ s \, ^ M < X|’ > M I M.' U B’I M.h l \H I\> i. 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XI I b < M" V < dM x I I. t ' I X’ - s 11\ XS dxsI xl XA 1'1 >< d*s »xl S' Mu v I ds, 1 b x V IM d dx. Txl S x M'S xs 'ds h xl x < ' S!l x<dx < lxu I x| < Uh S ' S -M i di XMSX. M m i V<d MM,| xH M < x ^A Am< X|> S X | V S. 'M I l>x> s.-> M> S > X I m i d xi Ih.d’ MuS’i’dH i d x x x l l‘5 d dM M xi 'MI’J v Ad'.'MS HX Xh. I Xi x U M 'd dM I x 11 S>xS < x Mfs (xi x M '" S "< 'IM ' -d S’ >< I <- ho b! i IS' s x M> U I xH IMS I >x UMx-mi'MMXl i I i <x|’ M M’ K i l I S ' K' M idi xs >b. IXI. I’M <»’> \ |Xs| Xi K l Sd M dMxmuh’ i x i i S 'M V M xlM M i '. M’ M M x I S i d x MM. d’ h. 'S’ i X f l S vM’ M.xi’- ’x ' | i s d x| M K M dM x' -K ' xS ed i |x,xi '<"< xux S S Sd. I M x U i!i M dVxsSM K.xi |;"s ' I -d -M i di xs dX I x S i i’x s sMhi ' di S^d I x ’ A.’ S’ H xl’ xi S S s x?" 'i \ ’ M1i I " - W xs X <xi" M x ’ > ’ s " I IK S M x MM. i xl X M H xs si’s; xs>oxx % Xx i l’M K M xi\ i S 'A sX^ i S V. XXiX s.x|<s A xx is ' V< MXM 'sx is Ms.dM m -jS i Xh ' MM sXS.i l UAXA - m - ', SM \XXxiM sXxS’ V'X">; Ss dX M’s dd.1 x x » dX <x 'S’"- ' x S s ' V dVxxI dM i M* x'Mxx S i’-d '" U ' MX <x-M’x >'Xh ' M ilM x-M?'’,;5 svx< xxh b x S <!xS's. T xSX s | X\ S A ^SX 'X xS’ Mi X S s ' v dX ' s > S’x \ I!< dM V i’< > S X -> < <x< Vd-d'x \ s K. M. K sxh<* < < Ti(^!’S'>? sU’i5Tunf\ '?s d > Ut' " 'XM MM d s i \ x 'Xh. X; S S' d. \ S S. dX!-'M S'V ' M < XdS.,xX i XxS.> MAXI’S i ^XS’S i xx iS.xSM’ X S' 'I M s > M dX ' v-dX ' I XX ' S,xh > VM > I x-> <. Xi’s > ■><- i I'X* > \ | UX”S > -iXi’x -s X i S < d '"’< x 'Px s ■> M MX dx < I'M. ixs; I V v'.h. IxMi i'l MX. 'Th M < T AXT ’x. > sxd i iX ' J'W ’< ST xJXiXxi'X X. < < l i d’s. XXI’X TM’. U K xV i’XS i ’' M SXJX KXA i '- x i i XIX ' I SX AS i S V-Axl’mXi’x X < ii d ASx.xx S S’><.. Ml ' dXM dX.'i xx Ss}dx <x -' ' I’->s.. U I 'Six < " SX S v < I WM’S iX$i< i X x i’ s is X 'XX M’-d ' V i 'h s X dx > '' XX| i..xS’s > XxIVix ■> Si. MX i s SX 'Xi I U< XXi’( i MX. M i s V.xxix > X'’x XX is UlX. ’i x X. iXx s -'|X. \ x|Xfi -> ii. Xs’I' i iVxS i i X xxx’X MX XS > | ’sXxxSX.xV S’ -'t. U S i -'SX.xxSU Vx S’ i i s 'X XX S i’d i M ’ sXix.xxi’-' -sx i i s M dx VxiW ii M dU s iMxs s i \ ■> "d’s ' S dev. \ Is,xs’s > XxWSGR Docket No. 56371-771.601Table 14-9s>< hl g. g j ® ggg s iiiii At i i. gtgggii..ggiiiiiiiii.iitittgi Jiiii t g ii:. ii ggggig;gg: i i:. 7it t; i.gi A t g t A A A. ii AA t ii A A A g i iiii i gt I; It > * s'g I UMt 1 lx st* J * X'o*$xlt <? A tt'iMt I Ps<, x { 4 < X't ti \ A s't <; xsix ' i? i * i\t< <\s H' i <">< 1 1 nt it* < i x ' v-it* < T A P U s i > <i< S T ti« i "t;: itt i M i S*' M x < Kt sM < { X x ssPs i ■-; Si < I \ W' / X i -APx X > H. R <1*4, Rt xu I Xtxtlt, XMt i ' St I ’ <‘{t M. M a gOstR iXMM XX «< K<n At HXb \ K < X|t ! •,<%!« < Mt « W< <! *-< i UXP* ’S-IPS PO O P «ps,-,t: PM < x i USP«,xtps xt:< u $.4ix ASPS xt n n * <sfnt <su? 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I XX B > MS i RS 4X4. i I X X sSPi. i VMS d XX U 'Six. \s i N; X 'RSh ixS f rM i X U iSPu Mt iXu i xxxs ’bxx ' Psb ’s h ^Puxs i PM x R txb i X i i Mt i I XX? < 'Sit itxPx XM < d 4' ' xs I PM i, X I fsxu; O S I PM i X f UMS, SXP-i X s 14 d <,p<.si sxpx t s b < B it <sx ' PM X B MS X\it < I oX d iXlS iXXi’-i XX i G H >iS d PRM < X x'ssP X i XMX 1 f xx 14 >xp iSSpsAx 141 R <ps > \MX i I Ms H SP4 As | PM < X R iXft iSStMV R i f 4. lit 4SSixx Xs R 1 n ilt 4. XxPs 41 SO R iX?t ><x IXU I ' A 4. iSxPS Xx f 4 i R ifs i UX, 4Si i f XXstIt 4Sxp< x s h 4 k ip4 f SsPt tMu n ilt 4 ht iX44 l \<x MS 4 X S't 4 KX h »Sit 4XX | pM 4 t h Mt 4 ft iM.4 I X x-iXR i XX t 4? Xs l UMt nt 04; X i XSSFS ( Ut iSU I X it'-AM itPSA -i H dUPU?i"<pX X’M U b ipustl pxR X U < SPV XMt d '-< 4 x h iS’S.xspo X S R i UPu bt sU ' Ssxxlt 4 bt < X4 I \<> Wt 4ts 14XX44 X R iXit Xxlt i xx R 4xpx s sPs x x n 4 h ib 4 1 4t i'ou 1 x ssMtsi it it<4fi x.ssxlt 4 xxit 4; >h 1 < ixu ox 1 VXR X 't iSPHXM PXh X | 4' <xpuospx. 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U XXxS'S iXS f lUu X l u siU 4 I rt 4X44 I Xtxxit iXX- >\ XX lu 144lt iS< X I Psx 4 x 144SIX ' I R 4S< 4 ' X X ssit < s S. P-44 i X I i UP f I 4 its I PM 4 Xd < 4Xlt ittpx Xx H 4 h,*X 4 AMt > I X\I« 'Sit 4 1 ft i s< 4 1 XxoslS 4XSPSAX I U t i 4 4lt 4XX: S Xx l 4 d i >it 4 Xspi d ts 14 AIS. VXPXi i i ' I ' 4 its I Ux, X I 44MX iO,xPX X s l i 4 If iit i { ft Si 41 XXSSit iXXPS XS b i h ilt 4 X’ois 4 ■ SS i i 4WSGR Docket No. 56371-771.601Table 14-10XTESs, X safe XArffe y >4S> XX< 4 < A £ iiS A 'X > Xl S 4 Xfe fe S X'A’S A XX? S < MX (XX, S’Ml > X 4 £ sS4S fefe X'x 4 £ > i t;4\ i rss \ss s MAX <: 4s - 4 XSXMS < x \4’t ' 4 4 *Sx4s * 4 fe* - XTOSN fei fe < *~s fes AAIA x vn si;?rs AIS M > r xsxx?s > MAT’XS » x r< M> FS ANIF < S V<x\4S < X x*S -. xx 4 i < X< S > 44S <x£ > 4 X sxJxA ^ XSM 4 A xs is r-js - xsrs A xx 4s A4s A is AS J""' xsx^s A 4\ A XW-AS Ax rfe? x n ^XN AA 4 > x 4 ( My-x 4 4‘b x s £ s> S SMS < ' xx 4 i >$4S feAS V? K. 44 AS -xx 4 s X 4 £ MAS > j j XAA XM< A? 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S A l PI si 'i-x N M W H i i I M Xi I Pi n! P A IM <"< I IMAP A* sR i X i l I R I S H l*M i < A \Ps <\| p s i _ A I S _ i Xi' J I «A PW iISsI x 1 1 RM <. s\ sJS >xRAi iSP i X I I A i i I Al X X i Pi " A siS. iXi R X I M - xi 1 IS; I V A IPI SMS x” Xi P-> P i x f S i t >xi!v: > M!' -> n H > I x I I I’M i n AiS > I xi x M RI Xi sH R M x i SRlS s i sI x X I Pi MilS sSi R X I Si iSl HX xx: R X IMiSi I PiixR Xi i xp; A i l, i J A I i J iM Gi Ih. MHM i xMS iM l’ M M iM iR dSA V i I Al XA ' i xi JS N I’ A l Ai NI I lS iSSi S X I PI snFi, l x 1 1 PM S,|A < XP Xi xRI x 1 1 I i, I x| x?s I PI Si, FS s Si? X P\i »XI I P* R Xi X X I R? Si < Pi; S? XifAP I x ~l I i »XR Xi ’Sl't M I I (, I'M! R M UW si SA Rs ^, RR; %i s X I Pi si iR i i xi s S i Ri'SS -IX ixi P S i > R;x| } n,>! R S s WAI I PiiS'1XiiAP I S 11 l ii Ex i i PAi iiS Xi’id M i PM iiX XFnsi P A t A< -SR'i Pn l Si i x x i ^ xi RX Rsn psi § M ’v i ' FPi MiRR’RvH PsH d APi d SI S X Tpl M spnSI p X TM SAI TRnTM'A XTPI SnRi sM R S i SAxi H’i i l xl x s i pi \i siS, l x R p;xi i n< XiS iSP Xi sSPl M i i n i si x X l P M R isi i*j VI si iXi: R » i Si x S HS Si »X IS? Xi < AP i A i I I i A< P Xi?XP - X? M i, IM I PM i,x SIS * I xWSGR Docket No. 56371-771.601Table 14-13MFAXsitw ’ A H xs > SX<| '■ S H’S xs >fx < x"» s ’ s<< X x ’ V H’s 'H' M t \ s’s >M M >; '> \ \ v x V *s -> H H ' <r M ' ->^r< ' i bx ’ W' M i t.' M x un M 'V ixii i’’ WNM 4 X W M iNO) BVSuXl 'IM’if x ni Xi V< < M B MWxs > H sH B HK ’ h'i ^N i'V 'bv j b. sy 1 x» < IV 'O' Wf < 11 I WsWIx M | < b n rs H < X XNsMl X \ I '” M -iVx! x Vi'l ■>< <!>> J v o h'i xi <lV ->l IWs ^l I N<x* ' X?xs > O MX thtM’S’l M* I xM s’M s v MW WI i VK ol V H s ' u <"""< <’ M >'! <iMnN 6''M’f <i M xMi,i > 11 H. M’ M ' O'KH l < V \s >x >'l > L B> h: Vtbs IMS?xl I - X H HU Vl’l,-<• OX O / X I xs < V JM 1 ->.,s- W’l MiB< xl I’M sS >x| HWI x \ M' xS Xf ’xH I’xl oVIM O’ SU O’ Kl ' i u i '' x V’l xVX <x| |H H<v H's < VI x V '1 S<<|M V Xi x**i V1! u O'M - V xB ' h h I M' -b.x MXd ^ S X M’I xs BX Mxj x t OM-BO x x \!<! U’Ux I l"s XsX M UM S’ Ss s W M h o B l M t x \ V ' X ’ I W A X x xi ’ \ s -< xl *!» < i.,„no NV. I ""v '><7,7.:<" '4?)? v N ">">i ' ux TM 'M i r'fu M?'