Soluble recombinant human podoplanin receptor

Abstract

Disclosed is a composition of matter and a method for using that composition to treat, e.g., cancer or inflammatory joint disease. The composition is a soluble recombinant human podoplanin receptor (srhPDPN) that includes a first amino acid sequence at least 95% homologous to SEQ ID NO: 1. The srhPDPN may include a tag peptide or polypeptide (such as a polyhistidine tag) fused to the first amino acid sequence. The srhPDPN may include a signal peptide fused to the first amino acid sequence. The signal peptide may include an amino acid sequence at least 95% homologous to SEQ ID NO:2. A plurality of threonine residues of the srhPDPN may be glycosylated with sialic acid moi eties, and in some embodiments, 17 threonine residues of the srhPDPN glycosylated with sialic acid moieties. Treatments may include allowing the composition to act as a decoy receptor or ligand trap to inhibit PDPN signaling.

Description

[0001] SOLUBLE RECOMBINANT HUMAN PODOPLANIN RECEPTOR

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U.S. Provisional Patent Application No. 63 / 537,975, filed September 12, 2023, the contents of which are incorporated by reference herein in its entirety.

[0004] STATEMENT REGARDING SEQUENCE LISTING

[0005] The instant application contains a Sequence Listing which has been submitted electronically in ST.26 XML file format, created on August 22, 2024, is named SENTRI002 SL.xml and is 3,534 bytes in size. The ST.26 XML file is hereby incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] The present disclosure relates to PDPN receptors, and specifically, to soluble recombinant human PDPN receptors and uses thereof.

[0008] BACKGROUND

[0009] This section is intended to introduce the reader to various aspects of art, which may be related to various aspects of the present invention that are described and / or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.

[0010] The Podoplanin (PDPN) receptor has been identified as a biologically relevant target. Modulation of PDPN can, e.g., inhibit human cancer cell growth and motility.

[0011] BRIEF SUMMARY

[0012] Various deficiencies in the prior art are addressed below by the disclosed compositions of matter and techniques.

[0013] In various aspects, a composition of matter may be provided. The composition of matter may include a soluble recombinant human podoplanin receptor (srhPDPN) including a first amino acid sequence at least 95% homologous to SEQ ID NO: 1, and a tag peptide or polypeptide fused to the first amino acid sequence, such as a polyhistidine tag. The srhPDPN may include a signal peptide fused to the first amino acid sequence. The signal peptide may include, e.g., an amino acid sequence at least 95% homologous to SEQ ID NO:2. A plurality of threonine residues (such as at least 15) of the first amino acid sequence may be glycosylated with sialic acid moieties. In some aspects, 17 threonine residues of the first amino acid sequence are glycosylated with sialic acid moieties.

[0014] In various aspects, a cell line comprising a gene encoding the composition of matter as disclosed herein may be provided. The cell line may be a human cell line.

[0015] In various aspects, a pharmaceutical composition may be provided. The composition may include the composition of matter as disclosed herein, and a pharmaceutically acceptable carrier. The pharmaceutical composition may also include, e.g., a flavor additive, a lubricant, a binder, a preservative, an encapsulating material, a diluting agent, an artificial coloring agent, a flavor additive, a binder, a stabilizer, a natural or artificial sweetener, a thickener, a tabletdisintegrating substance, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, stiffeners, gelatins, tragacanth, methylcellulose, and / or sodium carboxymethylcellulose.

[0016] In various aspects, a method for treating cancer or inflammatory joint disease may be provided. The method may include providing an effective amount of the composition of matter of claim 1. The method may include allowing the composition of matter to act as a decoy receptor or ligand trap to inhibit PDPN signaling. The cancer may be, e.g., carcinoma, leukemia, lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and / or breast cancer. The inflammatory joint disease may be arthritism, such as osteoarthritis or rheumatoid arthritis.

[0017] In various aspects, a method of inhibiting Pdpn expressed on a cell may be provided. The method may include providing a cell culture comprising tumor cells and / or normal cells. The method may include subjecting the tumor cells to a sufficient amount of the composition of matter as disclosed herein. The method may include allowing the composition of matter to act as a decoy receptor or ligand trap to inhibit PDPN signaling.

