Expansion, propagation, and modulation of immune cell subsets by peptides

Abstract

Methods and compositions for expansion, propagation, and modulation of immune cell subsets using N-terminal domains of an FGFBP or fusion proteins thereof.

Description

93597 / 7296 EXPANSION, PROPAGATION, AND MODULATION OF IMMUNE CELL SUBSETS BY PEPTIDES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 634,541, filedApril 16, 2024, the contents of which are hereby incorporated by reference. STATEMENT OF GOVERNMENTAL INTEREST

[0002] This invention was made with government support under grant numbers DK128801,AG067014, and DK103155 awarded by the National Institutes of Health. The government has certain rights in the invention. REFERENCE TO SEQUENCE LISTING

[0003] This application incorporates-by-reference nucleotide and / or amino acid sequenceswhich are present in the file named “250415_92401-A-PCT_93597- 7296_Sequence_Listing_AWG.xml”, which is 26,046 bytes in size, and which was created on April 10, 2025 in the IBM-PC machine format, having an operating system compatibility with MS-Windows, which is contained in the XML file filed April 16, 2025 as part of this application. BACKGROUND

[0004] Immune cells, such as T cells including alpha-beta, gamma-delta or natural killer Tcells (NKT), and such as natural killer (NK) cells, undergo self-renewal after they become activated. Current therapeutics are limited by mechanisms that diminish immune cell function by causing their inactivation. New methods or treatments to enhance self-renewal are needed to enhance the ability to propagate and promote the effector function of T cells or Natural Killer cells for use in immunotherapies, such as to treat infectious diseases or cancer. SUMMARY

[0005] An expression construct encoding (i) an N-terminal domain of a fibroblast growthfactor binding protein 2 (FGFBP2), but not encoding a full length and / or mature FGFBP2 protein, 1 4896-4870-0471v.193597 / 7296 or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length and / or mature FGFBP3 protein.

[0006] An expression construct encoding a fusion protein comprising (A) (i) an N-terminaldomain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0007] A composition comprising the expression construct described herein.

[0008] A protein domain comprising (a) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein, or (b) an N- terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein.

[0009] A fusion protein comprising (A) (i) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0010] A method of promoting propagation of, function of, and / or increasing viability of, Tcells, optionally alpha-beta or gamma-delta T cells or natural killer T cells, comprising contacting said cells with an amount of a composition comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, T cells.

[0011] A method of promoting propagation of, function of, and / or increasing viability of,Natural Killer (NK) cells, comprising contacting said cells with an amount of a composition comprising a (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells.

[0012] A method of promoting propagation of, function of, and / or increasing viability of, Tcells in a subject, optionally alpha-beta or gamma-delta T cells or natural killer T cells, comprising administering to said subject an expression construct which encodes (i) an N-terminal domain of an FGFBP2, or (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, T cells, or 2 4896-4870-0471v.193597 / 7296 a method of promoting propagation of, function of, and / or increasing viability of, Natural Killer (NK) cells, comprising administering to said subject an expression construct which encodes (i) an N-terminal domain of an FGFBP2, or (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, NK cells.

[0013] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0014] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the cancer or neoplasia.

[0015] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0016] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the cancer or neoplasia.

[0017] A method of treating an infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have 3 4896-4870-0471v.193597 / 7296 been contacted with an protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0018] A method of treating an infectious disease in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the infectious disease.

[0019] A method of treating an infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0020] A method of treating an infectious disease in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the infectious disease.

[0021] A cell engineered to express an expression construct described herein.

[0022] A cell engineered to express a protein domain or peptide described herein.

[0023] A cell engineered to express a fusion protein described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIGS.1A-1E. Annotated exemplary protein sequences of FGFBP1 (human 1A, mouse1B), FGFBP2 (human 1C), and FGFBP3 (human 1D, mouse 1E). Signal peptides as predicted by SignalP6.06are annotated in grey. Putative heparin-binding domain (dark green) and fibroblast growth factor (FGF)-binding domain (light green) are annotated, as predicted by AlphaFold7. 4 4896-4870-0471v.193597 / 7296

[0025] FIGS.2A-2D. Annotated protein sequences of expressed recombinant proteins. Signalpeptides (grey), native protein sequences (yellow), putative heparin-binding domains (dark green) and C-terminal tags (blue) are annotated. 2A. Mouse FGFBP1 T34-G163. 2B. Human FGFBP1 K34-N158.2C. Human FGFBP2 G30-G146.2D. Human FGFBP2 M1-G146.

[0026] FIGS. 3A-3B. FGFBP1 N-terminal domain (NTD) augments human CD8 (3A) andCD4 (3B) T cell proliferation in response to anti-CD3 stimulation. Human T cells were isolated from peripheral blood of a healthy patient volunteer using antibody mediated depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE) to track cell division. Unstimulated T cells (top), or T cells stimulated with anti-CD3 antibody (UCHT1) + / - anti-CD28 antibody (CD28.2; middle, bottom) were incubated for 4 days with increasing concentration of recombinant mouse FGFBP1 NTD-His (as indicated). Relative cell number is indicated on the Y-axis and CFSE stain is indicated on the X-Axis. Gates indicate proportion of cells that have undergone cell division. Notably, mouse FGFBP1 NTD-His enhances both CD8 and CD4 T cell division in a dose-dependent manner in the context of anti-CD3 stimulation.

[0027] FIGS. 4A-4B. Human FGFBP2 NTD, human FGFBP1 NTD, and mouse FGFBP1-NTD all augment anti-CD3-induced human CD8 T cell proliferation in a dose-dependent manner. Human T cells were isolated from peripheral blood of a healthy patient volunteer using antibody mediated depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE) to track cell division. T cells were incubated for 4 days with indicated concentrations of the following recombinant peptides: Human FGFBP2 NTD-His, Human FGFBP2 NTD-Fc, Human FGFBP1 NTD-His, and Mouse FGFBP1 NTD-His. (4A) Relative cell number (Y-axis) and CFSE (X-axis) with gates indicating cells that have undergone cell division. (4B). Graph indicating proportion of cells that have undergone cell division with the indicated recombinant peptides. Frequency of cells undergoing cell division with anti-CD3 only control is indicated in red on Y-axis. Notably, all recombinant peptides induce CD 8 T cell division above what is observed with anti-CD3 alone.

[0028] FIGS. 5A-5B. Human FGFBP2 NTD, human FGFBP1 NTD, and mouse FGFBP1-NTD augment anti-CD3-induced CD4 T cell proliferation in a dose-dependent manner. Human T cells were isolated from peripheral blood of a healthy patient volunteer using antibody mediated 5 4896-4870-0471v.193597 / 7296depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidylester (CFSE) to track cell division. T cells were incubated for 4 days with indicated concentrations of recombinant Human FGFBP2 NTD-His, Human FGFBP2 NTD-Fc, Human FGFBP1 NTD-His, and Mouse FGFBP1 NTD-His. (4A) Relative cell number (Y-axis) and CFSE (X-axis) with gates indicating cells that have undergone cell division. (4B). Graph indicating proportion of cells that have undergone cell division within indicated recombinant peptides. Frequency of cells undergoing cell division with anti-CD3 only control is indicated in red on Y-axis. . Notably, all recombinant peptides induce CD4 T cell division above what is observed with anti-CD3 alone.

[0029] FIG. 6. FGFBP1-NTD does not augment anti-CD3-induced proliferation of mouse Tcells. Mouse splenic CD8 T cells were labeled with carboxyfluorescein succinimidyl ester (CFSE)and stimulated with anti-CD3 (17A2) and anti-CD28 (37.51) in the presence of increasing concentrations of mouse FGFBP1-NTD. Gates indicate cells that have undergone cell division.

[0030] FIGS. 7A-7D. FGFBP2-NTD augments anti-CD3-mediated cell division, primarily incytotoxic memory CD4 and CD8 T cells by enhancing cell division in cells that normally respond to anti-CD3 stimulation and are clonally expanded at baseline. Human T cells were isolated from peripheral blood of a healthy patient donor (RosetteSep). T cells from the same sample were split and cultured for 4 days in media alone, with anti-CD3 stimulation, or with anti-CD3 stimulation + 300nM FGFBP2-NTD. Single-cell RNA-sequencing and TCR sequencing (10X genomics Chromium) was performed on all groups of T cells. (7A) Unsupervised clustering based on single- cell transcriptomes by Uniform Manifold Approximation and Projection (UMAP) shown with cell phenotypes assigned by SingleR (left) and FGFBP2 RNA expression indicated (right). (7B) Expression of CD8A, CD4, and marker of cytotoxicity NKG7. (7C) FGFBP2 NTD augments clonal expansion of cytotoxic T cells which have a similar phenotype in all groups. Clonally expanded T cell clones are colored by relative frequency in the dataset normalized to cell number. (7D) FGFBP2 NTD augments anti-CD3-induced proliferation of T cells that normally respond to anti-CD3. Cells are colored based on T cell clones shared between stimulated (anti-CD3, left; anti-CD3 + FGFBP2 NTD, right) and control groups.

[0031] FIGS. 8A-8B. FGFBP2-NTD enhances inflammatory cytokine production by viral-specific CD8 T cells in response to prolonged stimulation. Human T cells from 3 Epstein-Barr Virus (EBV) positive patient donors were stimulated for 2 weeks in the presence of EBV peptides, 6 4896-4870-0471v.193597 / 7296 IL-2 and IL-7, with or without FGFBP2-NTD. After 2 weeks, cells were harvested and restimulated again. T cells were analyzed by intracellular cytokine staining with TNFalpha (left) and IFNgamma (right). Upon FGFBP2-NTD treatment, CD8 T cells augment their inflammatory cytokine production upon re-encountering EBV peptides in all (n=3) patient volunteer donors.

[0032] FIG 9. FGFBP1 NTD and FGFBP2 NTD both enhance division in NK cells andincreases the frequency of cytotoxic CD56lowNK cells after culture in IL-2 and IL-15. Human NK cells were isolated from peripheral blood using antibody mediated depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE). NK cells were cultured for 4 days in the presence of IL-2 / IL-15 (control), IL-2 / IL-15 + 300nM hFGFBP2 NTD, IL-2 / IL-15 + 300nM hFGFBP1 NTD. On left, relative frequency of CD56lowand CD56highNK cells is shown. On right, CFSE intensity is shown with gates indicated cells that have undergone division. Notably, both FGFBP1 NTD and FGFBP2 NTD exhibit this same effect. DETAILED DESCRIPTION

[0033] An expression construct encoding (i) an N-terminal domain of a fibroblast growthfactor binding protein 2 (FGFBP2), but not encoding a full length and / or mature FGFBP2 protein, or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length and / or mature FGFBP3 protein.

[0034] In some embodiments, the N-terminal domain of FGFBP2 comprises SEQ ID NO:3.

[0035] In some embodiments, the N-terminal domain of FGFBP3 comprises SEQ ID NO:5 orSEQ ID NO:6.

[0036] In some embodiments, the expression construct further encodes a signal sequenceand / or a promoter.

[0037] An expression construct encoding a fusion protein comprising (A) (i) an N-terminaldomain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0038] In some embodiments, (A) (i) does not comprise a full length FGFBP2 and wherein(A) (ii) does not comprise a full length FGFBP3. 7 4896-4870-0471v.193597 / 7296

[0039] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

[0040] In some embodiments, the expression construct comprises DNA or comprises mRNA.

[0041] A composition comprising an expression construct described herein.

[0042] A protein domain comprising (a) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein, or (b) an N- terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein.

[0043] In some embodiments, the N-terminal domain of FGFBP2 comprises SEQ ID NO:3.

[0044] In some embodiments, the N-terminal domain of FGFBP3 comprises SEQ ID NO:5 orSEQ ID NO:6.

[0045] In some embodiments, the protein domain further comprises a signal sequence.

[0046] In some embodiments, the protein domain does not comprise a signal sequence.

[0047] A fusion protein comprising (A) (i) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0048] In some embodiments, (A) (i) does not comprise a full length or mature FGFBP2 andwherein (A) (ii) does not comprise a full length or mature FGFBP3.

[0049] In some embodiments, (A) (i) comprises a full length or mature FGFBP2 or wherein(A) (ii) comprises a full length or mature FGFBP3.

[0050] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. In some embodiments, (B) comprises a single chain variable fragment (scFv).

[0051] A method of promoting propagation of, function of, and / or increasing viability of, Tcells, optionally alpha-beta or gamma-delta T cells or natural killer T cells, comprising contacting said cells with an amount of a composition comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, T cells. 8 4896-4870-0471v.193597 / 7296

[0052] In some embodiments, (i) does not comprise a full length or mature FGFBP2, andwherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

[0053] In some embodiments, (i) comprises a full length or mature FGFBP2, wherein (ii)comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

[0054] A method of promoting propagation of, function of, and / or increasing viability of,Natural Killer (NK) cells, comprising contacting said cells with an amount of a composition comprising a (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells.

[0055] In some embodiments of the various methods described herein, the cells are in vivo. Insome embodiments of the various methods described herein, the cells are in vitro. In some embodiments of the various methods described herein, the cells are ex vivo, and have been removed from a subject, and are optionally later administered to a subject. In some embodiments of the various methods described herein, the cells are in situ.

[0056] A method of promoting propagation of, function of, and / or increasing viability of, Tcells in a subject, optionally alpha-beta or gamma-delta T cells or natural killer T cells, comprising administering to said subject an expression construct which encodes (i) an N-terminal domain of an FGFBP2, or (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, T cells, or a method of promoting propagation of, function of, and / or increasing viability of, Natural Killer (NK) cells, comprising administering to said subject an expression construct which encodes (i) an N-terminal domain of an FGFBP2, or (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, NK cells.

[0057] In some embodiments, the expression construct does not encode (i) a full length ormature FGFBP2, (ii) a full length or mature FGFBP3, or (iii) a full length or mature FGFBP1.

[0058] In some embodiments, the expression construct does encode (i) a full length or matureFGFBP2, (ii) a full length or mature FGFBP3, or (iii) a full length or mature FGFBP1. 9 4896-4870-0471v.193597 / 7296

[0059] In some embodiments, the expression construct encodes a fusion protein comprising(A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0060] In some embodiments, the composition comprises a fusion protein comprising (A) (i)an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N- terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0061] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. In some embodiments, (B) comprises a single-chain variable fragment (scFv).

[0062] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0063] In some embodiments, the T cells have been cultured with the protein domain prior toadministering to the subject.

[0064] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the cancer or neoplasia.

[0065] In some embodiments, (i) does not comprise a full length or mature FGFBP2, andwherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1. 10 4896-4870-0471v.193597 / 7296

[0066] In some embodiments, (i) comprises a full length or mature FGFBP2, wherein (ii)comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

[0067] In some embodiments, the protein domain is part of a fusion protein comprising (A) (i)an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N- terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3) or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0068] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. In some embodiments, (B) comprises a single-chain variable fragment (scFv).

[0069] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0070] In some embodiments, the T cells have been cultured with or transformed with theexpression construct prior to administering to the subject.

[0071] A method of treating a cancer or neoplasia in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the cancer or neoplasia.

[0072] In some embodiments, the NK cells have been cultured with or transformed with theexpression construct prior to administering to the subject.

[0073] In some embodiments, (i) does not comprise a full length or mature FGFBP2, andwherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1. 11 4896-4870-0471v.193597 / 7296

[0074] In some embodiments, (i) comprises a full length or mature FGFBP2, wherein (ii)comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

[0075] In some embodiments, the expression construct encodes a fusion protein comprising(A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3) or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0076] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. In some embodiments, (B) comprises a single-chain variable fragment (scFv).

[0077] A method of treating an infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with an protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0078] In some embodiments, the T cells have been cultured with the protein domain prior toadministering to the subject.

[0079] A method of treating an infectious disease in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the infectious disease.

[0080] In some embodiments, (i) does not comprise a full length or mature FGFBP2, andwherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

[0081] In some embodiments, (i) comprises a full length or mature FGFBP2, wherein (ii)comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1. 12 4896-4870-0471v.193597 / 7296

[0082] In some embodiments, the protein domain is part of a fusion protein comprising (A) (i)an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N- terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non- FGFBP protein or peptide or polypeptide.

[0083] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. In some embodiments, (B) comprises a single-chain variable fragment (scFv).

[0084] A method of treating an infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0085] In some embodiments, the T cells have been cultured with or transformed with theexpression construct prior to administering to the subject.

[0086] A method of treating an infectious disease in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the infectious disease.

[0087] In some embodiments, the NK cells have been cultured with or transformed with theexpression construct prior to administering to the subject.

[0088] In some embodiments, (i) does not comprise a full length or mature FGFBP2, andwherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

[0089] In some embodiments, (i) comprises a full length or mature FGFBP2, wherein (ii)comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1. 13 4896-4870-0471v.193597 / 7296

[0090] In some embodiments, the expression construct encodes a fusion protein comprising(A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

[0091] In some embodiments, (B) comprises (a) an Immunoglobulin G Fc, optionally a humanImmunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. In some embodiments, (B) comprises a single-chain variable fragment (scFv). An scFv can be chosen to facilitate local or localized delivery to a target based on, e.g,, an antigenic target bound by the scFv. For example, any of the antigenic targets described herein.

[0092] A cell engineered to express an expression construct described herein.

[0093] A cell engineered to express a protein domain described herein.

[0094] A cell engineered to express a fusion protein described herein.

[0095] In some embodiments of the various methods described herein, the cells have beenremoved from a subject of the same species as the subject the cells are being administered to. In some embodiments of the various methods described herein, the cells have been removed from the same subject as the subject the cells are being administered to.

[0096] An expression construct encoding a putative Heparin-binding domain of a fibroblastgrowth factor binding protein 2 (FGFBP2), but not encoding a full length FGFBP2 protein. A composition comprising an expression construct encoding a putative Heparin-binding domain of a fibroblast growth factor binding protein 2 (FGFBP2), but not encoding a full length FGFBP2 protein.

[0097] An expression construct encoding a fusion protein comprising (i) a putative Heparin-binding domain of a fibroblast growth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp2 gene. A composition comprising an expression construct encoding a fusion protein comprising (i) a putative Heparin-binding domain of a fibroblast growth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp2 gene.

[0098] An expression construct encoding a domain of an N-terminal portion of a fibroblastgrowth factor binding protein 2 (FGFBP2), but not encoding a full length FGFBP2 protein. A composition comprising an expression construct encoding a domain of an N-terminal portion of a 14 4896-4870-0471v.193597 / 7296 fibroblast growth factor binding protein 2 (FGFBP2), but not encoding a full length FGFBP2 protein.

[0099] An expression construct encoding a fusion protein comprising (i) an N-terminal portionof a fibroblast growth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp2 gene. A composition comprising an expression construct encoding a fusion protein comprising (i) an N-terminal portion of a fibroblast growth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp2 gene.

[0100] In some embodiments, the expression construct comprises a promoter sequence (e.g.in non-limiting examples, CMV promoter, or E1A promoter).

[0101] A protein domain comprising a putative heparin-binding domain of a fibroblast growthfactor binding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein. A composition comprising a protein domain comprising a putative heparin-binding domain of a fibroblast growth factor binding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein.

[0102] A protein domain comprising an N-terminal portion of a fibroblast growth factorbinding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein. A composition comprising a protein domain comprising an N-terminal portion of a fibroblast growth factor binding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein.

[0103] A fusion protein comprising (i) a putative Heparin-binding domain of a fibroblastgrowth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp1 gene. In some embodiments, (ii) comprises an immunoglobulin Fc.

[0104] A method of promoting propagation, function and / or increasing viability of T cells,such as alpha-beta or gamma-delta T cells or natural killer T cells, in culture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells.

[0105] A method of promoting propagation, function and / or increasing viability of T cells inculture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells. 15 4896-4870-0471v.193597 / 7296

[0106] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in culture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of Natural Killer (NK) cells. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell-derived NK cells.