< u Fx?; \v x; v"<x >\y<~ V? v™V i VHisMV b I sixP UMB’I x t) J I I xI x MPl XMX I xl s!x> < Mb < B' x X l lS x$ < IX o r Vxu xMlv I 0 ' Bi.' M X X' i’WiM 'Bj y x xH'l Xf ib iiX! I I IV s >x xlV V Vi 'ilM x l l H O <1 < MI’I xs > B<xn’ \ W 'X, MX A x| x v 0,4s OX W 1V. M'i xi! M'inw’i xH HJ xb Ox- S > A MW A X I A xW AI A X W J ’< 0 x' x X H'i OUU sM |< VM < X| HVI H l xVI 0 xi H ' < B ' N I MB ': | TV V I xv > x i SfX \n.si,«'V”xii u> ix i uxu<*,i:,t -uHVf,! V'B<xn'Vxt A no xubuxi H 1SV) H<t >{<3 x Ml’l xs4)x uxM FM G ' Xps < T M x X M I '-< < M V O ' I XMS I ' S jXp V.xpi xH S S AI' WH U kJ xf w I' ^ S A VO M i o X I BI xs >|Mx| I’ M MX V xl X V ”) Xs OM xl S ’ V xS 'XS ' fM x' A X H'" * 0’S > V r i f v u < XIM'< B M < AV X: H S I7XS < v:i VVMXI - N X V, Vx -> $ V > M x ’■> V Si IX V X' x ’>tH V»A. M xvru ii* > HB b! X ”S! sh' s; Vs^ x O B B 'xB x U' S S > 1 A ' ) Ml < 'X s ix >xl SV s X i XI W I WIWM IV ux MV I X i s Wx sus. xVXs M'x r i s< M ' MS s < VVs A xl x x 1 5 M’l xs vuxl 1’ X Hi Al I sx 0 SI x % | Pi -> MVM V OM < M HX ' l O '> V 0 x>,jx 1 V I i OM s -X UX Vxl s W -0 OX -V> Mf'4>~xH5< V 'xFTxt | - sO? o.?xO7 XT;1; -7 <;s x v i'i x<iVu x iH4\s « vb» > ' >i ’v o x<ox -o s' x i xs o ixo x v n> y>it < M,'VViM I IX H XJ X VI'I VM S Wi”>s <xl*Hb h HI V W* 4W I i' Vx<> M iIX O xs WI XVX sXl’ V M’ixH J 'XVSsXl’H h V 1 x U f’xj s;x M’s - I V V i’l XS > IX < 1V x X M’l xs OX Hxl x vi'i X< JX X )’V v < X’ x? X> V U'V xuWI l H ’l xG PxU <"> f< V ^xi |? X 1 0 -XV * XI x M ' i ux vxd V I ib; s < XW< IS IHM 6 HB4xH I’M s ^M'« 1V I l’x| s >-> M’« >x)' V- > 'Pi O i hs HH 1* 4 ux MXGV V W O >lx x i> W.x5 BX I x> X s (B xuPuM l‘ X I Mx) ’IV Ixv V I'l MB» HXH 'M i iVl'td M V 10 xs OX o-O’ W’l x: I $ >x V 1 s WIXH i < xl’ WOS Io Ks lxl x V V u SX <; X M IM sn WU M Wi MlVxi i V X I XS < X1 I |*S > I X' X v 1'1 AS, IX > 0 Is’> X> > X| | X < I V ' |’| " S4SX I x $ Mx s <x \|X < X ’ V< X|’>\) | H < > X x v n WAV r V 1 x i iv ^ws> V 'V >"'I H B XBM APIM s B. IMs IN l sOb sbi > V «'} xWTv x VB x< h. Hi » s l H xt V s > SI I' V x< x| | H v I' ’> I xs > M ' IS » 0’ Xi >?0’ X > 1 1 < 11 X > I I’XJ < V.t.lxll 1’xs s >x x _ N > xl? \ | xs I IV I xl A -V IS xl >17 i I A ) 1 r _ xi v<< \ ~' no xM<xr> vtxm n v o xi x v>i s<uvsi P M 'MXI UM SH W. xwi s; i I Ml S 'XMX OXM I’xl ux wi xl l px’ GVIls hl l BM i>x MM4\i <? X1 < >4- MV I X t I I rxH sx xlx^xI’ M iXrtxri I Vxh pxl ssX MV rx X VI’S AUMM HNh's’ HMM I; s V 1’1 xs BX. Xl F \ I Si > M HX^ Xs x M '’ v<'VixH I’x| s sMn *h x\JX xWX i 'MGxH’M I I M V M sx'''V<l l UiXKb’PlXtl I <! V I X W SurXi W Ml s A MM I I xl AM ’ H O sIVxl H IM x I 'Xi l xl X X IPI xs > A >1 'M l xsiXl HSf| x' x \ HS| xtil’ I 1 s s > I 'M l I'sXA W N'M txPIM ' HsBKM I'l xs, B<< M I’ M Mxl HWI x \ ) B) x< - I N iAB XHXf V n l s<xB \s >xMxtl VW: BSI s A xfx W x X'IV AS M O XI X UFO 'A s >)X< XI x \ 1 X' \< XX <x5I’M Xs <x| I A < AJ ox i xl <x| HMM’ ’W I M I s HM I W < 1A MX ■“M l |’ sWSGR Docket No. 56371-771.601Table 14-14s <$««.< ‘ xl4 <i' \ ’ Ki M. PM K > u»* t>< <n M i A KI H X. PI M pi'< M Px hi 'Si ih 'i xi I X 1 PI P ''' AS MX. K N PM A U MS. K H FX| M S A PM? S M P ^ Uii ^dV I f?x| I. X XN I X 1 1 P-o A s X 'S »sp Xt ssp' x 1 I i A t S 11 PM t s XPA KK X I P' St < A,xj i M I S.i xl x X ii'i xi. Kxi PP 'U. M U’S. bh M r M>ff <i 'tiH’M ( A M’S> i Si S UP! XUPi sSP Xl. SPKFI U-' PM<xPK7M A. SPXAxPT'SU H< TV S XFIM sOPi' K i PoM.x Xss K xX i PI M N. M P M SMM IS. AAHm ^ ^ h' I • <}| M "- X I PI XAPM K M Px| As MS. XP MP. P K H I KM M H’S M.iS. M PX KMM 1 I i IS M A s,x ics <4 is;xp xt AP'K H s t sxP Xis xPi 'M i u, Ms CJ> H ^ W I SI S VPI s i i s.lS I si xX Pi VilS flM x ui’l S< MS P. I P X KMPI I PMx.' PX l S(V I is.x." x< < MA x i II K < Ix-|i KI A X SPP KI I PM AS MS. Xl P XKASl CPM I M S X XK I ' X 1 ^1 I Pul si I PA: n s Xi'S s is'll PA M" MS. Ki I X I Pi S-MP? I SS sxl l’l M. IS s 4K s 'PKM ' i <1 XI x X IPI " nKxl K PA* I IS < I S' > x I is xt.iS. K' l Px| ns MS. I si - PM I sX MV Lx 11 Kl I X <\ I:■> 11 PSI » KAIS? I S 11 PM ALMS s K I: Ki A -'i XPi KP X <. M!i x 1 1 Ms' x 1 1 KI <Ss six. i si <. s i pi M.is 'Xi p x i -a > xi i is <: M -■> s i PI xi sis. SI r X I M M | 'X ' | s| S X4IS M. Pn \ 1 1 PM 1 ' s MK KK X I P' M K. M' Xt Kpi X I M t,, x P M x? I M I I t.sF M.sIM s 11 I M I SI s X I PI si. |S < | \ 1 1 p\. t >s MX > C XI s % r PI M, ISsi M P X Kl. M US 'lsi sS US Xi.iS.xl IM KMSI IS > I M S \ I IS sMlX I "- 1 1 I’S' 5 M* I I I < M5%i ' sIM X: I H M s| X S. H IX Su|X ISI I’ X I si.x| 5 IS < Kl " K I |X M,l‘(.xP V.xP I X |; | I M X" MMMM -'? I I U I VI Psi MX XIS s i S' x \ M!< M K, KI X X IIs! SS sIX M Sl s X IIX X I I six s> K T XI >sl 7 FS sS> IsX ” > M. SI I |X > V M sSP I s7 I I M I s Fl K' s. X X Is M x 11 KI i s s MX. si Iss, I M.si | A s I xl x S I M Ms s ' IS XMJX. I S L PSI AXMKKI X V' 1‘1 X. SS. XI KM XM’M I IS, I s I: KH 'X ’M’M KI I l> xl I -X \M, Txl x VPI > A. Pi Al s XT pl xl K. SP XI.xpTxTI 1 1 A5 \ XTPI'M KKM K I I MM I PK SK A | PKI < IX. K I I PXK A XIM IX 11 KI MS ^S M xl I KI MX MS > | s, | |5 KI « <x MX ' I x 11 K: K x \? X x. x 1 1 IK u’s MS. S? M. API s 11 K M s p PSI $. X VS < I x K x pp M PMM K KMSI I lA'Msl x VPI sVKiM P xTM' sl UX i? S' " A?pl SMPI M Ml KI MS MS. I M sS l Pl xl K XP XMMM S I I > MXKKXP K I I I MSP XMSPI x 11 I I I XK X I Pi X< K x F x 1 1?"'| |,s VS 11 Al S X I IS X|. IS < xl P X I s^ Kl I CS. I x$ X I PI S» 4' MX! K KM XI I IS. M,! A S MS Xi. ISMS' ' Px| M > XK <xP M' x|< M. J H. PJ:>?< IIS AM KsM p x 1 S< »xl I I’M- 1 S’ s A4PI XI six <xP M. Xp I x I! I V Xp XI sW 'V I I M I V I P 'M,x I XIS I xl x \ 'pl X<| six. KI S X'IPI XMlV IX? X \ | A' s< IS.4' P A l xi s-'i Hs.sl P S' XMS I x i K K U K MS M7' MKM JS~M K7K~M p ' I Xl A -X W< > I M SA 1 PI M. K.xl PA: SUM I IS. K 11 PM A KMX > I 's 11 IS. ’ < X XK. '. M x I I M PI < UpM SI "> X I pl XMM KP SMXP K M M ' K4S X MS M IS. X' P X I xi s'sl I IS. KI I x x HS' M.n K H rU A -x XPMKM PM UXAPU K H IKK s. MS I " I I P' I MS. XPM K I I KI MX MK I X 11 KM. S XIS. '-.? SUSP! SI M M K 11 PSI ’ x XM s I Xl x X I PI S’ s IS M K X | Xl > M I PM KI x X ' PI s< <11 > M P M xA K| I IS I SI x A ' Pi M 'PM | x 1 1 pxl M'X MX > I ". I S x | p. Xx AS Kp \| > x|M V I I MXP M sxPX " M I M <xp \< <xp I A 11 M M xK X I Pi M.p I A.1 x 11 Px. M.x XPMl Xl x X I PI XMIS. XI P S KA '"'. I IM ' KI x X I Pi xl. M sxi PX I XMSI ' I IS s I Xi SA I IS Xl 'IS' I M I pxl A. X MS. SPAA. x? I x I M M KA x X I M M 'IS. xl p X I xMx. IPA' M-' X M PI XI 'M KP XMXP K M I t sxP AMxPK-.i l M. l s| I PxM.s Xis.l xi xs i pi M. IS S I \| A X I Pi M ' X < I xi X X I PI Si s|s Al p A i S<. Xl 1 ps, S x| p A 1 %l > M I IS K4M 'XP _ _ A I “?!<1 KM M I IS S PA I -S. S.' MS sSPXt sxPK I i M. KK X IM M. M. Ki i Ki I'sx MS 'K? I I' PM «. X MS 'XP X« -SP ■ S 11 I A I ". 11 PS? MS AM. KM PM M x X IS > KI X X I PI "1 sIS. I s i I I!Ki i.xXM. KI xS. PI XMlSsxl PA xi.lxl I A S K. MKI MX XPM K M Ki i.x MSs i I M X X I Pi:x< six. Ki X X I Pi M <|S 'Xi4Xl 'XP I X 11 i M I SI X X I Pi M. IS ' M p x I "si ' M I IS I xi?- S I PI M AS. K I I Pxi i sx AiSsKM Pxl M"-. MS. ""<l iMM.x VS s K I i PSI I x SP A.1 S i I Px| i <x XPi < I x 11 PXI GS AJS. SP KSP K i l I A ' K I I Pxi Mx SPi'. t xl x X I PI Si. I rs.x I p XT " A -M' T A »TS> X X" pi M. Pit"? P A PSI sxl TPS. TS ' x XT'P' XA K " P xT| p <4MX I MS i xK X Pi XA.iS sXPAi sSPK I4i A.xP XMSpI xi l M. M' XI.xP KH t s i xi x >< |p| I M. M. KM " M M-' AM. I xl x X tPI Si slx.sl P VSAP-. I I Pt s KI x X I PI: M -M. A "< A I SM I I M HS. KK A I P' M. IS I s I PPS' x.x XiA sSP XMSPKI I M KK X. P' xi PS.si P X K I I. Xi l iS. l xi s X. PI xA|s. X'>AA.xPK M | A xp AAM'K I I I M K I I Ps' MX MS. KI 7 X TPi Xi sPS.7"-? ATP: M M 'T SI X X PPI S<. IS sSI p S'4xl S M MS. SI P STM i'll ris Ap xt ' M'l sH I A. I s | |XI AX X I si V I A 'x< PX I xs.s< i IS. Si'XA. SPK 11 I is KK X IPI XM|S. I xl i Psi i.sXlS. I SlWSGR Docket No. 56371-771.601Table 14-15M PSxmltM x<l<lSw4i', I’M i f\ MS 'SP XI sSPI < ' I i < l x ' I F"-t t, S Vt 'N n PM i, X XIS I Xl X X: IS XI,pt, I, I I'l’M i «x Xis, I xl X X I IS M sN iXl FX i x# »\> NX; l x \' 'X t (X VS f I x I I I’xl Ox XlX J XI s x’pt Si sFuTxl x xns xt sFMxF Xt <VI x7’ UsTSI x X TH x<.rxj sSl p xl xt 'Xl TPt I x| x X I IS M> K >: M | |>x| i <xW < I x | I FM I ' x XIS:; x x PSI t ^ %< S > | x U I'M l <x \F t d X | > pxl i ' x XPt < I 'J HM t; x X 'S )X^ Xt sr i x l l ' t < l x l! rxl < 'X XIS > xi x X I F' x<}IS, X5 P X l 'xt iXl I IS < | Xl "> X I IS X^N. X- P X l xl ' Xl I IS > | \ \ X l?> Xt > IS '. X ' I’V SA sis. i 'xi -x x i ss M <:s <xs> 'xt >'xr‘ i '-' i i i s >'xp x? <xi>i x i H. X < xt 'xr i \ i i S X P S Si;|S, 15 H P:x| t;-x Xis > t Xl > X: Fl 5? 