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US20180141991A1 - Methods and polypeptides for modulation of immunoresponse - Google Patents

Methods and polypeptides for modulation of immunoresponse Download PDF

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US20180141991A1
US20180141991A1 US15/735,949 US201615735949A US2018141991A1 US 20180141991 A1 US20180141991 A1 US 20180141991A1 US 201615735949 A US201615735949 A US 201615735949A US 2018141991 A1 US2018141991 A1 US 2018141991A1
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polypeptide
tlt
amino acid
seq
acid sequence
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Yen-Ta Lu
Chia-Ming Chang
Tsai-Yin Wei
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MacKay Memorial Hospital
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MacKay Memorial Hospital
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    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction

Definitions

  • the present invention relates to modulation of an immunoresponse.
  • the present invention relates to methods and polypeptides for modulation of an immunoresponse by binding TLT-1 directly to immune cells and triggering cells to express immunosuppressive phenotypes.
  • TREM-like transcript-1 was observed exclusively in the alpha-granule of resting platelet megakaryocytes and on the surface of activated platelets.
  • TLT-1 is a member of the TREM family consisting of a single V-set immunoglobulin (Ig) domain, a short cytoplasmic tail, and a charged residue in the transmembrane domain.
  • 7,553,936 B2 relates to methods and compositions for modulating platelet activity, and methods and compositions for treating a disease or disorder associated with platelet activity in a subject, comprising administering a single chain anti-TREM-like transcript-1 (TLT-1) antibody or a functional fragment or variant thereof in an amount effective to modulate platelet activity.
  • TLT-1 single chain anti-TREM-like transcript-1
  • TLT-1 Small soluble fragments of the TLT-1 extracellular domain (12 and 14 kDa) were observed in normal human serum but not in plasma. Studies have shown that TLT-1 may serve as a regulator for hemostasis by linking with fibrinogen to facilitate platelet aggression, and have also demonstrated significant correlations between high levels of soluble TLT-1 (sTLT-1) and disseminated intravascular coagulation scores.
  • sTLT-1 soluble TLT-1
  • US 20040180409 A1 provides TLT-1 nucleic acid and protein molecules useful as modulating agents in regulating a variety of cellular processes, e.g., blood clotting and immune response.
  • sTLT-1 may bind to the soluble TREM-1 ligand, thus interfering with leukocyte activation (Derive M Bouazza Y, Sennoun N, Marchionni S, Quigley L, et al. (2012) Soluble TREM - like transcript -1 regulates leukocyte activation and controls microbial sepsis. J Immunol 188: 5585-5592).
  • the invention provides a method for modulating an immunoresponse, comprising binding a TREM-like transcript 1 (TLT-1) polypeptide to an immune cell, wherein the binding of the TLT-1 polypeptide to the immune cell suppresses immunoresponse.
  • TLT-1 polypeptide the immune cell treats and/or prevents a disease associated with immune hyper-reactivity; preferably, the disease is an autoimmune disease, hypersensitivity reaction, transplantation rejection or graft versus host disorder.
  • the TLT-1 polypeptides are those described herein below.
  • the invention also provides a polypeptide, comprising an amino acid sequence comprising at least 5 amino acids of SEQ ID NO: 1, 2 or 42 or at least about 50% amino acid sequence identity to SEQ ID NO: 1, 2 or 42, or a biologically active fragment or a variant thereof.
  • the polypeptide comprises an amino acid sequence having at least about 80% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 1, 2 or 42; preferably, the polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 1, 2 or 42.
  • the said polypeptide is recombinant polypeptide or synthetic polypeptide.
  • the polypeptide is pegylated or conjugated with a tissue target molecule, an albumin or a serum albumin binding peptide. In some embodiments, the polypeptide is fused with a tissue target molecule, an albumin or a serum albumin binding peptide.
  • the invention further provides a composition comprising a TLT-1 polypeptide of the invention and a pharmaceutically acceptable carrier. Also provided is a method for treating and/or preventing a disease associated with immune hyper-reactivity, comprising administering the TLT-1 polypeptide of the invention or a composition comprising the TLT-1 polypeptide to a subject.