[0107] A method of treating cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0108] A method of treating cancer or neoplasia in a subject comprising administering to thesubject T cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0109] A method of treating cancer or neoplasia in a subject comprising administering to thesubject Natural Killer cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of Natural Killer cells, so as to treat the cancer or neoplasia. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell- derived NK cells.

[0110] In some embodiments, the cancer is a melanoma, a glioblastoma, a head and neckcancer or a lung cancer. In some embodiments, the cancer is a bladder cancer, kidney cancer, Hodgkin lymphoma, esophageal cancer, gastric cancer, colorectal cancer, gynecologic cancers, pancreatic cancer, or a renal cell carcinoma.

[0111] In some embodiments, the cancer is an acute lymphoblastic leukemia, acute myeloidleukemia, chronic lymphocytic leukemia, a multiple myeloma, or a B-cell lymphoma.

[0112] A method of treating infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have 16 4896-4870-0471v.193597 / 7296 been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0113] A method of treating infectious disease in a subject comprising administering to thesubject Natural Killer cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of Natural Killer cells, so as to treat the infectious disease. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell- derived NK cells.

[0114] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological malignancy.

[0115] A method of treating cancer in a subject comprising administering to the subject anamount of an expression construct encoding a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological malignancy.

[0116] A method of treating infectious disease in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0117] A method of treating infectious disease in a subject comprising administering to thesubject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0118] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to treat a cancer or neoplasia. A method of treating cancer or neoplasia in a subject 17 4896-4870-0471v.193597 / 7296 comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP2 effective to treat a cancer or neoplasia. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic malignancy.

[0119] A method of treating infectious disease in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to treat an infectious disease. A method of treating infectious disease in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP2 effective to treat an infectious disease.

[0120] A method of promoting propagation, function and / or increasing viability of T cells ina subject comprising administering to the subject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0121] A method of promoting propagation, function and / or increasing viability of T cellssubject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0122] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in a subject comprising administering to the subject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of Natural Killer cells in the subject.

[0123] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP2 effective to promote propagation, function and / or increase viability of Natural Killer cells in the subject.

[0124] In some embodiments of the methods herein, the NK cells are autologous to the subjectbeing treated. In some embodiments, the NK cells are allogeneic to the subject being treated.

[0125] In some embodiments, the NK cells are engineered to express a chimeric antigenreceptor (CAR). In some embodiments, CAR is directed to a human tumor antigen. In some embodiments, the CAR is directed to a human PD-L1, HLA-G, B7-H3, HER2, NKG2DL, EGFR, 18 4896-4870-0471v.193597 / 7296 TF, MSLN, alphaFR, GPC3, CD25, CD19, SDF-1, CD123, CD33, CD7, CD5, CD38 or FLT3. In some embodiments, the NK cells are not engineered to express a chimeric antigen receptor.

[0126] In some embodiments of the methods herein, the T cells are autologous to the subjectbeing treated. In some embodiments, the T cells are allogeneic to the subject being treated.

[0127] In some embodiments, the T cells are engineered to express a chimeric antigen receptor(CAR). In some embodiments, CAR is directed to a human tumor antigen. In some embodiments, the CAR is directed to a human CD19, CD20, CD22, BCMA, GD2, Mesothelin, TAG-72, CEA, EGFR, B7H3, HER2, IL13Ra2, MUC1, EpCAM, PSMA, PSCA, NKG2D, PLAP, CS1 (SLAMF7), CLDN, FLT3, CD7, CD5, CD26, CLEC14A, GUY2C, TEM8 / ANTXR1, PDPN, PTK7, PODXL, or CD44. In some embodiments, the T cells are not engineered to express a chimeric antigen receptor.

[0128] In some embodiments, the T cells are CD4+. In some embodiments, the T cells areCD8+. In some embodiments, the T cells are gamma-delta T cells. In some embodiments, the T cells are alpha-beta T cells. In some embodiments, the T cells are CD4- / CD8-.

[0129] A composition comprising a fusion protein which comprises a domain of an N-terminalportion of an FGFBP2.

[0130] A method disclosed herein, wherein the administration of, or contacting with, acomposition comprising a domain of an N-terminal portion of an FGFBP2 does not comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP2. A method disclosed herein, wherein the administration of, or contacting with a composition comprising a domain of an N-terminal portion of an FGFBP2 does comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP2.

[0131] An expression construct encoding a putative Heparin-binding domain of a fibroblastgrowth factor binding protein 3 (FGFBP3), but not encoding a full length FGFBP3 protein. A composition comprising an expression construct encoding a putative Heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length FGFBP3 protein.

[0132] An expression construct encoding a fusion protein comprising (i) a putative Heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene. A composition comprising an expression construct encoding 19 4896-4870-0471v.193597 / 7296 a fusion protein comprising (i) a putative Heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene.

[0133] An expression construct encoding a domain of an N-terminal portion of a fibroblastgrowth factor binding protein 3 (FGFBP3), but not encoding a full length FGFBP3 protein. A composition comprising an expression construct encoding a domain of an N-terminal portion of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length FGFBP3 protein.

[0134] An expression construct encoding a fusion protein comprising (i) an N-terminal portionof a fibroblast growth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene. A composition comprising an expression construct encoding a fusion protein comprising (i) an N-terminal portion of a fibroblast growth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene.

[0135] In some embodiments, the expression construct comprises a promoter (e.g. in non-limiting examples, a CMV promoter, or E1A promoter).

[0136] A protein domain comprising a putative Heparin-binding domain of a fibroblast growthfactor binding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein. A composition comprising a protein domain comprising a putative Heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein.

[0137] A protein domain comprising an N-terminal portion of a fibroblast growth factorbinding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein. A composition comprising a protein domain comprising an N-terminal portion of a fibroblast growth factor binding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein.

[0138] A fusion protein comprising (i) a putative Heparin-binding domain of a fibroblastgrowth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene. In some embodiments, (ii) comprises an immunoglobulin Fc.

[0139] A method of promoting propagation, function and / or increasing viability of T cells,such as alpha-beta or gamma-delta T cells or natural killer T cells, in culture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells. 20 4896-4870-0471v.193597 / 7296

[0140] A method of promoting propagation, function and / or increasing viability of T cells inculture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells.

[0141] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in culture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of Natural Killer (NK) cells. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell-derived NK cells.

[0142] A method of treating cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0143] A method of treating cancer or neoplasia in a subject comprising administering to thesubject T cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0144] A method of treating cancer or neoplasia in a subject comprising administering to thesubject Natural Killer cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of Natural Killer cells, so as to treat the cancer or neoplasia. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell- derived NK cells.

[0145] In some embodiments of the methods herein, the cancer is a melanoma, a glioblastoma,a head and neck cancer or a lung cancer. In some embodiments, the cancer is a bladder cancer, kidney cancer, Hodgkin lymphoma, esophageal cancer, gynecologic cancers, pancreatic cancer, or a renal cell carcinoma. 21 4896-4870-0471v.193597 / 7296

[0146] In some embodiments, the cancer is a hematological cancer. In some embodiments, thecancer is an acute lymphoblastic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, a multiple myeloma, or a B-cell lymphoma.

[0147] A method of treating infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0148] A method of treating infectious disease in a subject comprising administering to thesubject Natural Killer cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of Natural Killer cells, so as to treat the infectious disease.

[0149] In some embodiments, the NK cells are obtained from a subject’s peripheral blood orumbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell-derived NK cells.

[0150] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological malignancy.

[0151] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological malignancy.

[0152] A method of treating infectious disease in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0153] A method of treating infectious disease in a subject comprising administering to thesubject an amount of an expression construct encoding a domain of an N-terminal portion of an 22 4896-4870-0471v.193597 / 7296 FGFBP3 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0154] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to treat a cancer or neoplasia. A method of treating cancer or neoplasia in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP3 effective to treat a cancer or neoplasia. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic malignancy.

[0155] A method of treating infectious disease in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to treat an infectious disease. A method of treating infectious disease in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP3 effective to treat an infectious disease.

[0156] A method of promoting propagation, function and / or increasing viability of T cells ina subject comprising administering to the subject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0157] A method of promoting propagation, function and / or increasing viability of T cellssubject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0158] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in a subject comprising administering to the subject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of Natural Killer cells in the subject.

[0159] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP3 effective to promote propagation, function and / or increase viability of Natural Killer cells in the subject. 23 4896-4870-0471v.193597 / 7296

[0160] In some embodiments of the methods herein, the NK cells are autologous to the subjectbeing treated. In some embodiments, the NK cells are allogeneic to the subject being treated.

[0161] In some embodiments of methods herein, the NK cells are engineered to express achimeric antigen receptor (CAR). In some embodiments, CAR is directed to a human tumor antigen. In some embodiments, the CAR is directed to a human PD-L1, HLA-G, B7-H3, HER2, NKG2DL, EGFR, TF, MSLN, alphaFR, GPC3, CD25, CD19, SDF-1, CD123, CD33, CD7, CD5, CD38 or FLT3. In some embodiments, the NK cells are not engineered to express a chimeric antigen receptor.

[0162] In some embodiments of the methods herein, the T cells are autologous to the subjectbeing treated. In some embodiments, the T cells are allogeneic to the subject being treated.

[0163] In some embodiments, the T cells are engineered to express a chimeric antigen receptor(CAR). In some embodiments, CAR is directed to a human tumor antigen. In some embodiments, the CAR is directed to a human CD19, CD20, CD22, BCMA, GD2, Mesothelin, TAG-72, CEA, EGFR, B7H3, HER2, IL13Ra2, MUC1, EpCAM, PSMA, PSCA, NKG2D, PLAP, CS1 (SLAMF7), CLDN, FLT3, CD7, CD5, CD26, CLEC14A, GUY2C, TEM8 / ANTXR1, PDPN, PTK7, PODXL, or CD44. In some embodiments, the T cells are not engineered to express a chimeric antigen receptor.

[0164] In some embodiments, the T cells are CD4+. In some embodiments, the T cells areCD8+. In some embodiments, the T cells are gamma-delta T cells. In some embodiments, the T cells are alpha-beta T cells. In some embodiments, the T cells are CD4- / CD8-.

[0165] A composition comprising a fusion protein which comprises a domain of an N-terminalportion of an FGFBP3.

[0166] A method disclosed herein, wherein the administration of, or contacting with, acomposition comprising a domain of an N-terminal portion of an FGFBP3 does not comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP3. A method disclosed herein, wherein the administration of, or contacting with a composition comprising a domain of an N-terminal portion of an FGFBP3 does comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP3.

[0167] An expression construct encoding a putative heparin-binding domain of a fibroblastgrowth factor binding protein 1 (FGFBP1), but not encoding a full length FGFBP1 protein. A 24 4896-4870-0471v.193597 / 7296 composition comprising an expression construct encoding a putative heparin-binding domain of a fibroblast growth factor binding protein 1 (FGFBP1), but not encoding a full length FGFBP1 protein.

[0168] An expression construct encoding a fusion protein comprising (i) a putative heparin-binding domain of a fibroblast growth factor binding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene. A composition comprising an expression construct encoding a fusion protein comprising (i) a putative heparin-binding domain of a fibroblast growth factor binding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene.

[0169] An expression construct encoding a domain of an N-terminal portion of a fibroblastgrowth factor binding protein 1 (FGFBP1), but not encoding a full length FGFBP1 protein. A composition comprising an expression construct encoding a domain of an N-terminal portion of a fibroblast growth factor binding protein 1 (FGFBP1), but not encoding a full length FGFBP1 protein.

[0170] An expression construct encoding a fusion protein comprising (i) an N-terminal portionof a fibroblast growth factor binding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene. A composition comprising an expression construct encoding a fusion protein comprising (i) an N-terminal portion of a fibroblast growth factor binding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene.

[0171] In some embodiments, the expression construct comprises a promoter (e.g. CMVpromoter, or E1A).

[0172] A protein domain comprising a putative heparin-binding domain of a fibroblast growthfactor binding protein 1 (FGFBP1), but not comprising a full length FGFBP1 protein. A composition comprising a protein domain comprising a putative heparin-binding domain of a fibroblast growth factor binding protein 1 (FGFBP1), but not comprising a full length FGFBP1 protein.

[0173] A protein domain comprising an N-terminal portion of a fibroblast growth factorbinding protein 1 (FGFBP1), but not comprising a full length FGFBP1 protein. A composition comprising a protein domain comprising an N-terminal portion of a fibroblast growth factor binding protein 1 (FGFBP1), but not comprising a full length FGFBP1 protein. 25 4896-4870-0471v.193597 / 7296

[0174] A fusion protein comprising (i) a putative heparin-binding domain of a fibroblastgrowth factor binding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene. In some embodiments, (ii) comprises an immunoglobulin Fc.

[0175] A method of promoting propagation, function and / or increasing viability of T cells,such as alpha-beta or gamma-delta T cells or natural killer T cells, in culture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells.

[0176] A method of promoting propagation, function and / or increasing viability of T cells inculture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells.

[0177] A method of promoting propagation, function and / or increasing viability of NaturalKiller (NK) cells in culture comprising contacting said cells with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of NK cells. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell-derived NK cells.

[0178] A method of treating cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0179] A method of treating cancer or neoplasia in a subject comprising administering to thesubject T cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

[0180] A method of treating cancer in a subject comprising administering to the subjectNatural Killer cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of Natural Killer cells, so as to treat the cancer. In some embodiments, the NK cells are 26 4896-4870-0471v.193597 / 7296 obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell-derived NK cells.

[0181] In some embodiments of the methods herein in regard to cancer, the cancer is amelanoma, a glioblastoma, a head and neck cancer or a lung cancer. In some embodiments, the cancer is a bladder cancer, kidney cancer, Hodgkin lymphoma, esophageal cancer, gynecologic cancers, pancreatic cancer, or a renal cell carcinoma. In some embodiments, the cancer is a cancer of a breast, nasopharynx, pharynx, lung, bone, brain, sialaden, stomach, esophagus, testes, ovary, uterus, endometrium, liver, small intestine, appendix, colon, rectum, bladder, gall bladder, pancreas, kidney, urinary bladder, breast, cervix, vagina, vulva, prostate, thyroid or skin, head or neck, or is a glioma.

[0182] In some embodiments, the cancer is a hematological cancer. In some embodiments, thecancer is an acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, a multiple myeloma, or a B-cell lymphoma.

[0183] A method of treating infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

[0184] A method of treating infectious disease in a subject comprising administering to thesubject Natural Killer cells that have been cultured with an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of Natural Killer cells, so as to treat the infectious disease. In some embodiments, the NK cells are obtained from a subject’s peripheral blood or umbilical blood. In some embodiments, the NK cells are obtained from an NK cell line or are induced pluripotent cell- derived NK cells.

[0185] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological malignancy. 27 4896-4870-0471v.193597 / 7296

[0186] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological malignancy.

[0187] A method of treating infectious disease in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0188] A method of treating infectious disease in a subject comprising administering to thesubject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0189] A method of treating cancer or neoplasia in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to treat a cancer or neoplasia. A method of treating cancer or neoplasia in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP1 effective to treat a cancer or neoplasia. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic malignancy.

[0190] A method of treating infectious disease in a subject comprising administering to thesubject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to treat an infectious disease. A method of treating infectious disease in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP1 effective to treat an infectious disease.

[0191] A method of promoting propagation, function and / or increasing viability of T cells ina subject comprising administering to the subject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0192] A method of promoting propagation, function and / or increasing viability of T cellssubject comprising administering to the subject an amount of an expression construct encoding a 28 4896-4870-0471v.193597 / 7296 domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of T cells in the subject.

[0193] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in a subject comprising administering to the subject an amount of a composition comprising a domain of an N-terminal portion of an FGFBP1 effective to promote propagation, function and / or increase viability of Natural Killer cells in the subject.

[0194] A method of promoting propagation, function and / or increasing viability of NaturalKiller cells in a subject comprising administering to the subject an amount of an expression construct encoding a domain of an N-terminal portion of an FGFBP1, FGFBP2 or FGFBP3 effective to promote propagation, function and / or increase viability of Natural Killer cells in the subject.

[0195] In some embodiments of the methods herein, the NK cells are autologous to the subjectbeing treated. In some embodiments, the NK cells are allogeneic to the subject being treated.

[0196] In some embodiments, the NK cells are engineered to express a chimeric antigenreceptor (CAR). In some embodiments, CAR is directed to a human tumor antigen. In some embodiments, the CAR is directed to a human PD-L1, HLA-G, B7-H3, HER2, NKG2DL, EGFR, TF, MSLN, alphaFR, GPC3, CD25, CD19, SDF-1, CD123, CD33, CD7, CD5, CD38 or FLT3. In some embodiments, the NK cells are not engineered to express a chimeric antigen receptor.

[0197] In some embodiments of the methods herein, the T cells are autologous to the subjectbeing treated. In some embodiments, the T cells are allogeneic to the subject being treated.

[0198] In some embodiments, the T cells are engineered to express a chimeric antigen receptor(CAR). In some embodiments, CAR is directed to a human tumor antigen. In some embodiments, the CAR is directed to a human CD19, CD20, CD22, BCMA, GD2, Mesothelin, TAG-72, CEA, EGFR, B7H3, HER2, IL13Ra2, MUC1, EpCAM, PSMA, PSCA, NKG2D, PLAP, CS1 (SLAMF7), CLDN, FLT3, CD7, CD5, CD26, CLEC14A, GUY2C, TEM8 / ANTXR1, PDPN, PTK7, PODXL, or CD44. In some embodiments, the T cells are not engineered to express a chimeric antigen receptor.

[0199] In some embodiments, the T cells are CD4+. In some embodiments, the T cells areCD8+. In some embodiments, the T cells are gamma-delta T cells. In some embodiments, the T cells are alpha-beta T cells. In some embodiments, the T cells are CD4- / CD8-. 29 4896-4870-0471v.193597 / 7296

[0200] A composition comprising a fusion protein which comprises a domain of an N-terminalportion of an FGFBP1, FGFBP2 or FGFBP3.

[0201] A method disclosed herein, wherein the administration of, or contacting with, acomposition comprising a domain of an N-terminal portion of an FGFBP1 does not comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP1. A method disclosed herein, wherein the administration of, or contacting with a composition comprising a domain of an N-terminal portion of an FGFBP1 does comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP1. A method disclosed herein, wherein the administration of, or contacting with, a composition comprising a domain of an N-terminal portion of an FGFBP2 does not comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP2. A method disclosed herein, wherein the administration of, or contacting with a composition comprising a domain of an N-terminal portion of an FGFBP2 does comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP2. A method disclosed herein, wherein the administration of, or contacting with, a composition comprising a domain of an N- terminal portion of an FGFBP3 does not comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP3. A method disclosed herein, wherein the administration of, or contacting with a composition comprising a domain of an N-terminal portion of an FGFBP3 does comprise a fusion protein comprising the domain of an N-terminal portion of an FGFBP3.

[0202] In some embodiments, a full length FGFBP protein is a full length FGFBP proteinincluding a signal sequence. In some embodiments, a mature FGFBP protein excludes a signal sequence.

[0203] In some embodiments, the methods comprise stimulating the T cells. In someembodiments, the methods comprise stimulating the T cells with IL-2 stimulation or anti-CD3 Ab stimulation.

[0204] A method of preparing a population of immune cells against an antigenic targetcomprising providing a population of immune cells comprising T cells, stimulating said cells in the presence of one or more peptide or polypeptide antigens of the antigenic target and in the presence of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enhance inflammatory cytokine production in said T cells and thereby prepare a population of immune cells against the antigenic target. In some embodiments, the method is for 30 4896-4870-0471v.193597 / 7296 preparing the population of cells for an immunotherapy. In some embodiments, the T cells are CD8 T cells. In some embodiments, the T cells are CD4 T cells. In some embodiments, the antigenic target is a virus. In some embodiments, the antigenic target is a virus that infects humans. In some embodiments, the antigenic target is a tumor antigen. In some embodiments, the antigenic target is a human tumor antigen. In some embodiments, the antigenic target is a bacterium. In some embodiments, the antigenic target is a bacterium that infects humans. In some embodiments, the antigenic target is a parasite. In some embodiments, the antigenic target is a parasite that infects humans. In some embodiments, the population of immune cells comprising T cells has been obtained from a human subject. In some embodiments, the population of immune cells are stimulated in the presence of also IL-2 and / or IL-7.

