US2022193232A1PendingUtilityA1

Kappa myeloma antigen chimeric antigen receptors and uses thereof

56
Assignee: HAEMALOGIX PTY LTDPriority: Apr 23, 2015Filed: Feb 28, 2022Published: Jun 23, 2022
Est. expiryApr 23, 2035(~8.8 yrs left)· nominal 20-yr term from priority
Inventors:Kenneth MicklethwaiteRosanne DunnDavid GottliebGrant Logan
A61K 38/204A61K 40/42A61K 40/31A61K 40/11A61K 2239/46A61K 2239/31A61K 2239/38C12N 5/0636C07K 2317/526C07K 2319/03C07K 14/70521C07K 14/5412C07K 16/2896C07K 2317/53C07K 2317/56A61K 39/395C07K 2319/035C07K 14/5434C07K 14/7051A61P 35/00A61K 2039/505C07K 16/2887C12N 2510/00C07K 16/30A61P 43/00A61K 35/17
56
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Claims

Abstract

The present invention provides compositions and methods for treating KMA-expressing malignancies including chimeric antigen receptors (CARs) and T cells containing CARs (CAR T-cells). The invention also provides methods and compositions comprising CAR T-cells co-expressing other anti-tumoral agents including cytokines and antibodies.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A chimeric antigen receptor (CAR) comprising one or more intracellular signaling domains and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes kappa myeloma antigen (KMA). 
     
     
         2 . The CAR of  claim 1 , wherein the one or more intracellular signaling domains comprises one or more co-stimulatory endodomains. 
     
     
         3 . The CAR of  claim 2 , wherein the one or more co-stimulatory endodomains is one or more of a CD28 domain, a CD3ζ domain, a 4-1BB domain or OX-40 domain or combinations thereof. 
     
     
         4 . The CAR of  claim 3 , wherein the co-stimulatory endodomains are a CD3ζ domain and a CD28 domain. 
     
     
         5 . The CAR of  claim 3 , wherein the co-stimulatory endodomains are a CD3ζ domain and an OX-40 domain. 
     
     
         6 . The CAR of  claim 4 , further comprising an OX-40 domain. 
     
     
         7 . The CAR of  claim 3 , wherein the co-stimulatory endodomains are a CD3ζ domain and a 4-1BB domain. 
     
     
         8 . The CAR of  claim 4 , further comprising a 4-1BB domain. 
     
     
         9 . The CAR of  claim 7 , further comprising an OX-40 domain. 
     
     
         10 . The CAR of  claim 1 , wherein the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recognizes KMA. 
     
     
         11 . The CAR of  claim 10 , wherein the scFv comprises the complementarity determining regions (CDRs) derived from the KappaMab monoclonal antibody, wherein the KappaMAb CDRs comprise SEQ ID NOS: 3-8. 
     
     
         12 . The CAR of  claim 10 , wherein the scFv comprises the VL chain and VH chain from KappaMab wherein the VL chain comprises SEQ ID NO: 2 and a VH chain comprises SEQ ID NO: 1. 
     
     
         13 . The CAR of  claim 11 , wherein the VL chain and VH chain from KappaMab are attached via a glycine-serine linker. 
     
     
         14 . The CAR of  claim 13 , wherein the glycine-serine linker is a 15-20 amino acid linker. 
     
     
         15 . The CAR of  claim 14 , wherein the 15 amino acid linker comprises (Gly 4 Ser) 3 . 
     
     
         16 . The CAR of  claim 10 , wherein the scFv is attached to the one or more intracellular signaling domains via a spacer. 
     
     
         17 . The CAR of  claim 16 , wherein the spacer is an immunoglobulin constant region or a CD8α chain. 
     
     
         18 . The CAR of  claim 17 , wherein the immunoglobulin constant region comprises one or more of an IgG hinge domain, an IgG CH2 domain and an IgG CH3 domain. 
     
     
         19 . The CAR of  claim 18 , wherein the immunoglobulin constant region comprises an immunoglobulin hinge domain. 
     
     
         20 . The CAR of  claim 19 , wherein the immunoglobulin constant region further comprises an IgG CH3 domain. 
     