'IS < xl P \ I St; x| 1 pt: SI Win M < IS *51 F X t # < XI I IS; I M X X I Fl Xi 'S > X | | pxl i < W X AP St >'xP X I M < X ' ~, < ( |X xt <|S; XJ |> v x <; Sl DS, C ’< X X HS M, JS; X|' V,xF| x n I WxPX<f,xC’l x H i t, I XU PX| ^x XIX, | >. x X I IS xt,|X ' I,1 X \ c Fl Xi 'IS S I M X X I XS; IS x< p x I xt, x? I IS,x| » X | >x< | ' |S,xlxu, xF I x l i | ss| x | | FXI t 'X XIS ' I x? i IM s,\ X'S,x| P X | M,x' |S, I xl x ' si u x < t,x X'S s lXI M l s’l xt slS 'M F X l St NI ' X Nt P X I xi x| ' IS 'X'* \,,x|^|.s1 1 | |s| xf x x I PI xt <|S ' LX I I psi t '"; MS; H 11 psi t > X Xis --F Xt; xp | x 11 1 <, | -W | psi; '-■> t.|s, > x U FSI t,x XIS > I xl \ X I IS xi slS M x l l FM t 'X XIS ' l M %VP| M slSs x’ F t I xs M | 's, I X I: F'xi s <x(x|S > I x 1 1 pxl i <x XlS > C xl x X JS 'xt >'t <:\ x t. l t\ xt <|S.x|> \t -F I S H S t W x, W in ->s < IS,x| P X I Xt, Sl HS, I x| x x.:’' xt '|S< | s| ' t,x X|X, |S H ISK 'X MS,! X I I I'xl i x Xis M X ' ' 'Ml t < S XIX M 'x | t x tiS M s t > S X F <xp Xt M / l " M > > t I x l l P S t; S Xn WM X X MF XMIS, X, F \ I S< MS M xl ' X ' FI * 'Is; X Pt 'M Ai CP t < I M S X I IM -i six ' I X M rs ' i;X XIS M s? X v 'S xi 'IS -xxp St, SF I S: ' I I < X? M ' I s I? ' i sxF XtiSF'TsTl I i s^M XAIPI st,pt M xlFFx? s 'X xfs Ts| s \7p| Mi >pt x| p x lxi, x- l is. l x x X MM Xt six st p t | Xt,,l I M X x S t i | xt,|S M, M t, > MS < M’ St ><- >' I > I I '? t < ' st s X 171 XMIFfV IsX I XS sM I s < I v X r T' XS; Pt ' xF V x|M x 1 1 '< t, xF Xs#M» I x 1 1 1 1, 15 1 1 PM t 'S SIX ' I M 5 X I Fl M 'Ps < I S' x M 'I xt 'IS I x| > % | p| y A,'M F X I x s; SI I PMsl PX I x<,:x'' MS PxF Xi sSF I M s I t M 'M I pM t’S XlX M x W I's; t'x WMxl P S I M ol I Ps MM X X MS CS 'IS MS M PSPI StsPt, Ts7l P >l t!x xFl, SP Xt 'S’4TX7l U M xM PM ux XM MxT? PM?, x tPt 'TSl ^ X I IS xt, F? 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Fxt t x i s '\r«., xvf< *- x ’ w xit? rt ( ivw*s v< n ♦ M sis « i is PX?,? xsss:s pn I pst » x i?, »$n, x -, 1 u i x < \,xs < I XxxSh 'V-s J*M, X Is AptM. > 'Mt ' Ft »TPt < M »T Xxxxpt,xsl Fxi < V(- xpt; TPt t V <1 XSxSFt Pxx T'x<, XTt < SF1 'XxTFxt, XT < »SFs < xSPX Sx | < M< >|S ASFX Sx I t, I t, IS < SxlS, I xx | ( PMS M Ft < M M XSxx y< U X |S,xxF> VM t d t ilS iXXFx V-Mt - l t 'pt M iS St, I XxxxlS iXx I FxI ' X l l sSFt 'Xxpx XS l I ' i?fS; t xpt, 1 >xl?, MS MFt < St? T X^SMS, Sx | PSt i XTt nfi, T Ft Mt s I X xVxCX * X SPU Tss i I UMS, X'xM U x" M< xpt M IS <xt I XxsxXi; s ilt ' PSI, STt iSpi M M; St ' I XM> S|S MSI pM > X ft iMS, SST PSt; X It Ftp? (XX'X X xTU ft sFMXX I FS XMt MUP? SMS M> M t >xpl M IS,y A XSxx|S <xx I’M, X I t; X|S,xSpx X X l t > I t >|S,SSPx XX 1 I s n (Ft; ASpt, 1 & 1 t, SIS t AsFWSGR Docket No. 56371-771.601Table 14-16MW« \ salts'GM * sxG". > > R\ > I'GI MIX < SM4> t <? G?4t > fiTsxt TVMXG. >'> HG < \ i t'Gis <xv4x ’s X M A A'X ' XMM ' > X | 4 - IM I IMXM'- \X t-s A - s 4 x< M''' xx'M SF*.5s xM s 7s -> 7t SSFA HMM “ S v^ ^’ i’V. x“< AM X^l’t slxx’* '-^ s m 4s _ * \<f'?< \ TGrGGGGMGG'M”^^^ hMl sx|A < I:'4t i X* A s x *MX sSx I Fxt X? S *xM s ' IS. sX' * I X -> x'x'X » X M'S > *"xx (4 < MX s % M4S A x xA sXlM IS sXl 4 VSN’MX 'A FM S X I MXFM VF< I S - hA”! > i X< M i ^ ^ xx x<(4x i -. SX M SXIM XXFX X xih h iiMSM'Ms a f M X » MX < X J \> XX;\ > XX B4X< ' S ' ( S MX X^1X VsCHGft, XSpt A Sx 14 > MX A FAX* > " X S Sx|X sSx I '4M;\ |t.x’X AFM I \x >xN X X'X s ‘ Ml XIS s XX; M? X x ii‘<h s I Xs <i * XX ' <i,xx4FX<, >4<,,v<|>j, jx<4,,>>s, I IX xt I Xxx AS '-’X » \ xxl » \X B s x -, < xMI 4 ' XX MNM X I M: M,A WM I 'H O’M 7 xx 744 -sF4 S sFx SX l A lMlS. sxxl>x X::x A!lM4t s M,M *', ' l 'S XXX'S.xMF'xt S M MX --xF x Xx A U sX XXIX s: xx l 4 > MX M A JXM sCxxlX I'M 'Xb X A sx'x MIX / M I SXxx X X MX s C^xK SIX s XxJX S I XM AXF* s I IM-M I $XX-\fX >x\ I FMs X A -xCM XxF* M^xtAAS I IX ' x« I ’sXXMX iXX I '4X4 s X I < 'MX 'XM’X \ x |M I Ml4* «{S XX I A A six 'XX I4X4 X 14 x|4A xx I FM s X I ( sMXfX -MX ’ I xS I l sMX * \MX s I x> A -M’l \X|X, | x> |< - -,|X > I |X, x \O < A \ I xx M sMX MlXsV < I AVxMX sAMX d xx A. MX > XsA A Mx M v^X. XxM Mx\ | 4-MX< \M*4 s I X'x A sXF* < 7 IX M I S xXxF* 'Xx 1 FXi s X It s MS s I sMx| A X MX*4? s > M A- 4 s< M SXXMX Xx I FXt s ’< A sXlM-' -s I Fxs s X A sMMXX M I '-. A s 4 '< AXXFX XM< | < \ shSl! < MX A |X < M i I VxxxIXsKMFxJ X M sXIX - xMX-' M M < M < IX sx< Fs \X;< >*< >4i < v / x - ISMS (MX i s MX ' I xx I i iMX «xx I I'M < s:sx >x>|’ -> \x 1% < A. MX < X MX >. ^ -> <. X" I*X M ' S > M s X < UX > M M XXXMX AM f s SI i Ms. s X XX ' M -six s Xlx s | XX I MXlX i | IX -XS s I \'---^ X < \'x|X -vXXvI X''X - S MX I | < XIX s S M4M l x M Mx|X < SMX s | XX A < X? X M |X sS4 s I S" XX|X Ax I I’M s W. M'i < I M s M I \> xX'X -xx TPM s xTMXlX sTiX - >s M S < X'x|x MX'R M S T? < MX SX^MM S \T< MX < x M5--- \Mh < Ts s|X s XxF ' S x l M A IX ' SXlX M " s xSX s 'sx JXS S - S X -s MX sxM Fxs > s IMXJX sXxAx M}|< s' I 'Sxrx \x I M I MIX s S xlX ' I XX 5 » sMX 4 SXIX S I XX;< x X,x> I r -A U! VX|S< sXMSx XX M s r I MX XxFs s 3 sx IMXIX - SxlM SM i > I M'X X| - 1 \xxx M -XX | s' -A - x M xA XX ' I'M < S: _ _ * '''77'MXX'S """'"'7;";" ™ »"f7sT7^XS sT XXXXIA S sxls 'T'KTMMX S S MX? T -ATs s'xfX - SXFs MxxTX < -IIA s X r xXM < \lx AS* A XXSsXlX -X-- I rx« > x U sX|S 14X >-■>< < I SxyMX SXX ' SMI - S I * <x<x s i IX s -X I s XXX'X X x I pxM S I * sxix, Xx I FM - S 11 sxix 'XxFx Xx K - Is sIX - < -< Fx > x I A M six, x x" A I xx Is sxF I I < S I IX s\M I X XXMS sXx I FAS s X I MXIXsxMfx X x 15 H?F< xMM \x I s - A5IX s Xx'X < I xx I M I xM < X MS s I xx I; <xsX,xx I Tx’l s X M s'X M'x x x | M I s -ISsX x|X A xx I s s x A >xx?x V A ' K S IA S A4! s-x< - 1 Xx x XFOXM l4S* s X A sxIA s x A FxssX A. sXlA < V-IA < I Ss A M X I ' \ s I 'MA C A l4x<! X I AMS. i SMA A x I * sx*A s 7 IX s'-x - 1 \xxxr<. xx | |4S* s % '\ A - -<x *Fxi S X I Axis sXS I '4xM S I AMS sXM4S *X < |x s|\ s *x X < IXX lMMx, S MX ' xx |s sx|S s l IS (M s I SXXxIS s XXA s l xS M sMX s X s|\ I xx I AM4M X XIA S I xx k xFi < XX|s < IxM. * < MA I IS -XJ I Xx -s ' slA s\x | <4v. s X I A xlX A A sxs - I \ x ^SIX - ->x I j'xl, \ A >x|A ' |\ >x< I Xxxxr S SSX ' FXM X I MMA S XM I^ S X I M slA sXMM Sx ll A X x> Fx \X A s -s slS' Xx|S < xx M X'X s: IX s’M I XSXMX s'-x I I'M s \ sA >}\XJ'X X X | S > I S MAX X|> X A IM« - A > XFA A x M 4.x|X < X X X - 1 XX I S sXlS sXX I s’XS s X A sx > Mxx|> X \ X 4 HsIS. M X I XX I S ' xlx sXx'> X \ -A _ _ '" M'AIA'X 'T^rATM’Tv^VrMA^^* - 1 XX I i S xix sXX I Fxs - \: ASH - X-S I AV s X A s'xix s S X'X I Xx 14SM\ s I V xxi <vV x MX, XX I I |'X4 < X I ( SXIX SSX I |4M > X I MSFMXX | " XS Vl bxi'f xx"x Sxks M slS SMS - Xx |s sX|X > 4XxI’S ' l X'- H ' M’S s l l’s X* s I XXXXA * x X s ■> x I* < X|S - X -> M - 1 xx M, ^X s X MXs I -x M x > V l^.’ Ahs^ sra^ i’ SXXM'S s Mr-Xi. ' X'M M\ AS 'M sTM s sSFs sxx’Mxo S Ts s X'S, JX SXI | V XxsX sx s I F-sM X Mxs’s sXX| |iM > S l< 'XFMxx >x V' M s k M -x. Mx SX i - 74 SFM SSFG I -X A 'Xl^rl l^sM s I SSs slMxx! F'M > X A sXFs 'xx?x \ - A ' A - A s '-'Ax XX' 4 - k slX s SXk I Xx | s sX|\ s * x|S s I xx A 'x X s xx M'M s VA MMXxFx VMM li sFM *x S Xi.! -' s i x ' 7 s s A sXlA sS sF -s SXH sA six sTIA s St s F XXxxM, XMX <"xXT4 MM \ T> AS '"^xlt 'M^t SSF 4 M x-' A SXK 'SX A^A S 4 -MS XX I AXS S S I MXFM SMX I S-' A sX'A s l 'Mxt sXXx|< Mxxi 714M s S Is SM\ S? S I FV s X I AMA < X s> I " S< X 74 sMA 'X sl4X Xx I s A s sIM X x| v" S A * sXk <WSGR Docket No. 56371-771.601Table 14-17\ ' X& MX® 3u4XOWftt' ~ „ ™3$N J 'v- { I > X41 s Bl M s 4 313Xp>< s Xx<l, ' XX H sl?l, \'xP», I XS * Asi ' A'l i I '■>'<■ I », X,!», wi < 4 sx 4 AMI <??i < v s s VAMI? *'M MI AH;? n < i x VVMX <xs i rv xpi, TN \wxVt sAAT p A i \ Ti sAfl ^-\T^ifM< sxp4,x 4Px lx~t Ti sP? ' MPx 3 xT4, 4t sti> wi < s XMUXIIA II > M< j \wt<'i*<: rx’ s x i» <x?i SXM’X XX « <4 i;<4i > S3P"- ix? UH^ s XxPt, I M I V M1, -5. Mlsjsx?!