[0205] Non-limiting examples of antigens / antigenic targets are listed hereinbelow.

[0206] In some embodiments, the antigen or antigenic targets as discussed in relation to themethods disclosed herein are human tumor antigens. Such antigens are well known in the art, for example, see www.zhang-lab.org / caatlas / caantigen (1007 members as of March 27, 2025 - The cancer antigen atlas (caAtlas)). See Yi, X., Liao, Y., Wen, B., Li, K., Dou, Y., Savage, S. R., & Zhang, B. (2021). caAtlas: an immunopeptidome atlas of human cancer. Iscience, 24(10). https: / / doi.org / 10.1016 / j.isci.2021.103107, hereby incorporated by reference. See also the cancer testis CTantigen list at www.zhang-lab.org / caatlas / ctantigen and post-translationally-modified PTM antigen list at www.zhang-lab.org / caatlas / ptmantigen.

[0207] In some embodiments, the antigens or antigenic targets as discussed in relation to themethods disclosed herein are human viral antigens. Human viral antigens are well known in the art, for example, including arenaviridae, bunyaviridae, Flaviviridae, orthomyxaviridae, Reoviridae, rhaboviridae and togaviridae. Human viruses known in the art also include the listing at viralzone.expasy.org / 678.

[0208] In some embodiments, the antigens or antigenic targets as discussed in relation to themethods disclosed herein are viral antigens. Non-limiting examples include from:

[0209] Adeno-Associated Virus (AAV) Antigens,

[0210] Adenovirus Antigens

[0211] ASFV

[0212] Chikungunya Virus31 4896-4870-0471v.193597 / 7296

[0213] Coronavirus Antigens

[0214] Coxsackie Virus Antigens

[0215] Crimean-Congo Hemorrhagic Fever Virus Antigens

[0216] Cytomegalovirus Antigens

[0217] Dengue Virus Antigens

[0218] Eastern Equine Encephalitis Virus (EEEV) Antigens

[0219] Ebola Virus

[0220] Echovirus

[0221] Enterovirus

[0222] Epstein–Barr Virus Antigens

[0223] HAV

[0224] HBV

[0225] HCMV

[0226] HCV

[0227] HDV

[0228] HEV

[0229] HIV

[0230] HPV

[0231] HSV

[0232] HTLV

[0233] Influenza A Virus

[0234] Influenza B Virus

[0235] Japanese Encephalitis

[0236] Leukemia Virus

[0237] Marburg Virus Antigens

[0238] Measles Virus

[0239] Metapneumovirus Antigens

[0240] Molluscum Contagiosum

[0241] Mumps Virus Antigens

[0242] Nipah Virus32 4896-4870-0471v.193597 / 7296

[0243] Norovirus

[0244] Orf Virus

[0245] Other Viral Antigens

[0246] Parainfluenza Virus Antigens

[0247] Parvovirus

[0248] Poliovirus

[0249] Rabies Virus

[0250] Respiratory Syncytial Virus

[0251] Rhinovirus

[0252] Rift Valley Fever Virus

[0253] Rotavirus

[0254] Rubella Virus

[0255] Simian (Macaque) Immunodeficiency Virus

[0256] TBEV

[0257] Tobacco Etch Virus

[0258] Varicella Zoster Virus

[0259] Variola

[0260] Venezuelan Equine Encephalitis Virus Antigens

[0261] West Nile Virus

[0262] Yellow Fever Virus, or

[0263] Zika Virus.

[0264] In some embodiments, the antigens or antigenic targets as discussed in relation to themethods disclosed herein are bacterial antigens. Bacterial antigens include:

[0265] Burkholderia pseudomallei Antigens

[0266] Legionella Pneumophila Antigens

[0267] Neisseria gonorrhoeae Antigens

[0268] Salmonella Antigens

[0269] Staphylococcus Antigens

[0270] Ureaplasma urealyticum Antigens

[0271] Vibrio cholerae Antigens33 4896-4870-0471v.193597 / 7296

[0272] Aeromonas Antigens

[0273] Arthrobacter Globiformis Antigens

[0274] Bacillus Antigens

[0275] Bordetella Pertussis Antigens

[0276] Borrelia Antigens

[0277] Brucella Abortus Antigens

[0278] Campylobacter Jejuni Antigens

[0279] Candida Albicans Antigens

[0280] Chlamydia Trachomatis Antigens

[0281] Chlamydophila Pneumoniae Antigens

[0282] Clostridium tetani Antigens

[0283] Corynebacterium Diphtheriae Antigens

[0284] E.coli Antigens

[0285] Haemophilus influenza Antigens

[0286] Helicobacter pylori Antigens

[0287] Leptospira biflexa Antigens

[0288] Listeria Monocytogenes Antigens

[0289] Mycobacterium Tuberculosis Antigens

[0290] Mycoplasma Pneumoniae Antigens

[0291] Other Bacterial Antigens

[0292] Salmonella typhimurium Antigens

[0293] Streptococcus Pneumoniae Antigens

[0294] Streptomyces Avidinii Antigens

[0295] Treponema Pallidum Antigens, and

[0296] Yersinia Enterocolitica Antigens.

[0297] In some embodiments, the antigens or antigenic targets as discussed in relation to themethods disclosed herein are fungal antigens. Fungal antigens include, for example, aspergillus and saccharomyces antigens.

[0298] In some embodiments, the antigens or antigenic targets as discussed in relation to themethods disclosed herein are parasite antigens. Parasitic antigens include: 34 4896-4870-0471v.193597 / 7296

[0299] Leishmania Antigens

[0300] Plasmodium Falciparum Antigens

[0301] Plasmodium Vivax Antigens

[0302] Plasmodium Antigens

[0303] Toxoplasma Gondii Antigens

[0304] Acanthamoeba Antigens

[0305] Caenorhabditis Elegans Antigens

[0306] Echinococcus Granulosus Antigens

[0307] Malaria Antigens

[0308] Schistosoma Japonicum Antigens

[0309] Trichomonas Vaginalis Antigens, and

[0310] Trypanosoma cruzi (T. cruzi) Antigens.

[0311] In some embodiments, the cells are stimulated in the presence of an N-terminalfragment or N-terminal domain of FGFBP1. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP2. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP3. In some embodiments, the FGFBP1, 2 or 3 is, or has the same sequence as, a human FGFBP1, 2 or 3, respectively.

[0312] A method of expanding a population of immune cells comprising providing apopulation of immune cells comprising NK cells, culturing said population of immune cells comprising NK cells in the presence of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enhance cell division in said NK cells and thereby prepare a population of immune cells. In some embodiments, the method is for preparing the population of cells for an immunotherapy. In some embodiments, the cells are cultured also in the presence of IL-2 and / or IL-15. In some embodiments, the NK cells have been obtained from a human subject. A method of expanding a population of immune cells for an immunotherapy comprising providing a population of immune cells comprising NKT cells, culturing said population of immune cells comprising NKT cells in the presence of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enhance cell division in said NKT cells and thereby prepare a population of immune cells for an immunotherapy. In some embodiments, 35 4896-4870-0471v.193597 / 7296 the cells are cultured also in the presence of IL-2 and / or IL-15. In some embodiments, the NKT cells have been obtained from a human subject. A method of enriching a population of immune cells for cytotoxic CD56lowNK cells comprising providing a population of immune cells comprising NK cells, culturing said population of immune cells comprising NK cells in the presence of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enrich the population for cytotoxic CD56lowNK cells and thereby prepare a population of immune cells. In some embodiments, the method is for preparing the population of cells for an immunotherapy. In some embodiments, the cells are cultured also in the presence of IL-2 and / or IL-15. In some embodiments, the NK cells have been obtained from a human subject. A method of enriching a population of immune cells for cytotoxic CD56lowNKT comprising providing a population of immune cells comprising NKT cells, culturing said population of immune cells comprising NKT cells in the presence of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enrich the population for cytotoxic CD56lowNKT cells and thereby prepare a population of immune cells for an immunotherapy. In some embodiments, the cells are cultured also in the presence of IL-2 and / or IL-15. In some embodiments, the NK cells have been obtained from a human subject. In some embodiments, the cells are cultured in the presence of an N-terminal fragment or N-terminal domain of FGFBP1. In some embodiments, the cells are cultured in the presence of an N-terminal fragment or N-terminal domain of FGFBP2. In some embodiments, the cells are cultured in the presence of an N-terminal fragment or N-terminal domain of FGFBP3. In some embodiments, the FGFBP1, 2 or 3 is, or has the same sequence as, a human FGFBP1, 2 or 3, respectively.

[0313] A method of enhancing anti-CD3 mediated cell division in a population of immunecells comprising providing a population of immune cells comprising cytotoxic memory CD4 and / or CD8 T cells, stimulating said cells in the presence anti-CD3 and / or anti-CD28 and in the presence of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enhance anti-CD3 mediated cell division in a population of immune cells comprising cytotoxic memory CD4 and / or CD8 T cells. In some embodiments, the method is for preparing the population of cells for an immunotherapy. In some embodiments, the population of immune cells are stimulated in the presence of also IL-2 and / or IL-7. In some embodiments, the population of immune cells comprising cytotoxic memory CD4 and / or CD8 T cells has been obtained from a 36 4896-4870-0471v.193597 / 7296 human subject. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP2. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP3. In some embodiments, the cells are stimulated in the presence anti-CD3. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP1.

[0314] In some embodiments, the cells are stimulated in the presence of an N-terminalfragment or N-terminal domain of FGFBP1. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP2. In some embodiments, the cells are stimulated in the presence of an N-terminal fragment or N-terminal domain of FGFBP3. In some embodiments, the FGFBP1, 2 or 3 is, or has the same sequence as, a human FGFBP1, 2 or 3, respectively.

[0315] A method of enhancing anti-CD3-induced CD8 T cell proliferation, comprisingproviding a population of immune cells comprising CD8 T cells, culturing said population of immune cells comprising CD8 T cells in the presence of anti-CD3 and of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enhance anti-CD3- induced CD8 T cell proliferation. In some embodiments, the CD8 T cells have been obtained from a human subject. In some embodiments, the method is for preparing the population of cells for an immunotherapy. A method of enhancing anti-CD3-induced CD4 T cell proliferation, comprising providing a population of immune cells comprising CD4 T cells, culturing said population of immune cells comprising CD4 T cells in the presence of anti-CD3 and of an N-terminal fragment or N-terminal domain of FGFBP1, FGFBP2 or FGFBP3, so as to thereby enhance anti-CD3- induced CD4 T cell proliferation. In some embodiments, the CD4 T cells have been obtained from a human subject. In some embodiments, the method is for preparing the population of cells for an immunotherapy. In some embodiments, the cells are cultured in the presence of an N-terminal fragment or N-terminal domain of FGFBP1. In some embodiments, the cells are cultured in the presence of an N-terminal fragment or N-terminal domain of FGFBP2. In some embodiments, the cells are cultured in the presence of an N-terminal fragment or N-terminal domain of FGFBP3. In some embodiments, the FGFBP1, 2 or 3 is, or has the same sequence as, a human FGFBP1, 2 or 3, respectively. 37 4896-4870-0471v.193597 / 7296

[0316] The methods herein using an N-terminal domain of, or a domain of an N-terminalportion of, an FGFBP protein are also disclosed, mutatis mutandis, comprising using an N-terminal portion of an FGFBP protein, the sequence of which portion is primarily in the N-terminal half of the protein. The compositions herein comprising an N-terminal domain of, or a domain of an N- terminal portion of, an FGFBP protein are also disclosed, mutatis mutandis, comprising an N- terminal portion of an FGFBP protein, the sequence of which portion is primarily in the N-terminal half of the protein, but wherein the compositions do not contain a full length FGFBP protein. The fusion proteins herein comprising an N-terminal domain of, or a domain of an N-terminal portion of, an FGFBP protein are also disclosed, mutatis mutandis, comprising an N-terminal portion of an FGFBP protein, the sequence of which portion is primarily in the N-terminal half of the protein. In some embodiments, the fusion proteins do not contain a full length FGFBP protein. In some embodiments, the fusion proteins can contain a full length FGFBP protein.

[0317] In some embodiments of the methods and compositions, an N-terminal domain of, or adomain of an N-terminal portion of, an FGFBP protein, e.g., FGFBP2, is a domain of the protein which is primarily in the N-terminal half of the protein, for example, a domain of an FGFBP protein whose primary sequence is mainly (>50%) in the N-terminal half of the protein’s primary sequence. In some embodiments, such a domain is the heparin-binding domain of an FGFBP. In some embodiments of the methods and compositions employing the N-terminal domain, the composition is a portion, fragment, section or sequence of an FGFBP protein lacking a C-terminal FGF binding domain of FGFBP. In some embodiments of the fusion proteins employing the N- terminal domain, the fusion protein comprises a portion, fragment, section or sequence of an FGFBP protein lacking a C-terminal FGF binding domain of FGFBP. In some embodiments of the methods and compositions employing the N-terminal domain, the composition comprises a fragment of a full length FGFBP protein, for example encompassing a heparin-binding domain of FGFBP2, but lacks the C-terminal FGF binding domain. In some embodiments of the compositions, the compositions do not contain a full length or mature FGFBP protein. In some embodiments of the fusion proteins, the compositions do not contain a full length or mature FGFBP protein. In some embodiments of the fusion proteins, the compositions do contain a full length or mature FGFBP protein. In some embodiments of the methods, the methods comprise administering a full length or mature FGFBP protein. In some embodiments of the methods, the 38 4896-4870-0471v.193597 / 7296 methods comprise administering a portion or a domain of a FGFBP protein but not a full length or mature FGFBP protein. The FGFBP protein domains, fragments, portions, and sequences of the disclosure can be produced recombinantly. Thus, in some embodiments, the protein domains, fragments, and portions are not actual physical parts obtained from physical native full length proteins, but rather they have sequence identity therewith. For example, an N-terminal domain having the same sequence, or a modified version of, an N-terminal domain of the native protein sequence is readily producible by, e.g., recombinant means. In some embodiments, said FGFBP protein is an FGFBP1 protein. In some embodiments, said FGFBP protein is an FGFBP2 protein. In some embodiments, said FGFBP protein is an FGFBP3 protein. In some embodiments, said FGFBP protein is a human FGFBP protein or has a sequence identical to an FGFBP protein. In embodiments, the peptides or fragments herein are not naturally-occurring.

[0318] A composition comprising an expression construct described herein. In someembodiments, the composition is the expression construct. In some embodiments, the composition comprises the expression construct and one or more other ingredients.

[0319] A lipid nanoparticle composition is provided comprising an expression constructdescribed herein. In some embodiments, the liposomal nanoparticle comprises one or more of 306Oi10, tetrakis(8-methylnonyl) 3,3′,3″,3‴-(((methylazanediyl) bis(propane-3,1 diyl))bis (azanetriyl))tetrapropionate; 9A1P9, decyl (2-(dioctylammonio)ethyl) phosphate; A2-Iso5- 2DC18, ethyl 5,5-di((Z)-heptadec-8-en-1-yl)-1-(3-(pyrrolidin-1-yl)propyl)-2,5-dihydro-1H- imidazole-2-carboxylate; ALC-0315, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2- hexyldecanoate); ALC-0159, 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide; β- sitosterol, (3S,8S,9S,10R,13R,14S,17R)-17-((2R,5R)-5-ethyl-6-methylheptan-2-yl)-10,13- dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol; BAME-O16B, bis(2-(dodecyldisulfanyl)ethyl) 3,3′-((3-methyl-9-oxo-10-oxa-13,14-dithia-3,6- diazahexacosyl)azanediyl)dipropionate; BHEM-Cholesterol, 2-(((((3S,8S,9S,10R,13R,14S,17R)- 10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17- tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)-N,N-bis(2- hydroxyethyl)-N-methylethan-1-aminium bromide; C12-200, 1,1′-((2-(4-(2-((2-(bis(2- hydroxydodecyl)amino)ethyl) (2-hydroxydodecyl)amino)ethyl) piperazin-1-yl)ethyl)azanediyl) bis(dodecan-2-ol); cKK-E12, 3,6-bis(4-(bis(2-hydroxydodecyl)amino)butyl)piperazine-2,5- 39 4896-4870-0471v.193597 / 7296 dione; DC-Cholesterol, 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol; DLin-MC3- DMA, (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOSPA, 2,3-dioleyloxy-N-[2- (sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; DOTAP, 1,2- dioleoyl-3-trimethylammonium-propane; DOTMA, 1,2-di-O-octadecenyl-3- trimethylammonium-propane; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; ePC, ethylphosphatidylcholine; FTT5, hexa(octan-3-yl) 9,9′,9″,9‴,9″″,9‴″- ((((benzene-1,3,5- tricarbonyl)yris(azanediyl)) tris (propane-3,1-diyl)) tris(azanetriyl))hexanonanoate; Lipid H (SM- 102), heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6- (undecyloxy)hexyl)amino) octanoate; OF- Deg-Lin, (((3,6-dioxopiperazine-2,5-diyl)bis(butane-4, 1-diyl))bis(azanetriyl))tetrakis(ethane- 2,1-diyl) (9Z,9′Z,9″Z,9‴Z,12Z,12′Z,12″Z,12‴Z)-tetrakis (octadeca-9,12-dienoate); PEG2000- DMG, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000; TT3, N1,N3,N5-tris(3- (didodecylamino)propyl)benzene-1,3,5-tricarboxamide, and ionizable amphiphilic Janus dendrimers (IAJDs). In some embodiments, the composition comprises hybrid lipid-polymer nanoparticles comprising a PLGA core and a dipalmitoylphosphatidylcholine (DPPC) shell. In some embodiments, the lipid nanoparticles are GalNAc-lipid nanoparticles.

[0320] In some embodiments, the compositions or methods employing an NTD of a humanFGFBP2, but not a full length human FGFBP2, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:3 but does not comprise SEQ ID NO:1, nor SEQ ID NO:1 without its native signal sequence.

[0321] In some embodiments, the compositions or methods employing an NTD of a humanFGFBP3, but not a full length human FGFBP3, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:5 but does not comprise SEQ ID NO:4, nor SEQ ID NO:4 without its native signal sequence. In some embodiments, a portion comprising an N-terminal domain of human FGFBP3 has the sequence of SEQ ID NO:19.

[0322] In some embodiments, the compositions or methods employing an NTD of a mouseFGFBP3, but not a full length mouse FGFBP3, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:6 but does not comprise a full length mouse FGFBP3 with or without its signal sequence. 40 4896-4870-0471v.193597 / 7296

[0323] In some embodiments, the compositions or methods employing an NTD of a humanFGFBP1, but not a full length human FGFBP1, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:8 but does not comprise SEQ ID NO:7, nor SEQ ID NO:7 without its native signal sequence. In some embodiments, a portion comprising an N-terminal domain of human FGFBP1 has the sequence of SEQ ID NO:14.

[0324] In some embodiments, the compositions or methods employing an NTD of a mouseFGFBP1, but not a full length mouse FGFBP1, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:9 but does not comprise a full length mouse FGFBP1 with or without its signal sequence. In some embodiments, a portion comprising an N-terminal domain of Mouse FGFBP1 has the sequence of SEQ ID NO:13.

[0325] In some embodiments, an expression construct encoding a human FGFBP2 NTD canencode SEQ ID NO:2. In some embodiments, an expression construct encoding a human FGFBP1 NTD can encode SEQ ID NO:10. In some embodiments, an expression construct encoding a mouse FGFBP1 NTD can encode SEQ ID NO:18. In some embodiments, a fusion protein comprising a human FGFBP2 NTD can be SEQ ID NO:11. In some embodiments, the expression constructs are adenoviral expression constructs. In some embodiments, an adenoviral expression construct encoding a human FGFBP2 NTD can encode SEQ ID NO:22. In some embodiments, an adenoviral expression construct encoding a mouse FGFBP1 NTD can encode SEQ ID NO:21.