     
         21 . The CAR of  claim 19  or  20 , wherein the immunoglobulin constant region further comprises an IgG CH2 domain. 
     
     
         22 . The CAR of any one of  claims 17 - 21 , wherein the spacer is attached to the scFV via a glycine-serine linker. 
     
     
         23 . The CAR of  claim 22 , wherein the glycine-serine linker is a 15-20 amino acid linker. 
     
     
         24 . The CAR of  claim 23 , wherein the 15 amino acid linker comprises (Gly 4 Ser) 3 . 
     
     
         25 . A genetically modified T cell engineered to express the CAR of any one of  claims 1 - 24 . 
     
     
         26 . The genetically modified T cell of  claim 25  further engineered to express one or more additional biological molecules. 
     
     
         27 . The genetically modified T cell of  claim 26 , wherein the one or more additional biological molecules comprises one or more of IL-12, GAL3C or SANT7. 
     
     
         28 . The genetically modified T cell of  claim 26 , wherein the one or more additional biological molecules is IL-12 and the IL-12 is expressed by a single chain polypeptide comprising one IL-12 p35 subunit and one IL-12 p40 subunit joined by a flexible linker. 
     
     
         29 . The genetically modified T cell of  claim 28 , wherein the flexible linker is a (G 4 S) 3  linker. 
     
     
         30 . The genetically modified T cell of  claim 29 , wherein the single chain polypeptide comprising one IL-12 p35 subunit and one IL-12 p40 subunit joined by a flexible linker forms a bioactive p70 IL-12 heterodimer. 
     
     
         31 . The genetically modified T cell of  claim 26  engineered to express IL-12 and a selectable marker. 
     
     
         32 . The genetically modified T cell of  claim 26  engineered to express SANT-7. 
     
     
         33 . The genetically modified T cell of  claim 26  engineered to express SANT-7 and a selectable marker. 
     
     
         34 . The genetically modified T cell of  claim 31  further engineered to express SANT7. 
     
     
         35 . The genetically modified T cell of  claim 26  engineered to express GAL3C. 
     
     
         36 . The genetically modified T cell of  claim 26  engineered to express GAL3C and a selectable marker. cm  37 . The genetically modified T cell of  claim 31  further engineered to express GAL3C. 
     
     
         38 . The genetically modified T cell of  claim 31  further engineered to express GAL3C and SANT7. 
     
     
         39 . The genetically modified T cell of  claim 33  further engineered to express GAL3C. 
     
     
         40 . A method for producing a genetically modified T cell comprising introducing an expression vector encoding a CAR comprising one or more intracellular signaling domain and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes kappa myeloma antigen (KMA) into a T cell. 
     
     
         41 . The method of  claim 40 , wherein the expression vector is a transposable vector expression system. 
     
     
         42 . The method of  claim 40 , wherein the expression vector is a PiggyBac transposon expression vector. 
     
     
         43 . The method of  claim 40 , wherein the introducing comprises electroporation. 
     
     
         44 . The method of  claim 40 , wherein the one or more intracellular signaling domain comprises one or more co-stimulatory endodomains. 
     
     
         45 . The method of  claim 44 , wherein the one or more co-stimulatory endodomains is one or more of a CD28 domain, a CD3ζ domain, a 4-1BB domain or OX-40 domain or combinations thereof. 
     
     
         46 . The method of  claim 45 , wherein the co-stimulatory endodomains are a CD3ζ domain and a CD28 domain. 
     
     
         47 . The method of  claim 45 , wherein the co-stimulatory endodomains are a CD3ζ domain and an OX-40 domain. 
     
     
         48 . The method of  claim 46 , wherein the CAR further comprises an OX-40 domain. 
     
     
         49 . The method of  claim 45 , wherein the co-stimulatory endodomains are a CD3ζ domain and a 4-1BB domain. 
     
     
         50 . The method of  claim 46 , wherein the CAR further comprises a 4-1BB domain. 
     
     
         51 . The method of  claim 50 , wherein the CAR further comprises an OX-40 domain. 
     
     
         52 . The method of  claim 40 , wherein the extracellular binding domain comprises a scFv the specifically recognizes KMA. 
     
