US2022227831A1PendingUtilityA1

Tigit- and light-based chimeric proteins

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Assignee: SHATTUCK LABS INCPriority: Feb 27, 2017Filed: Apr 6, 2022Published: Jul 21, 2022
Est. expiryFeb 27, 2037(~10.6 yrs left)· nominal 20-yr term from priority
Inventors:Taylor SchreiberGeorge FrommSuresh De Silva
A61K 38/00C07K 2319/00A61P 37/02A61P 35/00C07K 14/70503C07K 14/70596C07K 14/70521C07K 14/70575C07K 14/525A61K 2039/585A61K 2039/82A61K 38/177A61K 38/1793C07K 14/705C07K 2319/30C07K 14/70578A61K 39/39A61P 29/00A61K 38/1774
81
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Claims

Abstract

The present invention relates, inter alia, to compositions and methods, including TIGIT- and/or LIGHT-based chimeric proteins that find use in the treatment of disease, such as cancer and an inflammatory disease.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A chimeric protein of a general structure of:
   N terminus-(a)-(b)-(c)-C terminus,   wherein:
 (a) is a first domain comprising an extracellular domain of a Type I transmembrane protein, the transmembrane protein being TIGIT, 
 (b) is a linker comprising at least one cysteine residue capable of forming a disulfide bond, and 
 (c) is a second domain comprising an extracellular domain of Type II transmembrane protein, the transmembrane protein being selected from 4-1BBL, GITRL, TL1A, and LIGHT, wherein: 
 the linker connects the first domain and the second domain and optionally comprises one or more joining linkers, such joining linkers being selected from SEQ ID NOs: 49-95. 
   
     
     
         2 . The chimeric protein of  claim 1 , wherein the second domain is 4-1BBL. 
     
     
         3 . The chimeric protein of  claim 1 , wherein the second domain is GITRL. 
     
     
         4 . The chimeric protein of  claim 1 , wherein the second domain is TL1A. 
     
     
         5 . The chimeric protein of  claim 1 , wherein the second domain is LIGHT. 
     
     
         6 . A chimeric protein of a general structure of:
   N terminus-(a)-(b)-(c)-C terminus,   wherein:
 (a) is a first domain comprising an extracellular domain of a Type I transmembrane protein, the transmembrane protein being selected from PD-1, CD172a(SIRPα), and TIGIT, 
 (b) is a linker comprising at least one cysteine residue capable of forming a disulfide bond, and 
 (c) is a second domain comprising an extracellular domain of Type II transmembrane protein, the transmembrane protein being LIGHT, wherein: 
 the linker connects the first domain and the second domain and optionally comprises one or more joining linkers, such joining linkers being selected from SEQ ID NOs: 49-95. 
   
     
     
         7 . The chimeric protein of  claim 6 , wherein the first domain is PD-1. 
     
     
         8 . The chimeric protein of  claim 6 , wherein the first domain is CD172a(SIRPα). 
     
     
         9 . The chimeric protein of  claim 6 , wherein the first domain is TIGIT. 
     
     
         10 . The chimeric protein of any one of  claims 1  to  9 , wherein the linker is a polypeptide selected from a flexible amino acid sequence, an IgG hinge region, or an antibody sequence. 
     
     
         11 . The chimeric protein of any one of  claims 1  to  10 , wherein the linker comprises hinge-CH2-CH3 Fc domain derived from IgG4. 
     
     
         12 . The chimeric protein of  claim 11 , wherein the hinge-CH2-CH3 Fc domain is derived from human IgG4. 
     
     
         13 . The chimeric protein of  claim 11  or  claim 12 , wherein the linker comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 46 or SEQ ID NO: 47. 
     
     
         14 . The chimeric protein of  claim 11  or  claim 12 , wherein the linker comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 48. 
     
     
         15 . The chimeric protein of any one of  claims 10  to  14 , wherein the linker comprises one or more joining linkers, such joining linkers independently selected from SEQ ID NOs: 49-95. 
     
     
         16 . The chimeric protein of  claim 15 , wherein the linker comprises two or more joining linkers each joining linker independently selected from SEQ ID NOs: 49-95; wherein one joining linker is N terminal to the hinge-CH2-CH3 Fc domain and another joining linker is C terminal to the hinge-CH2-CH3 Fc domain. 
     
     
         17 . The chimeric protein of any one of  claims 1  to  16 , wherein the chimeric protein is a recombinant fusion protein. 
     
     
         18 . The chimeric protein of any one of  claims 1  to  17 , wherein the chimeric protein is capable of forming a stable synapse between cells. 
     
     
         19 . The chimeric protein of  claim 18 , wherein the stable synapse between cells provides spatial orientation that favors tumor reduction. 
     
     
         20 . The chimeric protein of  claim 18  or  claim 19 , wherein the spatial orientation positions T cells to attack tumor cells and/or sterically prevents a tumor cell from delivering negative signals, including negative signals beyond those masked by the chimeric protein of the invention. 
     
     
         21 . The chimeric protein of any one of  claims 1  to  20 , wherein binding of either or both of the extracellular domains to its respective binding partner occurs with slow off rates (K off ), which provides a long interaction of a receptor and its ligand. 
     