[0326] In some embodiments, an isolated protein domain comprising an N-terminal domain ofa human fibroblast growth factor binding protein 2 (FGFBP2), but not comprising a full length

[0327] In some embodiments, an isolated protein domain comprising an N-terminal domainof a human fibroblast growth comprises from one to twenty additional amino acids at the N- terminal and / or C-terminal thereof, where the amino acids are independent of the N-terminal and / or C-terminal amino acids of the native FGFBP sequence.

[0328] Compositions of the invention can comprise the naked peptide or the peptide and oneor more additional agents. For example, a pharmaceutically acceptable carrier or a physiologically acceptable carrier. 41 4896-4870-0471v.193597 / 7296

[0329] In another aspect, provided are compositions comprising two or more peptides of theinvention, e.g. comprising an NTD of an FGFBP2 and an NTD of an FGFBP3, or comprising an NTD of an FGFBP2 and an NTD of an FGFBP1, or comprising an NTD of an FGFBP3 and an NTD of an FGFBP1. In another aspect, provided are compositions comprising three different peptides of the invention, e.g., comprising an NTD of an FGFBP2 and an NTD of an FGFBP3 and an NTD of an FGFBP1.

[0330] In another aspect, provided are the methods disclosed herein but which employcompositions comprising two or more peptides of the invention, e.g. comprising an NTD of an FGFBP2 and an NTD of an FGFBP3, or comprising an NTD of an FGFBP2 and an NTD of an FGFBP1, or comprising an NTD of an FGFBP3 and an NTD of an FGFBP1. In another aspect, provided are the methods disclosed herein but which employ compositions comprising three different peptides of the invention, e.g., comprising an NTD of an FGFBP2 and an NTD of an FGFBP3 and an NTD of an FGFBP1.

[0331] In some embodiments, the methods further comprise administration of animmunological adjuvant. In some embodiments, the methods do not further comprise administration of an immunological adjuvant.

[0332] The term “subject” as used in this application means an animal with an immune systemsuch as avians and mammals. Mammals include canines, felines, rodents, bovine, equines, porcines, ovines, and primates. Avians include, but are not limited to, fowls, songbirds, and raptors. Thus, the invention can be used in veterinary medicine, e.g., to treat companion animals, farm animals, laboratory animals in zoological parks, and animals in the wild. The invention is particularly desirable for human medical and cosmetic applications.

[0333] Human FGFBP2 is known in the art, For example, UniProt Q9BYJ0. E.g.,NP_114156.1 (encoded by NM_031950.4). Chicken, monkey, chimpanzee, dog, hamster, horse, bat, pigeon, reptile, amphibian, avian, and other FGFBP2 orthologs are also encompassed.

[0334] A full-length FGFBP2 protein sequence (Human):MKFVPCLLLVTLSCLGTLGQAPRQKQGSTGEEFHFQTGGRDSCTMRPSSLGQGAGEVW LRVDCRNTDQTYWCEYRGQPSMCQAFAADPKPYWNQALQELRRLHHACQGAPVLRPS VCREAGPQAHMQQVTSSLKGSPEPNQQPEAGTPSLRPKATVKLTEATQLGKDSMEELG 42 4896-4870-0471v.193597 / 7296 KAKPTTRPTAKPTQPGPRPGGNEEAKKKAWEHCWKPFQALCAFLISFFRG (SEQ ID NO:1)

[0335] An exemplary expressed tagged construct comprising an active N-terminal domain ofFGFBP2 (human) is (Human N terminal FGFBP2 (G30-G146) Avitag-FLAG-His with a signal peptide): MKWVTFISLLFLFSSAYSGEEFHFQTGGRDSCTMRPSSLGQGAGEVWLRVDCRNTDQT YWCEYRGQPSMCQAFAADPKPYWNQALQELRRLHHACQGAPVLRPSVCREAGPQAH MQQVTSSLKGSPEPNQQPEAGRGLNDIFEAQKIEWHEDYKDDDDKHHHHHH (SEQ ID NO:2)

[0336] An exemplary active N-terminal domain of FGFBP2 (human) (F33-E138) is:FHFQTGGRDSCTMRPSSLGQGAGEVWLRVDCRNTDQTYWCEYRGQPSMCQAFAADPK PYWNQALQELRRLHHACQGAPVLRPSVCREAGPQAHMQQVTSSLKGSPE (SEQ ID NO:3)

[0337] The FGFBP2 protein is not expressed in mice. There are homologs in primates, birds,reptiles, amphibians, and other species, but not rodents. Other (non-human) homologs of FGFBP2 are within the scope of the invention.

[0338] Human FGFBP3 is known in the art, for example, NP_689642.3 (encoded byNM_152429.5). For example, UniProt Q8TAT2. Genes encoding FGFBP3 are known in the art, for example, Gene ID: 143282, as updated on 8-Feb-2025. Mouse FGFBP3 is also known in the art, e.g., Uniprot Q8CDW7, and NP_082539.2 (encoded by NM_028263.1). Rat, chicken, monkey, chimpanzee, dog, hamster, horse, bat, pigeon, reptile, amphibian, avian, and other FGFBP3 orthologs are also encompassed

[0339] An exemplary full-length FGFBP3 protein sequence (Human), including the signalsequence is: MTPPKLRASLSPSLLLLLSGCLLAAARREKGAASNVAEPVPGPTGGSSGRFLSPEQHACS WQLLLPAPEAAAGSELALRCQSPDGARHQCAYRGHPERCAAYAARRAHFWKQVLGGL RKKRRPCHDPAPLQARLCAGKKGHGAELRLVPRASPPARPTVAGFAGESKPRARNRGR TRERASGPAAGTPPPQSAPPKENPSERKTNEGKRKAALVPNEERPMGTGPDPDGLDGNA ELTETYCAEKWHSLCNFFVNFWNG (SEQ ID NO:4) 43 4896-4870-0471v.193597 / 7296

[0340] An exemplary active N-terminal domain (e.g. a heparin binding domain (HBD)) ofFGFBP3 (Human) (G42-A151) is predicted to be:GPTGGSSGRFLSPEQHACSWQLLLPAPEAAAGSELALRCQSPDGARHQCAYRGHPERCA AYAARRAHFWKQVLGGLRKKRRPCHDPAPLQARLCAGKKGHGAELRLVPRA (SEQ ID NO:5)

[0341] An exemplary full-length FGFBP3 protein sequence (mouse), including the signalsequence is: MSPPRPRASLSPLTLLLLLGGCLLSAAGRDKGAAGREVTRASRPTVGSSGRFVSPEQHAC SWQLLVPAPGTPTGGELALRCQTPGGASLHCAYRGHPERCAATGARRAHYWRRLLGA LRRRPRPCLDPAPLPPRLCARKTAGSDLHSPAHPSLPARPSEPPRSRARSPARSRQSVRSP SSQPEKKPLLVKSNSGGRKAGSDPVPEPPAAAGFQPNGLDQNAELTETYCTEKWHSLCN FFVNFWNG (SEQ ID NO:16)

[0342] An exemplary active N-terminal domain (e.g., HBD) of FGFBP3 (mouse) (S54-P156)is predicted to be: SGRFVSPEQHACSWQLLVPAPGTPTGGELALRCQTPGGASLHCAYRGHPERCAATGAR RAHYWRRLLGALRRRPRPCLDPAPLPPRLCARKTAGSDLHSPAHP (SEQ ID NO:6)

[0343] FGFBP1 (human) is well known – e.g., Uniprot entry Q14512. E.g., NP_005121.1(encoded by NM_005130.5). FGFBP1 (mouse) is well known – e.g., Uniprot entry Q62399. E.g., NP_001258545.1 (encoded by NM_001271616.1). Rat, chicken, monkey, chimpanzee, dog, hamster, horse, bat, pigeon, reptile, amphibian, avian, and other FGFBP1 orthologs are also encompassed.

[0344] An exemplary full-length FGFBP1 protein sequence (Human), including the signalsequence is: MKICSLTLLSFLLLAAQVLLVEGKKKVKNGLHSKVVSEQKDTLGNTQIKQKSRPGNKG KFVTKDQANCRWAATEQEEGISLKVECTQLDHEFSCVFAGNPTSCLKLKDERVYWKQV ARNLRSQKDICRYSKTAVKTRVCRKDFPESSLKLVSSTLFGNTKPRKEKTEMSPREHIKG KETTPSSLAVTQTMATKAPECVEDPDMANQRKTALEFCGETWSSLCTFFLSIVQDTSC (SEQ ID NO:7)

[0345] An exemplary active N-terminal domain of FGFBP1 (Human) (S52-S153) is:44 4896-4870-0471v.193597 / 7296 SRPGNKGKFVTKDQANCRWAATEQEEGISLKVECTQLDHEFSCVFAGNPTSCLKLKDE RVYWKQVARNLRSQKDICRYSKTAVKTRVCRKDFPESSLKLVSS (SEQ ID NO:8)

[0346] An exemplary full-length FGFBP1 protein sequence (mouse), including the signalsequence is: MRLHSLILLSFLLLATQAFSEKVRKRAKNAPHSTAEEGVEGSAPSLGKAQNKQRSRTSK SLTHGKFVTKDQATCRWAVTEEEQGISLKVQCTQADQEFSCVFAGDPTDCLKHDKDQI YWKQVARTLRKQKNICRNAKSVLKTRVCRKRFPESNLKLVNPNARGNTKPRKEKAEVS AREHNKVQEAVSTEPNRVKEDITLNPAATQTMAIRDPECLEDPDVLNQRKTALEFCGES WSSICTFFLNMLQATSC (SEQ ID NO:17)

[0347] An exemplary active N-terminal domain of FGFBP1 (mouse) (S58-R162) is:SKSLTHGKFVTKDQATCRWAVTEEEQGISLKVQCTQADQEFSCVFAGDPTDCLKHDKD QIYWKQVARTLRKQKNICRNAKSVLKTRVCRKRFPESNLKLVNPNAR (SEQ ID NO:9)

[0348] An exemplary FGFBP1 expression construct sequence encoded (K34-N158), includinga histidine tag (Human N terminal FGFBP1 (K34-N158) Avitag-His with a signal peptide):MKWVTFISLLFLFSSAYSKVVSEQKDTLGNTQIKQKSRPGNKGKFVTKDQANCRWAAT EQEEGISLKVECTQLDHEFSCVFAGNPTSCLKLKDERVYWKQVARNLRSQKDICRYSKT AVKTRVCRKDFPESSLKLVSSTLFGNSGRGLNDIFEAQKIEWHEHHHHHH (SEQ ID NO:10)

[0349] An exemplary FGFBP1 expression construct sequence encoded (T34-G163), includinga histidine tag (mouse N terminal FGFBP1 (T34-G163) Avitag-FLAG His with a signal peptide): MKWVTFISLLFLFSSAYSTAEEGVEGSAPSLGKAQNKQRSRTSKSLTHGKFVTKDQATC RWAVTEEEQGISLKVQCTQADQEFSCVFAGDPTDCLKHDKDQIYWKQVARTLRKQKNI CRNAKSVLKTRVCRKRFPESNLKLVNPNARGRGLNDIFEAQKIEWHEDYKDDDDKHHH HHH (SEQ ID NO:18)

[0350] An exemplary NTD-FGFBP2 – fusion protein comprising an IgG Fc (Human Nterminal FGFBP2 (M1-G146) Human-IgGFc) (using endogenous signal peptide): (Italics = a human FGFBP2 fragment containing NTD; underlined = human IgG Fc): MKFVPCLLLVTLSCLGTLGQAPRQKQGSTGEEFHFQTGGRDSCTMRPSSLGQGAGEVWL RVDCRNTDQTYWCEYRGQPSMCQAFAADPKPYWNQALQELRRLHHACQGAPVLRPSVCRE AGPQAHMQQVTSSLKGSPEPNQQPEAGGENLYFQSGASTKGPSVFPLAPSSKSTSGGTAA 45 4896-4870-0471v.193597 / 7296 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK (Entire fusion protein is SEQ ID NO:11; IgG Fc portion is SEQ ID NO:12)

[0351] Exemplary sequences of active fragments containing N-terminal domains:

[0352] Mouse FGFBP1 T34-G163:TAEEGVEGSAPSLGKAQNKQRSRTSKSLTHGKFVTKDQATCRWAVTEEEQGISLKVQC TQADQEFSCVFAGDPTDCLKHDKDQIYWKQVARTLRKQKNICRNAKSVLKTRVCRKRF PESNLKLVNPNARG (SEQ ID NO:13)

[0353] Human FGFBP1 K34-N158KVVSEQKDTLGNTQIKQKSRPGNKGKFVTKDQANCRWAATEQEEGISLKVECTQLDHE FSCVFAGNPTSCLKLKDERVYWKQVARNLRSQKDICRYSKTAVKTRVCRKDFPESSLKL VSSTLFGN (SEQ ID NO:14)

[0354] Human FGFBP2 G30-G146GEEFHFQTGGRDSCTMRPSSLGQGAGEVWLRVDCRNTDQTYWCEYRGQPSMCQAFAA DPKPYWNQALQELRRLHHACQGAPVLRPSVCREAGPQAHMQQVTSSLKGSPEPNQQPE AG (SEQ ID NO:15).

[0355] Human FGFBP3 fragment (M1-A155) including endogenous signal peptide:MTPPKLRASLSPSLLLLLSGCLLAAARREKGAASNVAEPVPGPTGGSSGRFLSPEQHACS WQLLLPAPEAAAGSELALRCQSPDGARHQCAYRGHPERCAAYAARRAHFWKQVLGGL RKKRRPCHDPAPLQARLCAGKKGHGAELRLVPRASPPA (SEQ ID NO:19)

[0356] Mouse FGFBP3 fragment (M1-A155) including endogenous signal peptide:MSPPRPRASLSPLTLLLLLGGCLLSAAGRDKGAAGREVTRASRPTVGSSGRFVSPEQHAC SWQLLVPAPGTPTGGELALRCQTPGGASLHCAYRGHPERCAATGARRAHYWRRLLGA LRRRPRPCLDPAPLPPRLCARKTAGSDLHSPAHPSLPA (SEQ ID NO:20)

[0357] Exemplary Adenovirus constructs:46 4896-4870-0471v.193597 / 7296

[0358] Ad mFGFBP1 NTD-Fc (signal peptide, mFGFBP1 NTD T34-G163, murine Fc,3xFLAG, 8xHis). Italics = a fragment containing an mFGFBP1 NTD; Underlined = a mouse Fc METDTLLLWVLLLWVPGSTGDTAEEGVEGSAPSLGKAQNKQRSRTSKSLTHGKFVTKDQA TCRWAVTEEEQGISLKVQCTQADQEFSCVFAGDPTDCLKHDKDQIYWKQVARTLRKQKNIC RNAKSVLKTRVCRKRFPESNLKLVNPNARGGSGLEPRGPTIKPCPPCKCPAPNLLGGPSVFIF PPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRV VSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKK QVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWV ERNSYSCSVVHEGLHNHHTTKSFSRTPGKGSDYKDHDGDYKDHDIDYKDDDDKGSHH HHHHHH- (SEQ ID NO:21)

[0359] Ad hFGFBP2 NTD-Fc (signal peptide, hFGFBP2 NTD G30-G146, murine Fc,3xFLAG, 8xHis). Italics = a fragment containing a hFGFBP2 NTD; Underlined = a mouse Fc METDTLLLWVLLLWVPGSTGDGEEFHFQTGGRDSCTMRPSSLGQGAGEVWLRVDCRNTD QTYWCEYRGQPSMCQAFAADPKPYWNQALQELRRLHHACQGAPVLRPSVCREAGPQAHMQ QVTSSLKGSPEPNQQPEAGGGSGLEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLM ISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQD WMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVT DFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSV VHEGLHNHHTTKSFSRTPGKGSDYKDHDGDYKDHDIDYKDDDDKGSHHHHHHHH- (SEQ ID NO:22)

[0360] The invention also provides an expression construct encoding polypeptide, thepolypeptide comprising a sequence of FGFBP1 or FGFBP2 or FGFBP3 amino acids which is located in an N-terminal portion of an FGFBP1 or FGFBP2 or FGFBP3 protein.

[0361] In some embodiments of the methods and compositions herein disclosed, the FGFBP1or FGFBP2 or FGFBP3 is human. In some embodiments of the methods and compositions herein disclosed, the FGFBP1 or FGFBP2 or FGFBP3 is mouse.

[0362] Without wishing to be bound by theory, there is no necessary reason that thecomposition, fragments, domains and portions described herein need actually bind to a heparin to effect the various method outcomes. 47 4896-4870-0471v.193597 / 7296

[0363] In some embodiments, the compositions or methods employing an NTD of a humanFGFBP2, but not a full length human FGFBP2, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:3 but does not comprise SEQ ID NO:1, nor SEQ ID NO:1 without its native signal sequence. In some embodiments, a portion comprising an N-terminal domain of human FGFBP2 has the sequence of SEQ ID NO:15.

[0364] In some embodiments, the compositions or methods employing an NTD of a humanFGFBP3, but not a full length human FGFBP3, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:5 but does not comprise SEQ ID NO:4, nor SEQ ID NO:4 without its native signal sequence. In some embodiments, a portion comprising an N-terminal domain of human FGFBP3 has the sequence of SEQ ID NO:19.

[0365] In some embodiments, the compositions or methods employing an NTD of a mouseFGFBP3, but not a full length mouse FGFBP3, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:6 but does not comprise a full length mouse FGFBP3 with or without its signal sequence.

[0366] In some embodiments, the compositions or methods employing an NTD of a humanFGFBP1, but not a full length human FGFBP1, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:8 but does not comprise SEQ ID NO:7, nor SEQ ID NO:7 without its native signal sequence. In some embodiments, a portion comprising an N-terminal domain of human FGFBP1 has the sequence of SEQ ID NO:14.

[0367] In some embodiments, the compositions or methods employing an NTD of a mouseFGFBP1, but not a full length mouse FGFBP1, comprise a fragment, domain, portion or sequence, or comprise use of a fragment, domain, portion or sequence, which comprises SEQ ID NO:9 but does not comprise a full length mouse FGFBP1 with or without its signal sequence. In some embodiments, a portion comprising an N-terminal domain of mouse FGFBP1 has the sequence of SEQ ID NO:13.

[0368] In some embodiments, an expression construct encoding a human FGFBP2 NTD canencode SEQ ID NO:2. In some embodiments, an expression construct encoding a human FGFBP1 48 4896-4870-0471v.193597 / 7296 NTD can encode SEQ ID NO:10. In some embodiments, an expression construct encoding a mouse FGFBP1 NTD can encode SEQ ID NO:18. In some embodiments, a fusion protein comprising a human FGFBP2 NTD can be SEQ ID NO:11. In some embodiments, the expression constructs are adenoviral expression constructs. In some embodiments, an adenoviral expression construct encoding a human FGFBP2 NTD can encode SEQ ID NO:22. In some embodiments, an adenoviral expression construct encoding a mouse FGFBP1 NTD can encode SEQ ID NO:21.

