IP Library › Granted Patent US 8,202,841

Granted Patent B2

US 8,202,841 · App. 11/156,253 · Granted Jun 19, 2012

SSX-2 peptide analogs

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Quick Facts

Patent No.: US 8,202,841
App. No.: 11/156,253
Granted: Jun 19, 2012
Kind: B2

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Abstract

Some embodiments relate to analogs of peptides corresponding to class I MHC-restricted T cell epitopes and methods for their generation. These analogs can contain amino acid substitutions at residues that directly interact with MHC molecules, and can confer improved, modified or useful immunologic properties. Additionally classes of analogs, in which the various substitutions comprise the non-standard residues norleucine and/or norvaline, are disclosed.

Claims (137)

1. An isolated peptide consisting essentially of the sequence:

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO 2 ), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}V{I, L, V, Nle, or Nva}XXX (SEQ ID NO. 151); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{I, Nva, MeVal, or Abu}XXX (SEQ ID NO. 152); or

XXX{F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 153); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{L, V, I, M, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 154); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys} {A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 155); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys} {A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 156); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys} {A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 157);

wherein X specifies any amino acid or no amino acid.

2. The isolated peptide of claim 1 consisting essentially of the sequence:

K{L, V, M, I, D-Val, Nal-2, Aib, Abu, Nle, or Nva}SEKIFYV (SEQ ID NO. 116); or

{F, Phg, Y, Phe(4-F), Phe(4-NO 2 ), O-methyl-Tyr, or β-(3-benzothienyl-Ala}ASEKIFYV (SEQ ID NO. 117); or

{Y, F, or W}{V, M, or I}SEKIFYV (SEQ ID NO. 118); or

{F or W}LSEKIFYV (SEQ ID NO. 119); or

K{A, V, or L}SEKIFYI (SEQ ID NO. 120); or

K{L or V}SEKIFYV-NH 2 (SEQ ID NO. 121); or

FVSEKIFY{I, A, Nva, Abu, or MeVal} (SEQ ID NO. 122); or

FVS{Q, Nle, Nva}KIFYV (SEQ ID NO. 123); or

FVSEK{L, V, Nle, or Nva}FYV (SEQ ID NO. 124); or

FVSEKIF{F, Phe(4-F)}V (SEQ ID NO. 125); or

KASEKIFYV{I, L,} (SEQ ID NO. 126); or

KVSEKIFYV {I, L, V, or Nle} (SEQ ID NO. 127); or

KLSEKIFYV {L, V, Nle, or Nva} (SEQ ID NO. 128).

3. The isolated peptide of claim 2 consisting essentially of the sequence:

K{L, V, M, Abu, Nle, or Nva} SEKIFYV (SEQ ID NO. 129); or

{F or Phg}A SEKIFYV (SEQ ID NO. 130); or

YVSEKIFYV (SEQ ID NO. 131); or

F{L, V, or I}SEKIFYV (SEQ ID NO. 132); or

W{L or I}SEKIFYV (SEQ ID NO. 133); or

K{V or L}SEKIFYI (SEQ ID NO. 134); or

FVSEKIFY{I or Nva} (SEQ ID NO. 135).

4. The isolated peptide of claim 3 consisting essentially of the sequence:

K{V or L}SEKIFYV (SEQ ID NO. 136); or

{F or Y}ASEKIFYV (SEQ ID NO. 137); or

FVSEKIFYI (SEQ ID NO. 138); or

KVSEKIFYV (SEQ ID NO. 139).

5. The isolated peptide of claim 3 , consisting essentially of the sequence KVSEKIFYV (SEQ ID NO. 139).

6. The isolated peptide of claim 1 , wherein the peptide has affinity for a class I MHC peptide binding cleft.

7. The isolated peptide of claim 6 wherein the class I MHC is HLA-A2.

8. A class I MHC/peptide complex wherein the peptide has the sequence of the peptide of claim 1 and is complexed with the MHC protein.

9. The class I MHC/peptide complex of claim 8 that is cross-reactive with a TCR that recognizes a class I MHC/SSX-2 41-49 complex.

10. The class I MHC/peptide complex of claim 9 wherein the class I MHC/complex is an HLA-A2/SSX-2 41-49 complex.

11. A polypeptide comprising the peptide sequence of claim 1 in association with a liberation sequence.

12. An immunogenic composition comprising the peptide of claim 1 .

13. An immunogenic composition comprising the polypeptide of claim 11 .

14. An isolated peptide comprising the sequence:

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{I, Nva, MeVal, or Abu}XXX (SEQ ID NO. 152); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 155); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys} {A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 157);

wherein X specifies any amino acid or no amino acid.