     
         22 . The chimeric protein of  claim 21 , wherein the long interaction provides sustained negative signal masking effect. 
     
     
         23 . The chimeric protein of  claim 21  or  claim 22 , wherein the long interaction delivers a longer positive signal effect. 
     
     
         24 . The chimeric protein of  claim 23 , wherein the longer positive signal effect allows an effector cell to be adequately stimulated for an anti-tumor effect. 
     
     
         25 . The chimeric protein of any one of  claims 21  to  24 , wherein the long interaction provides T cell proliferation and allows for anti-tumor attack. 
     
     
         26 . The chimeric protein of any one of  claims 21  to  25 , wherein the long interaction allows sufficient signal transmission to provide release of stimulatory signals. 
     
     
         27 . The chimeric protein of  claim 26 , wherein the stimulatory signal is a cytokine. 
     
     
         28 . The chimeric protein of  claim 1 , wherein the chimeric protein has an amino acid sequence that is at least 95% identical to the amino acid sequence of one of SEQ ID NOs: 14, 17, or 20. 
     
     
         29 . The chimeric protein of  claim 6 , wherein the chimeric protein has an amino acid sequence that is at least 95% identical to the amino acid sequence of one of SEQ ID NOs: 5, 8, or 11. 
     
     
         30 . An expression vector, comprising a nucleic acid encoding the chimeric protein of any one of  claims 1  to  29 . 
     
     
         31 . A host cell, comprising the expression vector of  claim 30 . 
     
     
         32 . A pharmaceutical composition, comprising a therapeutically effective amount of the chimeric protein of any one of  claims 1  to  29 . 
     
     
         33 . A method of treating cancer or an inflammatory disease, comprising administering an effective amount of a pharmaceutical composition of  claim 32  to a subject in need thereof. 
     
     
         34 . A method of modulating a patient's immune response, comprising administering an effective amount of a pharmaceutical composition of  claim 32  to a subject in need thereof. 
     
     
         35 . The method of  claim 33  or  claim 34 , wherein the patient's T cells are activated. 
     
     
         36 . The method of any one of  claims 33  to  35 , wherein the patient has a tumor and one or more tumor cells are prevented from transmitting an immunosuppressive signal. 
     
     
         37 . A method for treating cancer or an inflammatory disease comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising a chimeric protein comprising:
 (a) a first domain comprising an extracellular domain of a Type I transmembrane protein, the transmembrane protein being TIGIT,   (b) a linker comprising at least one cysteine residue capable of forming a disulfide bond, and   (c) a second domain comprising an extracellular domain of a Type II transmembrane protein, the transmembrane protein selected from 4-1 BBL, GITRL, TL1A, and LIGHT.   
     
     
         38 . A method for treating cancer or an inflammatory disease comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising a chimeric protein comprising:
 (a) a first domain comprising an extracellular domain of a Type I transmembrane protein, the transmembrane protein selected from PD-1, CD172a(SIRPα), and TIGIT,   (b) a linker comprising at least one cysteine residue capable of forming a disulfide bond, and   (c) a second domain comprising an extracellular domain of Type II transmembrane protein, the transmembrane protein being LIGHT.   
     
     
         39 . The method of  claim 37  or  38 , wherein the subject's T cells are activated when bound by the second domain of the chimeric protein and:
 (a) one or more tumor cells are prevented from transmitting an immunosuppressive signal when bound by the first domain of the chimeric protein, 
 (b) a quantifiable cytokine response in the peripheral blood of the subject is achieved, and/or 
 (c) tumor growth is reduced in the subject in need thereof as compared to a subject treated with antibodies directed to the Type I or Type II protein, or their respective ligands or receptors. 
 
     
     
         40 . The method of any of  claims 33  to  39 , wherein the method stimulates signaling of one or more of LIGHT, 4-1BBL, GITRL, and TL1A and activates antigen-presenting cells. 
     
     
         41 . The method of any of  claims 33  to  40 , wherein the method reduces the amount or activity of regulatory T cells (Tregs) as compared to untreated subjects or subjects treated with antibodies directed to the Type I or Type II protein, or their respective ligands or receptors. 
     
     
         42 . The method of any of  claims 33  to  41 , wherein the method increases priming of effector T cells in draining lymph nodes of the subject as compared to untreated subjects or subjects treated with antibodies directed to the Type I or Type II protein, or their respective ligands or receptors. 
     
     
         43 . The method of any of  claims 33  to  42 , wherein the method causes an overall decrease in immunosuppressive cells and a shift toward a more inflammatory tumor environment as compared to untreated subjects or subjects treated with antibodies directed to the Type I or Type II protein, or their respective ligands or receptors. 
     
     
         44 . The chimeric protein of any one of  claims 1  to  29 , for use as a medicament. 
     
     
         45 . The chimeric protein of any one of  claims 1  to  29 , for use in the treatment of cancer. 
     
     
         46 . The chimeric protein of any one of  claims 1  to  29 , for use in the treatment of an inflammatory disease. 
     
     
         47 . Use of the chimeric protein of any one of  claims 1  to  29 , in the manufacture of a medicament.

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