  • the invention further provides a TLT-1 fusion protein, comprising the TLT-1 polypeptide of the invention fused with one or more heterogeneous polypeptide or other TLT-1 polypeptide of the invention.
  • the invention further provides a pegylated TLT-1 polypeptide, comprising one or more polyethylene glycol (PEG) molecules operably linked to at least one amino acid residue in the N-terminal of the TLT-1 polypeptide of the invention.
  • PEG polyethylene glycol
  • the invention further provides a TLT-1 polypeptide conjugate, comprising a TLT-1 polypeptide of the invention conjugated to an immunosuppressive agent.
  • FIG. 1 shows interaction between TLT-1 and leukocytes.
  • PBMCs were incubated with rsTLT-1 for 1 hour and stained with biotin-goat anti-TLT-1 antibodies APC-avidin to detect the surface binding of TLT-1.
  • A depicts representative FACS histogram of various leukocytes in the presence or absence of rsTLT-1 treatment. Monocytes, PMNs, and lymphocytes are gated based on their FSC/SSC properties (heavy-line histogram, rsTLT-1 treated cells; dashed-line histogram, untreated cells; thin dashed-line histogram, appropriate isotype control). TLT-1 bound to monocytes and PMNs, but not to lymphocytes.
  • (B) depicts binding of various concentrations of rsTLT-1 to monocytes and PMNs. PMNs and monocytes were able to bind with rsTLT-1 in a dose dependent manner. Values are presented as mean ⁇ SEM from 3 independent experiments.
  • FIG. 2 shows the effect of sTLT-1 on the surface expression of HLA-DR and PD-L1 molecules in monocytes.
  • A Monocytes were incubated with rsTLT-1 (10 ⁇ g/mL) for 3 days. At the indicated time point, the cells were harvested and the HLA-DR and PD-L1 molecules were analyzed using flow cytometry. Treatment with rsTLT-1 leads to a trend with down-regulation of HLA-DR expression. By contrast, rsTLT-1 priming up-regulated the levels of PD-L1 expression on monocytes.
  • Monocytes were cultured with different concentrations of rsTLT-1 for 2 days.
  • the cells were then harvested and the HLA-DR and PD-L1 molecules were analyzed using flow cytometry.
  • Surface molecule expression is presented as the mean fluorescence intensity (MFI) relative to each day that the cells were treated with the control medium (dashed line). Values are presented as mean ⁇ SEM from 3 independent experiments.
  • FIG. 3 shows the effect of TLT-1 polypeptides on the surface expression of PD-L1 molecules in monocytes.
  • A depicts structural characteristics of extracellular domain of TLT-1 and designed TLT-1 polypeptides.
  • B shows that monocytes were cultured with different lengths of TLT-1 polypeptide (10 ⁇ g/ml) and 10 ⁇ g/ml rsTLT-1 for 1 day. The cells were then harvested and the PD-L1 molecules were analyzed using flow cytometry. Surface molecule expression is presented as the MFI relative to each day that the cells were treated with the medium control (dashed line).
  • FIG. 4 shows the effect of TLT-1 15-63 polypeptides on the surface expression of HLA-DR molecules in monocytes.
  • Monocytes were cultured with 10 ⁇ g/ml TLT-1 15-63 polypeptide and 10 ⁇ g/ml rsTLT-1 for 2 days. The cells were then harvested and the HLA-DR molecules were analyzed using flow cytometry. Surface molecule expression is presented as the MFI relative to each day that the cells were treated with the medium control (dashed line).
  • TLT-1 directly binds to immune cells and trigger cells to express immunosuppressive phenotypes; i.e., down-regulation of HLA-DR and up-regulation of PD-L1 by binding.
  • immunosuppressive phenotypes i.e., down-regulation of HLA-DR and up-regulation of PD-L1 by binding.
  • the induction of PD-L1 and reduction of HLA-DR by TLT-1 or TLT-1 polypeptides can therefore be useful in treating diseases associated with immune hyper-reactivity, such as autoimmune diseases, hypersensitivity reactions, transplantation rejections and graft versus host disorders.
  • amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).
  • PD-L1 refers to programmed death-ligand 1 (PD-L1), cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1).
  • PD-L1 is a 40 kDa type 1 transmembrane protein that plays a major role in suppressing the immune system during particular events such as pregnancy, autoimmune disease, cancer, sepsis, and other infectious diseases such as mycobacterium tuberculosis , cytomegalovirus, and hepatitis.
  • monocyte also called mononuclear white cell
  • monocytes belongs to a type of white blood cell involved in first-line defensive mechanism and is recognized as able to differentiate into a dendritic cell or macrophage precursor.
  • Monocytes normally move in the blood system.
  • monocytes secrete many immuno-regulatory cytokines, move to the site of infection in the tissues and differentiate into macrophages.
  • the term “modulating” includes “increasing” or “stimulating,” as well as “decreasing” or “reducing,” typically in a statistically significant or a physiologically significant amount as compared to a control.
  • identity refers to a relationship between two or more polypeptide or protein sequences, as determined by comparing the sequences. In the art, “identity” also refers to the degree of sequence relatedness between polypeptides or proteins, as determined by the match between strings of such sequences. “Identity” can be readily calculated by known bioinformational methods. The “percent identity” of two polynucleotide or two polypeptide sequences is determined by comparing the sequences using the GAP computer program (a part of the GCG Wisconsin Package, version 10.3) using its default parameters.
  • biologically active fragment means an amino acid fragment of a polypeptide encompassed by the invention, said fragment also having the efficacy of the polypeptide described herein.
  • variant refers to an amino acid sequence which is of the wild type or which has been altered by substitution, insertion, cross-over, deletion, and/or other genetic operation.
  • a variant is not limited to a particular method by which it is generated.
  • a variant sequence can have increased, decreased, or substantially similar activities or properties in comparison to the parental sequence.
  • the polypeptide may contain one or more amino acid residues that have been mutated as compared to the amino acid sequence of the wild type polypeptide.
  • one or more amino acid residues of the polypeptide can be held constant, invariant, or not substituted as compared to a parent polypeptide in the variant polypeptides making up the plurality.
  • the parent polypeptide is used as the basis for generating variants with improved robustness or other properties.
  • Variants can also differ in at least one of secondary structure, tertiary structure, and degree of foldedness.
  • peptide As used herein, the terms “peptide,” “polypeptide” and “protein” each refer to a molecule comprising two or more amino acid residues joined to each other by peptide bonds. These terms encompass, e.g., native and artificial proteins, protein fragments and polypeptide analogs (such as variants, and fusion proteins) of a protein sequence as well as post-translationally, or otherwise covalently or non-covalently, modified proteins.
  • a peptide, polypeptide, or protein may be monomeric or polymeric.
  • polypeptide fragment refers to a polypeptide that has an amino-terminal and/or carboxy-terminal deletion as compared to a corresponding full-length protein. Fragments can also result from proteolytic (or other) processing, which, for example, results in variation in the amino and/or carboxy terminus of from one to five amino acids from that predicted. A fragment can further comprise, at either or both of its ends, one or more additional amino acids, for example, a sequence of amino acids from a different naturally-occurring protein or an artificial amino acid sequence (e.g., an artificial linker sequence or a tag protein).
  • pharmaceutically acceptable carrier refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • the term “subject” refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, humans, farm animals, sport animals, and pets.
  • an effective amount refers to an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • an effective amount is an amount that is sufficient to diagnose, palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • treatment generally refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.
  • preventing refers to a preventative or prophylactic measure that stops a disease state or condition from occurring in a patient or subject. Prevention can also include reducing the likelihood of a disease state or condition from occurring in a patient or subject and impeding or arresting the onset of said disease state or condition.
  • the present invention unexpectedly found that the direct binding of TLT-1 to immune cells and triggers cells to express immunosuppressive phenotypes through down-regulation of HLA-DR and up-regulation of PD-L1.