15. The isolated of claim 14 comprising the sequence:

K{L, V, M, I, D-Val, Nal-2, Aib, Abu, Nle, or Nva}SEKIFYV (SEQ ID NO. 116); or

{F, Phg, Y, Phe(4-F), Phe(4-NO 2 ), O-methyl-Tyr, or β-(3-benzothienyl-Ala}ASEKIFYV (SEQ ID NO. 117); or

{Y, F, or W}{V, M, or I}SEKIFYV (SEQ ID NO. 118); or

{F or W}LSEKIFYV (SEQ ID NO. 119); or

K{A, V, or L}SEKIFYI (SEQ ID NO. 120); or

K{L or V}SEKIFYV-NH 2 (SEQ ID NO. 121); or

FVSEKIFY{I, A, Nva, Abu, or MeVal} (SEQ ID NO. 122); or

FVS{Q, Nle, Nva}KIFYV (SEQ ID NO. 123); or

FVSEK{L, V, Nle, or Nva}FYV (SEQ ID NO. 124); or

FVSEKIF{F, Phe(4-F)}V (SEQ ID NO. 125); or

KASEKIFYV{I, L,} (SEQ ID NO. 126); or

KVSEKIFYV {I, L, V, or Nle} (SEQ ID NO. 127); or

KLSEKIFYV {L, V, Nle, or Nva} (SEQ ID NO. 128).

16. The isolated peptide of claim 15 comprising the sequence:

K{L, V, M, Abu, Nle, or Nva} SEKIFYV (SEQ ID NO. 129); or

{F or Phg}A SEKIFYV (SEQ ID NO. 130); or

YVSEKIFYV (SEQ ID NO. 131); or

F{L, V, or I}SEKIFYV (SEQ ID NO. 132); or

W{L or I}SEKIFYV (SEQ ID NO. 133); or

K{V or L}SEKIFYI (SEQ ID NO. 134); or

FVSEKIFY{I or Nva} (SEQ ID NO. 135).

17. The isolated peptide of claim 16 comprising the sequence:

K{V or L}SEKIFYV (SEQ ID NO. 136); or

{F or Y}ASEKIFYV (SEQ ID NO. 137); or

FVSEKIFYI (SEQ ID NO. 138); or

KVSEKIFYV (SEQ ID NO. 3).

18. The isolated peptide of claim 17 comprising the sequence KVSEKIFYV (SEQ ID NO. 3).

19. The isolated peptide of claim 14 , wherein the peptide has affinity for a class I MHC peptide binding cleft.

20. The isolated peptide of claim 19 wherein the class I MHC is HLA-A2.

21. A class I MHC/peptide complex wherein the peptide has the sequence of the peptide of claim 14 and is complexed with the MHC protein.

22. The class I MHC/peptide complex of claim 21 that is cross-reactive with a TCR that recognizes a class I MHC/SSX-2 41-49 complex.

23. The class I MHC/peptide complex of claim 22 wherein the class I MHC/complex is an HLA-A2/SSX-2 41-49 complex.

24. A polypeptide comprising the peptide sequence of claim 14 , in association with a liberation sequence.

25. An immunogenic composition comprising the peptide of claim 14 .

26. An immunogenic composition comprising the polypeptide of claim 24 .

27. The isolated peptide of claim 14 consisting of the sequence:

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys}{A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{Y, F, Phe(4-F)}{I, Nva, MeVal, or Abu}XXX (SEQ ID NO. 152); or

XXX{K, F, Y, W, Phg, Phe(4-F), Phe(4-NO2), MeTyr, β-(3-benzothienyl)-Ala, or D-Lys} {A, L, V, I, M, D-Ala, Nal-2, Abu, Aib, Nle, or Nva}S{E, Q, Nle, or Nva}K{I, L, V, Nle, or Nva}F{F, Phe(4-F)}{V, A, I, Nva, MeVal, Abu, or V-NH2}XXX (SEQ ID NO. 157);

wherein X specifies any amino acid or no amino acid.