„,-•>"<?,x\ I ps< s 3 44 vll sxxpx xx H, M 41 > XlPt PI i 31?< Ml s xxpxA >!u H 41 J III, M s 4 3$3>fl3s. s' 43 X 4 x31 i sX'43 i 3'< Pt i I Al'It sl41,1x7 -< 1X 1?, ”4 Al s? Pi s3< s I MxXfl s 3 All, K's A 'All < 317< i J lx I i < xll s 1M1 s KA?,x?l <33 ' PM, 3 4 < si?l, Sx 17M, s U < M1 - 3 MX ' WAV MX > I P 4 i'-g < i AXVMI <sx s rxi > 3 h < MI < SX 4 PM. > % i t,x4i r-v 4 PM, W AAI,’XXFXAX ihX>n < 3141 4 XX? i <3?1 s 13? X< 4X144 > M1 <? 41 < M > 4 '<3XX|1 < Xx?^, 4 x3 4 Ml < 33 X > 4 xA U >xr 4, MAX A SH? 'MX > VMI < 1 Ms 1 i,3?! s??1 > M, 4 3X1141 <"--1 | PM A H sill <, |1 sM A W M1 s « 4 PM, X H iXps s 4 P<,34, { 333MX M } p3( s 4 41S3fX iVX 4 PS4 X M > XP4 ' xxpx X 3 h s HSP? S33P\ bX) 5< iM < VM3 MXXM < MX < nx M,’ \xXxM r,\ 4 'Mu x M MXsXxP'i W M M < P« s3M*x VMM M six, AMX JxMb MX,, VMX' M XM M MXsxx? PM > X M, xPM xM’ x \3 M < M < SX > \MX M x3 M > MX ^M'x 3 x M > M > M M SX,34 M Xxxx^x <xx ' PX4 V M <x4X,xx 4 Px i u X M PMX s MM‘4SM' V »< \ I xx 4 s <xpi > M3s\( M VMv^X, X MX,) \MbMX < VM3 A xx M <: MX s X MX M x\ M < MX <> Ap %AM 4 S KMX < 4 JX,34 4SSXXMXfA3K ' 4 x.x 4 «SMX > XM\ s I,xx: 4;MX, \MX < 1 x34 U3§X <\ 3? PS4 > X? 4 'MXfX3? P-A t Mi!34X VAX S I XX A x? X S MX iXi S 4 M< Xx,'X sxx I s X 44 Vp uxx I PM sA 4? M4X S XX 4 PM s X 4 < <xPi sX3Px< \x J 4 44 s4x > \34X A MS M J3|X? i,34x A xx 4 i < MX < 44Asx<,? 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A Xx 44,34As334As4 XX 44 t'A3 < 334 *4, 4 xA A <x4x, 3x41 ' 43x 44 <341 A 41 M < 4 333x43 <xx PM < 3 4t,341 A 41134 < 4 333X43,3344'3» < 34 «,341 A 43, A A AXXM1 < XX x 4’14 > 34 « < X4\ >334 PM > 3 43 A4X > 134’ " V-Ats 44s43, X3pX 3SU A4sP4 s 3311 si xx?4 s SIM: S 4 'M A xxXxPMxxC Pxs, 3T4SX43,3X S33 "4 14, 44 43 334’x 334 U A s43 s 3341! 4 X34:, 4x433 ’ t > 4 133x41,3' I Mi > 1 4U3,4>4 ASS'' 3 X 44 > 4U4X < X\p3 ’> X 44 > 44,41 <x\ 4 PX4 > 34 S sX'l >33PS3 S A A ' Sil S AX'l < 4 X344 S X 43, 3x41 S 4 XX: 3s'MX, VAA s ■ xX 44,34'1 < 443 s3<, 4, 3X1141 sA 141 S 4 '33 v,x4X 3143 s 113 ' t sX43, 3 Ml < 4 xS 44,3 X,\ SPx Xx 4 i s 4 »,,43 s 4 IX Xis? 3 v<x4X > 3S41 < 4 3341 <\4’(, XMX, 4 S3?< 'MX, Xx As' 33? <, X? X < 334 PM < 3 ' V M1 >xX ' PM, 3 4 »,,x4> 4 » i 3341 s 41X1 s, M1 < 441 < V s t XxxxPi sXx 4 PM < \ M -X43,3314'3) < 3 44 >3? X < \3??’3< < 14 >4 'MX >33pX S\4 S,?4 'S3 < 33434 A3XM < MX < 3MX > 4 XX 44 <141 > 4? X < M, 4 333X43 3MX <? 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(., 4 ( s? 1 JX'M’3 3x 4 i ' 4 ( s?l 1 1 iA s I 3141 <141 ' 441 < M s 4 3XxS4X 314 Px i 4, 3 4 MX41 >3MM 33|< > 4U41 > X3?'X 3x? s,?4<|1 < 33?1 <, XX?i PMl sAx?! > 4 3xAi <xsl '3S?I’M s 3 M -Sfl s -'4PX X -A s. sT» ’Pi s 3xfX, 1X3 " I? -H sl3px s AM, M Ml si |\,3< sT 3x1 Ml sXx j TP34,4'X 4 X J XX? 4 >3 A < 4 p<, M <? 3\x3?l < Xx 4 px4. > 3 4* <xil >3XpX Xl sM 4 £ <4’4 > 334P< 1344 AM 3> W '<’Ms \;v Alls 3'4 ' Pxt S 34» SX41 > 3x41, 4 MM <"-414 3 " MP A Xl?t,3M < 3341s 4xxli < Mls 4 ~3, A '73 SMP4 s 3SP1 si "4x74fX?l, 3 IPX MMTi sx?l, 3 IPi s Tx\T< A, Pt sXlM 31'1*, T1,74 < 141,34. s? lxx\4'( s 3MX s 433 f <4 <xj3, \xps, ' 3'3? <,3441 < 3141, 1 X3 t 3?1 < 33?’ A, 3 4*,xx- 1,13? 7S<, A'14 xMl, MIX s 13341 APi s i 41,x>; r 4" 313X41,33f s\ j,,3^ <3 x I Pit- 31« s Ml >33 4 Pxt, 341 >3?1, XMf3 3S 4« > 4 i >41,5 MX > 4 xx 4 » <x4X < 3M1 s 433 '-4 >x41 > J 43 <3» < 4 1 31X41 > 3x41 s? x\ M< MXs VAX A XI?i,xK < 3’M3 < 4XX?i'MT< 1X41M 314* < X41 A? X,li > 4 3'IAAPx slxTPxi, XU sMl,7Px s V, T 1331P» iXlTPlM ♦ \7? < M1 -TPt,34 si 3 xMp4 sxxTPS 44, 3 44,341 SXX 4 ’’M S x 44 v41 slxPx 13 K s A < XM’’X 3S 41 s M Al, 3 MX, " xx 4 s,343 A 41 <WSGR Docket No. 56371-771.601Table 14-18Wlw V, I4 XS^SMIMS,- Vs»ii- M > S M X|’s, -> | PxA X | s. sXps > > px s > | s < 5 s’s S’’X \ Is. I «’S V< A, > S < XA, X x A < I W’ i(M’i <'> > H<M sVb'ilsi <’> ^C SHs lt >h f X xps < 1 xx | s. s'-> A A'K M; V l VPA l A < M S I VASA SXX I " V s x;<. MA S-M i i'xs, \ V AA - MAVs"1n I Y'< *< < SA s I A; V '7 V-<xX A sXx I PM s M s A A s SSI's '1 XS 1 < AA '? A < M > * %X xS’ s xx ’A'rf < M VXA X's|’x <s \ | S. s U o'l < x"spx 1' ' 5 >!( <p i^1|M s X U S^AA > I Pxl „ \ < 'MM X XIM I^X | A VM IMA < I'A ' S, SXA > SAP< vxx U sX'M r'M xV’v- A ' I xs 'i 'K f \M’M\5lKlW'x$S! Uhh A <■-<; •. V' -AA s xxA V x Ms sSP t < xx A - ’ xx i MXA ’ xxix <; x's i i 'MX, +■< i PM - x <• -six S'"> I < X M x A, XXAsi:< < X A > I IX < M s I XxxxiX s’-> ■■ I Px4 s X I < x|’S XX ’ I’ xS ' X i s < x”< < Xx ’ I’xs > X I S v'X X -,, I s, i s < A i XXIX i Xx V sXlX s XXIX s S's l MxA I OS sS?; XxXMX X XA I XX ' S 'XA X X 'X I •- X l< xA s? X xA l"'X A sXl’X s XXA s I x -< A <xA s ' A < SV l AMXA >x-> | M s X A AA > l |XfX V; XXX xA sS x l I’Ms X IV'xA J I 'X; -'S < I X X -''-.l\sxx |" >< - X I S ' -> A s x x l lM s \ V sXb AXp Mx l l | GIX < XM’x XX IS ' I S >|X < XX|X < I xx WM UM ^ d XXXSA AX F ’ ■>< < M s, x|Vx sI’ -s X x h s A SX jXXlA X X I t s lS PV MA I x x. S ^JX < X ->|X, | \x | i --.|XsS P'-x, X I%-,.|> S <x M> S M I S s ' V A XxA < ' xx I s SXIX sXX ’X XX I s A jl’t s I S’< xi - 1 Xxx x A sXX I ■ ’x4 X A < xlX iXx I O'XS j / i tS iSIX s X xIX sh M: 'six f S W M I V 1 S six, Sxpx VI s » I S. MsI p( sxs < | x X 'Xpl XX1Pxs X I s 'X A xM> X XX I s ' I 4;A S XX A, I xx A sx A S I IX "|> s I XXxXA sX'- I IM, Xf< A A s I |X As s I X xA > X XI’S s I Xx I GXI’S ' XXI’S s I XX A fXIX A |X <x$ ' | VAX ’S '~A ' i’xs > X I s < x X, X x<v -SX I S A-x I A XV I Xxxxlx sXX I PM, X 11 < SI'X sXXl’ X Xx V f Is six 'XXp-x XX I A 11 six 'XX:? AS s X? S s'sf < s'A VAS s X I s AIX ' xx|x s? xx b ASX s X Xs'< I xs’OxPv \ x|X ' X xX ’>| ' xFX s T l1X ' X< 'X XX x XIX s X xIX s S 'sAs i s sXIX s X xIX s XA V 'V’i SA> X < I x^ l s > >> X 'X x|A X x | s >;« > X < A AS. S I X XXxlX - > VX s I XS X s vxlX s X xlX s I xs V s xA s X Xi’s5I XX 14 s ',ps < xx | rxs < X I S. s xps -xx I IAS - X V s-'I’S s xsl’s < sXl’S S ’ |S( sXV | x x X X A xx ' |«xs X IS 'X'S ' x'x - 1 V < \ >xA -A | |‘x * < X ' I sx-A 'VxS’A Xx 'V A sA > X xA ' | XX ASS’S > ’vA ' ' vx l Axss, sx -xs, I \-,xxs>s > ’< A|’ l sS\Tb ^A -«-Ax’h ^f -4 5^Tx,’, v Pi s X A svx < A A s TA sA < T > > <-x A s -> -■■ I As ' l ( s A I A s s I x x s sA V IsS X v X x, s x ss, s’ sss >$ 'x'x I I’M ' -k A 'XA sAx’A Vs I S ' A S A 'VxI’X k'x A s I s,SA > ’-AA S I x'x I < Al’S s * A AS s I VAXs’ I ><x 1 |As s ’•> I s sXSA " Al’S X xl s. S U si's sXX> \x!s 14 'Is < \ x|S > I -X A xA < SMS < Vs V % I x'xSvxA s'xx / A Vx'A > Ts sA s'xxlA ksV / A A s'f A <x si VAXA '-A ’IAS - %?s xA xxp ’■x ’sx s s | 4, A s kXIS s I xx(A <x|X s I A < V s SXX'xlX sXX l TV s % 4 > SA < I l’S sXX s I six < \ SA S1AST4 A A S \SA s 1 xSTs, A A APsf<s, T \ Ss< A5S; TAxS. s \?s AA, s. SA s TSS Ts;-xA - | S»s XS I ■’•AXxA AM l’x< ' % A x|S sXX?5x sx l v I s six x-xl’ x X M i > I S M xx ' |’xssx I S sX:}V\X MAS s s i s > -> A \ > A s \ M S SM S A A ' ASM A | X ' <■ M*> A X« s M A s X A sS x V sSA s X sA s ’ S x I s. < A Xx X A x x k sxA s px x A u A A < ’ x xSA x -xxs A X xA s i xx I s xA s X x A I x'x '< AA S X \A s I 'x'x A ' x A ' xx I '’M S I < SA I As?WxA s XxA s W AAs VMV s l M xxA ' X I’ M X I s XA AA. IW M S A, X XS. I’X A ’>. S sXA sXX ’S XX A s ’S sA s X xA ' I XX 4 >x’X < S VX < XXH > -xA x< < I S X s xA < Vxs’ V l 'x x l S ssA ’-AA I v- H sxA XAA s l '-A V XA S 'AA * I " A " X|M | I VAxpUXx A'Sk s X A sSA s? A s XS s I S xSSIS 'XX A’xS ' < r ssxA I ASxS ' | X SX-S s'X SS T l’ M s X I s xA xX l I’xS X ' S -M AX'”x Xx | S | ( >|S AXl' x ’' X ' S ' I s si's < X xlX < I XS l S s xA < A s X< s S wS'< < sSx l iW X U s xA Vxl'" S M S s sSxA A M'x X A S IVIM X'- A ' I X'X A xA ' X'- A > | \ x | S ' '- A i x'x I A< s X V s'x A AV A X S V s V sA XX”s >I -sX lV xIS sSx V XS A s I t sA sSxlA Xx I s s l s sS s l l’VSX s l XXxSA x x, |< S s X I «, xsx As< x XS 11 I ( six i X"- A < I xM S M’S, i I A A< < I xx 'Xi’s AX | IMS M ' s sS A, i |’S s'-Ms| X x As\ XIM I I-A I V sA < V'IM | XX ' $ s’sA ' I A >'>s - l S x’-AsX xx ' S< W s > ->'X ' \ > SM ' x x |S"> A - T A - " S A x AX A sS" PP M ♦ X A V AfS'- Px 4 s F<,1 s, A - vPx v V A s pSss\TS;-V’ S " s p'sS M I l s < A '< XA < x > |f W V M - X XSW'XA | < xA s A x< i V x XA S XxA s I Xx A AA S XSA S: XX |< Al’s, s XXIX s I XX I A \A SXXIM'XX I $ S V? S. s! A AS s I X XxSA WX sl xS V xA M xA TxSlV xFX M'xA i Xx^ XFX AXTPM ' SU VA AXT I’SS X A s’xA s XXl’v I XM S s’xI’S s ’ A sXS s l SXX-SH SXM I’-M S X V S XA XM I’XA X I s, XA <\M |'X 4 S STS APVS XPX XXA MAA S XXA MSX V A- A s X iA sTSsV sXp, AM sXv T Xx'xXA5XXP < > I XX l I s4s A % XA ’ I xx | ssxA \ xA s I x M AxA ' 1XI’< ' I X x i s 'xA i I ’X s'xS ' I ’Ax'xA Ax I WsM ( sXA < I A s xssM xx-s A S'x I PM P< I l sX A - 1 A sXA 1 k x’-sX A -XX I I’M A 11 sXA s xx l pxs \ |< V-s I s A sIX ' XX 'x XX K I vA s \x|X s I x-ss K sXA s I I I \XxSp I sXX ' pxs > ’•> | S. AA -xxl’x v I s J IASS Axl’x v< |s <! (sl*i < SXA > | XX xA M xA - 1 xMM XA s\< | »A A sXA sXxPx XX A > I s, A, SSA > I Xx I s5xA sMTx Xx A Av A s 1 A AV I Axxxix xS I I’WSGR Docket No. 56371-771.601Table 14-19— nxpFsP M'7xi'T?rs'^UH '- PA S S S * SM v"- xSH ' i xs - U PS <*UU M P M ^ *M H-X ss *A 3 MXS S x S i KHhK ^ PS M H’ SH A V*!. X I N fi ' W! M \ \ P- > AA, x i i AUA \ X > hi ', < 5’ V^AH’ \ i -MXS f p«f: JH^ hS 'h fhn su t AXhi’s; wiw x vps S sxY i x i i HU v s t h1' XS J’AM M ' xs;xi 3 SM 3 -> * $ h’> CMS M 3!’v < A V't< U 3 S SU b f MXi h S KI < A \h > M i ^B A-^(U UNS -" MH s' xS S S’xs s -KUsS i’ XS sXp i x i s H <i \U Px' ( AM^ N X Ml’S xM’« M S’ U x xi UXilM X \ S >' x<. < U xi? H '( A! S hJM 8 \ S i's -4 -31 - 3 x 3 3 P-3 Ux XU » 3x’ < K S Pi 'X X M’ V MUXV 3 M'xP' XA xPi -s i i i spXP XV xP i. M i Ms 3x3 x X S PS M.»|X! $ H!>xS * '-<? X M 'M,s <xi - SM S M s X 33H xi U sXi M I Xi M SU SU M S '1xs sX <vX U PxU> - MV’. 'M fM'UH H. HU H H V fh AUU 'x< M Hs hH U xl, UH H3 W fA W UH \ H'i st^ H M S H h x U > „ ss x 'M 3’ t ^ Ai P X 'MN S SI -si (U i xs AH U ''lUhM’U S 3 i < ix H N bWK f^ h ’X M M PJ ’ UHM W HI -< K C xH S’XS AX SU UP M SP ’x U U Ux H S'-s ux xu s: -i: 3 P < H <s xu s x- x M S* M -SH5X> H X ' x< ss;, N M U S XJ XS „ u M;M<h ’ M, A P S '1' W! (I!’! < M P H V Al S U s i xi s-i i H xuU sM PVSG'i i 'x xi x < ' S’S VsiU S x s H P -x i. s'-s 8U sixP. V xxr i x 3 3 3 < ' 3 " A X M S’S U 'U,xi S’A 3 'v xi S U <; x. XA: Hs -><; U s'-> s P V APU H HAP VAP’ X D S < US U S'Xi GMft 3V - S UH X« UUXI s \ r MsU > 3 xi X,s UH XS > U AH!U 'xi <xi $ U < X> p \ Ks < -? U - xi' <<s. >">!' K i H « U H P- ' » <x M' _; < j x u Pxu A su HU r s j x> <xs: u » i u x \ s?s x< s sxj i s' -4? -x y,-- s x _ SH ' ' P i x xs >xU 4’M As’Hs ' x X UH M U 3 - S 3 i’. UA VlAi’ y M> x’ j i < M H' xU < X \UA K U rxu >x VH U X* X \; u X* fU M r % x>, s >i i U - x> A S XS AS ' M<xp M! U x U I f ^ xl X S hH X$ ft.un! V i > Ah > Mi SSUi - H'! -!’ W - S ' s s.< i '- i i - PM S A MU X U ISHA ^ H M XH P! UH i'M b^U. hl xx s pi -AiMxi s V'\ s xi M r u u x u PM <-x xu s: x s s HXIifx \u, < i xi x u u xs. «usvxf x x s IH X<, U > X s rM -M’U H U H x X S UH XS XHU xs,xK U. Lx \ s’i v. K U " \u. s i \H px? b^Kf Mi PxU -x XSX H x U SM AX \U J X H 5'XHA S S J I X U pC' S s x XH:: S sX>xSi sXsU X H U! H X Xxp >: s M~X!;Murn H>1^ \ i TH x» spi M f' VTxi <4 T~x J x- sTpl xt, U U xT? f.'UM x U PY isX SU s K U KU tX S SX s ' x H1<X' AX '- UU 'S *’X4 >u vstx U A. i ^ MS A P UMU S U H > K U PY AX XU USS x V PI x. P> U P M A 4; UU xi > S u\ X' u’s U »H x( > 4 HSHSi H \ S?x M 4Ui xH Pxi S ' - SU A 'U X \ f H M < U - xP Ss A 'U h i UXP SAXP K M H \P M SHSP A, Ki x i «:'s x< PX | - | i M i x xpiU xI X U Ps xi U M? \ I •>( iXl ’ UfI xs x S I U -KS -Pi M S S XS <xs TUU x* -< S U\ xj <u - U Pxl s5x s SPAx ’ SUXM XU S s U Xi X X i Pi Xi jU M P s XA'--S | Xfi x- x S 3 i’i xS ips5xp *3 AU X i S 3 U - XP SAXP K K I G K U PXH SXAU K!X M S’I XUPA KS X M Pi U. U < < X; X \: P ’ XS > PAX>! U SiAHH M i’i U X>! f V 'S A i i i i I S P- i A Vt x U Px _ _M XM P S ““x ’iS ixU s'xPSi sxPK S s U < HU '- % UH x< PxH sx S Yxp xi xp AH > * < i XH P sS s < UP sUH Psi t sXAU - I M M P: XS < U S'-: P S X - 4: U xS P X I M -xS ' psfxp x< xps X '? f s < ' xi x \ S'H M,$ - 3 x? i pxs s >x xU - > j Psi < A XU xp \s M'vx U s < < J x i: Pxi i <x \ U s '. X U pxi i i > \U - 3 xj XA 3 PS Px U S' 4 s x \ U S U,x X 3 Pi xs »P< <xi PM xi sM HU M, Pxi Ux XU sS xU Px> S s x \P» s? xS X U U -4 U H 4 x \ SPi xs -PUx PUs sxpp- H i »x! < ' U PS xs sUs'P p i 'xs M JU 3? x > x VU xs -Ps < Kv' PXU -X YX S i x i i pxH >-K i>f A ’< HUM 'x SPsM x H P-H AX XU < x i i pxi i x \UJ x? i px s > > \p s s sxP Ss sxS'H x i i S U i '- i S s'1'- ’ s,x MX < ixi x \ US Mp-Pxi p \ p-> S, \s ’'Pt s s xS x x 3 pfxs > U < <3 ’ M Y OKU S S si x M PS xs -U d x U P'i' s sx xpu) x£ x \ F- ^s > U xp xs MU M - S UxP U sXp ' M S S isxS’SUXSU M S S is i xi "- \ S Pi 'H sU -S x ’S S’M iK Wu S x x \ | pi Y xU AX.1 p K Xi sXi 1 Pi(TSS x \ FTP x< s? H - xi p xi x4 5 } r,s u pr }-,,,<:-i AXSU <xS”UsxPi x 3 i i i- i xs X \ 33'3 M < U - -3 3' ’> S XJ sXi; u S x3 xV S’S xs, U<x?’ V <xi> s i i i 3 U'- P U ^SS’I i s S^ U SUS U x SS'f s I x X M PS XAU S M > US'S s' U 3 xs \ 3 PS "--3 s*H M P xi xi sM 3i U.(X3 P M \i,--i 3 U M* XS -x'»I M > U >1 xi 3 pxS i x x Ps,'1 x3 3 33 * X Xi >--> U <\ 3 xx i X i MX <*i < x 3 --x 3 X i XU sX sX i x' XP-*< i M'S x i - - 3 \ xU sX x i xx ii 3 XPs sS''i S: x ’ i’S Xi S X XXS’s,>-> r->3 xPXi S I XU;* X3’X<, S -. X ” X U S X 3 xi -pxs S S V'UM x'sWSGR Docket No. 56371-771.601Table 14-20XTFV' 'M^M XN M XI’XMI xx? MX S M M’-xs,! XIMxlxl XI-M, MX » ■ x. N(> I xx XIX.xIx - xI‘-M;! ’< IX x S' M’M > J t IX A I xl Xi'V ' I X IX ' $ S SH M X xlX <'* I xl \<’X4 > I XIX J I x I:’I X4 JX \ MX <x 3 xx I XI x*X IX. >x hS I XI XIX A<h) l’« x< <s xxix, -ti I M M’M i I XIX i s '-< I -’I SS <\ VMS I is I I' "<i -\ XMX »X 4 X! XI'M. I 'S'SA! M M’M -i XN > X*Xl '" INvI GXi'- IXAl X5 ‘^fh4\n SGXANXAI M hl'N*?! XI’ 4 A I M M'M.,: MXt’M N sx J's YM’MA I; M XIN* J I XIX sx I M SI’# > ' XIX > ' M l<l M,s \> N > I M'xx U -I o N'^-x ^< V MX < I, M*M. x v> s MX >x I x\ I V <\ MX, N I VI ->* < X X MA A I XI IM’X4 j C MX A ISM XI MS U5* s I A I I"1 v AAMX > 1X1 Pi X* > X XMX -S 1 AX C X’ SI’ I >sS > I M'M si x-x I Xis U M 1’1 xi \ S I X >\ I M sPxi S I XIS sS I XI Si’s* J,' Six < ' X I I’l \* A i X'IN <;. Ai'M <1 xS C, MX JA I xx 1 XI UN USsI SI" M <1 A A I AN A I US 1 XI A A A > M A-I I X: I xN six; WI'M; A A I XN. -< I M X? X<; I XlX >\I XI M'V, s I XIX A A I 1'1 M A WtX JX * M SIM i H > I XN A IM xj’xs A XIS M A I }’I xf s x,x Xis A I M M*ut < I XI* < A I; M AIM > ' XI5* A I xl SI’ i M 11 X A JX I xx:, X) MS,-N I sI*-M >. SS I XIS < I xx \x? XXAxU K, X X< SMX> XXN S I XXISJMX!XXI'‘XSXH!H ISiXxrxSxM Ji US JI'XsX*!! XSvMS sxXl px i i S '< I <. SXN XX'’S X x I « > M six > S x'S '■ IS x< S I * x'xxNtSx I I’XS X I i >xN > I IS s X< s I x'xxMX i XSIX s I xx 14.; X'S i XSIS ' I XX H JXIS » I IS > x* J I XSxXlx <xx I I’M > X MsXx IS S I XX 14;'--£X > US<\4 > I \\X'-, IX > xX I I!X4 > \ 14,'X’S < SM*X X'x I » < I i US sXSpx \X?4 s ’S >1'4:(\ X ■ I'-U > X I * iX S tSX 11 »X4 X '? > VX! vxlx > 4 XX M -MS s XX'S J I < X I », sxNsXxM I Xx I i sxp 4 < I NsM 11 AMsAN < X"> M ' I SA I * < MSsXSIS < I x. M* < MS<. VMS < 1 xixXsMS ' sMMAA 14 ' I * MS; i is ss* J: SSXSN < Xxcs i: 1 » u-ussxsis • i %s 11 xsrs v? i * <xis;xx i, x ISsXiSsXX H> X4 MSs VMS.'"xAlMSIS V'Ss" Msi XSSSN 'Xx^lMV X 14 AIS JXS 11"' < ' X I $ >xis >sx I UX4 > S ■■$ >x-X > " M'S V 14 s U AS. XMS > I xs $ i M'4: < xx S > I xx I * x 4 it XxxMSi xsts it SX IMS'S i \StSi7SxMiMS,< XStSi I'XXtSvX^nsISxI'xXtM ^Nt’ 4 > M> S NSxISiSxM’M < X.vxtS. 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[0167] The XTEN linker may comprise those described in Patent Cooperation Treaty Patent Application Nos: PCT / US2010 / 023106 and PCT / US2013 / 028116, each of which is incorporated by reference in its entirety. The BiTE described herein may comprise a linker as described herein.Various additional engineered polypeptides