  • the present invention provides a method for modulating an immunoresponse, comprising binding a TREM-like transcript 1 (TLT-1) polypeptide to an immune cell, wherein the binding of the TLT-1 polypeptide to the immune cell suppresses immunoresponse.
  • TLT-1 polypeptides are those described herein below.
  • the present invention provides a method of treating and/or preventing a disease associated with immune hyper-reactivity, comprising administering an effective amount of a TLT-1 polypeptide to a subject.
  • the diseases include but are not limited to, autoimmune diseases, hypersensitivity reactions, transplantation rejections and graft versus host disorder.
  • PD-L1 The expression of PD-L1 can be induced and HLA-DR can be reduced by binding a TLT-1 polypeptide to monocytes, whereby treating diseases associated with immune hyper-reactivity.
  • Any TLT-1 polypeptide capable of binding to immune cells can achieve the above-mentioned modulation on PD-L1 and HLA-DR, including full-length TLT-1 and polypeptide fragments thereof.
  • a sequence of the TLT-1 extracellular domain is responsible for binding to immune cells; preferably, a sequence comprising at least 30 amino acids (TLT-1 34-63), a sequence comprising at least 49 amino acids (TLT-1 15-63) or a sequence comprising at least 147 amino acids (TLT-1 16-162).
  • TLT-1 34-63 a sequence comprising at least 30 amino acids
  • TLT-1 15-63 a sequence comprising at least 49 amino acids
  • TLT-1 16-162 a sequence comprising at least 147 amino acids
  • the invention provides a polypeptide, comprising an amino acid sequence comprising at least 5 amino acids of SEQ ID NO: 1 or at least about 80% amino acid sequence identity to SEQ ID NO: 1, or a biologically active fragment or a variant thereof
  • the polypeptide has at least 80%, e.g., at least 80%, 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%, amino acid sequence identity to SEQ ID NO: 1.
  • the polypeptide comprises an amino acid sequence comprising 5 amino acids of SEQ ID NO: 2 or at least about 80% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 2, or a biologically active fragment or a variant thereof
  • the polypeptide has at least 80%, e.g., at least 80%, 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%, amino acid sequence identity to SEQ ID NO: 2.
  • the polypeptide comprises an amino acid sequence comprising 5 amino acids of SEQ ID NO: 3 or at least about 70% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 42, or a biologically active fragment or a variant thereof.
  • the polypeptide has at least 70%, e.g., at least 70%, 80%, 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%, amino acid sequence identity to SEQ ID NO: 3.
  • the invention provides a polypeptide comprising one or more insertion, substitution and/or deletion in any of TLT-1 amino acid sequences described herein.
  • the TLT-1 amino acid sequence is SEQ ID NO:1, 2 or 3.
  • Polypeptides can be produced through recombinant methods and chemical synthesis.
  • functionally equivalent polypeptides may find use, where the equivalent polypeptide may contain deletions, additions or substitutions of amino acid residues that result in a silent change, thus producing a functionally equivalent differentially expressed on pathway gene product.
  • Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
  • “Functionally equivalent,” as used herein, refers to a protein capable of exhibiting a substantially similar in vivo activity.
  • the polypeptides may be produced by recombinant DNA technology or synthetic technology using techniques well known in the art. Methods which are well known to those skilled in the art can be used to construct expression vectors containing coding sequences and appropriate transcriptional/translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques and in vivo recombination/genetic recombination. Alternatively, RNA capable of encoding the polypeptides of interest may be chemically synthesized.
  • the coding sequence is placed under the control of a promoter that is functional in the desired host cell to produce relatively large quantities of the gene product.
  • a promoter that is functional in the desired host cell to produce relatively large quantities of the gene product.
  • An extremely wide variety of promoters is well known and can be used in the expression vectors of the invention depending on the particular application. Ordinarily, the promoter selected depends upon the cell in which the promoter is to be active. Other expression control sequences such as ribosome binding sites, transcription termination sites and the like are also optionally included. Constructs that include one or more of these control sequences are termed “expression cassettes.” Expression can be achieved in prokaryotic and eukaryotic cells utilizing promoters and other regulatory agents appropriate for the particular host cell. Exemplary host cells include, but are not limited to, E. coli , other bacterial hosts, yeast, and various higher eukaryotic cells such as the COS, CHO and HeLa cells lines and myeloma cell lines.
