Glycan-dependent Immunotherapeutic Molecules

Abstract

The present invention relates to compositions and methods for treating cancer. The invention makes use of peptides, nucleic acids encoding such peptides, and cells expressing such peptides, where the peptide comprises a tumor-associated carbohydrate antigen (TACA)-binding domain.

What is claimed is: 
     
         1 . A composition comprising at least one selected from the group consisting of:
 a) a peptide comprising a tumor-associated carbohydrate antigen (TACA)-binding domain derived from a lectin, and an immune cell recognition domain that specifically binds to a receptor on an immune effector cell; and   b) an isolated nucleic acid molecule encoding a peptide, wherein the peptide comprises a TACA-binding domain derived from a lectin, and an immune cell recognition domain that specifically binds to a receptor on an immune effector cell,
 wherein the TACA-binding domain specifically binds to a TACA of a tumor cell, 
 wherein the TACA of the tumor cell is selected from the group consisting of β1, 6 branching, T antigen, sialyl-T epitopes, Tn epitopes, sialyl-Tn epitopes, α2, 6 sialylation, Sialylation, sialyl-Lewis x/a , di-sialyl-Lewis x/a  sialyl 6-sulfo Lexis x , Globo H, GD2, GD3, GM3, and Fucosyl GM1, and 
 wherein the immune effector cell is selected from the group consisting of T cells, natural killer (NK) cells, natural killer T (NKT) cells, macrophages, monocytes, dendritic cells, and neutrophils. 
   
     
     
         2 . The composition of  claim 1 , wherein the TACA of the tumor cell is β1,6GlcNAc-branched N-glycans of a tumor cell. 
     
     
         3 . The composition of  claim 1 , wherein the peptide is an Fc fusion peptide comprising the TACA-biding domain linked to an Fc domain. 
     
     
         4 . The composition of  claim 1 , wherein the immune cell recognition domain comprises a T-cell-binding domain, where the T-cell-binding domain specifically binds to a T-cell. 
     
     
         5 . The composition of  claim 4 , wherein the T-cell-binding domain binds to at least one of the group consisting of CD3, T-cell receptor, CD2, CD28, and CD25. 
     
     
         6 . The composition of  claim 6 , wherein the T-cell binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9 and an amino acid sequence having greater than about 90% homology to SEQ ID NO: 9. 
     
     
         7 . The composition of  claim 1 , wherein the immune cell recognition domain comprises a NK-cell-binding domain, where the NK-cell-binding domain specifically binds to a NK-cell. 
     
     
         8 . The composition of  claim 7 , wherein the NK-cell-binding domain binds to at least one of the group consisting of CD16 and NKG2D. 
     
     
         9 . An isolated nucleic acid molecule encoding an immunotherapeutic molecule comprising a tumor-associated carbohydrate antigen (TACA)-binding domain derived from a lectin;
 wherein the immunotherapeutic molecule is:
 (i) a fusion protein comprising a tumor-associated carbohydrate antigen (TACA)-binding domain derived from a lectin and a domain that specifically binds to an immune effector cell; or 
 (ii) a chimeric antigen receptor (CAR) comprising an antigen recognition domain that comprises the TACA-binding domain derived from a lectin, a transmembrane domain, and an intracellular signaling domain; 
 wherein the TACA-binding domain specifically binds to a TACA of a tumor cell; and 
 wherein the lectin is selected from the group consisting of a galectin, a siglec, a selectin; a C-type lectin; CD301, L-PHA ( Phaseolus vulgaris  leukoagglutinin); E-PHA ( Phaseolus vulgaris  erythroagglutinen); tomato lectin ( Lycopersicon esculentum  lectin; LEA); peanut lectin ( Arachis hypogaea  Agglutinin; PNA); potato lectin ( Solanum tuberosum  lectin), pokeweek mitogen ( Phytolacca  American lectin), wheat germ agglutinin ( Triticum  Vulgaris lectin);  Artocarpus polyphemus  lectin (Jacalin letin);  Vicia villosa  Agglutinin (VVA);  Helix pomatia  Agglutinin (HPA);  Wisteria floribunda  Agglutinin (WFA);  Sambucus nigra  Agglutinin (SNA), BC2LCM (lectin from the gram negative bacteria  Burkholderia cenocepacia ),  Maackia amurensis  leukoagglutinin (MAL),  Psathyrella velutina  (PVL),  Sclerotium rolfsii  lectin (SRL),  Eucheuma serra  agglutinin (ESA), CLEC17A (Prolectin),  Aleuria aurantia  lectin,  Sambucus sieboldiana  lectin (SSA),  Glechoma hederacea  lectin (Gleheda),  Morus nigra  agglutinin (Morniga G),  Salvia sclarea  lectin,  Salvia bogotensis  lectin,  Salvia horminum  lectin,  Clerodendrum trichotomum  lectin,  Moluccella laevis  lectin,  Griffonia simplicifolia  (GsLA4),  Psophocarpus tetragonolobus  (acidic WBAI),  Abrus precatorius  lectin,  Molucella laevis  lectin (MLL),  Amaranthus caudatus  lectin,  Amaranthus leucocarpus  lectin,  Laelia autumnalis  lectin,  Artocarpus integrifolia  lectin,  Maclura pomifera  lectin,  Artocarpus lakoocha  lectin,  Dolichos biflorusagglutinin, Dolichos biflorus  lectin,  Glycine max  lectin, and  Agaricus bisporus  lectin. 
   