[0168] In some cases, disclosed herein are various additional engineered polypeptides. In some cases, the various additional polypeptides can comprise one or more of the following: an integrin, an immune response activator, a TGF-beta inhibitor, a dendritic cell (DC) activator, an anticoagulant, an angiogenesis inhibitor, a bispecific antibody, an extracellular matrix modulator, a Fms-related tyrosine kinase 3 ligand (Flt3 ligand), a CD47 inhibitor, a CSF-1R inhibitor, a Granulocyte-macrophage colony-stimulating factor (GM-CSF), an epigenetic regulator, IL-2, a checkpoint inhibitor, a decoy cytokine receptor, a co-stimulatory ligand, a CD89 activator, a metabolic regulator, or a suicidal protein, or a combination thereof. In some cases, the additional engineered polypeptide may comprise an integrin. In some cases, the additional engineered polypeptide may comprise an immune response activator. In some cases, the additional engineered polypeptide may comprise a TGF-beta inhibitor. In some cases, the additional engineered polypeptide may comprise a dendritic cell (DC) activator. In some cases,WSGR Docket No. 56371-771.601the additional engineered polypeptide may comprise an anticoagulant. In some cases, the additional engineered polypeptide may comprise an angiogenesis inhibitor. In some cases, the additional engineered polypeptide may comprise a bispecific antibody. In some cases, the additional engineered polypeptide may comprise an extracellular matrix modulator. In some cases, the additional engineered polypeptide may comprise a Fms-related tyrosine kinase 3 ligand (Flt3 ligand). In some cases, the additional engineered polypeptide may comprise a CD47 inhibitor. In some cases, the additional engineered polypeptide may comprise a CSF-1R inhibitor. In some cases, the additional engineered polypeptide may comprise a Granulocytemacrophage colony-stimulating factor (GM-CSF). In some cases, the additional engineered polypeptide may comprise an epigenetic regulator. In some cases, the additional engineered polypeptide may comprise IL-2. In some cases, the additional engineered polypeptide may comprise a checkpoint inhibitor. In some cases, the additional engineered polypeptide may comprise a decoy cytokine receptor. In some cases, the additional engineered polypeptide may comprise a co-stimulatory ligand. In some cases, the additional engineered polypeptide may comprise a CD89 activator. In some cases, the additional engineered polypeptide may comprise a metabolic regulator. In some cases, the ad...