  • the recombinant polypeptides can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, ion exchange and/or size exclusivity chromatography, gel electrophoresis and the like (see, generally, R. Scopes, Protein Purification, Springer-Verlag, N.Y. (1982), Guider, Methods in Enzymology Vol. 182: Guide to Protein Purification, Academic Press, Inc. N.Y. (1990)).
  • polypeptides can be chemically synthesized. Such methods typically include solid-state approaches, but can also utilize solution based chemistries and combinations or combinations of solid-state and solution approaches. Examples of solid-state methodologies for synthesizing proteins are described by Merrifield (1964) J. Am. Chem. Soc. 85:2149; and Houghton (1985) Proc. Natl. Acad. Sci., 82:5132. Fragments of polypeptides of the invention protein can be synthesized and then joined together. Methods for conducting such reactions are described by Grant (1992) Synthetic Peptides: A User Guide, W.H. Freeman and Co., N.Y.; and in “Principles of Peptide Synthesis,” (Bodansky and Trost, ed.), Springer-Verlag, Inc. N.Y., (1993).
  • the invention provides a TLT-1 fusion protein, comprising the TLT-1 polypeptide of the invention fused with one or more heterogeneous polypeptide or other TLT-1 polypeptide of the invention.
  • the TLT-1 polypeptide covalently links to one or more heterogeneous polypeptide or another TLT-1 polypeptide of the invention, either directly or via an amino acid linker.
  • the polypeptides forming the fusion protein are typically linked C-terminus to N-terminus, although they can also be linked C-terminus to C-terminus, N-terminus to N-terminus, or N-terminus to C-terminus.
  • the polypeptides of the fusion protein can be in any order and may include more than one of either or both of the constituent polypeptides.
  • heterogeneous polypeptide examples include, but are not limited to, an albumin, a serum albumin binding peptide, a cell penetrating peptide (CPP), a tissue targeting molecule and an immunosuppressive peptide.
  • the heterogeneous polypeptide is an albumin or a serum albumin binding peptide.
  • the invention also provided a pegylated TLT-1 polypeptide, comprising one or more polyethylene glycol (PEG) molecules operably linked to at least one amino acid residue in the N-terminal of the TLT-1 polypeptide of the invention.
  • PEGylation of the molecules can be carried out, e.g., according to the methods described in Youngster et al., Curr Pharm Des (2002), 8:2139.
  • Any kind of polyethylene glycol is suitable for the present invention provided that the PEG-polypeptide is still functionally active which can be assayed according to methods known in the art.
  • the polyethylene glycol of the present invention is PEG 1000, 2000, 3000, 5000, 10000, 15000, 20000, 30000, 40000 or 50000.
  • the pegylated TLT-1 polypeptide comprises a monomeric TLT-1 polypeptide.
  • the pegylated molecule comprises is an oligomeric TLT-1 polypeptide.
  • the pegylated TLT-1 polypeptide comprises a multiarm PEG, wherein one or more monomeric TLT-1 polypeptide are operably linked to the multiarm PEG.
  • the invention also comprises a TLT-1 polypeptide conjugate, comprising a TLT-1 polypeptide of the invention conjugated to an immunosuppressive agent, a tissue target molecule, an albumin or a serum albumin binding peptide.
  • the present invention provides compositions comprising a TLT-1 polypeptide of the invention.
  • such compositions may be administered to subjects.
  • the TLT-1 polypeptide of the invention may be provided in a composition that comprises one or more other components, including, but not limited to, pharmaceutically acceptable carriers, adjuvants, wetting or emulsifying agents, pH buffering agents, preservatives, and/or any other components suitable for the intended use of the compositions.
  • Such compositions can take the form of solutions, suspensions, emulsions and the like.
