COMPOSITIONS AND METHODS OF IDENTIFYING TUMOR SPECIFIC NEOANTIGENS
First Claim
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1. A method of identifying a neoantigen comprising:
- a. identifying a tumor specific mutation in an expressed gene of a subject having cancer;
b. wherein when said mutation identified in step (a) is a point mutation;
i. identifying a mutant peptide having the mutation identified in step (a), wherein said mutant peptide binds to a class I HLA protein with a greater affinity than a wild-type peptide; and
has an 1050 less than 500 nm;
c. wherein when said mutation identified in step (a) is a splice-site, frameshift, read-through or gene-fusion mutation;
i. identifying a mutant polypeptide encoded by the mutation identified in step (a), wherein said mutant polypeptide binds to a class I HLA protein.
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Abstract
The present invention related to immunotherapeutic peptides and their use in immunotherapy, in particular the immunotherapy of cancer. Specifically, the invention provides a method of identifying tumor specific neoantigens that alone or in combination with other tumor-associated peptides serve as active pharmaceutical ingredients of vaccine compositions which stimulate anti-tumor responses.
60 Citations
39 Claims
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1. A method of identifying a neoantigen comprising:
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a. identifying a tumor specific mutation in an expressed gene of a subject having cancer; b. wherein when said mutation identified in step (a) is a point mutation; i. identifying a mutant peptide having the mutation identified in step (a), wherein said mutant peptide binds to a class I HLA protein with a greater affinity than a wild-type peptide; and
has an 1050 less than 500 nm;c. wherein when said mutation identified in step (a) is a splice-site, frameshift, read-through or gene-fusion mutation; i. identifying a mutant polypeptide encoded by the mutation identified in step (a), wherein said mutant polypeptide binds to a class I HLA protein. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 35)
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22. A method of vaccinating or treating a subject for cancer comprising:
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a. identifying a plurality of tumor specific mutations in an expressed gene of the subject wherein when said mutation identified is a; i. point mutation further identifying a mutant peptide having the point mutation; and
/orii. splice-site, frameshift, read-through or gene-fusion mutation further identifying a mutant polypeptide encoded by the mutation; b. selecting one or more mutant peptides or polypeptides identified in step (a) that binds to a class I HLA protein; c. selecting the one or more mutant peptides or polypeptides identified in step (b) that is capable of activating anti-tumor CD8 T-cells; and d. administering to the subject the one or more peptides or polypeptides, autologous dendritic cells or antigen presenting cells pulsed with the one or more peptides or polypeptides selected in step (c). - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)
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36. A composition comprising at least two distinct:
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a. SF3B1 peptides wherein each peptide is equal to or less than 50 amino acids in length and contains i. a leucine at amino acid position 625; ii. a histidine at amino acid position 626; iii. a glutamic acid at amino acid position 700; iv. an aspartic acid at amino acid position 742;
orv. an arginine at amino acid position 903, when numbered in accordance with wild-type SF3B1; b. MYD88 peptides wherein each peptide is equal to or less than 50 amino acids in length and contains i. a threonine at amino acid position 232; ii. a leucine at amino acid position 258;
oriii. a proline at amino acid position 265, when numbered in accordance with wild-type MYD88; c. TP53 peptides wherein each peptide is equal to or less than 50 amino acids in length and contains i. an arginine at amino acid position 111; ii. an arginine at amino acid position 215; iii. a serine at amino acid position 238; iv. a glutamine at amino acid position 248; v. a phenylalanine at amino acid position 255; vi. a cysteine at amino acid position 273 or vii. an asparagine at amino acid position 281, when numbered in accordance with wild-type TP53; d. ATM peptides wherein each peptide is equal to or less than 50 amino acids in length and contains i. a phenylalanine at amino acid position 1252; ii. an arginine at amino acid position 2038; iii. a histidine at amino acid position 2522;
oriv. a cysteine at amino acid position 2954, when numbered in accordance with wild-type ATM; e. abl peptides wherein each peptide is equal to or less than 50 amino acids in length and contains i. a valine at amino acid position 244; ii. a valine at amino acid position 248; iii. a glutamic acid at amino acid position 250; iv. an alanine at amino acid position 250; v. a histidine at amino acid position 252; vi. an arginine at amino acid position 252; vii. a phenylalanine at amino acid position 253; viii. a histidine at amino acid position 253; ix. a lysine at amino acid position 255; x. a valine at amino acid position 255; xi. a glycine at amino acid position 276; xii. an isoleucine at amino acid position 315; xiii. an asparagine at amino acid position 315; xiv. a leucine at amino acid position 317; xv. a threonine at amino acid position 343; xvi. a threonine at amino acid position 351; xvii. a glycine at amino acid position 355; xviii. a valine at amino acid position 359; xix. an alanine at amino acid position 359; xx. an isoleucine at amino acid position 379; xxi. a leucine at amino acid position 382; xxii. a methionine at amino acid position 387; xxiii. a proline at amino acid position 396; xxiv. an arginine at amino acid position 396; xxv. a tyrosine at amino acid position 417;
orxxvi. a serine at amino acid position 486, when numbered in accordance with wild-type abl; f. FBXW7 peptides wherein each peptide is equal to or less than 50 amino acids in length and contains; i. a leucine at amino acid position 280; ii. a histidine at amino acid position 465; iii. a cysteine at amino acid position 505;
oriv. a glutamic acid at amino acid position 597, when numbered in accordance with wild-type FBXW7; g. MAPK1 peptides wherein each peptide is equal to or less than 50 amino acids in length and contains i. an asparagine at amino acid position 162; ii. a glycine at amino acid position 291;
oriii. a phenylalanine at amino acid position 316, when numbered in accordance with wild-type MAPK1;
orh. GNB1 peptides wherein each peptide is equal to or less than 50 amino acids in length and contains a threonine at amino acid position 180, when numbered in accordance with wild-type GNB1. - View Dependent Claims (37)
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38. A method of treating a subject with an imatinib resistant tumor comprising administering to a HLA-A3 positive subject a composition a Bcr-abl peptide equal to or less than 50 amino acid in length that contains a lysine at position 255 when numbered in accordance with wild-type bcr-abl.
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39. A method of treating a subject with an imatinib resistant tumor comprising administering to said subject one or more peptides containing a bcr-abl mutation wherein said peptide is equal to or less than 50 amino acid and binds to a class I HLA protein with an 1050 less than 500 nm.
Specification