Claims

1. WSGR Docket No. 56371-771.601CLAIMSWhat is claimed is:

1. A composition comprising a nucleic acid encoding at least two chimeric fusion proteins (CFPs) comprising a first CFP and a second CFP,wherein the first CFP comprises (a) a first extracellular domain (ECD) comprising a first antigen-binding domain (ABD) and (b) a first transmembrane domain (TD) operatively linked to the first ECD;wherein the second CFP comprises (c) a second ECD comprising a second ABD and (d) a second TD operatively linked to the second ECD;wherein the first TD comprises a TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell;wherein the second TD comprises a TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell; andwherein the first and second cells comprise any two of: a natural killer (NK) cell, a monocyte, a T cell, or a B cell.

2. The composition of claim 1, wherein the nucleic acid comprises a first nucleic acid molecule comprising a sequence encoding the first CFP and a second nucleic acid molecule comprising a sequence encoding the second CFP.

3. The composition of claim 2, wherein the first nucleic acid molecule and the second nucleic acid molecule are encapsulated in an LNP.

4. The composition of claim 2 or 3, wherein the first nucleic acid molecule is encapsulated in a first LNP.

5. The composition of any one of claims 2-4, wherein the second nucleic acid molecule is encapsulated in a second LNP.

6. The composition of claim 4 or 5, wherein the first or second LNP does not comprise a targeting moiety that specifically binds to a cell surface receptor.

7. The composition of any one of claims 4-6, wherein the first or second LNP comprises a targeting moiety that specifically binds to a cell surface receptor.

8. The composition of claim 7, wherein the first and second LNP comprise a targeting moiety that specifically binds to a cell surface receptor.WSGR Docket No. 56371-771.6019. The composition of claim 8, wherein the first LNP comprises a targeting moiety that specifically binds to a first cell surface receptor and the second LNP comprises a targeting moiety that binds to a second cell surface receptor.

10. The composition of claim 9, wherein the first and second cell surface receptor are a same cell surface receptor.

11. The composition of claim 9, wherein the first and second cell surface receptor are different.

12. The composition of claim 1, wherein the first and second CFP are encoded by a same nucleic acid molecule.

13. The composition of claim 12, wherein the nucleic acid molecule is encapsulated in an LNP.

14. The composition of claim 13, wherein the LNP comprises a targeting moiety that specifically binds to a cell surface receptor.

15. The composition of any one of claims 7-11 and 14, wherein the targeting moiety comprises an antibody, a VHH, a scFv, a DARPin, or an antigen binding fragment thereof.

16. The composition of any one of claims 7-11, 14, and 15, wherein the cell surface receptor is CD2, CD3, CD4, CD5, CD7, or CD8.

17. The composition of any one of claims 12-16, wherein the sequence encoding the first CFP and the sequence encoding the second CFP are coupled via an intermediate sequence that is configured to facilitate polycistronic expression of the first and second CFPs.

18. The composition of any one of claims 1-17, wherein the first ABD or the second ABD is configured to bind a first antigen selected from the group consisting of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor-associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), HER2, CD30, or Folate Receptor alpha (FRa).

19. The composition of any one of claims 1-18, wherein the first and second ABDs are a same ABD.

20. A composition comprising a nucleic acid encoding at least three chimeric fusion proteins (CFPs) comprising a first CFP, a second CFP, and a third CFP,wherein the first CFP comprises (a) a first extracellular domain (ECD) comprising a first antigen-binding domain (ABD) and (b) a first transmembrane domain (TD) operatively linked to the first extracellular domain;WSGR Docket No. 56371-771.601wherein the second CFP comprises (c) a second ECD comprising a second ABD and (d) a second TD operatively linked to the second ECD;wherein the third CFP comprises (e) a third ECD comprising a third ABD and (f) a third TD operatively linked to the third ECD;wherein the first TD comprises a TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell;wherein the second TD comprises a TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell;wherein the third TD comprises a TD from a third protein capable of multimerizing with a cell surface receptor expressed by a third cell such that the third CFP is expressed on a cell surface of the third cell;wherein the first; second; and third cells are different types of cells; and wherein the first, second, or third ABD is configured to bind at least one of Cluster of Differentiation 19 (CD 19), CD20, B-cell maturation antigen (BCMA), Tumor- associated calcium signal transducer 2 (Trop-2), Glypican 3 (GPC3), HER2, CD30 or FRa.

21. The composition of claim 20, wherein the nucleic acid comprises two or more nucleic acid molecules.

22. The composition of claim 20, wherein the first, second, and third CFP is encoded by a same nucleic acid molecule.

23. The composition of any one of claims 20-22, wherein two sequences encoding two of the at least three CFPs are coupled via an intermediate sequence that is configured to facilitate polycistronic expression of the two of the at least three CFPs.