  • pharmaceutically acceptable carrier includes various diluents, excipients and/or vehicles in which, or with which, the TLT-1 polypeptides, proteins, and/or protein complexes of the invention can be provided.
  • the pharmaceutically acceptable carrier includes, but is not limited to, carriers known to be safe for delivery to human and/or other animal subjects, and/or approved by a regulatory agency of the federal or a state government, and/or listed in the U.S. Pharmacopeia, and/or other generally recognized pharmacopeia, and/or receiving specific or individual approval from one or more generally recognized regulatory agencies for use in humans and/or other animals.
  • Such pharmaceutically acceptable carriers include, but are not limited to, water, aqueous solutions (such as saline solutions, buffers, and the like), organic solvents (such as certain alcohols and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil) and the like.
  • aqueous solutions such as saline solutions, buffers, and the like
  • organic solvents such as certain alcohols and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil
  • the TLT-1 polypeptide of the invention may be provided in a composition that comprises one or more additional active components, such as one or more additional immunosuppressors.
  • the immunosuppressors include but are not limited to glucocorticoid, cytostatic, alkylating agent, antimetabolite, methotrexate, azathioprine, mercaptopurine, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, anti-CD20 antibody, muromonab-CD3, basiliximab, daclizumab, cyclosporin, tacrolimus, sirolimus, interferon, opioid, TNF binding protein, mycophenolate, fingolimod and myriocin.
  • compositions of the invention comprise an “effective amount” of a TLT-1 polypeptide of the invention.
  • An “effective amount” is an amount required to achieve a desired end result.
  • the amount of a TLT-1 polypeptide of the invention that is effective to achieve the desired end result will depend on a variety of factors including, but not limited to, the species of the intended subject (e.g. whether human or some other animal species), the age and/or sex of the intended subject, the planned route of administration, the planned dosing regimen, the seriousness of any ongoing diseases or conditions, and the like.
  • the effective amount (which may be a range of effective amounts—can be determined by standard techniques without any undue experimentation, for example using in vitro assays and/or in vivo assays in the intended subject species or any suitable animal model species. Suitable assays include, but are not limited to, those that involve extrapolation from dose-response curves and/or other data derived from in vitro and/or in vivo model systems. In some embodiments the effective amount may be determined according to the judgment of a medical or veterinary practitioner based on the specific circumstances.
  • an effective amount of the TLT-1 polypeptide ranges from about 0.0002 mg/kg to about 20 mg/kg body weight per administration.
  • the present invention provides methods that comprise administering the TLT-1 polypeptide of the invention to a subject.
  • Such methods may comprise methods for treating subjects suffering from a disease associated with immune hyper-reactivity, such as autoimmune diseases, hypersensitivity reactions, transplantation rejections and graft versus host disorders.
  • Subjects to which the TLT-1 polypeptides of the invention, or compositions comprising such TLT-1 polypeptide, can be administered include any and all animal species.
  • the subjects are mammalian species. Mammalian subjects include, but are not limited to, humans, non-human primates, rodents, rabbits, and ferrets.
  • compositions of the present invention may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
  • dosing regimens may comprise a single administration. In other embodiments, dosing regimens may comprise multiple administrations.
  • PBMCs peripheral blood mononuclear cells
  • GE Healthcare Ficoll-Paque Plus
  • pET28a(+)-rsTLT-1 encoding a human TLT-1 extracellular domain (Glu16-Pro162) with a polyhistidine tag at the N-terminus was expressed using E. coli and purified using Ni-NTA columns (Novagen). The purity of the recombinant protein determined using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and visualized using a coomassive blue stain was >95%. The endotoxin contamination of the purified proteins was examined using a LAL assay (QCL-1000). All proteins were sterile and the endotoxin concentration was lower than the detectable limit ( ⁇ 0.1 EU/ ⁇ g protein). The TLT-1 polypeptides were chemically synthesized by Kelowna International Scientific Inc. (Taipei, Taiwan).
  • PBMCs were incubated overnight in an AIM-V medium (Life Technologies) at 37° C. in a 5% CO 2 humidified atmosphere to allow platelet shedding from the cell surface.