[0369] In some embodiments, a protein domain or peptide comprising an N-terminal domainof a human fibroblast growth factor binding protein 1 (FGFBP1) or mouse FGFBP1, but not comprising a full length or mature FGFBP1 protein, can comprise at the N-terminal end of, e.g., SEQ ID NO:8 or 9, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more contiguous amino acids of the sequence of the full length FGFBP1 sequence extending beyond the N-terminus of SEQ ID NO:7 or 17. The same applies to the NTD of FGFBP2, and FGFBP3, e.g., with regard to SEQ ID NO:3 versus SEQ ID NO:1, or with regard to SEQ ID NOS: 5 or 6 versus SEQ ID NOS: 4 or 16, respectively. For example, in the case of FGFBP2, as set forth in Fig. 1C, the heparin binding domain of human FGFBP2, which can be utilized as an protein domain or peptide comprising an N-terminal domain of a human fibroblast growth factor binding protein 2 (FGFBP2), has the sequence QAPRQKQGSTGEE (SEQ ID NO:23) (hFGFBP2 Q20-E32) in between the C-terminus of the signal sequence and the N- terminus of heparin-binding domain sequence of human FGFBP2. In some embodiments, a protein domain or peptide comprising an N-terminal domain of a human fibroblast growth factor binding protein 2 (FGFBP2), but not comprising a full length or mature FGFBP2 protein, can comprise QAPRQKQGSTGEE (SEQ ID NO:23) (hFGFBP2 Q20-E32) or any shorter sequence thereof that is contiguous with the N-terminus of SEQ ID NO:3, whether it be one, two, three, four, five, etc. or more contiguous amino acids from the sequence. The same applies, mutatis mutandis, to the C- terminal end of, e.g., SEQ ID NO:3. Thus in some embodiments, a protein domain or peptide comprising an N-terminal domain of a human fibroblast growth factor binding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein, can comprise at the C-terminus of, e.g., SEQ ID NO:3, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more contiguous amino acids of the sequence of the full length FGFBP2 sequence extending beyond the C-terminus of SEQ ID NO:3. Thus, with reference to Fig.1C, the 49 4896-4870-0471v.193597 / 7296 C-terminal end can extend one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more contiguous amino acids of the sequence of the full length human FGFBP2 sequence extending beyond the C-terminus of SEQ ID NO:3, i.e., any contiguous portion of the sequence of SEQ ID NO:1 starting after the C-terminal end of the heparin-binding domain up to the start of the N-terminal end of the FGF-binding domains (i.e., any C-terminal contiguous portion of PNQQPEAGTPSLRPKATVKLTEATQLGKDSMEELGKAKPTTRPTAKPTQ (SEQ ID NO:24) (hFGFBP2 P139-Q187) whether one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen etc. or more contiguous amino acids thereof. In some embodiments, the same applies to peptide or protein domains comprising an N-terminal domain of a human fibroblast growth factor binding protein 1 (FGFBP1), but not comprising a full length or mature FGFBP1 protein, and also to peptide or protein domains comprising an N-terminal domain of a human fibroblast growth factor binding protein 3 (FGFBP3), but not comprising a full length or mature FGFBP3 protein.

[0370] In some embodiments, a protein domain comprising an N-terminal domain of a humanfibroblast growth comprises from one to twenty additional amino acids at the N-terminus and / or C-terminus thereof, where the amino acids are independent of the N-terminal and / or C-terminal amino acids of the native FGFBP sequence.

[0371] Fragments of full length FGFBP1, FGFBP2, or FGFBP3 can include the signalsequence and an NTD, but exclude the FGF-binding domain. Fragments of full length FGFBP1, FGFBP2, or FGFBP3 containing an NTD can also exclude the native the signal sequence, and exclude the FGF-binding domain. Examples of such fragments are:

[0372] Fragments of full length FGFBP1 protein sequence (Human) (SEQ ID NO:7)containing an N-terminal domain (NTD) (e.g., S52-S153) can include, at the N-terminal portion thereof, any contiguous residues K24-K51 (i.e., the entire or less than the entire sequence between end of signal peptide and beginning of heparin binding domain), and / or, independently, at the C- terminal portion thereof any contiguous residues T154-D200 (i.e., the entire or less than the entire sequence between end of Heparin Binding Domain and start of FGF-binding domain).

[0373] Fragments of full length FGFBP1 protein sequence (mouse) (SEQ ID NO:17)containing an NTD (e.g., S58-R162) can include, at the N-terminal portion thereof, any contiguous residues E21-T57 (i.e., the entire or less than the entire sequence between end of signal peptide 50 4896-4870-0471v.193597 / 7296 and beginning of heparin binding domain), and / or, independently, at the C-terminal portion thereof any contiguous residues G163-D211 (i.e., the entire or less than the entire sequence between end of heparin binding domain and start of FGF-binding domain).

[0374] Fragments of full length FGFBP2 protein sequence (Human) (SEQ ID NO:1)containing an NTD (F33-E138) can include, at the N-terminal portion thereof, any contiguous residues Q20-E32 (i.e., the entire or less than the entire sequence between end of signal peptide and beginning of heparin binding domain), and / or, independently, at the C-terminal portion thereof any contiguous residues P139-Q187 (i.e., the entire or less than the entire sequence between end of heparin binding domain and start of FGF-binding domain).

[0375] Fragments of full length FGFBP3 protein sequence (Human) (SEQ ID NO:4)containing an NTD (G42-A151) can include, at the N-terminal portion thereof, any contiguous residues A26-P41 (i.e., the entire or less than the entire sequence between end of signal peptide and beginning of heparin binding domain), and / or, independently, at the C-terminal portion thereof any contiguous residues S152-L230 (i.e., the entire or less than the entire sequence between end of heparin binding domain and start of FGF-binding domain).

[0376] Fragments of full length FGFBP3 protein sequence (mouse) (SEQ ID NO:16)containing an NTD (S49-P151) can include, at the N-terminal portion thereof, any contiguous residues K31-S48 (i.e., the entire or less than the entire sequence between end of signal peptide and beginning of heparin binding domain), and / or, independently, at the C-terminal portion thereof any contiguous residues S152-N215 (i.e., the entire or less than the entire sequence between end of heparin binding domain and start of FGF-binding domain).

[0377] The compositions, peptides, fusion proteins, expression constructs, or methods of theinvention can in some embodiments apply or embody or encode any of the fragments described herein. In some embodiments, the peptide is a fragment.

[0378] It will be understood that, for the particular FGFBP polypeptides described here,natural variations can exist. These variations may be demonstrated by (an) amino acid difference(s) in the overall sequence or by deletions, substitutions, insertions, inversions or additions of (an) amino acid(s) in said sequence. Amino acid substitutions which do not essentially alter biological and immunological activities, have been described, e.g. by Neurath et al in "The Proteins" Academic Press New York (1979). Amino acid replacements between related amino 15 acids or 51 4896-4870-0471v.193597 / 7296 replacements which have occurred frequently in evolution are, inter alia, Ser / Ala, Ser / Gly, Asp / Gly, Asp / Asn, Ile / Val (see Dayhof, M. D., Atlas of protein sequence and structure, Nat. Biomed. Res. Found., Washington D.C., 1978, vol. 5, suppl. 3). Other amino acid substitutions include Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Thr / Phe, Ala / Pro, Lys / Arg, Leu / Ile, Leu / Val and Ala / Glu. Based on this information, Lipman and Pearson developed a method for rapid and sensitive protein comparison (Science (1985) 227:1435) and determining the functional similarity between homologous proteins. Such amino acid substitutions of the exemplary embodiments of this invention, as well as variations having deletions and / or insertions are within the scope of the invention as long as the resulting proteins retain at least some of the one or more activities described herein. In some embodiments of the methods and compositions and fusion proteins, the N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP) comprises a variant having a sequence identity of 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more with a complete N-terminal domain as set forth in one of SEQ ID NOS: 3, 5, 6, 8 or 9. In some embodiments of the methods and compositions and fusion proteins, the N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP) comprises a variant having a sequence identity of 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more with a complete N-terminal domain as set forth in one of SEQ ID NOS: 3, 5, 6, 8 or 9. Sequence identity can be determined using any of a number of publicly available sequence comparison algorithms, such as BLAST, FASTA, DNA Strider, and GCG (Genetics Computer Group, Program Manual for the GCG Package, Version 7, Madison, Wisconsin). To determine the percent identity between two amino acid sequences or two nucleic acid molecules, the sequences are aligned for optimal comparison purposes. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., percent identity = number of identical positions / total number of positions (e.g., overlapping positions) x 100). In one embodiment, the two sequences are, or are about, of the same length. The percent identity between two sequences can be determined using techniques similar to those described below, with or without allowing gaps. 52 4896-4870-0471v.193597 / 7296

[0379] In some embodiments of the methods and compositions and fusion proteins, the N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP) comprises the complete domain (e.g. as set forth in SEQ ID NOS: 3, 5, 6, 8 or 9). In further aspects of the methods and compositions and fusion proteins herein, an active fragment of the N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP) is employed or as part of the composition or fusion protein, i.e., a fragment of the N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP) which is less than the entire N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP) but which still retains some activity, e.g., some ability to promote propagation of, function of, and / or increasing viability of, T cells or NK cells. Such fragments may be as few as 8 amino acids of the N-terminal domain of the FGFBP (or the heparin- binding domain of the FGFBP) and of any amino acid number in length up to one less amino acid than the entire length of the N-terminal domain of the FGFBP (or the heparin-binding domain of the FGFBP). For example, a fragment of SEQ ID NO:5 (117 amino acids in length) that is an 8 to 116 amino acids fragment of SEQ ID NO:5 is encompassed. For example, a fragment of SEQ ID NO:6 (103 amino acids in length) that is an 8 to 102 amino acids fragment of SEQ ID NO:6. For example, a fragment of SEQ ID NO:3 (106 amino acids in length) that is an 8 to 105 amino acids fragment of SEQ ID NO:3. For example, a fragment of SEQ ID NO:8 (102 amino acids in length) that is an 8 to 101 amino acids fragment of SEQ ID NO:8. For example, a fragment of SEQ ID NO:9 (102 amino acids in length) that is an 8 to 101 amino acids fragment of SEQ ID NO:9. Fragments may be of any length as long as they retain some activity as described herein, e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 etc. amino acids in length. All individual integer fragment lengths between the stated ranges are encompassed by the invention. In addition, all fragment length sub-ranges within the stated ranges are encompassed by the invention, e.g.20-30, 30-40, 40-50 etc. amino acids in length.

[0380] Full length FGFBP1 sequences are set forth in SEQ ID NOS:7 and 17. The matureFGFBP1 does not comprise the signal sequence, e.g. as set forth in FIG.1. Full length FGFBP2 sequence (Human only) is set forth in SEQ ID NO:1. The mature FGFBP2 does not comprise the signal sequence, e.g. as set forth in FIG.1. Full length FGFBP3 sequences are set forth in SEQ ID NOS:4 and 16. The mature FGFBP3 does not comprise the signal sequence, e.g. as set forth in FIG.1. 53 4896-4870-0471v.193597 / 7296

[0381] In some embodiments, the peptides or fusion proteins containing the N-terminaldomain of the FGFBP are modified in their backbones. Backbone modification includes the substitution of one or more L-amino acids by D-amino acids, insertion of one or more methylamino acids, and the incorporation of one or more β-amino acids and one or more peptoids. In some embodiments, the peptides are not modified in their backbones.

[0382] In some embodiments, the peptides or fusion proteins containing the N-terminaldomain of the FGFBP comprise one or more side chain modifications achieved by replacing the natural amino acids with their analogues during peptide synthesis, to improve their binding affinity and target selectivity. Variants of natural amino acid analogues encompassed include homoarginine, benzyloxytyrosine, and β-phenylalanine. In some embodiments, the peptides containing the N-terminal domain do not comprise one or more side chain modifications.

[0383] In some embodiments, the peptides or fusion proteins containing the N-terminaldomain of the FGFBP are PEGylated. PEG is formed by repetitive units of ethylene oxide and is a non-biodegradable, non-toxic, low-immunogenic polymer. PEGylation can increase the effective molecular weight of proteins to reduce their renal clearance by kidneyfiltration. The PEG moiety can also shield the proteins from digestion by proteolytic enzymes via increased steric hindrance, and help increase absorption by increasing the target protein’s water solubility. These advantages make PEGylation a prevalent strategy for modifying therapeutic proteins, and PEGylation has been applied for optimizing protein therapeutics since the 1970s, with great success. Conventional PEGylation often occurs at Lys or Cys residues. PEGylation can also be effected via genetic code expansion when making the peptides, e.g., recombinantly. Azide (e.g., p-azido-phenylalanine) or acetyl (e.g., p-acetylphenylalanine) groups can be introduced into therapeutic peptides and proteins by genetic code expansion to allow downstream PEGylation modifications including, e.g. mono- PEGylation. Different sized PEG chains are encompassed, e.g., PEG4, PEG8, PEG12, or PEG24.

[0384] Along with serum albumin or immunoglobulin Fc fusions, plasma half-life of thecompositions of, and used in, the invention herein can be increased by conjugations. For example, in some embodiments, the peptides or fusion proteins containing the N-terminal domain of the FGFBP are conjugated to C14 / 16 / 18 fatty acids which can increase plasma circulation times and decrease kidney elimination. 54 4896-4870-0471v.193597 / 7296

[0385] In some embodiments, proximity-enabled reactive therapeutic strategy can be usedsuch as incorporating a non-canonical amino acid into the peptides or fusion proteins containing the N-terminal domain of the FGFBP, e.g. afluorosulfate-L-tyrosine.

[0386] In some embodiments, compositions comprising the peptides or fusion proteinscontaining the N-terminal domain of the FGFBP are formulated with permeation enhancers such as fatty acids or, e.g., with sodium N-[8-(2-hydroxybenzoyl amino]caprylate (SNAC). In some embodiments, the compositions are formulated with hydrogels or enzyme inhibitors.

[0387] Protein domains comprising an N-terminal domain of a human fibroblast growth factorbinding protein can be referred to herein as peptides.

[0388] The domains of the invention can be used in regard to the methods herein, thecompositions of the invention can be used in regard to the methods herein, the peptides of the invention can be used in regard to the methods herein, the fragments of the invention can be used in regard to the methods herein, the fusion proteins of the invention can be used in regard to the methods herein, and the expression constructs of the invention can be used in regard to the methods herein.

[0389] In some embodiments, the domain of the N-terminal portion of an FGFBP1 comprisesSEQ ID NO:8 or SEQ ID NO:9. In some embodiments, the domain of the N-terminal portion of an FGFBP1 comprises SEQ ID NO:8. In some embodiments, the protein domain comprises SEQ ID NO:8, but does not comprise a full length FGFBP1 protein having SEQ ID NO:7 or the protein domain comprises SEQ ID NO:9, but does not comprise a full length FGFBP1 protein having SEQ ID NO:17. In some embodiments, the domain of the N-terminal portion of FGFBP2 is not a full length FGFBP2 protein having SEQ ID NO:1. In some embodiments, the domain of the N-terminal portion of FGFBP2 has SEQ ID NO:3. In some embodiments, the FGFBP2 protein domain comprises SEQ ID NO:3, but does not comprise a full length FGFBP2 protein having SEQ ID NO:1. In some embodiments, the domain of the N-terminal portion of FGFBP3 has SEQ ID NO:5 or 6. In some embodiments, the protein domain comprises SEQ ID NO:5, but does not comprise a full length FGFBP1 protein having SEQ ID NO:4 or the protein domain comprises SEQ ID NO:6, but does not comprise a full length FGFBP1 protein having SEQ ID NO:16.

[0390] In some embodiments of the methods and compositions, peptides, fragments, fusionproteins and expression constructs, a domain of an N-terminal portion of an FGFBP1, 2 or 3 is a 55 4896-4870-0471v.193597 / 7296 domain of the protein which is primarily in the N-terminal half of the protein. For example, a domain of FGFBP1, 2 or 3 whose primary sequence is mainly (>50%) in the N-terminal half of the protein’s primary sequence. In some embodiments of the methods and compositions, the composition is a portion of an FGFBP1, 2 or 3 lacking the C-terminal fibroblast growth factor (FGF) -binding domain. In some embodiments of the methods and compositions, the composition comprises a fragment of a full length FGFBP1, 2 or 3 but lacks the C-terminal FGF binding domain. The protein domains, fragments, and portions can be produced recombinantly. Thus, In some embodiments, the protein domains, fragments, and portions are not actual physical parts of the full length proteins, but have sequence identity therewith. For example, a domain having the same sequence, or a modified version of, a domain of the native full length protein sequence is readily producible by, e.g., recombinant means.

[0391] The domains, fragments and portions disclosed herein can be produced in a variety ofways, including production and recovery of natural or nonnatural polypeptides, production and recovery of recombinant polypeptides, and chemical synthesis of the polypeptides. In one embodiment, a recombinant domain, fragment, peptide or portion is produced by culturing a cell capable of expressing the domains, fragments, peptides and portions under conditions effective to produce the domains, fragments, peptides and portions. The recombinant domains, fragments and portions may subsequently be secreted from the cell, e.g., if expressed with a signal sequence, and recovered, or extracted from the cell and recovered, and is preferably purified away from contaminating molecules. It may or may not be further modified chemically or enzymatically. A preferred cell to culture is a recombinant cell. Effective culture conditions include, but are not limited to, effective media, bioreactor, temperature, pH and oxygen conditions that permit domain, fragment or portion production. An effective medium refers to any medium in which a cell is cultured to produce a polypeptide defined herein. Such medium typically comprises an aqueous medium having assimilable carbon, nitrogen and phosphate sources, and appropriate salts, minerals, metals and other nutrients, such as vitamins. Cells defined herein can be cultured in conventional fermentation bioreactors, shake flasks, test tubes, microtiter dishes, and petri plates. Culturing can be carried out at a temperature, pH and oxygen content appropriate for a recombinant cell. Such culturing conditions are within the expertise of one of ordinary skill in the art. 56 4896-4870-0471v.193597 / 7296 Recombinant cells can be eukaryotic or prokaryotic. Non-limiting examples include mammalian or insect or bacterial or fungal expression systems.

[0392] In some embodiments, a composition herein consists essentially of the protein domainof an N-terminal portion of an FGFBP1 and contains no other active ingredients. In some embodiments, the composition comprises the protein domain of an N-terminal portion of an FGFBP1 and contains a physiological or pharmaceutically acceptable carrier. In some embodiments, composition herein comprises a carrier comprising saline or a culture medium. In some embodiments, the composition comprises a portion of an FGFBP1. In some embodiments, the composition comprises a fusion protein comprising a protein domain of an N-terminal portion of an FGFBP1.

[0393] In some embodiments, composition herein consists essentially of the protein domain ofan N-terminal portion of an FGFBP2 and contains no other active ingredients. In some embodiments, the composition comprises the protein domain of an N-terminal portion of an FGFBP2 and contains a physiological or pharmaceutically acceptable carrier. In some embodiments, a composition herein comprises a carrier comprising saline or a culture medium. In some embodiments, the composition comprises a portion of an FGFBP2. In some embodiments, the composition comprises a fusion protein comprising a protein domain of an N-terminal portion of an FGFBP2.

[0394] In some embodiments, the composition herein consists essentially of the proteindomain of an N-terminal portion of an FGFBP3 and contains no other active ingredients. In some embodiments, the composition comprises the protein domain of an N-terminal portion of an FGFBP3 and contains a physiological or pharmaceutically acceptable carrier. In some embodiments, the composition herein comprises a carrier comprising saline or a culture medium. In some embodiments, the composition comprises a portion of an FGFBP3. In some embodiments, the composition comprises a fusion protein comprising a protein domain of an N-terminal portion of an FGFBP3.

[0395] An expression construct is provided encoding a heparin-binding domain of a fibroblastgrowth factor binding protein 1 (FGFBP1), but not encoding a full length FGFBP1 protein. In some embodiments, the expression construct does not encode an FGF binding domain. An expression construct is provided encoding a heparin-binding domain of a fibroblast growth factor 57 4896-4870-0471v.193597 / 7296 binding protein 2 (FGFBP2), but not encoding a full length FGFBP2 protein. In some embodiments, the expression construct does not encode an FGF binding domain. An expression construct is provided encoding a heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length FGFBP3 protein. In some embodiments, the expression construct does not encode an FGF binding domain.