28. The isolated of claim 27 consisting of the sequence:

K{L, V, M, I, D-Val, Nal-2, Aib, Abu, Nle, or Nva}SEKIFYV (SEQ ID NO. 116); or

{F, Phg, Y, Phe(4-F), Phe(4-NO 2 ), O-methyl-Tyr, or β-(3-benzothienyl-Ala}ASEKIFYV (SEQ ID NO. 117); or

{Y, F, or W}{V, M, or I}SEKIFYV (SEQ ID NO. 118); or

{F or W}LSEKIFYV (SEQ ID NO. 119); or

K{A, V, or L}SEKIFYI (SEQ ID NO. 120); or

K{L or V}SEKIFYV-NH 2 (SEQ ID NO. 121); or

FVSEKIFY{I, A, Nva, Abu, or MeVal} (SEQ ID NO. 122); or

FVS{Q, Nle, Nva}KIFYV (SEQ ID NO. 123); or

FVSEK{L, V, Nle, or Nva}FYV (SEQ ID NO. 124); or

FVSEKIF{F, Phe(4-F)}V (SEQ ID NO. 125); or

KASEKIFYV{I, L,} (SEQ ID NO. 126); or

KVSEKIFYV {I, L, V, or Nle} (SEQ ID NO. 127); or

KLSEKIFYV {L, V, Nle, or Nva} (SEQ ID NO. 128).

29. The isolated peptide of claim 28 consisting of the sequence:

K{L, V, M, Abu, Nle, or Nva} SEKIFYV (SEQ ID NO. 129); or

{F or Phg}A SEKIFYV (SEQ ID NO. 130); or

YVSEKIFYV (SEQ ID NO. 131); or

F{L, V, or I}SEKIFYV (SEQ ID NO. 132); or

W{L or I}SEKIFYV (SEQ ID NO. 133); or

K{V or L}SEKIFYI (SEQ ID NO. 134); or

FVSEKIFY{I or Nva} (SEQ ID NO. 135).

30. The isolated peptide of claim 29 consisting of the sequence:

K{V or L}SEKIFYV (SEQ ID NO. 136); or

{F or Y}ASEKIFYV (SEQ ID NO. 137); or

FVSEKIFYI (SEQ ID NO. 138); or

KVSEKIFYV (SEQ ID NO. 3).

31. The isolated peptide of claim 30 consisting of the sequence KVSEKIFYV (SEQ ID NO. 3).

32. The isolated peptide of claim 27 , wherein the peptide has affinity for a class I MHC peptide binding cleft.

33. The isolated peptide of claim 32 wherein the class I MHC is HLA-A2.

34. A class I MHC/peptide complex wherein the peptide has the sequence of the peptide of claim 27 and is complexed with the MHC protein.

35. The class I MHC/peptide complex of claim 34 that is cross-reactive with a TCR that recognizes a class I MHC/SSX-2 41-49 complex.

36. The class I MHC/peptide complex of claim 35 wherein the class I MHC/complex is an HLA-A2/SSX-2 41-49 complex.

37. A polypeptide comprising the peptide sequence of claim 27 , in association with a liberation sequence.

38. An immunogenic composition comprising the peptide of claim 27 .

39. An immunogenic composition comprising the polypeptide of claim 37 .

40. A method of inducing, maintaining, or amplifying a CTL response comprising intranodal administration of the composition of claim 12 .

41. A method of entraining a class I MHC-restricted T cell response comprising intranodal administration of the composition of claim 12 plus an immunopotentiating agent.

Assignments (4)

RELEASE OF SECURITY INTEREST Recorded Apr 5, 2024

From: MIDCAP FINANCIAL TRUST, AS AGENT

To: MANNKIND CORPORATION; MANNKIND LLC

Reel/Frame 067024/0082 →

RELEASE OF SECURITY INTEREST Recorded Aug 13, 2019

From: DEERFIELD PRIVATE DESIGN FUND II, L.P.; DEERFIELD PRIVATE DESIGN INTERNATIONAL II, L.P.; HORIZON SANTE FLML SARL

To: MANNKIND CORPORATION

Reel/Frame 050044/0138 →

SECURITY INTEREST Recorded Aug 13, 2019

From: MANNKIND CORPORATION; MANNKIND LLC

To: MIDCAP FINANCIAL TRUST, AS AGENT

Reel/Frame 050044/0181 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2005

From: LIU, LIPING; XIE, ZHIDONG; DIAMOND, DAVID C.

To: MANNKIND CORPORATION

Reel/Frame 017019/0846 →