  • AIM-V medium Life Technologies
  • PMNs polymorphonuclear leukocytes
  • the cells were incubated for 30 minutes on ice in the dark with the following mAbs diluted in phosphate-buffered saline (PBS) containing 1% BSA: HLA-DR-PE, PD-L1-FITC, CD14-PerCP (BD Biosciences).
  • PBS phosphate-buffered saline
  • BSA phosphate-buffered saline
  • HLA-DR-PE HLA-DR-PE
  • PD-L1-FITC PD-L1-FITC
  • CD14-PerCP BD Biosciences
  • TLT-1 binds to leukocytes
  • 10 ⁇ g/mL rsTLT-1 for 1 hour
  • the detected cell surface binding of TLT-1 by using flow cytometry.
  • FIG. 1A we detected the binding of rsTLT-1 with PMNs and monocytes, but not with lymphocytes.
  • FIG. 1B we observed that the binding of PMNs and monocytes bound rsTLT-1 was dose-dependent ( FIG. 1B ).
  • TLT-1 Alters the Surface Expression of HLA-DR and PD-L1 Molecules in Monocytes
  • HLA-DR was significantly up-regulated by rsTLT-1 within the first 24 hours followed by a rapid down-regulation of its expression at later time points.
  • PD-L1 was also significantly increased in its expression within 24 hours but remained up-regulated throughout the following 3-day experiment ( FIG. 2A , right).
  • FIG. 2A we studied the dose-effect of sTLT-1 on the expression of HLA-DR and PD-L1.
  • TLT-1 15-63 Polypeptides Alter the Surface Expression of PD-L1 and HLA-DR Molecules in Monocytes
  • TLT-1 has a single extracellular Ig variable (Ig V) domain which contains 9 beta strands forming 2 antiparallel beta sheets locked together by a conserved disulfide bond between strands B and strands F.
  • Ig V Ig variable
  • TLT-1 has another disulfide bridge to stabilize its C-C′ beta hairpin.
  • FIG. 3A To screen the functional domain of sTLT-1, we synthesized different lengths of polypeptides according to its V-type Ig-structure ( FIG. 3A ). The polypeptide sequences are shown in Table I. Human monocytes were incubated with different polypeptides (10 ⁇ g/mL) and the expression of PD-L1 was examined for 24 hours. As shown in FIG.
  • TLT-1 15-63 was significantly increased in its expression within 24 hours in TLT-1 15-63 peptide-treated monocytes.
  • treatment with TLT-1 34-63 peptide also induced PD-L1 expression.
  • the expression of HLA-DR on monocytes was also decreased at 48 hours of incubation with TLT-1 15-63 peptide ( FIG. 4 ).
  • TLT-1 15-63 can serve as a therapeutic agent to treat hyper-immune related disease through up-regulating PD-L1 expression and down-regulating HLA-DR expression.
  • TLT-1 polypeptides of the inventions were designed mimicking different parts of its extracellular domain Polypeptide name Sequence TLT-1 20-39 GSLPEVLQAPVGSSILVQCH (SEQ ID NO: 4) TLT-1 15-46 GQGIVGSLPEVLQAPVGSSILVQCHYRLQ DVK (SEQ ID NO: 5) TLT-1 15-53 GQGIVGSLPEVLQAPVGSSILVQCHYRLQ DVKAQKVWCR (SEQ ID NO: 6) TLT-1 15-63 GQGIVGSLPEVLQAPVGSSILVQCHYRLQ DVKAQKVWCRFLPEGCQPLV (SEQ ID NO: 7) TLT-1 40-63 YRLQDVKAQKVWCRFLPEGCQPLV (SEQ ID NO: 8) TLT-1 34-63 ILVQCHYRLQDVKAQKVWCRFLPEGCQP LV (SEQ ID NO: 9)

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AU2016276509B2 (en) 2021-04-01
WO2016197974A1 (en) 2016-12-15
US11685785B2 (en) 2023-06-27
KR20180012856A (ko) 2018-02-06

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