[0396] In some embodiments, an expression construct herein encodes SEQ ID NO:10, 2, or18. In some embodiments, an expression construct herein encodes SEQ ID NO:13, 14, or 15. In some embodiments, an expression construct herein encodes SEQ ID NO:1. In some embodiments, an expression construct herein SEQ ID NO:7. In some embodiments, an expression construct herein encodes SEQ ID NO:11. In some embodiments, an expression construct herein encodes SEQ ID NO:21 or 22. In some embodiments, an expression construct herein encodes SEQ ID NO:18. In some embodiments, an expression construct herein encodes SEQ ID NO:19 or 20. In some embodiments, the expression construct herein encodes any one of the sequences in the SEQ ID NOS. disclosed herein. In some embodiments, the expression construct herein encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP1, 2 or 3. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP1, wherein the signal peptide is not naturally found in a gene encoding the full length FGFBP1 protein. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP2, wherein the signal peptide is not naturally found in a gene encoding the full length FGFBP2 protein. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP3, wherein the signal peptide is not naturally found in a gene encoding the full length FGFBP3 protein. Examples of signal peptides include a gp67 signal peptide. Other signal peptides include NSP4, PelB5, DsbAss, baculoviral gp64, modified human serum albumin (mSA), human azurocidin (AZ), modified Cricetulus griseus Ig kappa chain V III region MOPC 63 like (mIgkC) and modified human Ig kappa chain V III region VG (mIgkH).

[0397] An expression construct is provided encoding a heparin-binding domain of a fibroblastgrowth factor binding protein 2 (FGFBP2), but not encoding a full length FGFBP2 protein. An expression construct is provided encoding a heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length FGFBP3 protein. In some 58 4896-4870-0471v.193597 / 7296 embodiments, the expression construct does not encode an FGF binding domain. In some embodiments, the FGFBP2 is human. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP2. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP2, wherein the signal peptide is not naturally found in a gene encoding the full length FGFBP2 protein. In some embodiments, the FGFBP3 is human or mouse. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP3. In some embodiments, the expression construct encodes a signal peptide that controls secretion of the heparin-binding domain of an FGFBP3, wherein the signal peptide is not naturally found in a gene encoding the full length FGFBP3 protein. Non-limiting examples of signal peptides include a gp67 signal peptide, NSP4, PelB5, DsbAss, baculoviral gp64, modified human serum albumin (mSA), human azurocidin (AZ), modified Cricetulus griseus Ig kappa chain V III region MOPC 63 like (mIgkC) and modified human Ig kappa chain V III region VG (mIgkH) signal peptides.

[0398] An expression construct encoding a fusion protein comprising (i) a heparin-bindingdomain of a fibroblast growth factor binding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene. An expression construct encoding a fusion protein comprising (i) a heparin-binding domain of a fibroblast growth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp2 gene. An expression construct encoding a fusion protein comprising (i) a heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene.

[0399] A protein domain comprising a heparin-binding domain of a fibroblast growth factorbinding protein 1 (FGFBP1), but not comprising a full length or mature FGFBP1 protein. In some embodiments, the FGFBP1 is human or mouse. The heparin-binding domain is also referred to herein as a putative heparin binding domain. In some embodiments, the heparin-binding domain comprises SEQ ID NO:8. In some embodiments, the heparin-binding domain comprises SEQ ID NO:9. In some embodiments, the protein domain comprises SEQ ID NO:8, but not comprising a full length FGFBP1 protein having SEQ ID NO:7. In some embodiments, the protein domain comprises SEQ ID NO:9, but not comprising a full length FGFBP1 protein having SEQ ID NO:17. 59 4896-4870-0471v.193597 / 7296

[0400] A protein domain comprising a heparin-binding domain of a fibroblast growth factorbinding protein 2 (FGFBP2), but not comprising a full length or mature FGFBP2 protein. In some embodiments, the FGFBP2 is human. In some embodiments, the protein domain comprises SEQ ID NO:3, but not comprising a full length FGFBP2 protein having SEQ ID NO:1.

[0401] A protein domain comprising a heparin-binding domain of a fibroblast growth factorbinding protein 3 (FGFBP3), but not comprising a full length or mature FGFBP3 protein. In some embodiments, the FGFBP3 is human or mouse. The heparin-binding domain is also referred to herein as a putative heparin binding domain. In some embodiments, the protein domain comprises SEQ ID NO:5, but not comprising a full length FGFBP1 protein having SEQ ID NO:4. In some embodiments, the protein domain comprises SEQ ID NO:6, but not comprising a full length FGFBP1 protein having SEQ ID NO:16.

[0402] A fusion protein comprising (i) a heparin-binding domain of a fibroblast growth factorbinding protein 1 (FGFBP1) and (ii) a peptide or a protein not encoded by a fgfbp1 gene. A fusion protein comprising (i) a heparin-binding domain of a fibroblast growth factor binding protein 2 (FGFBP2) and (ii) a peptide or a protein not encoded by a fgfbp2 gene. A fusion protein comprising (i) a heparin-binding domain of a fibroblast growth factor binding protein 3 (FGFBP3) and (ii) a peptide or a protein not encoded by a fgfbp3 gene. In some embodiments, (ii) comprises an immunoglobulin Fc. In some embodiments, (ii) comprises a human serum albumin.

[0403] A fusion protein of the heparin-binding domain of an FGFBP1 described hereincomprises the domain joined either directly, or indirectly through a linker, via a peptide bond at its N- or C-terminus to a second peptide or protein or polypeptide or protein domain which is heterologous relative to the FGFBP1 (not encoded by the same gene). Examples of such second peptide, protein, polypeptide or protein domain include, e.g., an immunoglobulin Fc portion, human serum albumin (HSA), transferrin, ELP repeat sequence (Phase Bio), proline-alanine- serine polymer, PAS (XL-protein GmbH), homo-amino acid polymer, HAP (homopolymer of glycine resides), gelatin-like protein GLK, or a non-structured polypeptide such as XTEN, a self- assembling protein nanoparticle carrier, all either directly or through a linker peptide sequence. The first protein domain and second protein, polypeptide or protein domain may be directly linked (for example, the C-terminus of the first protein domain is linked to the N-terminus of the second protein by a peptide bond), or indirectly linked (for example, the C-terminus of the first protein 60 4896-4870-0471v.193597 / 7296 domain is directly linked to the N-terminus of a peptide linker by a peptide bond, and the C- terminus of the peptide linker is directly linked to the N-terminus of the second protein by a peptide bond). The invention also encompasses the protein domain described herein joined to second moiety to extend serum half-life such as a self-assembling protein nanoparticle carrier by a non-peptide chemical linker (such as a Sulfo-SIAB linker) or PEGylation. In an embodiment of the fusion protein comprising an Fc, the fusion protein can comprise glycosylation at a residue on the Fc portion corresponding to Asn297. In some embodiments, the second peptide or protein or polypeptide or protein domain comprises a single-chain variable fragment (scFv).

[0404] A fusion protein of the heparin-binding domain of an FGFBP2 described hereincomprises the domain joined either directly, or indirectly through a linker, via a peptide bond at its N- or C-terminus to a second peptide or protein or polypeptide or protein domain which is heterologous relative to the FGFBP1 (not encoded by the same gene). Examples of such second peptide, protein, polypeptide or protein domain include, e.g., an immunoglobulin Fc portion, human serum albumin (HSA), transferrin, ELP repeat sequence (Phase Bio), proline-alanine- serine polymer, PAS (XL-protein GmbH), homo-amino acid polymer, HAP (homopolymer of glycine resides), gelatin-like protein GLK, or a non-structured polypeptide such as XTEN, a self- assembling protein nanoparticle carrier, all either directly or through a linker peptide sequence. The first protein domain and second protein, polypeptide or protein domain may be directly linked (for example, the C-terminus of the first protein domain is linked to the N-terminus of the second protein by a peptide bond), or indirectly linked (for example, the C-terminus of the first protein domain is directly linked to the N-terminus of a peptide linker by a peptide bond, and the C- terminus of the peptide linker is directly linked to the N-terminus of the second protein by a peptide bond). The invention also encompasses the protein domain described herein joined to second moiety to extend serum half-life such as a self-assembling protein nanoparticle carrier by a non-peptide chemical linker (such as a Sulfo-SIAB linker) or PEGylation. In an embodiment of the fusion protein comprising an Fc, the fusion protein can comprise glycosylation at a residue on the Fc portion corresponding to Asn297. In some embodiments, the second peptide or protein or polypeptide or protein domain comprises a single-chain variable fragment (scFv).

[0405] A fusion protein of the heparin-binding domain of an FGFBP3 described hereincomprises the domain joined either directly, or indirectly through a linker, via a peptide bond at 61 4896-4870-0471v.193597 / 7296 its N- or C-terminus to a second peptide or protein or polypeptide or protein domain which is heterologous relative to the FGFBP3 (not encoded by the same gene). Examples of such second peptide, protein, polypeptide or protein domain include, e.g., an immunoglobulin Fc portion, human serum albumin (HSA), transferrin, ELP repeat sequence (Phase Bio), proline-alanine- serine polymer, PAS (XL-protein GmbH), homo-amino acid polymer, HAP (homopolymer of glycine resides), gelatin-like protein GLK, or a non-structured polypeptide such as XTEN, a self- assembling protein nanoparticle carrier, all either directly or through a linker peptide sequence. The first protein domain and second protein, polypeptide or protein domain may be directly linked (for example, the C-terminus of the first protein domain is linked to the N-terminus of the second protein by a peptide bond), or indirectly linked (for example, the C-terminus of the first protein domain is directly linked to the N-terminus of a peptide linker by a peptide bond, and the C- terminus of the peptide linker is directly linked to the N-terminus of the second protein by a peptide bond). The invention also encompasses the protein domain described herein joined to second moiety to extend serum half-life such as a self-assembling protein nanoparticle carrier by a non-peptide chemical linker (such as a Sulfo-SIAB linker) or PEGylation. In an embodiment of the fusion protein comprising an Fc, the fusion protein can comprise glycosylation at a residue on the Fc portion corresponding to Asn297. In some embodiments, the second peptide or protein or polypeptide or protein domain comprises a single-chain variable fragment (scFv).

[0406] In an embodiment, the fusion protein comprises, between the heparin-binding domainand the second peptide, protein, polypeptide or protein domain, a linker peptide from 5 to 30 amino acid residues long. In an embodiment, the linker peptide comprises one or more of glycine, serine and threonine residues. In some embodiments, the linker peptide is 10-25 amino acids in length.

[0407] The protein domains of the invention can, in some embodiments, be modified by oneor more of site-specific mutations, incorporation of unnatural amino acids (e.g., for conjugating multiple copies of the protein domains in close proximity to enhance avidity), PEGylated, attached to other non-PEG polymers. Fusion proteins of the invention also encompass the protein domain fused, e.g. via a peptide bond or via a peptide, to an antibody, a single-chain variable fragment (e.g., to make a bispecific drug), a nanobody, an Fc, a Human serum albumin, as a polypeptide fusion (e.g., XTEN, a superhydrophilic zwitterionic peptide, a tannic acid modified protein), or 62 4896-4870-0471v.193597 / 7296 an scFv. In some embodiments, the protein domains can be glycoengineered. In some embodiments, the protein domains can lipidated or made into lipid conjugates.

[0408] The protein domains herein can be as set forth in the relevant SEQ ID NOS. or have1,2, 3, 4, 5, 6, 7, 8, 9, 10 additional amino acids at the N-terminal, C-terminal, or independently in length at the N-terminal and C-terminals thereof. In some embodiments, the additional amino acids are consecutive from the full length or mature FGFBP1 or FGFBP2 or FGFBP3 sequence. In some embodiments, the peptides have up to 15 amino acids at one or both terminals thereof. In some embodiments, the peptides have up to 20 amino acids at one or both terminals thereof. In some embodiments, the peptides have up to 25 amino acids at one or both terminals thereof.

[0409] In some embodiments, unless the SEQ ID NO for a NTD or a heparin-binding domainof an FGFBP1 is specifically set forth, a NTD or a heparin-binding domain of an FGFBP1 can mean a protein domain having the same sequence as a NTD or a heparin-binding domain of an FGFBP1 regardless of whether that sequence was produced from an fgfbp1 gene or was produced by some other means, e.g., recombinant expression, e.g., from a cDNA. Thus, a human heparin- binding domain of an FGFBP1 peptide will have the sequence of a heparin-binding domain of an FGFBP1 encoded by a human gene, but without necessarily having been produced from a human gene. Similarly, a mouse heparin-binding domain of an FGFBP1 peptide has the sequence of a heparin-binding domain of an FGFBP1 encoded by a mouse gene, but not necessarily produced from a mouse gene.

[0410] In some embodiments, unless the SEQ ID NO for a NTD or a heparin-binding domainof an FGFBP2 is specifically set forth, a NTD or a heparin-binding domain of an FGFBP2 can mean a protein domain having the same sequence as a NTD or a heparin-binding domain of an FGFBP2 regardless of whether that sequence was produced from an fgfbp2 gene or was produced by some other means, e.g., recombinant expression, e.g., from a cDNA. Thus, a human heparin- binding domain of an FGFBP2 peptide will have the sequence of a heparin-binding domain of an FGFBP2 encoded by a human gene, but without necessarily having been produced from a human gene.

[0411] In some embodiments, unless the SEQ ID NO for a NTD or a heparin-binding domainof an FGFBP3 is specifically set forth, a NTD or a heparin-binding domain of an FGFBP3 can mean a protein domain having the same sequence as a NTD or a heparin-binding domain of an 63 4896-4870-0471v.193597 / 7296 FGFBP3 regardless of whether that sequence was produced from an fgfbp3 gene or was produced by some other means, e.g., recombinant expression, e.g., from a cDNA. Thus, a human heparin- binding domain of an FGFBP3 peptide will have the sequence of a heparin-binding domain of an FGFBP3 encoded by a human gene, but without necessarily having been produced from a human gene. Similarly, a mouse heparin-binding domain of an FGFBP3 peptide has the sequence of a heparin-binding domain of an FGFBP3 encoded by a mouse gene, but not necessarily produced from a mouse gene.

[0412] A host cell transfected with an expression construct described herein, or progenythereof, is provided.

[0413] A method of producing an isolated heparin-binding domain of an FGFBP1 or FGFBP2or FGFBP3, or fusion protein thereof, comprising culturing the host cell or progeny thereof described herein in culture media, and isolating a secreted heparin-binding domain of an FGFBP1 or FGFBP2 FGFBP3 or fusion protein thereof, respectively, from a supernatant thereof.

[0414] In some embodiments, the protein domains of the invention can be administered in“naked” form, or as fusion proteins or fusion molecules with moieties that aid in delivery, serum half-life time and / or stability and resistance to degradation, or as any of these forms in a composition. Examples of delivery systems for “naked” forms of the peptides, or as fusion proteins or fusion molecules thereof, include lipid-based nanocarriers such as oil-in-water nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes and micelles.

[0415] In some embodiments of the compositions comprising the protein domains of theinvention, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein is encapsulated in nanoparticles. In some embodiments, the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots, superparamagnetic nanoparticles, dendrimers, or nanorods. In other embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein is attached to liposomes. In some instances, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein is conjugated to the surface of liposomes. In some instances, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein is encapsulated within the shell of a liposome. In some instances, the liposome is a cationic liposome. 64 4896-4870-0471v.193597 / 7296

[0416] In regard to fusion proteins or fusion molecules comprising the heparin-binding domainof an FGFBP1 or FGFBP2 or FGFBP3 described herein, i.e., comprising a second moiety which is not the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein, exemplary second moieties include permeation enhancers, assisted for example by enteric coatings and / or the presence of peptidase-inhibiting excipients or direct-acting inhibitors, medium chain fatty acids (sodium caprylate C8, sodium caprate, C10) and derivatives (the Eligen® candidate, salcaprozate sodium (SNAC)), EDTA, bile salts, acyl carnitines, and SNAC.

[0417] The isolated heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 describedherein, whether “naked” or not in fusion protein or fusion molecule form, can be unmodified or modified. Modifications can be made anywhere in the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein, including the peptide backbone, the amino acid side-chains thereof, and the amino or carboxyl termini thereof. Certain common peptide modifications that are useful for modification of heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 described herein include glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation, blockage of the amino or carboxyl group in a polypeptide, or both, by a covalent modification, and ADP-ribosylation.

[0418] In some embodiments of the inventions described herein, the heparin-binding domainof an FGFBP1 or FGFBP2 or FGFBP3 is isolated. As used herein, the term "isolated " refers to a heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3 that by virtue of its origin or source of derivation has one, two, three, or four of the following: (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, and (4) does not occur in nature absent the hand of man.

[0419] In some embodiments, peptide or fusion protein described herein is recombinantlyproduced. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, is produced in a eukaryotic expression system. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, is produced in a prokaryotic expression system.

[0420] Compositions or pharmaceutical compositions comprising the heparin-binding domainof an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein or fusion molecule comprising such, or 65 4896-4870-0471v.193597 / 7296 the described expression constructs, are provided. Compositions or pharmaceutical compositions comprising the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein or fusion molecule comprising such or the described expression constructs disclosed herein are preferably comprise stabilizers to prevent loss of activity or structural integrity of the protein due to the effects of denaturation, oxidation or aggregation over a period of time during storage and transportation prior to use. The compositions or pharmaceutical compositions can comprise one or more of any combination of salts, surfactants, pH and tonicity agents such as sugars can contribute to overcoming aggregation problems. Where a composition or pharmaceutical composition of the present invention is used as an injection, it is desirable to have a pH value in an approximately neutral pH range, it is also advantageous to minimize surfactant levels to avoid bubbles in the formulation which are detrimental for injection into subjects. In an embodiment, the composition or pharmaceutical composition is in liquid form and stably supports high concentrations of bioactive heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such in solution and is suitable for inhalational or parenteral administration. In an embodiment, the composition or pharmaceutical composition is suitable for intravenous, intramuscular, intraperitoneal, intradermal and / or subcutaneous injection. In an embodiment, the composition or pharmaceutical composition is in liquid form and has minimized risk of bubble formation and anaphylactoid side effects. In an embodiment, the composition or pharmaceutical composition is isotonic. In an embodiment, the composition or pharmaceutical composition has a pH or 6.8 to 7.4.

[0421] In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2, orFGFBP3 or fusion protein comprising such disclosed herein are lyophilized and / or freeze dried and are reconstituted for use.

[0422] In some embodiments, the compositions herein comprise a pharmaceuticallyacceptable carrier. Examples of pharmaceutically acceptable carriers include, for the pharmaceutical compositions of the invention, but are not limited to, phosphate buffered saline solution, sterile water (including water for injection USP), emulsions such as oil / water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline, for example 0.9% sodium chloride solution, USP. Compositions comprising such carriers are formulated by well-known conventional methods 66 4896-4870-0471v.193597 / 7296 (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000, the content of each of which is hereby incorporated in its entirety).

[0423] In non-limiting examples, this can comprise one or more of dibasic sodium phosphate,potassium chloride, monobasic potassium phosphate, polysorbate 80 (e.g. 2-[2-[3,5-bis(2- hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate), disodium edetate dehydrate, sucrose, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate dihydrate.

[0424] The compositions, or pharmaceutical compositions described herein can also belyophilized or provided in any suitable forms including, but not limited to, injectable solutions or inhalable solutions, gel forms and tablet forms.

[0425] In some embodiments the composition or pharmaceutical composition comprising theheparin-binding domain of an FGFBP or FGFBP2 or FGFBP3, or fusion protein comprising such, described herein is substantially pure with regard to the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such. A composition or pharmaceutical composition comprising the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, described herein is "substantially pure" with regard to the heparin- binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such when at least 60% to 75% of a sample of the composition or pharmaceutical composition exhibits a single species of the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such. A substantially pure composition or pharmaceutical composition comprising the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, described herein can comprise, in the portion thereof which is the heparin- binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, 60%, 70%, 80% or 90% of the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, of the single species, more usually about 95%, and preferably over 99%. Purity or homogeneity may be tested by a number of means well known in the art, such as polyacrylamide gel electrophoresis or HPLC.