     
         53 . The method of  claim 52 , wherein the scFv comprises the complementarity determining regions (CDRs) derived from the KappaMab monoclonal antibody wherein the CDRs comprise SEQ ID NOS: 3-8. 
     
     
         54 . The method of  claim 53 , wherein the scFv comprises the VL chain and VH chain of the KappaMab monoclonal antibody, wherein the VL chain comprises SEQ ID NO: 2 and the VH chain comprises SEQ ID NO: 1. 
     
     
         55 . The method of  claim 54 , wherein the VL CDRs and VH CDRs are attached via a glycine-serine linker. 
     
     
         56 . The method of  claim 55 , wherein the glycine-serine linker is a 15-20 amino acid linker. 
     
     
         57 . The method of  claim 56 , wherein the 15 amino acid linker comprises (Gly 4 Ser) 3 . 
     
     
         58 . The method of  claim 52 , wherein the scFv is attached to the one or more intracellular signaling domains via a spacer. 
     
     
         59 . The method of  claim 58 , wherein the spacer is an immunoglobulin constant region or a CD8α chain. 
     
     
         60 . The method of  claim 59 , wherein the immunoglobulin constant region comprises one or more of an IgG hinge domain, an IgG CH2 domain and an IgG CH3 domain. 
     
     
         61 . The method of  claim 59 , wherein the immunoglobulin constant region comprises an immunoglobulin hinge domain. 
     
     
         62 . The method of  claim 61 , wherein the immunoglobulin constant region further comprises an IgG CH3 domain. 
     
     
         63 . The method of  claim 61  or  62 , wherein the immunoglobulin constant region further comprises an IgG CH2 domain. 
     
     
         64 . The CAR of any one of  claims 59 - 63 , wherein the spacer is attached to the scFV via a glycine-serine linker. 
     
     
         65 . The CAR of  claim 22 , wherein the glycine-serine linker is a 15-20 amino acid linker. 
     
     
         66 . The CAR of  claim 23 , wherein the 15 amino acid linker comprises (Gly 4 Ser) 3 . 
     
     
         67 . The method of  claim 40 , further comprising introducing one or more additional expression vectors capable of expressing one or more additional biological molecules. 
     
     
         68 . The method of  claim 67 , wherein the one or more additional biological molecules comprises one or more of IL-12, GAL3C or SANT7. 
     
     
         69 . The method of  claim 68 , wherein the one or more additional biological molecules is IL-12 and said IL-12 is expressed by a single chain construct comprising a IL-12 p35 subunit and a IL-12 p40 subunit joined by a flexible linker. 
     
     
         70 . The method of  claim 69 , wherein the flexible linker is a (G 4 S) 3  linker. 
     
     
         71 . The method of  claim 70 , wherein the single chain construct comprising an IL-12 p35 subunit and an IL-12 p40 subunit joined by a flexible linker forms a bioactive p70 IL-12 heterodimer. 
     
     
         72 . The method of  claim 67 , wherein the one or more additional biological agents is expressed via a construct further encoding a selectable marker. 
     
     
         73 . The method of  claim 72 , wherein the construct encodes IL-12 and a selectable marker, wherein the coding sequences for the selectable marker and IL-12 are joined by a sequence encoding a 2A ribosomal skip. 
     
     
         74 . The method of  claim 72 , wherein the construct encodes SANT7 and a selectable marker, wherein the coding sequences for the selectable marker and SANT7 are joined by a sequence encoding a 2A ribosomal skip. 
     
     
         75 . The method of  claim 72 , wherein the construct encodes GAL3C and a selectable marker, wherein the coding sequences of the selectable marker and GAL3C are joined by a sequence encoding a ribosomal skip 
     
     
         76 . The method of  claim 74 , wherein the construct further encodes GAL3C and wherein the coding sequence for GAL3C is joined to the coding sequence of SANT7 in the construct via an additional 2A ribosomal skip. 
     
     
         77 . The method of  claim 73 , wherein the construct further encodes SANT7 and wherein the coding sequence for SANT7 is joined to the coding sequence for IL-12 in the construct via an additional coding sequence for a 2A ribosomal skip. 
     
