Granted Patent B2

US 12,246,067 · App. 17/254,128 · Granted Mar 11, 2025

Inventor: Vikram Juneja (Waltham, MA)

Assignee: BioNTech US Inc.

A61K47/20A61K39/001164A61K39/4611A61K39/4632A61K39/464401A61K39/464464A61K45/06A61K47/26C07K14/62C12N5/0638A61K38/00A61K2039/55511A61K2039/575A61K2039/645

Abstract

Claims (108)

1. A composition comprising T cells specific to an HLA-peptide complex comprising at least one mutant RAS peptide sequence, wherein the HLA-peptide complex comprises a protein encoded by an HLA-C03:04 allele, and the at least one mutant RAS peptide sequence consists of

(SEQ ID NO: 2064)

GAVGVGKSA.

2. The composition of claim 1 , wherein the composition comprises:

(i) T cells specific to a first HLA-peptide complex comprising a first mutant RAS peptide sequence, wherein the first HLA-peptide complex comprises the protein encoded by the HLA-C03:04 allele and the first mutant RAS peptide sequence consists of GAVGVGKSA (SEQ ID NO: 2064); and

(ii) T cells specific to a second HLA-peptide complex comprising a second mutant RAS peptide sequence selected from the group consisting of

(SEQ ID NO: 2034)

VVVGAVGVGK, 

(SEQ ID NO: 2028)

VVGAVGVGK, 

(SEQ ID NO: 2032)

GAVGVGKSAL,

(SEQ ID NO: 1918)

VVVGADGVGK, 

(SEQ ID NO: 1950)

VVVGARGVGK, 

(SEQ ID NO: 1875)

VVVGACGVGK, 

(SEQ ID NO: 2044)

AVGVGKSAL,

(SEQ ID NO: 1900)

GADGVGKSAL

and

(SEQ ID NO: 1913)

GADGVGKSA.

3. A method of preparing the composition of claim 1 , comprising priming T cells with antigen presenting cells (APCs) comprising

(i) a polypeptide comprising the at least one mutant RAS peptide sequence, wherein

the polypeptide has the formula (Xaa N ) N -(Xaa RAS ) P -(Xaa C ) C ;

wherein (Xaa RAS ) P comprises the at least one mutant RAS peptide sequence;

N is (i) 0 or (ii) an integer greater than 2 and less than 100;

(Xaa N ) N is any amino acid sequence heterologous to the mutant RAS protein;

C is (i) 0 or (ii) an integer greater than 2 and less than 100;

(Xaa C ) C is any amino acid sequence heterologous to the mutant RAS protein;

P is an integer greater than 7;

wherein the polypeptide is not

 (SEQ ID NO: 20)

KLVVVGAVGVGKSALTIQL;

and wherein if N is 0 C is not 0 and if C is 0 N is not 0;

or

(ii) at least one polynucleotide encoding the polypeptide of (i).

4. The method of claim 3 , wherein C is 0.

5. The method of claim 3 , wherein (Xaa N ) N is a polylysine sequence.

6. The method of claim 3 , wherein N is an integer less than 50.

7. The method of claim 6 , wherein N is 2, 3, 4, 5, or 6.

8. The method of claim 3 , wherein the T cells and the APCs are autologous to a subject with a cancer, wherein the cancer cells express the at least one mutant RAS peptide sequence.

9. The method of claim 3 , further comprising priming the T cells with APCs in the presence of one or more additional mutant RAS peptide sequences, wherein the one or more additional mutant RAS peptide sequences comprises an amino acid sequence of

(SEQ ID NO: 2034)

VVVGAVGVGK,

(SEQ ID NO: 2028)

VVGAVGVGK,

(SEQ ID NO: 2032)

GAVGVGKSAL,

(SEQ ID NO: 2044)

AVGVGKSAL,

(SEQ ID NO: 1918)

VVVGADGVGK,

(SEQ ID NO: 1900)

GADGVGKSAL,

(SEQ ID NO: 1913)

GADGVGKSA,

(SEQ ID NO: 1950)

VVVGARGVGK,

or

(SEQ ID NO: 1875)

VVVGACGVGK.

10. The method of claim 3 , wherein the polypeptide comprises an amino acid sequence of

(SEQ ID NO: 191)

GKSALTIQL

or

(SEQ ID NO: 192)

GKSALTI.

11. The method of claim 3 , wherein the APCs and the T cells are from a peripheral blood mononuclear cell (PBMC) sample of a human subject.

12. A pharmaceutical composition comprising (i) the composition of claim 1 ; and (ii) a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 , wherein the T cells comprise CD4+ and CD8+ T cells.

14. A method of preparing the composition of claim 2 , the method comprising priming T cells with antigen presenting cells (APCs) comprising: (i) (a) the first mutant RAS peptide sequence; and (i) (b) the second mutant RAS peptide sequence or (ii) APCs comprising one or more polynucleotides encoding the first mutant peptide sequence and the second mutant peptide sequence; wherein:

(a) the APCs express a protein encoded by an HLA-A03:01 or HLA-A30:01 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 2034)

VVVGAVGVGK;

(b) the APCs express a protein encoded by an HLA-A30:01 or HLA-A68:01 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 2028)

VVGAVGVGK;

(c) the APCs express a protein encoded by an HLA-C03:03, or HLA-C03:04 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 2032)

GAVGVGKSAL;

(d) the APCs express a protein encoded by an HLA-A03:01 or HLA-A68:01 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 1918)

VVVGADGVGK;

(e) the APCs express a protein encoded by an HLA-A03:01, HLA-A30:01 or HLA-A68:01 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 1950)

VVVGARGVGK;

(f) the APCs express a protein encoded by an HLA-A03:01 or HLA-A68:01 allele and the second mutant RAS peptide sequence comprise:

(SEQ ID NO: 1875)

VVVGACGVGK;

(g) the APCs express a protein encoded by an HLA-C01:02 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 2044)

AVGVGKSAL;

or

(h) the APCs express a protein encoded by an HLA-C08:02 allele and the second mutant RAS peptide sequence comprises

(SEQ ID NO: 1900)

GADGVGKSAL 

or

(SEQ ID NO: 1913)

GADGVGKSA.

15. The method of claim 3 , wherein the at least one polynucleotide encoding the polypeptide is RNA.

16. The method of claim 3 , wherein the T cells are from a human subject with a cancer that expresses the at least one mutant RAS peptide sequence and wherein the human subject's genome comprises an HLA-allele encoding the HLA protein of the HLA-peptide complex.

17. A method of treating a human subject with a cancer comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 12 .

18. The method of claim 17 , wherein the cancer is a KRAS-mutated cancer selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.

19. The method of claim 3 , wherein the APCs express a protein encoded by the HLA-C03:04 allele.

Assignments (2)

Continuity (3)

References Cited (400)