[0018] BRIEF DESCRIPTION OF FIGURES

[0019] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the present invention and, together with a general description of the invention given above, and the detailed description of the embodiments given below, serve to explain the principles of the present invention. Figure 1 is a schematic illustration of an embodiments of a synthetic recombinant human PDPN (srhPDPN) sequence.

[0020] Figure 2 is an image of SDS-PAGE results, where shrPDPN (5 ug per lane) was resolved by reducing 12% SDS-PAGE and visualized by staining along with molecular weight markers as indicated.

[0021] Figure 3 is a graph illustrating the migration of cells treated with 0 nM, 770 nM, 1440 nM, or 2880 nM srhPDPN over 24 hours, evaluated by wound healing assays with data normalized and shown as the percent of untreated controls (mean+SEM, n=2) with single, double, and triple asterisks indicating p < 0.05, p<0.01, and p<0.001, respectively, by test as indicated.

[0022] Figure 4 is a graph illustrating the viability of cells treated with 0 nM, 770 nM, 1440 nM, or 2880 nM srhPDPN for 24 hours, evaluated by alamarBlue assays with data normalized and shown as the percent of untreated controls (mean+SEM, n=2) with double, triple, and quadruple asterisks indicating p <0.01, p<0.001, and p<0.0001, respectively, by test as indicated.

[0023] It should be understood that the appended drawings are not necessarily to scale, presenting a somewhat simplified representation of various features illustrative of the basic principles of the invention. The specific design features of the sequence of operations as disclosed herein, including, for example, specific dimensions, orientations, locations, and shapes of various illustrated components, will be determined in part by the particular intended application and use environment. Certain features of the illustrated embodiments have been enlarged or distorted relative to others to facilitate visualization and clear understanding. In particular, thin features may be thickened, for example, for clarity or illustration.

[0024] DETAILED DESCRIPTION

[0025] The following description and drawings merely illustrate the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements that, although not explicitly described or shown herein, embody the principles of the invention and are included within its scope. Furthermore, all examples recited herein are principally intended expressly to be only for illustrative purposes to aid the reader in understanding the principles of the invention and the concepts contributed by the inventor(s) to furthering the art and are to be construed as being without limitation to such specifically recited examples and conditions. Additionally, the term, "or," as used herein, refers to a nonexclusive or, unless otherwise indicated (e.g., “or else” or “or in the alternative”). Also, the various embodiments described herein are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments.

[0026] The numerous innovative teachings of the present application will be described with particular reference to the presently preferred exemplary embodiments. However, it should be understood that this class of embodiments provides only a few examples of the many advantageous uses of the innovative teachings herein. In general, statements made in the specification of the present application do not necessarily limit any of the various claimed inventions. Moreover, some statements may apply to some inventive features but not to others. Those skilled in the art and informed by the teachings herein will realize that the invention is also applicable to various other technical areas or embodiments.

[0027] In various aspects, a composition of matter may be provided. The composition of matter may include a soluble recombinant human podoplanin receptor (srhPDPN).

[0028] Referring to FIG. 1, the srhPDPN (100) may include a first amino acid sequence (110). The first amino acid sequence may include at least a portion of human PDPN. In some embodiments, this may include amino acids 23-132 of human PDPN:

[0029] ASTGQPEDDT ETTGLEGGVA MPGAEDDVVT PGTSEDRYKS GLTTLVATSV NSVTGIRIED LPTSESTVHA QEQSPSATAS NVATSHSTEK VDGDTQTTVE KDGLSTVTLV (SEQ ID NO: 1)

[0030] In some embodiments, the first amino acid sequence may be a variant having at least 99% homologous to SEQ ID NO: 1 . In some embodiments, the first amino acid sequence may be a variant having at least 98% homologous to SEQ ID NO: 1. In some embodiments, the first amino acid sequence may be a variant having at least 97% homologous to SEQ ID NO:1. In some embodiments, the first amino acid sequence may be a variant having at least 96% homologous to SEQ ID NO: 1. In some embodiments, the first amino acid sequence may be a variant having at least 95% homologous to SEQ ID NO: 1. “Variants” is intended to mean substantially similar sequences. For nucleic acid molecules, a variant comprises a nucleic acid molecule having deletions (i.e., truncations) at the 5' and / or 3' end; deletion and / or addition of one or more nucleotides at one or more internal sites in the native polynucleotide; and / or substitution of one or more nucleotides at one or more sites in the native polynucleotide. In preferred embodiments, the threonine residues in SEQ ID NO: 1 are not deleted or substituted. In preferred embodiments, the threonine residues in SEQ ID NO: 1 are not deleted or substituted. In some embodiments, neither the serine nor the threonine residues in SEQ ID NO: 1 are deleted or substituted. In various aspects, the serine and threonine residues may be glycosylation sites for the first amino acid sequence.