     
     
         10 . The isolated nucleic acid molecule of  claim 9 , wherein the galectin is selected from the group consisting of galectin-1, galectin-2, galectin-3, galectin-4, galectin-5, galectin-6, galectin-7, galectin-8, galectin-9, galectin-10, galectin-11, galectin-12, galectin-13, galectin-14 and galectin-15. 
     
     
         11 . The isolated nucleic acid molecule of  claim 9 , wherein the siglec is selected from the group consisting of siglec-1 (sialoadhesion), siglec-2 (CD22), siglec-3 (CD33), siglec-4 (myelin associated glycoprotein), siglec-5, siglec-6, siglec-7, siglec-8, siglec-9, siglec-10, siglec-11, siglec-12, siglec-13, siglec-14, siglec-15, siglec-16, siglec-17, Siglec E, Siglec F, siglec G and siglec H. 
     
     
         12 . The isolated nucleic acid molecule of  claim 9 , wherein the TACA-binding domain binds to a TACA selected from the group consisting of β1, 6 branching, T antigen, sialyl-T epitopes, Tn epitopes, sialyl-Tn epitopes, α2, 6 sialylation, Sialylation, sialyl-Lewis x/a  sialyl 6-sulfo Lexis x , Globo H, GD2, GD3, GM3, and Fucosyl GM1. 
     
     
         13 . The isolated nucleic acid molecule of  claim 9 , wherein the TACA-binding domain binds to β1,6GlcNAc-branched N-glycans of a tumor cell. 
     
     
         14 . The isolated nucleic acid molecule of  claim 9 , wherein:
 (i) the TACA of the tumor cell is a β1,6GlcNAc-branched N-glycan-modified protein of a tumor cell and the TACA-binding domain is derived from L-PHA;   (ii) the TACA of the tumor cell is a Tn epitope-modified protein of a tumor cell and the TACA-binding domain is derived from  Vicia villosa  Agglutinin (VVA) or CD301;   (iii) the TACA of the tumor cell is a sialyl-Tn epitope-modified protein of a tumor cell and the TACA-binding domain is derived from CD301, the extracellular domain of siglec 1-17, or the extracellular domain of a galectin 1-15;   (iv) the TACA of the tumor cell is a GD2-modified protein of a tumor cell and the TACA-binding domain is derived from CD301;   (v) the TACA of the tumor cell is a β1, 6 branching-, a Sialylation-, a GM3-, or a di-sialyl-Lewis x/a -modified protein of a tumor cell and the TACA-binding domain is derived from the extracellular domain of siglec 1-17;   (vi) the TACA of the tumor cell is a β1, 6 branching on N-glycan-modified protein of a tumor cell and the TACA-binding domain is derived from  Lycopersicon esculentumlectin  (LEA), the extracellular domain of a siglec 1-17, or the extracellular domain of a galectin 1-15;   (vii) the TACA of the tumor cell is a T antigen-modified protein or lipid of a tumor cell and the TACA-binding domain is derived from the extracellular domain of galectin 1-15; or   (viii) the TACA of the tumor cell is a Globo H-modified protein of a tumor cell and the TACA-binding domain is derived from the extracellular domain of a siglec 1-17 or the extracellular domain of a galectin 1-15.   
     
     
         15 . The isolated nucleic acid molecule of  claim 9 , wherein the TACA-binding domain comprises an amino acid sequence:
 (a) having at least 90% homology to SEQ ID NO: 1, 2, 3, 4, 5, 6, or 7; or   (b) selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7.   
     
     
         16 . The isolated nucleic acid molecule of  claim 9 , wherein the fusion protein is:
 (a) is an Fc fusion protein comprising the TACA-biding domain and a domain that specifically binds to the immune effector cell linked to an Fc domain; or   (b) comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 11, an amino acid sequence having at least 90% homology to SEQ ID NO: 11, SEQ ID NO: 12, an amino acid sequence having at least 90% homology to SEQ ID NO: 12, SEQ ID NO: 13, an amino acid sequence having at least 90% homology to SEQ ID NO: 13, SEQ ID NO: 14, an amino acid sequence having at least-90% homology to SEQ ID NO: 14, SEQ ID NO: 15, an amino acid sequence having at least 90% homology to SEQ ID NO: 15, SEQ ID NO: 16, an amino acid sequence having at least 90% homology to SEQ ID NO: 16, SEQ ID NO: 17, and an amino acid sequence having at least 90% homology to SEQ ID NO: 17.   
     
     
         17 . The isolated nucleic acid molecule of  claim 9 , wherein the T-cell-binding domain:
 (a) binds to CD3, a T-cell receptor, CD2, CD28, or CD25; or   (b) comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9 and an amino acid sequence having at least 90% homology to SEQ ID NO: 9.   
     
     
         18 . A recombinant cell comprising the composition of  claim 1 . 
     
     
         19 . A recombinant cell comprising the isolated nucleic acid molecule of  claim 9 . 
     
     
         20 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the recombinant cell of  claim 19 .