     
         78 . The method of  claim 73 , wherein the construct further encodes GAL3C and wherein the coding sequence for GAL3C is joined to the coding sequence for IL-12 in the construct via an additional coding sequence for a 2A ribosomal skip. 
     
     
         79 . The method of  claim 78  wherein the construct further encodes SANT7 and wherein the coding sequence for each of IL-12, SANT7, GAL3C and the selectable marker are joined via a 2A ribosomal skip. 
     
     
         80 . A method of treating a KMA-expressing malignancy in a subject in need thereof comprising administering genetically modified T cells engineered to express one or more intracellular signaling domain and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes kappa myeloma antigen (KMA). 
     
     
         81 . The method of  claim 80 , wherein the KMA-expressing malignancy is multiple myeloma, Waldenstroms macroglobulinemia, diffuse large B cell lymphoma (DLBCL), or amyloidosis. 
     
     
         82 . The method of  claim 80 , wherein the one or more intracellular signaling domain comprises one or more co-stimulatory endodomains. 
     
     
         83 . The method of  claim 82 , wherein the one or more co-stimulatory endodomains is one or more of a CD28 domain, a CD3ζ domain, a 4-1BB domain or OX-40 domain or combinations thereof. 
     
     
         84 . The method of  claim 83 , wherein the co-stimulatory endodomains are a CD3ζ domain and a CD28 domain. 
     
     
         85 . The method of  claim 83 , wherein the co-stimulatory endodomains are a CD3ζ domain and an OX-40 domain. 
     
     
         86 . The method of  claim 84 , wherein the intracellular signaling domain further comprises an OX-40 domain. 
     
     
         87 . The method of  claim 83 , wherein the co-stimulatory endodomains are a CD3ζ domain and a 41-BB domain. 
     
     
         88 . The method of  claim 84 , further comprising a 41-BB domain. 
     
     
         89 . The method of  claim 80 , wherein the extracellular binding domain comprises a scFv that specifically recognizes KMA. 
     
     
         90 . The method of  claim 89 , wherein the scFv recognizes KMA and comprises the complementarity determining regions (CDRs) derived from the KappaMab monoclonal antibody, wherein the CDRs comprise SEQ ID NOs: 3-8. 
     
     
         91 . The method of  claim 89 , wherein the scFv comprises the VL chain and VH chain of the KappaMab monoclonal antibody, wherein the VL chain comprises SEQ ID NO: 2 and the VH chain comprises SEQ ID NO:1. 
     
     
         92 . The method of  claim 91 , wherein the VL of SEQ ID NO: 2 and VH of SEQ ID NO: 1 are attached via a glycine-serine linker. 
     
     
         93 . The method of  claim 92 , wherein the glycine-serine linker is a 15-20 amino acid linker. 
     
     
         94 . The method of  claim 93 , wherein the 15 amino acid linker comprises (Gly 4 Ser) 3 . 
     
     
         95 . The method of  claim 89 , wherein the scFv is attached to the one or more intracellular signaling domains via a spacer. 
     
     
         96 . The method of  claim 95 , wherein the spacer is an immunoglobulin constant region or a CD8a chain. 
     
     
         97 . The method of  claim 96 , wherein the immunoglobulin constant region comprises one or more of an IgG hinge domain, and IgG CH2 domain and an IgG CH3 domain. 
     
     
         98 . The method of  claim 97 , wherein the immunoglobulin constant region comprises an immunoglobulin hinge domain. 
     
     
         99 . The method of  claim 98 , wherein the immunoglobulin constant region further comprises an IgG CH3 domain. 
     
     
         100 . The method of  claim 98  or  99 , wherein the immunoglobulin constant region further comprises an IgG CH2 domain. 
     
     
         101 . The CAR of any one of  claims 96 - 100 , wherein the spacer is attached to the scFV via a glycine-serine linker. 
     
     
         102 . The CAR of  claim 101 , wherein the glycine-serine linker is a 15-20 amino acid linker. 
     
     
         103 . The CAR of  claim 102 , wherein the 15 amino acid linker comprises (Gly 4 Ser) 3 . 
     
     
         104 . The method of  claim 80 , wherein the genetically modified T cells are further engineered to express one or more additional biological molecules. 
     