[0031] In various aspects, one or more of the threonine residues of the first amino acid sequence may be glycosylated with sialic acid moieties. In preferred embodiments, a plurality of threonine residues of the first amino acid sequence may be glycosylated with sialic acid moieties. In some embodiments, this may include where at least 5, at least 10, or at least 15 threonine residues of the first amino acid sequence are glycosylated with sialic acid moieties. In some embodiments, 17 threonine residues of the first amino acid sequence are glycosylated with sialic acid moieties. In some embodiments, at least one threonine residue of the first amino acid sequence is free of glycosylation.

[0032] In some embodiments, at least one serine residue of the first amino acid sequence is glycosylated. In some embodiments, a plurality of serine residues are glycosylated. In some embodiments, 8 serine residues are glycosylated. In some embodiments, at least one serine residue is free of glycosylation. In some embodiments, at least one serine residue is free of glycosylation.

[0033] The srhPDPN may include a second amino acid sequence, such as tag peptide(s) or polypeptide(s) fused to the first amino acid sequence. Referring to FIG. 1, the srhPDPN (100) may include tag peptide(s) or polypeptide(s) (120) fused to the first amino acid sequence.

[0034] The tag peptide or polypeptide may include affinity tags (e.g., peptides or polypeptides that bind to certain agents or matrices), solubilization tags (e.g., peptides or polypeptides that assist in proper folding of proteins and prevent precipitation), chromatography tags (e.g., peptides or polypeptides that alter the chromatographic properties of a protein to afford different resolution across a particular separation techniques), epitope tags (e.g., peptides or polypeptides that are bound by antibodies), fluorescence tags (e.g., peptides or polypeptides that fluoresce when exposed to a predetermined wavelength of light), or self-cleaving tags (e.g., peptides or polypeptides that possess inducible proteolytic activity, such as Sortase tag, Npro tag, FrpC module, CPD), or combinations thereof.

[0035] Non-limiting examples of affinity tags include maltose binding protein (MBP) tag, glutathione-S-transferase (GST) tag, poly(His) tag, SBP-tag, Strep-tag, and calmodulin-tag. Non-limiting examples of solubility tags include thioredoxin (TRX) tag, poly(NANP) tag, MBP tag, SUMO tag, GB1 tag, NUSA CBD tag, and GST tag. Non-limiting examples of chromatography tags include poly anionic amino acid tags (e.g., FLAG-tag) and polyglutamate tag. Non-limiting examples of epitope tags include V5-tag, VSV-tag, E-tag, NE-tag, hemagglutinin (Ha)-tag, Myc-tag, and FLAG-tag. Non-limiting examples of fluorescence tags include green fluorescent protein (GFP) tag, blue fluorescent protein (BFP) tag, cyan fluorescent protein (CFP) tag, yellow fluorescent protein (YFP) tag, orange fluorescent protein (OFP) tag, red fluorescent protein (RFP) tag, and derivatives thereof. In some embodiments, a polyhistidine affinity tag may be used, such as DHHHHHH ([SEQ ID NO: 3]).

[0036] In some embodiments, the second amino acid sequence may be fused to a first end (such as a C-terminus) of the first amino acid sequence.

[0037] The srhPDPN may include a third amino acid sequence (such as signal peptide(s) or polypeptide(s)) fused to the first amino acid sequence. Referring to FIG. 1, the srhPDPN (100) may include signal peptide(s) or polypeptides (130) fused to the first amino acid sequence. The srhPDPN (100) may include both tag peptide(s) or polypeptide(s) (120) and signal peptide(s) or polypeptide(s) (130) fused to the first amino acid sequence.