[0426] Administration as referred to in the methods disclosed herein, to a subject or to an organif relevant, can be auricular, buccal, conjunctival, cutaneous, subcutaneous, endocervical, 67 4896-4870-0471v.193597 / 7296 endosinusial, endotracheal, enteral, epidural, via hemodialysis, via catheter, via injection, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronary, intradermal, intradiscal, intraductal, intraepidermal, intraesophagus, intragastric, intravaginal, intragingival, intraileal, intraluminal, intralesional, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intraepicardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intraventricular, intravesical, intravitreal, laryngeal, nasal, nasogastric, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, rectal, inhalationally, retrobulbar, subarachnoid, subconjuctival, sublingual, submucosal, topically, transdermal, transmucosal, transplacental, transtracheal, ureteral, uretheral, vaginal, endoscopically, mucosally or by spray.

[0427] In some embodiments, administration is local or localized. In some embodiments,administration is systemic. In some embodiments of administration to a subject, the heparin- binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, is administered at a dose of 0.5mg / kg to 100 mg / kg. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, is administered at a dose of 101 mg / kg to 250 mg / kg. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such, is administered at a dose of 251 mg / kg to 500 mg / kg. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2, or fusion protein comprising such is administered at a dose of 501 mg / kg to 1000 mg / kg. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such is administered at a dose of 1001 mg / kg to 2000 mg / kg. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such is administered at a dose of up to 25 mg twice per daily, daily, every other day, weekly, monthly or every three months. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such is administered at a dose of 25 to 100 mg twice per daily, daily, every other day, weekly, monthly or every three months. In 68 4896-4870-0471v.193597 / 7296 some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such administered at a dose of 100 to 250 mg twice per daily, daily, every other day, weekly, monthly or every three months. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such is administered at a dose of 250 to 500 mg twice per daily, daily, every other day, weekly, monthly or every three months. In some embodiments, the heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such is administered at a dose of 500 to 1000 mg twice per daily, daily, every other day, weekly, monthly or every three months. In some embodiments, heparin-binding domain of an FGFBP1 or FGFBP2 or FGFBP3, or fusion protein comprising such is administered at a dose of 1000 to 2000 mg twice per daily, daily, every other day, weekly, monthly or every three months.

[0428] In some embodiments, the peptide further comprises a synthetic amino acid sequence.In some embodiments, the peptide does not comprise a synthetic amino acid sequence.

[0429] In some embodiments, the peptide further comprises an amino acid tag or signalsequence. In some embodiments, the peptide does not comprise an amino acid tag or signal sequence.

[0430] In some embodiments, the polypeptide consists of a sequence of FGFBP1 or FGFBP2or FGFBP3 amino acids which is located in an N-terminal portion of an FGFBP1 or FGFBP2 or FGFBP3 protein.

[0431] In some embodiments, subsequences of, or encoding for, FGFBP1, 2 or 3, are provided.“Subsequence” means, for a polynucleotide, a polynucleotide having one or more (e.g., several) nucleotides absent from the 5′ and / or 3′ end of a mature polypeptide coding sequence, wherein the subsequence encodes a fragment having at least some level of an immune cell activity described herein. In one aspect, a subsequence contains at least 85%, e.g., at least 90% or at least 95% of the contiguous nucleotides of the mature FGFBP coding sequence. “Subsequence” means, for a peptide / protein, a peptide / protein having one or more (e.g., several) amino acids absent from the N- and / or C- end of a mature polypeptide sequence, wherein the subsequence encodes a fragment having at least some level of an immune cell activity described herein. In one aspect, a subsequence contains at least 85%, e.g., at least 90% or at least 95% of the contiguous amino acids of the mature FGFBP sequence. In addition, all orthologs of FGFBP1, 2 and 3 (and their NTDs) are encompassed 69 4896-4870-0471v.193597 / 7296 by the invention for use in the methods or compositions, fusion proteins, peptides and fragments described herein. For example, UniProt Q9QY10 rat FGFBP1, Q9MZ06 bovine FGFBP1, D3ZVI0 rat FGFBP3, G3S6Y9 gorilla FGFBP2, and H2RAA8 chimpanzee FGFBP2 are all encompassed, as are other species’ FGFBP1, FGFBP2 and FGFBP3 set forth in UniProt. The encompassed NTD or N-terminal fragments or peptides are readily identifiable, e.g., by standard alignment techniques.

[0432] Expression constructs herein include expression vectors such a linear or circularpolynucleotide molecule (e.g., DNA) that comprises a polynucleotide encoding the peptides or fusion proteins described herein operably linked to control sequences that provide for its expression. Expression constructs are genetic constructs that are capable of expressing a nucleic acid sequence in a host cell. Such constructs can include segments of nucleic acids in a manner that would not otherwise exist in nature or which is synthetic, which comprises one or more (e.g., several) control sequences. In some embodiments, the constructs include one or more control sequences operably linked to the sequence to be expressed. The term “operably linked” means a configuration in which a control sequence is placed at an appropriate position relative to the coding sequence of a polynucleotide such that the control sequence directs expression of the coding sequence. Control sequences include promoter sequences, which are well known in the art. Such control sequences also include, but are not limited to, a leader, polyadenylation sequence, propeptide sequence, signal peptide sequence, and transcription terminator. In some embodiments, the control sequences at least include a promoter, and transcriptional and translational stop signals. The control sequences may be provided with linkers for the purpose of introducing specific restriction sites facilitating ligation of the control sequences with the coding region of the polynucleotide encoding a protein. Promoters include non-native promoters for the FGFBP N- terminal domain encoding polynucleotide. Promoters can be chosen based on the cell type one wishes to express the construct in. Promoters per se direct the initiation of transcription (e.g., binding sites for transcription factors and for DNA-dependent RNA-polymerase, TATA box, CAAT sequences, and 5′-capping elements). As long as this functionality of promoting transcription initiation is retained or substantially retained (e.g., at least 70%, at least 80%, at least 90% or at least 95% of wild-type activity, that is, activity of a full-length sequence), any truncated, mutated or otherwise modified variants of a (naturally occurring) wild-type promoter sequence are 70 4896-4870-0471v.193597 / 7296 also encompassed. The promoter sequence is operably linked to the transcriptional start site of the nucleic acid sequence to be expressed.

[0433] In some embodiments, a host cell containing an expression construct as describedherein is disclosed. Such host cells are not limited unless otherwise stated and can be, e.g., mammalian, insect, bacterial, yeast, fungal. In some embodiments, transformant cell transformed with an expression construct as described herein is disclosed. Such transformant cells are not limited unless otherwise stated and can be, e.g., mammalian, insect, bacterial, yeast, fungal.

[0434] One can construct an expression construct encoding the peptides / NTD of the inventiononce the NTD sequence is known. The degeneracy of the genetic code means that various sequences can be employed, but codon optimization can be used to select preferred sequences.

[0435] Expression constructs can be delivered as vectors, and known vectors for such deliveryare established in the art and encompassed herein, including adenoviral and lentiviral vectors as well as AAV and retroviral vectors.

[0436] Signal peptides of the NTD compositions or fusion proteins, or encoded by theexpression constructs therefor, can be native or can be exogenous (e.g., in a non-limiting example, human BSA signal peptide). Signal peptides may be selected by one skilled in the art to enhance secretion from a particular cell type over another cell type, as desired.

[0437] Peptides of the invention can be conjugated to a ligand, such as biotin (e.g., via acysteine or lysine residue), a lipid molecule (e.g., via a cysteine residue), or a carrier protein (e.g., serum albumin, immunoglobulin Fc domain, keyhole limpet hemocyanin (KLH) via e.g., a cysteine or lysine residue, or an scFv). Attachment to ligands, such as biotin, can be useful for associating the peptide with ligand receptors, such as avidin, streptavidin, polymeric streptavidin, or neutravidin. Avidin, streptavidin, polymeric streptavidin, or neutravidin, in turn, can be linked to a signaling moiety (e.g., an enzyme, such as horse radish peroxidase (HRP) or alkaline phosphatase (ALP), or other moiety that can be visualized, such as a metallic nanoparticle or nanoshell (e.g., colloidal gold) or a fluorescent moiety), or a solid substrate (e.g., nitrocellulose membrane). Alternatively, the peptides of the invention can be fused or linked to a ligand receptor, such as avidin, streptavidin, polymeric streptavidin, or neutravidin, thereby facilitating the association of the peptides with the corresponding ligand, such as biotin and any moiety (e.g., 71 4896-4870-0471v.193597 / 7296 signaling moiety) or solid substrate attached thereto. Examples of other ligand-receptor pairs are well-known in the art and can similarly be used.

[0438] Peptides of the invention can be fused to a fusion partner (e.g., a peptide or othermoiety) that can be used to improve purification, to enhance expression of the peptide in a host cell, to aid in detection, and to stabilize the peptide. Examples of suitable compounds for fusion partners include carrier proteins (e.g., serum albumin, immunoglobulin Fc domain, KLH), and enzymes (e.g., horse radish peroxidase (HRP), beta-galactosidase, glutathione-S-transferase, alkaline phosphatase). The fusion can be achieved by means of a peptide bond. For example, peptides of the invention and fusion partners can be fusion proteins and can be directly fused in- frame or can comprise a peptide linker.

[0439] An IgG portion of an IgG-containing fusion protein herein can be, in someembodiments, e.g., any of an IgG1, IgG2, IgG2a, IgG2b, IgG3 or IgG4 or a portion thereof. In an embodiment, the portion is an Fc region. In an embodiment the fusion protein comprises a sequence identical to an Fc portion of a human IgG1, human IgG2, human IgG2a, human IgG2b, human IgG3 or human IgG4. In an embodiment the fusion protein comprises a sequence identical to an Fc portion of a human IgG1. The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine of the Fc region may be removed, for example, by recombinantly engineering the nucleic acid encoding the fusion protein.

[0440] In some embodiments, the fusion protein components (e.g., a NTD and an Fc) arebound directly by a peptide bond from the NTD to the Fc domain. In an embodiment, the fusion protein components (e.g., a NTD and an Fc) are linked through a linker. In an embodiment a peptide linker is used which permits flexibility. In an embodiment, the linker is rigid. In an embodiment the linker is cleavable. Non-limiting examples of flexible linkers within the scope of the invention are Gn, and GGGGS, and (GGGGS)n where n = 2, 3, 4 or 5. Non-limiting examples of rigid linkers within the scope of the invention are (EAAAK)n, (XP)n. Non-limiting examples 72 4896-4870-0471v.193597 / 7296 of cleavable linkers within the scope of the invention include disulfide links and protease cleavable linkers. In a preferred embodiment, the linker is a peptide linker.

[0441] In some embodiments, the Fc domain has the same sequence or 95% or greatersequence similarity with a human IgG1 Fc domain. In an embodiment, the Fc domain has the same sequence or 95% or greater sequence similarity with a human IgG2 Fc domain. In an embodiment, the Fc domain has the same sequence or 95% or greater sequence similarity with a human IgG3 Fc domain. In an embodiment, the Fc domain has the same sequence or 95% or greater sequence similarity with a human IgG4 Fc domain. In an embodiment, the fusion protein described herein is recombinantly produced. In an embodiment, the fusion protein is produced in a eukaryotic expression system. In an embodiment, the fusion protein produced in the eukaryotic expression system comprises glycosylation at a residue on the Fc portion corresponding to Asn297. In an embodiment, the fusion protein is a homodimer. In an embodiment, the fusion protein is monomeric. In an embodiment, the fusion protein is polymeric.

[0442] In addition, peptides of the invention may be modified to include any of a variety ofknown chemical groups or molecules. Such modifications include, but are not limited to glycosylation, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment to polyethylene glycol (e.g., PEGylation), covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, ubiquitination, modifications with fatty acids, and transfer-RNA mediated addition of amino acids to proteins such as arginylation. Analogues of an amino acid (including unnatural amino acids) and peptides with substituted linkages are also included. Peptides of the invention that consist of any of the sequences discussed herein may be modified by any of the discussed modifications.

[0443] To produce a recombinant peptide of the invention, a nucleic acid encoding the peptidecan be inserted into a suitable expression system. Generally, a recombinant molecule or vector is constructed in which the polynucleotide sequence encoding the selected peptide is operably linked 73 4896-4870-0471v.193597 / 7296 to an expression control sequence permitting expression of the peptide. Numerous types of appropriate expression vectors are known in the art, including, e.g., vectors containing bacterial, viral, yeast, fungal, insect or mammalian expression systems. Methods for obtaining and using such expression vectors are well-known. For guidance in this and other molecular biology techniques used for compositions or methods of the invention, see, e.g., Sambrook et al., Molecular Cloning, A Laboratory Manual, current edition, Cold Spring Harbor Laboratory, New York; Miller et al, Genetic Engineering, 8:277-298 (Plenum Press, current edition), Wu et al., Methods in Gene Biotechnology (CRC Press, New York, N.Y., current edition), Recombinant Gene Expression Protocols, in Methods in Molecular Biology, Vol. 62, (Tuan, ed., Humana Press, Totowa, N.J., current edition), and Current Protocols in Molecular Biology, (Ausabel et al., Eds.,) John Wiley & Sons, NY (current edition), and references cited therein.

[0444] Compositions of the invention can comprise the naked peptide or the peptide and oneor more additional agents. For example, a pharmaceutically acceptable carrier or a physiologically acceptable carrier.

[0445] In another aspect, provided are compositions comprising two or more peptides of theinvention, e.g. comprising an NTD of an FGFBP2 and an NTD of an FGFBP3, or comprising an NTD of an FGFBP2 and an NTD of an FGFBP1, or comprising an NTD of an FGFBP3 and an NTD of an FGFBP1. In another aspect, provided are compositions comprising three different peptides of the invention, e.g., comprising an NTD of an FGFBP2 and an NTD of an FGFBP3 and an NTD of an FGFBP1.

[0446] In another aspect, provided are the methods disclosed herein but which employcompositions comprising two or more peptides of the invention, e.g. comprising an NTD of an FGFBP2 and an NTD of an FGFBP3, or comprising an NTD of an FGFBP2 and an NTD of an FGFBP1, or comprising an NTD of an FGFBP3 and an NTD of an FGFBP1. In another aspect, provided are the methods disclosed herein but which employ compositions comprising three different peptides of the invention, e.g., comprising an NTD of an FGFBP2 and an NTD of an FGFBP3 and an NTD of an FGFBP1.

[0447] A peptide is provided which consists of SEQ ID NO:8. A peptide is provided whichconsists of SEQ ID NO:9. A peptide is provided which comprises SEQ ID NO:8 but does not 74 4896-4870-0471v.193597 / 7296 comprise SEQ ID NO:7. A peptide is provided which comprises SEQ ID NO:9 but does not comprise SEQ ID NO:17.

[0448] In some embodiments, a peptide is provided which is or which comprises an N-terminaldomain of an FGFBP1. In some embodiments, said peptide is an N-terminal domain of an FGFBP1. In some embodiments, said peptide comprises an N-terminal domain of an FGFBP1, but is less than the full length FGFBP1 or is less than the mature FGFBP1 (without native signal sequence). In some embodiments, said peptide does not comprise a fibroblast growth factor- binding domain (FGF binding domain) of an FGFBP1. The FGF-binding domain is a C-terminal domain of FGFBP1. In some embodiments, said peptide comprising an N-terminal domain of an FGFBP1, but which is less than the full length FGFBP1 or is less than the mature FGFBP1, comprises one amino acid or more than one contagious amino acids at either the N-terminal or C- terminal thereof, independently, or at both the N-terminal and C-terminal thereof, independently, which amino acid or more than one contagious amino acids, are similarly existent in a naturally occurring FGFBP1 at the N-terminal and / or C-terminal, respectively, of the N-terminal domain of an FGFBP1. In some embodiments, said peptide has at the N-terminal residue of the N-terminal domain of an FGFBP1, one amino acid or two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or up to 30, or up to 35, or up to 40, contiguous amino acids which occur in the naturally occurring FGFBP1 (e.g. SEQ ID NO:7 or SEQ ID NO:17) N-terminal portion of FGFBP1 relative to the N-terminal residue of the N-terminal domain of an FGFBP1 (e.g., such as SEQ ID NO:8 or SEQ ID NO:9). Thus, with reference to Fig. 1A, a peptide comprising an N-terminal domain of an FGFBP1, but which is less than the full length FGFBP1 or is less than the mature FGFBP1, such as the heparin-binding domain peptide demarcated in the figure, can comprise prior to the first marked residue of the heparin-binding domain at the N- terminal end thereof from one up to the full number of contiguous amino acids shown between the predicted signal peptide and heparin-binding domain. Thus, also with reference to Fig. 1A, a peptide comprising an N-terminal domain of an FGFBP1, but which is less than the full length FGFBP1 or is less than the mature FGFBP1, such as the heparin-binding domain peptide demarcated in the figure, can additionally, or alternatively, comprise subsequent to the last marked residue of the heparin-binding domain at the C-terminal end thereof, from one up to the full number of contiguous amino acids shown between the C-terminal end residue thereof up to and including 75 4896-4870-0471v.193597 / 7296 the last residue prior to the FGF-binding domain thereof. SEQ ID NO:13 and SEQ ID NO:14 are non-limiting examples of such peptides.

[0449] In some embodiments, a peptide is provided which is or which comprises an N-terminaldomain of an FGFBP1, and which is a fragment of FGFBP1 less than the full length FGFBP1 or less than the mature FGFBP1 (without native signal sequence). Said peptide can comprise additional amino acids at the N- and / or -C-terminal thereof, the sequence or sequences of which do not naturally occur in a full length or mature FGFBP1.

[0450] Also in regard to compositions, fragments, fusion proteins and methods describedherein, mutatis mutandis, a peptide is provided, or employed in the methods, which is a fragment of an N-terminal domain of an FGFBP1, and has an amino acid sequence length which is less than the full amino acid sequence length of an N-terminal domain of an FGFBP1 (e.g., a fragment (less than full length) of SEQ ID NO:8 or SEQ ID NO:9). In some embodiments, said fragment has one or more of the activities of the NTD as described herein, even if at a lower activity amount than an entire NTD. In some embodiments, the peptide which is a fragment of an N-terminal domain of an FGFBP1 is one of from 10 to 20, from 20 to 30, from 30 to 40, from 40 to 50, from 50 to 60, from 60 to 70, from 70 to 80, from 80 to 90, from 90 to 100, or from 100 to 110 contiguous amino acids of the N-terminal domain of an FGFBP1 but less than the full length N-terminal domain of the FGFBP1. Expression constructs encoding such peptides are also provided. In embodiments of the peptides, fragments or fusion proteins disclosed herein, the peptides, fragments or fusion proteins are glycosylated. In embodiments of the peptides, fragments or fusion proteins disclosed herein, the peptides, fragments or fusion proteins are not glycosylated.

[0451] In some embodiments, peptides can be up to 100, up to 150, or up to 200 amino acidsin length. In some embodiments, peptides are 200-300 amino acids in length.

[0452] Peptide A, and Domain A, as used herein are exemplary embodiments of the N-terminalfragments or N-terminal domains (NTDs) as disclosed herein.

[0453] All sequences herein referred to by database designations are incorporated byreference.

[0454] Where a numerical range is provided herein, it is understood that all numerical subsetsof that range, and all the individual integers contained therein, are provided as part of the invention. 76 4896-4870-0471v.193597 / 7296

[0455] All combinations of the various elements, or the various embodiments, described hereinare within the scope of the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0456] “And / or” as used herein, for example, with option A and / or option B, encompasses theseparate embodiments of (i) option A, (ii) option B, and (iii) option A plus option B.

[0457] Definitions

[0458] The terms used in this specification generally have their ordinary meanings in the artwithin the context of this invention and the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the methods of the invention and how to use them. Moreover, it will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of the other synonyms. The use of examples anywhere in the specification, including examples of any terms discussed herein, is illustrative only, and in no way limits the scope and meaning of the invention or any exemplified term. Likewise, the invention is not limited to its preferred embodiments.

[0459] The term “subject” as used in this application means a mammal. Mammals includecanines, felines, rodents, bovine, equines, porcines, ovines, and primates including humans. Thus, the invention can be used in human medicine or also in veterinary medicine, e.g., to treat companion animals, farm animals, laboratory animals in zoological parks, and animals in the wild. The invention is particularly desirable for human medical and cosmetic applications. In a preferred embodiment the subject is a human.