     
         105 . The method of  claim 104 , wherein the one or more additional biological molecules comprises one or more of IL-12, GAL3C or SANT7. 
     
     
         106 . The method of  claim 104 , wherein the one or more additional biological molecules is IL-12 and said IL-12 is expressed as a single chain polypeptide comprising an IL-12 p35 subunit and an IL-12p40 subunit joined by a flexible linker. 
     
     
         107 . The method of  claim 106 , wherein the flexible linker is a (G 4 S) 3  linker. 
     
     
         108 . The method of  claim 106 , wherein the single chain polypeptide comprising an IL-12 p35 subunit and an IL-12p40 subunit joined by a flexible linker forms a bioactive p70 IL-12 heterodimer. 
     
     
         109 . The method of  claim 105 , wherein the CAR T-cells are engineered to express IL-12 and a selectable marker. 
     
     
         110 . The method of  claim 104 , wherein the CAR T-cells are engineered to express SANT7 and a selectable marker. 
     
     
         111 . The method of  claim 104 , wherein the CAR-T cells are engineered to express GAL3C and a selectable marker. 
     
     
         112 . The method of  claim 104 , wherein the CAR T-cells are engineered to express SANT7, IL-12 and a selectable marker. 
     
     
         113 . The method of  claim 104  wherein the CAR T-cells are engineered to express SANT7, GAL3C and a selectable marker. 
     
     
         114 . The method of  claim 104 , wherein the CAR T-cells are engineered to express IL-12, GAL3C and selectable marker. 
     
     
         115 . The method of  claim 104 , wherein the CAR T-cells are engineered to express IL-12, GAL3C, SANT7 and a selectable marker. 
     
     
         116 . The method of  claim 80 , further comprising administering one or more additional biologically or pharmaceutically active agents. 
     
     
         117 . The method of  claim 116 , wherein the one or more additional biologically active agents comprises IL-12, an IL-6 receptor antagonist or SANT7. 
     
     
         118 . The method of  claim 116 , wherein the additional pharmaceutically active agents comprise one or more chemotherapeutic agent. 
     
     
         119 . The method of  claim 116 , wherein the additional pharmaceutically active agent is an immunomodulatory drug. 
     
     
         120 . The method of  claim 119 , wherein the immunomodulatory drug is thalidomide or an analog thereof. 
     
     
         121 . The method of  claim 120 , wherein the thalidomide analog is actimid, lenalidomide or pomalidomide. 
     
     
         122 . The method of  claim 116 , wherein the additional pharmaceutical active agent is a histone deacetylase inhibitor. 
     
     
         123 . The method of  claim 122 , wherein the histone deacetylase inhibitor is panobinostat, vorinostat, trichostatin A, depsipeptides, phenylbutyrate, valproic acid, belinostat, LAQ824, entinostat, C1944, or mocetinostat. 
     
     
         124 . The method of  claim 116 , wherein the one or more additional biologically or pharmaceutically active agents is administered before, during or after treatment with the genetically modified T cells. 
     
     
         125 . The method of  claim 80 , wherein the genetically modified T cells are administered intravenously. 
     
     
         126 . The method of  claim 80 , wherein the genetically modified T cells are derived from the patient. 
     
     
         127 . The method of  claim 80 , wherein the genetically modified T cells are not derived from the patient. 
     
     
         128 . The genetically modified T cell of  claim 26  or  27  further engineered to express an HGF binding protein. 
     
     
         129 . The genetically modified T cell of  claim 128 , wherein the HGF binding protein is an HGF antibody or fragment thereof. 
     
     
         130 . The method of  claim 67  or  104 , wherein the one or more additional biological molecules is an HGF binding protein. 
     
     
         131 . The method of  claim 130 , wherein the HGF binding protein is an antibody or fragment thereof. 
     
     
         132 . The method of  claim 80  wherein the genetically modified T cells are administered before, during or after a stem cell transplant. 
     
     
         133 . The method of  claim 132 , wherein the stem cell transplant is an allogenic stem cell transplant. 
     
     
         134 . The method of  claim 132 , wherein the stem cell transplant is an allogeneic stem cell transplant.

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