[0038] In some embodiments, the signal peptide may be a 19 amino acid signal peptide from mouse Ig heavy chain V region BCL1 : MGWSCIIFFLVATATGVHS (SEQ ID NOG). However, other appropriate signal peptides may be utilized.

[0039] In some embodiments, the third amino acid sequence may be a variant having at least 94% homologous to SEQ ID NOG (e.g., including a single nucleotide deletion / substitution / addition). In some embodiments, the third amino acid sequence may be a variant having at least 89% homologous to SEQ ID NO: 3 (e.g., including no more than two nucleotide deletions / substitutions / additions).

[0040] The third amino acid sequence may be fused to an opposite end of the first amino acid sequence from the second amino acid sequence. In some embodiments, the third amino acid sequence may be fused to a second end (such as an N-terminus) of the first amino acid sequence.

[0041] In some embodiments, a pharmaceutical composition may be provided. The composition may include an embodiment of srhPDPN as disclosed herein, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0042] In some embodiments, the pharmaceutical composition may include a flavor additive, a lubricant, a binder, a preservative, an encapsulating material, a diluting agent, an artificial coloring agent, a flavor additive, a binder, a stabilizer, a natural or artificial sweetener, a thickener, a tablet-disintegrating substance, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, stiffeners, gelatins, tragacanth, methylcellulose, and / or sodium carboxymethylcellulose.

[0043] In various aspects, a cell line may be provided. The cell line may include one or more cells containing a gene encoding an embodiment of the disclosed srhPDPN. In some embodiments, the cell line may be a human cell line.

[0044] In various aspects, a method for treating cancer (such as carcinoma, leukemia, lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and / or breast cancer) or inflammatory joint disease (e.g, arthritis, such as osteoarthritis or rheumatoid arthritis) may be provided. The method may include providing an effective amount of an embodiment of the disclosed srhPDPN. The method may include allowing the srhPDPN to act as a decoy receptor or ligand trap to inhibit PDPN signaling.

[0045] In some embodiments, an effective concentration of the srhPDPN, in a fluid around a cancer cell, may be in the range of about 10 nM to about 5000 nM, such as from about 50 nM to about 2000 nM. In some embodiments, an effective amount of the srhPDPN may be within the range of about 1 pg / kg body weight to about 1 mg / kg body weight, which can be readily determined by considering the route of administration, the period over which the lectin is to be administered, and other factors known to those skilled in the art.

[0046] In various aspects, a method of inhibiting Pdpn expressed on a cell may be provided. The method may include providing a cell culture comprising tumor cells and / or normal cells. The method may include subjecting said cells to an embodiment of the disclosed srhPDPN. The method may include allowing the srhPDPN to act as a decoy receptor or ligand trap to inhibit PDPN signaling.

[0047] The total concentration of the srhPDPN, in a fluid around a cancer cell, may be in the range of about 10 nM to about 5000 nM, such as from about 50 nM to about 2000 nM.

[0048] Maackia amurensis lectins have been used in research for over 60 years. In particular, Maackia amurensis seed lectin (MASL) has been used as an agent that binds to a-2-3 -linked sialic acids. These glycosylation modifications are often found on extracellular protein receptors associated with viral infection, inflammation, and cancer. Consequentially, MASL can target these receptors to inhibit viral infection, arthritis development, and cancer progression. For example, MASL inhibits SARS-CoV-2 spike binding to the ACE2 receptor in cell culture. MASL also targets the PDPN receptor to inhibit osteoarthritis and rheumatoid arthritis progression in mice, and suppress psoriatic epidermal hyperproliferation in skin cultures. In addition, MASL targets the PDPN receptor to inhibit melanoma cell motility and viability in culture and tumor progression in mice. MASL also targets the PDPN receptor to inhibit oral squamous cell carcinoma (OSCC) cell growth and motility and is being assessed as an oral cancer treatment in an ongoing Phase 1 human clinical trial (NCT04188665). Maackia amurensis lectin can also target receptors to inhibit non-small cell lung cancer and childhood acute lymphoblastic leukemia cell viability.