24. The composition of claim 20-23, wherein the first, second, and third cells comprise any two of a natural killer (NK) cell, a monocyte, a T cell, or a B cell.

25. The composition of any one of claims 17-19, 23, and 24, wherein the intermediate sequence: (1) comprises or encodes an internal ribosome entry site (IRES), or (2) encodes a ribosomal skipping site, or (3) a combination of (l)-(2).

26. The composition of claim 25, wherein the intermediate sequence comprises or encodes the IRES.

27. The composition of claim 25 or 26, wherein the intermediate sequence encodes the ribosomal skipping site.WSGR Docket No. 56371-771.60128. The composition of claim 27, wherein the ribosomal skipping site comprises at least one of E2A F2A, T2A, or P2A.

29. The composition of claim 27, wherein the ribosomal skipping site comprises at least two copies of E2A F2A, T2A, or P2A.

30. The composition of any one of claims 1-29, wherein the first cell or the second cell are a same cell type.

31. The composition of any one of claims 1-30, wherein the first or second cell is a NK cell.

32. The composition of claim 31, wherein the first or second TD comprises a TD of: CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof.

33. The composition of claim 32, wherein the first or second TD comprises a TD of NKp44.

34. The composition of any one of claims 31-33, wherein the first or second CFP further comprises a first intracellular domain (ICD).

35. The composition of claim 34, wherein the first or second ICD comprises an intracellular signaling domain of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3ζ, DAP 10, DAP 12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD137, or a combination thereof.

36. The composition of claim 34 or 35, wherein the first or second ICD comprises an ICD of CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof.

37. The composition of claim 36, wherein the first or second ICD comprises an ICD of NKp44.

38. The composition of any one of claims 31-37, wherein the first or second ECD further comprises an ECD of: CD39, CD56, CD57, CD94, CD159a, CD159c, CD314, CD335, CD336, CD337, DAP12, DAP10, NKG2C, NKG2D, NKG2E, Ly49D, Ly49D, NKp46, NKp30, or NKp44, or a combination thereof.

39. The composition of claim 38, wherein the first ECD further comprises an ECD of NKp44.

40. The composition of any one of claims 1-30, wherein the first or second cell is a monocyte.

41. The composition of claim 40, wherein the first or second TD comprises a TD of: CD16a, CD64, CD68, or CD89, or a combination thereof.

42. The composition of claim 41, wherein the first or second TD comprises a TD of CD89.WSGR Docket No. 56371-771.60143. The composition of any one of claims 40-42, wherein the first or second CFP further a second ICD.

44. The composition of claim 43, wherein the first or second ICD comprises an intracellular signaling domain of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3ζ, DAP 10, DAP 12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD137, or a combination thereof.

45. The composition of claim 43 or 44, wherein the first or second ICD comprises an ICD of: CD 16a, CD64, CD68, or CD89, or a combination thereof.

46. The composition of claim 45, wherein the first or second ICD comprises an ICD of CD89.

47. The composition of any one of claims 40-46, wherein the first or second ECD further comprises an ECD of: CD 16a, CD64, CD68, or CD89, or a combination thereof.

48. The composition of claim 47, wherein the first or second ECD further comprises an ECD of CD89.

49. The composition of any one of claims 1-30, wherein the first or second cell is a T cell.

50. The composition of claim 49, wherein the first or second TD comprises a TD of: CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3ε, CD3δ, CD3γ, CD3ζ, TCRα chain, TCRβ chain, TCRγ chain, or TCRδ chain, or a combination thereof.

51. The composition of claim 50, wherein the first or second TD comprises a TD of CD3α.

52. The composition of any one of claims 49-51, wherein the first or second CFP further comprises a first or second ICD.

53. The composition of claim 52, wherein the first or second ICD comprises an intracellular signaling domain of: Fc receptor g subunit, FcαR, FcεR, CD40, CD3ζ, DAP 10, DAP 12, 2B4, NTB-A, CRACC, 41BB, 0X40, CRTAM, CD28, or CD137, or a combination thereof.

54. The composition of claim 52 or 53, wherein the first or second ICD comprises an ICD of: CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3ε, CD3δ, CD3γ, CD3ζ, TCRα chain, TCRβ chain, TCRγ chain, or TCRδ chain, or a combination thereof.

55. The composition of claim 54, wherein the first or second ICD comprises an ICD of CD3α, CD3δ, or CD3γ.

56. The composition of any one of claims 49-55, wherein the first or second ECD further comprises an ECD of: CD3, CD4, CD5, CD7, CD8, CD28, CD48, CD3a, CD38, CD3y, CD3ζ, TCRa chain, TCRP chain, TCRy chain, or TCR6 chain, or a combination thereof.

57. The composition of claim 56, wherein the first or second ECD comprises an ECD of CD3α, CD3δ, or CD3γ.WSGR Docket No. 56371-771.60158. The composition of any one of claims 1-57, wherein the first or second ABD binds CD 19.

59. The composition of any one of claims 1-57, wherein the first or second ABD binds CD20.

60. The composition of any one of claims 1-57, wherein the first or second ABD binds BCMA.

61. The composition of any one of claims 1-57, wherein the first ABD binds CD19 and the second ABD binds CD20.

62. The composition of any one of claims 1-57, wherein the first ABD binds CD 19 and the second ABD binds BCMA.

63. The composition of any one of claims 1-57, wherein the first ABD binds CD20 and the second ABD binds BCMA.

64. The composition of any one of claims 1-57, wherein the first and second ABD binds CD 19.

65. The composition of any one of claims 1-57, wherein the first and second ABD binds CD20.

66. The composition of any one of claims 1-57, wherein the first and second ABD binds BCMA.

67. The composition of any one of claims 1-57, wherein the first or second ABD binds CD19, and wherein the first or second ABD comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH and / or VL sequence having at least 80% sequence identity to any sequence set forth in Table 1 or Table 19.

68. The composition of any one of claims 1-57, wherein the first or second ABD binds CD20, and wherein the first or second ABD comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH and / or VL sequence having at least 80% sequence identity to any sequence set forth in Table 3.

69. The composition of any one of claims 1-57, wherein the first or second ABD binds BCMA, wherein the first or second ABD comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, VH and / or VL sequence having at least 80% sequence identity to any sequence set forth in Table 2.

70. The composition of any one of claims 1-57, wherein the first or second ABD is configured to bind both BCMA and CD 19.

71. The composition of claim 70, wherein the first or second CFP comprises a sequence having at least 80% sequence identity to a sequence set forth in Table 19.WSGR Docket No. 56371-771.60172. The composition of any one of claims 1-57, wherein the first ABD binds HER2 and the second ABD binds TROP2.

73. The composition of any one of claims 1-57, wherein the first ABD and the second ABD bind GPC3.

74. The composition of any one of claims 1-19, wherein the composition further comprises a sequence encoding a third CFP, wherein the third CFP comprises a third ECD comprising a third ABD and a third TD operatively linked to the third ECD; and wherein the third TD comprises a TD from a third protein capable of multimerizing with a cell surface receptor expressed by a third cell such that the third CFP is expressed on a cell surface of the third cell.

75. The composition of any one of claims 20-74, wherein the third cell is a NK cell, a T cell, a B cell, a monocyte, or a macrophage.

76. The composition of any one of claims 1-75, wherein the first, second, or third CFP comprises a sequence having at least 80% sequence identity a sequence presented in Table 2077. A composition comprising(a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD 19, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and(b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind CD20, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

78. A composition comprising(a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD 19, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and(b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind BCMA, wherein the first CFP comprises a second TD from a second proteinWSGR Docket No. 56371-771.601capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

79. A composition comprising(a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD20, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and(b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind BCMA, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

80. A composition comprising(a) a first nucleic acid sequence encoding a first CFP comprising a first ECD comprising a first ABD, wherein the first ABD is configured to bind CD 19 and BCMA, wherein the first CFP comprises a first TD from a first protein capable of multimerizing with a cell surface receptor expressed by a first cell such that the first CFP is expressed on a cell surface of the first cell; and(b) a second nucleic acid sequence encoding a second CFP comprising a second ECD comprising a second ABD, wherein the second ABD is configured to bind a second antigen selected from CD 19, BCMA, or CD20, wherein the first CFP comprises a second TD from a second protein capable of multimerizing with a cell surface receptor expressed by a second cell such that the second CFP is expressed on a cell surface of the second cell.

81. The composition of any one of claims 1-80, wherein the composition comprises a nucleic acid sequence having at least 80% sequence identity to any sequence presented in Table 1282. The composition of any one of claims 1-81, wherein the composition comprises an unmodified nucleic acid.

83. The composition of claim 82, wherein the unmodified nucleic acid does not comprise a pseudouridine, 1-methyl-pseudouridine or 5-methoxyuridine.

84. The composition of claim 82 or 83, wherein a level of immune activation induced by the unmodified nucleic acid is substantially similar to a level of immune activation induced by a nucleic acid comprising one or more modifications, optionally wherein the one orWSGR Docket No. 56371-771.601more modifications comprise pseudouridine, 1-methyl-pseudouridine or 5- methoxyuridine.

85. The composition of any one of claim 1-84, wherein the composition comprises RNA.

86. The composition of any one of claims 1-85, wherein the composition comprises mRNA.

87. The composition of any one of claims 1-86, wherein the composition further comprises an additional agent.

88. The composition of claim 87, wherein the additional agent is selected from the group consisting of(a) an engineered cell surface receptor or a sequence encoding the engineered cell surface receptor;(b) an engineered cytokine receptor or a sequence encoding the engineered cytokine receptor;(c) a sequence encoding a cytokine;(d) a checkpoint inhibitor or a sequence encoding a checkpoint inhibitor; and (e) any combination of (a)-(d).

89. The composition of claim 88, wherein the engineered cell surface receptor or the engineered cytokine receptor comprises a sequence having at least 80% sequence identity to any sequence set forth in Tables 7-11.

90. The composition of claim 88, wherein the cytokine is IL-12 or IL-15.

91. The composition of claim 88, wherein the checkpoint inhibitor comprises an anti-PD-1 antibody, an anti-TIGIT antibody, an anti-PDLl antibody, or any combination thereof.

92. A pharmaceutical composition comprising (a) the composition of any one of claims 1-91 and (b) a pharmaceutically acceptable excipient.

93. The pharmaceutical composition of claim 92, wherein the pharmaceutical composition is formulated for systemic delivery or delivery by an intravenous route.

94. A method of treating a disease or condition in a subject in need thereof, comprising administering the composition of any one of claims 1-91 or the pharmaceutical composition of claim 92 or 93.

95. The method of claim 94, wherein the disease or condition comprises a neoplastic disease.

96. The method of claim 95, wherein the neoplastic disease comprises cancer.

97. The method of claim 94, wherein the disease or condition comprises autoimmunity.

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