[0460] The term “about” or “approximately” means within an acceptable error range for theparticular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system, i.e., the degree of precision required for a particular purpose, such as a pharmaceutical formulation. For example, “about” can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up 77 4896-4870-0471v.193597 / 7296 to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0461] Experimental results

[0462] Fibroblast growth factor binding protein 2 (FGFBP2; also known as KSP37) is asecretory protein selectively produced by cytotoxic immune cells, including T cells and NK cells1. Fibroblast growth factor binding protein 1 (FGFBP1) is a homolog that was recently described to mark intestinal stem cells2. Fibroblast growth factor binding protein 2 (FGFBP2) expression has been shown to be enriched in effector memory cytotoxic T cells mediating anti-tumor immunity, infectious disease and autoimmune diseases3-5. Fibroblast growth factor binding protein 3 (FGFBP3) is another homolog. The function of fibroblast growth factor binding protein 2 has not yet been described.

[0463] Examples - I

[0464] A recombinant N terminal fragment of FGFBP2 is produced. At a C terminal endthereof, tags for purification (e.g., His tags) can be added, and Avi-tags for biotinylation. The recombinant full-length protein or C terminal fragment can be produced also, including for controls.

[0465] Human peripheral blood mononuclear cells will be isolated. T cells, Natural Killer(NK) cells and B cells can be obtained by standard methods using commercially available purification kits. Immune cell subgroups are labeled, e.g., with carboxyfluorescein succinimidyl ester (CFSE) to track cell division

[0466] Immune cells are cultured with and without standard stimulation antibodies (for T cells:anti-CD3, anti-CD28, IL2; for NK cells: anti-CD4, IL15, IL2; for B cells: anti-IgM, anti-CD40) and with or without recombinant N terminal fragment of FGFBP2 at various concentrations. The effect of the N terminal fragment of FGFBP2 is assessed on cell division and expansion in the presence or absence of stimulation for all immune cell subtypes. Stimulation of T cells is predicted based on preliminary results. 78 4896-4870-0471v.193597 / 7296

[0467] T cell subsets are examined, including memory T cells (CD8 and CD4). T cellproliferation is determined (for example, after IL-2 stimulation or anti-CD3 Ab stimulation). The predicted T cell proliferation can be measured by known techniques, e.g., fluorescent tracking dyes or BrdU incorporation. Optionally, the various subsets after stimulation with FGFBP N-terminal fragments. CCR7-CD62L- CD8 T cells can be determined via, e.g,, FACS. Optionally, TCF1 expression can also be assessed.

[0468] Th experiments can be performed with each of the N-terminal fragment, C-terminalfragment, and full length FGFBP2. The same experiments can be repeated for the N-terminal fragment, C-terminal fragment, and full length FGFBP1 and the N-terminal fragment, C-terminal fragment, and full length of FGFBP3.

[0469] In vivo, the effect of the N terminal fragment of FGFBP2 N-terminal fragment (orFGFBP1 or FGFBP3 N-terminal fragment) on immune cells can be assessed, and its use in diseases to boost immune cell activity. These uses include but are not limited to cancer immunotherapy or infectious diseases.

[0470] The N-terminal fragment of FGFBP1 and FGFBP2 and FGFBP3 will stimulate T cellproliferation.

[0471] Examples – II

[0472] Exemplary annotated exemplary protein sequences of FGFBP are shown in FIG 1,including FGFBP1 in FIGS 1A-1E. (human 1A, mouse 1B), FGFBP2 (human 1C), and FGFBP3 (human 1D, mouse 1E). Signal peptides as predicted by SignalP6.06are annotated in grey. Putative heparin-binding domain (dark green) and fibroblast growth factor (FGF)-binding domain (light green) are annotated, as predicted by AlphaFold7.

[0473] Exemplary annotated protein sequences of expressed recombinant proteins are shownin FIGS 2A-2D. Signal peptides (grey), native protein sequences (yellow), putative heparin- binding domains (dark green) and C-terminal tags (blue) are annotated.2A. Mouse FGFBP1 T34- G163. 2B. Human FGFBP1 K34-N158. 2C. Human FGFBP2 G30-G146. 2D. Human FGFBP2 M1-G146.

[0474] FGFBP1 N-terminal domain (NTD) augments human CD8 (3A) and CD4 (3B) T cellproliferation in response to anti-CD3 stimulation, as shown in FIGS 3A-3B. Human T cells were isolated from peripheral blood of a healthy patient volunteer using antibody mediated depletion 79 4896-4870-0471v.193597 / 7296 (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE) to track cell division. Unstimulated T cells (top), or T cells stimulated with anti-CD3 antibody (UCHT1) + / - anti-CD28 antibody (CD28.2; middle, bottom) were incubated for 4 days with increasing concentration of recombinant mouse FGFBP1 NTD-His (as indicated). Relative cell number is indicated on the Y-axis and CFSE stain is indicated on the X-Axis. Gates indicate proportion of cells that have undergone cell division.

[0475] Human FGFBP2-NTD and human or mouse FGFBP1-NTD augment anti-CD3-induced human CD8 T cell proliferation in a dose-dependent manner as shown in FIGS 4A-4B. Human T cells were isolated from peripheral blood of a healthy patient volunteer using antibody mediated depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE) to track cell division. T cells were incubated for 4 days with indicated concentrations of recombinant Human FGFBP2 NTD-His, FGFBP2 NTD-Fc, Human FGFBP1 NTD-His, and Mouse FGFBP1 NTD-His. (4A) Relative cell number (Y-axis) and CFSE (X-axis) with gates indicating cells that have undergone cell division. (4B). Graph indicating proportion of cells that have undergone cell division within indicated recombinant proteins. Frequency of cells undergoing cell division with anti-CD3 only control is indicated in red on Y-axis.

[0476] Human FGFBP2-NTD and human or mouse FGFBP1-NTD augment anti-CD3-induced CD4 T cell proliferation in a dose-dependent manner as shown in FIGS 5A-5B. Human T cells were isolated from peripheral blood of a healthy patient volunteer using antibody mediated depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE) to track cell division. T cells were incubated for 4 days with indicated concentrations of recombinant human FGFBP2 NTD-His, FGFBP2 NTD-Fc, human FGFBP1 NTD-His, and mouse FGFBP1 NTD-His. (4A) Relative cell number (Y-axis) and CFSE (X-axis) with gates indicating cells that have undergone cell division. (4B). Graph indicating proportion of cells that have undergone cell division within indicated recombinant proteins. Frequency of cells undergoing cell division with anti-CD3 only control is indicated in red on Y-axis.

[0477] As shown in Fig. 6, FGFBP1-NTD does not augment anti-CD3-induced proliferationof mouse T cells. Mouse splenic CD8 T cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) and stimulated with anti-CD3 and anti-CD28 in the presence of increasing concentrations of mouse FGFBP1-NTD. Gates indicate cells that have undergone cell division. 80 4896-4870-0471v.193597 / 7296

[0478] FIGS 7A-7D show that FGFBP2-NTD augments anti-CD3-mediated cell division,primarily in cytotoxic memory CD4 and CD8 T cells by enhancing cell division in cells that normally respond to anti-CD3 stimulation and are clonally expanded at baseline. Human T cells were isolated from peripheral blood (RosetteSep). T cells from the same sample were split and cultured for 4 days in media alone, with anti-CD3 stimulation, or with anti-CD3 stimulation + 300nM FGFBP2-NTD. Single-cell RNA sequencing and TCR sequencing (10X genomics Chromium) was performed on all groups of T cells (7A) Unsupervised clustering based on single- cell transcriptomes by Uniform Manifold Approximation and Projection (UMAP) shown with cell phenotypes assigned by SingleR (left) and FGFBP2 RNA expression indicated (right). (7B) Expression of CD8A, CD4, and marker of cytotoxicity NKG7. (7C). FGFBP2 NTD augments clonal expansion of cytotoxic T cells which have a similar phenotype in all groups. Clonally expanded T cell clones are colored by relative frequency in the dataset normalized to cell number. (7D). FGFBP2 NTD augments anti-CD3-induced proliferation of T cells that normally respond to anti-CD3. Cells are colored based on T cell clones shared between stimulated (anti-CD3, left; anti-CD3 + FGFBP2 NTD, right) and control groups.

[0479] FGFBP2-NTD enhances inflammatory cytokine production by viral-specific CD8 Tcells in response to prolonged stimulation as shown in FIGS 8A-8B. T cells from 3 Epstein-Barr Virus (EBV) positive human patient donors were stimulated for 2 weeks in the presence of EBV peptides, IL-2 and IL-7 with or without FGFBP2-NTD. After 2 weeks, cells were harvested and restimulated again. T cells were analyzed by intracellular cytokine staining with TNFalpha (left) and IFNgamma (right).

[0480] FIG 9 shows that the N-terminal domain of FGFBP1 or FGFBP2 enhance division inNK cells and increases the frequency of cytotoxic CD56lowNK cells after culture in IL-2 and IL- 15. Human NK cells were isolated from peripheral blood using antibody mediated depletion (RosetteSep, Stemcell technologies) and labeled with carboxyfluorescein succinimidyl ester (CFSE). NK cells were cultured for 4 days in the presence of IL-2 / IL-15 (control), IL-2 / IL-15 + 300nM hFGFBP2 NTD, IL-2 / IL-15 + 300nM hFGFBP1 NTD. On left, relative frequency of CD56lowand CD56highNK cells is shown. On right, CFSE intensity is shown with gates indicated cells that have undergone division. 81 4896-4870-0471v.193597 / 7296

[0481] References

[0482] 1 Ogawa, K. et al. A novel serum protein that is selectively produced by cytotoxiclymphocytes. J Immunol 166, 6404-6412, doi:10.4049 / jimmunol.166.10.6404 (2001).

[0483] 2 Capdevila, C. et al. Time-resolved fate mapping identifies the intestinal uppercrypt zone as an origin of Lgr5+ crypt base columnar cells. Cell 187, 3039-3055 e3014, doi:10.1016 / j.cell.2024.05.001 (2024).

[0484] 3 van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8(+) T cell statesin human cancer: insights from single-cell analysis. Nat Rev Cancer 20, 218-232, doi:10.1038 / s41568-019-0235-4 (2020).

[0485] 4 Masuda, K. et al. Multiplexed single-cell analysis reveals prognostic and non-prognostic T cell types in human colorectal cancer. JCI Insight, doi:10.1172 / jci.insight.154646 (2022).

[0486] 5 Li, J. et al. KIR(+)CD8(+) T cells suppress pathogenic T cells and are active inautoimmune diseases and COVID-19. Science 376, eabi9591, doi:10.1126 / science.abi9591 (2022).

[0487] 6 Teufel, F. et al. SignalP 6.0 predicts all five types of signal peptides using proteinlanguage models. Nat Biotechnol 40, 1023-1025, doi:10.1038 / s41587-021-01156-3 (2022).

[0488] 7 Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold.Nature 596, 583-589, doi:10.1038 / s41586-021-03819-2 (2021). 82 4896-4870-0471v.1

Claims

93597 / 7296 Claims:

1. An expression construct encoding (i) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2), but not encoding a full length and / or mature FGFBP2 protein, or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not encoding a full length and / or mature FGFBP3 protein.

2. The expression construct of Claim 1, wherein the N-terminal domain of FGFBP2comprises SEQ ID NO:

3.

3. The expression construct of Claim 1, wherein the N-terminal domain of FGFBP3comprises SEQ ID NO:5 or SEQ ID NO:

6.

4. The expression construct of Claim 1, 2 or 3, which further encodes a signal sequence and / ora promoter.

5. An expression construct encoding a fusion protein comprising (A) (i) an N-terminaldomain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non- FGFBP protein or peptide or polypeptide.

6. The expression construct of Claim 5, wherein (A) (i) does not comprise a full lengthFGFBP2 and wherein (A) (ii) does not comprise a full length FGFBP3.

7. The expression construct of Claim 5 or 6, wherein (B) comprises (a) an ImmunoglobulinG Fc, optionally a human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

8. The expression construct of any of Claims 1 – 7 comprising, DNA or comprising mRNA.

9. A composition comprising the expression construct of any of Claims 1-8.83 4896-4870-0471v.193597 / 7296 10. A protein domain comprising (a) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2), but not comprising a full length FGFBP2 protein, or (b) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), but not comprising a full length FGFBP3 protein.

11. The protein domain of Claim 10, wherein the N-terminal domain of FGFBP2 comprisesSEQ ID NO:

3.

12. The protein domain of Claim 10, wherein the N-terminal domain of FGFBP3 comprisesSEQ ID NO:5 or SEQ ID NO:

6.

13. The protein domain of Claim 10, 11 or 12, further comprising a signal sequence.

14. The protein domain of Claim 10, 11 or 12, which does not comprise a signal sequence.

15. A fusion protein comprising (A) (i) an N-terminal domain of a fibroblast growth factorbinding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), linked to (B) a non-FGFBP protein or peptide or polypeptide.

16. The fusion protein of Claim 15, wherein (A) (i) does not comprise a full length or matureFGFBP2 and wherein (A) (ii) does not comprise a full length or mature FGFBP3.

17. The fusion protein of Claim 15, wherein (A) (i) comprises a full length or mature FGFBP2or wherein (A) (ii) comprises a full length or mature FGFBP3.

18. The fusion protein of Claim 16 or 17, wherein (B) comprises (a) an Immunoglobulin G Fc,optionally a human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

19. A method of promoting propagation of, function of, and / or increasing viability of, T cells,optionally alpha-beta or gamma-delta T cells or natural killer T cells, comprising 84 4896-4870-0471v.193597 / 7296 contacting said cells with an amount of a composition comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, T cells.

20. The method of Claim 19, wherein (i) does not comprise a full length or mature FGFBP2,and wherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

21. The method of Claim 19, wherein (i) comprises a full length or mature FGFBP2, wherein(ii) comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

22. A method of promoting propagation of, function of, and / or increasing viability of, NaturalKiller (NK) cells, comprising contacting said cells with an amount of a composition comprising a (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells.

23. The method of any of Claims 19-22, wherein the cells are in vivo.

24. A method of promoting propagation of, function of, and / or increasing viability of, T cellsin a subject, optionally alpha-beta or gamma-delta T cells or natural killer T cells, comprising administering to said subject an expression construct which encodes (i) an N- terminal domain of an FGFBP2, or (ii) an N-terminal domain of an FGFBP3, or (iii) an N- terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, T cells, or a method of promoting propagation of, function of, and / or increasing viability of, Natural Killer (NK) cells, comprising administering to said subject an expression construct which encodes (i) an N-terminal domain of an FGFBP2, or (ii) an N-terminal domain of an 85 4896-4870-0471v.193597 / 7296 FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation of, function of, and / or increase viability of, NK cells.

25. The method of Claim 24, wherein the expression construct does not encode (i) a full lengthor mature FGFBP2, (ii) a full length or mature FGFBP3, or (iii) a full length or mature FGFBP1.

26. The method of Claim 24, wherein the expression construct does encode (i) a full length ormature FGFBP2, (ii) a full length or mature FGFBP3, or (iii) a full length or mature FGFBP1.

27. The method of any of Claims 24-26, wherein the expression construct encodes a fusionprotein comprising (A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide, or a method of any of Claims 19-23, wherein the composition comprises a fusion protein comprising (A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

28. The method of Claim 27, wherein (B) comprises (a) an Immunoglobulin G Fc, optionallya human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

29. A method of treating a cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an 86 4896-4870-0471v.193597 / 7296 FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

30. The method of Claim 29, wherein the T cells have been cultured with the protein domainprior to administering to the subject.

31. A method of treating a cancer or neoplasia in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the cancer or neoplasia.

32. The method of Claim 29, 30 or 31, wherein (i) does not comprise a full length or matureFGFBP2, and wherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

33. The method of Claim 29, 30 or 31, wherein (i) comprises a full length or mature FGFBP2,wherein (ii) comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

34. The method of any of Claims 29-33, wherein the protein domain is part of a fusion proteincomprising (A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3) or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

35. The method of Claim 34, wherein (B) comprises (a) an Immunoglobulin G Fc, optionallya human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin. 87 4896-4870-0471v.193597 / 7296 36. A method of treating a cancer or neoplasia in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the cancer or neoplasia.

37. The method of Claim 36, wherein the T cells have been cultured with or transformed withthe expression construct prior to administering to the subject.

38. A method of treating a cancer or neoplasia in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the cancer or neoplasia.

39. The method of Claim 38, wherein the NK cells have been cultured with or transformedwith the expression construct prior to administering to the subject.

40. The method of any of Claims 36-39, wherein (i) does not comprise a full length or matureFGFBP2, and wherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

41. The method of any of Claims 36-39, wherein (i) comprises a full length or mature FGFBP2,wherein (ii) comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

42. The method of any of Claims 36-41, wherein the expression construct encodes a fusionprotein comprising (A) (i) an N-terminal domain of a fibroblast growth factor binding 88 4896-4870-0471v.193597 / 7296 protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3) or (iii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

43. The method of Claim 42, wherein (B) comprises (a) an Immunoglobulin G Fc, optionallya human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

44. A method of treating an infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with an protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

45. The method of Claim 44, wherein the T cells have been cultured with the protein domainprior to administering to the subject.

46. A method of treating an infectious disease in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with a protein domain comprising (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the infectious disease.

47. The method of Claim 44, 45 or 46, wherein (i) does not comprise a full length or matureFGFBP2, and wherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

48. The method of Claim 44, 45 or 46, wherein (i) comprises a full length or mature FGFBP2,wherein (ii) comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1. 89 4896-4870-0471v.193597 / 7296 49. The method of any of Claims 44-48, wherein the protein domain is part of a fusion proteincomprising (A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3), or (iii) N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

50. The method of Claim 49, wherein (B) comprises (a) an Immunoglobulin G Fc, optionallya human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

51. A method of treating an infectious disease in a subject comprising administering to thesubject T cells, optionally alpha beta or gamma delta T cells or natural killer T cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of T cells, so as to treat the infectious disease.

52. The method of Claim 51, wherein the T cells have been cultured with or transformed withthe expression construct prior to administering to the subject.

53. A method of treating an infectious disease in a subject comprising administering to thesubject Natural Killer (NK) cells, that have been contacted with, or genetically engineered / transformed with, an expression construct encoding (i) an N-terminal domain of an FGFBP2, (ii) an N-terminal domain of an FGFBP3, or (iii) an N-terminal domain of an FGFBP1, effective to promote propagation, function and / or increase viability of NK cells, so as to treat the infectious disease.

54. The method of Claim 53, wherein the NK cells have been cultured with or transformedwith the expression construct prior to administering to the subject. 90 4896-4870-0471v.193597 / 7296 55. The method of any of Claims 44-54, wherein (i) does not comprise a full length or matureFGFBP2, and wherein (ii) does not comprise a full length or mature FGFBP3, and wherein (iii) does not comprise a full length or mature FGFBP1.

56. The method of any of Claims 44-54, wherein (i) comprises a full length or mature FGFBP2,wherein (ii) comprises a full length or mature FGFBP3, and / or wherein (iii) comprises a full length or mature FGFBP1.

57. The method of any of Claims 44-56, wherein the expression construct encodes a fusionprotein comprising (A) (i) an N-terminal domain of a fibroblast growth factor binding protein 2 (FGFBP2) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 3 (FGFBP3) or (ii) an N-terminal domain of a fibroblast growth factor binding protein 1 (FGFBP1), linked to (B) a non-FGFBP protein or peptide or polypeptide.

58. The method of Claim 57, wherein (B) comprises (a) an Immunoglobulin G Fc, optionallya human Immunoglobulin G Fc, or (b) a serum albumin, optionally a human serum albumin.

59. A cell engineered to express an expression construct of any of Claims 1-8.

60. A cell engineered to express a protein domain of any of Claims 10-14.

61. A cell engineered to express a fusion protein of any of Claims 15-18.91 4896-4870-0471v.1

Images