[0049] The PDPN receptor has been identified as a biologically relevant MASL target. Sialic acids on PDPN are presumed to be relevant for MASL binding. Soluble recombinant human PDPN (srhPDPN) was produced in human HEK293F cells to verify sialic acid modification of this receptor.

[0050] Specifically, a sequence encoding a protein consisting of a 19 amino acid signal peptide (SEQ ID NO:2) from mouse Ig heavy chain V region BCL1 followed by the entire extracellular region containing amino acids 23-132 (SEQ ID NO: 1) of human PDPN terminating in a HIS tag (SEQ ID NO:3) was engineered into pcDNA3.1(+) and transfected into FREESTYLE™ HEK293F cells (ThermoFisher #R790-07). Resulting soluble recombinant human PDPN (srhPDPN) was purified on Ni Sepharose after tangential diafiltration of the medium, followed by exchange to PBS on SUPERDEX™ 200 increase columns and analysis by SDS-PAGE. For mass spectroscopy analysis, srhPDPN (0.5 pg / pl in 25 mM ammonium bicarbonate, pH 8) was digested with either trypsin (0.01 pg / pl) or GluC (0.01 pg / pl) (Sequencing Grade; Promega) for 16 hours at 37°C. The digestion reaction was stopped by adding trifluoroacetic acid to 1%. Peptides mixtures (10 pl) were injected for LC-MS / MS analysis on an DIONEX™ ULTIMATE™ 3000 RSLCnano system in-line connected to a Q EXTRACTIVE™ HF Biopharma mass spectrometer (Thermo). Trapping was performed at 20 pl / min for 2 min in loading solvent A (0.1% trifluoroacetic in water) on a 5 mm trapping column (Thermo scientific, 300 pm internal diameter (I.D.), 5 pm beads). The peptides were separated on a 250 mm Aurora Ultimate, 1.7pm Cl 8, 75 pm inner diameter (lonOpticks) kept at a constant temperature of 45°C. Peptides were eluted by a non-linear gradient starting at 0.5% solvent B reaching 26% solvent B (0.1% trifluoroacetic in acetonitrile) in 30 min, 44% solvent B in 38 min, followed by a 7-minute wash at 56% solvent B and re-equilibration with solvent A at a flow rate of 300 nl / min. The mass spectrometer was operated in data-dependent mode, automatically switching between MS and MS / MS acquisition for the 12 most abundant ion peaks per MS spectrum. Full-scan MS spectra (375-1500 m / z) were acquired at a resolution of 60,000 in the Orbitrap analyzer after accumulation to a target value of 3,000,000. The 12 most intense ions above a threshold value of 15,000 were isolated with a width of 1.5 m / z for fragmentation at a normalized collision energy of 28% after filling the trap at a target value of 100,000 for maximum 120 ms. MS / MS spectra (200-2000 m / z) were acquired at a resolution of 15,000 in the Orbitrap analyzer. The polydimethylcyclosiloxane background ion at 445.120028 Da was used for internal calibration (lock mass) and QCloud was used to control instrument longitudinal performance during the project. Data analysis was performed with BioPharma Finder software (Thermo Fisher Scientific), using the Peptide Mapping tool. Resulting MS / MS spectra were analyzed with BioPharma Finder 3.0 software (Thermo Fisher Scientific) and mapped onto the appropriate protein sequence with trypsin or Glu-C selected as proteases. For peptide identification, the following parameters were used: maximum peptide mass of 7000 Da, mass accuracy of 5 ppm and a minimum confidence of 0.80. Deamidation of asparagine and glutamine, and oxidation of methionine and tryptophan were set as variable modifications. The search for glycosylation modifications was enabled (human specific) and the maximum number of variable modifications per peptide was set at 2.

[0051] This protein migrated between with an estimated molecular weight of 24.6 kD instead of its expected 12 kD size by SDS-PAGE as shown in FIG. 2.

[0052] This protein was sequenced by LC-MS / MS to find that PDPN was glycosylated at 26 amino acids. These glycosylation events were exclusively on serine or threonine residues. Seventeen of these 26 modifications contained sialic acid, which include glycosylation of threonine at residues 34 and 52 as previously reported.

[0053] Soluble receptors can act as “ligand traps” to inhibit oncogenic signaling. To illustrate the potential of srhPDPN to inhibit oncogenic PDPN signaling, tests were conducted, exposing human oral squamous cell cancer (OSCC) cells to srhPDPN.

[0054] Specifically, Senlbs human OSCC cells were obtained from an oral cancer patient enrolled in a clinical trial (#NCT04188665). They were maintained in DMEM (Hyclone SH30021) supplemented with 25 mM HEPES (Hyclone SH30237) and FBS (Seradigm 1400- 500) at 37 °C in 5% CO2 and 100% humidity and grown to confluence on 6 well tissue culture cluster plates (Falcon 353224) as described. For migration assays, cell monolayers were scratched and visualized immediately before and 24 h after treatment with 0 nM, 770 nM, 1440 nM, and 2280 nM shPDPN from 24 h to 48 h after treatment, and migration was quantitated as the number of cells that entered 123 x 123 pm squares placed along the center of the wound. Sister plates treated with shPDPN for 48 h were incubated with alamarBlue (BioRad BUF012A) for 4 h and assayed (ex / em: 570 / 600 nm) to assess cell viability as metabolic activity by measuring the reduction of resazurin dye to resorufm as known in the art. All assays were run at least 3 times with similar results. srhPDPN inhibited cell motility and viability in a dosage dependent manner consistent with its potential to act as a PDPN ligand trap. srhPDPN decreased cell motility by 36 ±6.5%, 63 ±12%, and 39 ±1.4% at 770 nM, 1540 nM, and 3080 nM compared to untreated controls, respectively (mean ±SEM, n =2) as shown in FIG. 3. srhPDPN also decreased cell viability by 47 ±2.5%, 61 ±1.5%, and 70 ±3.0% at 770 nM, 1540 nM, and 3080 nM compared to untreated controls, respectively as shown in Fig. 4.

Claims

What is claimed is:

1. A composition of matter, comprising: a soluble recombinant human podoplanin receptor (srhPDPN) including: a first amino acid sequence at least 95% homologous to SEQ ID NO: 1 ; and a tag peptide or polypeptide fused to the first amino acid sequence.

2. The composition of matter of claim 1, wherein the tag peptide or polypeptide comprises a polyhistidine tag.

3. The composition of matter of claim 1, wherein the srhPDPN further comprises a signal peptide or polypeptides fused to the first amino acid sequence.

4. The composition of matter of claim 3, wherein the signal peptide or polypeptides comprises an amino acid sequence at least 95% homologous to SEQ ID NO:2.

5. The composition of matter of claim 1, wherein a plurality7of threonine residues of the first amino acid sequence are glycosylated with sialic acid moieties.

6. The composition of matter of claim 5, wherein at least 15 threonine residues of the first amino acid sequence are glycosylated with sialic acid moieties.

7. The composition of matter of claim 6, wherein 17 threonine residues of the first amino acid sequence are glycosylated with sialic acid moieties.

8. A cell line comprising a gene encoding the composition of matter of claim 1.

9. The cell line of claim 8, wherein the cell line is a human cell line.

10. A pharmaceutical composition, comprising: the composition of matter of claim 1; and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, further comprising a flavor additive, a lubricant, a binder, a preservative, an encapsulating material, a diluting agent, an artificial coloring agent, a flavor additive, a binder, a stabilizer, a natural or artificial sweetener, a thickener, a tablet-disintegrating substance, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, stiffeners, gelatins, tragacanth, methylcellulose, and / or sodium carboxymethylcellulose.

12. A method for treating cancer or inflammatory joint disease, comprising: providing an effective amount of the composition of matter of claim 1 ; and allowing the composition of matter to act as a decoy receptor or ligand trap to inhibitPDPN signaling.

13. The method of claim 12, wherein the cancer is carcinoma, leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and / or breast cancer.

14. The method of claim 12, wherein the inflammatory joint disease is arthritis.

15. The method of claim 14, wherein the arthritis is osteoarthritis or rheumatoid arthritis.

16. A method of inhibiting Pdpn expressed on a cell comprising: providing a cell culture comprising tumor cells and / or normal cells; subjecting the tumor cells to a sufficient amount of the composition of matter of claim 1; and allowing the composition of matter to act as a decoy receptor or ligand trap to inhibit PDPN signaling.

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