IP Library Patent Application 14343435
Patent Application
App. No. 14/343,435

NANOPARTICLE TUMOUR VACCINES

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Patent No.
US None
App. No.
14/343,435
Abstract

The present invention provides a vaccine for the prophylactic or therapeutic treatment of a tumour in a mammalian subject, as well as methods of using the vaccine, including in treatment of tumours and in generating a CTL response. The vaccine comprises a plurality of nanoparticles and a pharmaceutically acceptable carrier, salt or diluents. The nanoparticles comprise a core comprising a metal and/or a semiconductor atom; and a corona comprising a plurality of ligands covalently linked to the core, wherein at least a first ligand of said plurality comprises a carbohydrate moiety that is covalently linked to the core via a first linker, and wherein at least a second ligand of said plurality comprises an epitopic peptide that is covalently linked to the core via a second linker, said second linker comprising a peptide portion and a non-peptide portion, wherein said peptide portion comprises the sequence X 1 X 2 Z 1 , wherein X 1 is an amino acid selected from A and G; X 2 is an amino acid selected from A and G; and Z 1 is an amino acid selected from Y and F, and wherein said epitopic peptide forms at least a portion of or is derived from a Tumour-Associated Antigen (TAA).

Claims (108)

4 . The vaccine according to claim 1 , wherein said peptide portion of said second linker comprises or consists of an amino acid sequence selected from:

(i) AAY;

and

(SEQ ID NO: 91)

(ii) FLAAY.

5 . The vaccine according to claim 1 , wherein said second linker is selected from the group consisting of:

(i) HS—(CH 2 ) 2 —CONH-AAY;

(ii) HS—(CH 2 ) 2 —CONH-FLAAY;

(iii) HS—(CH 2 ) 3 —CONH-AAY;

(iv) HS—(CH 2 ) 3 —CONH-FLAAY;

(v) HS—(CH 2 ) 10 —(CH 2 OCH 2 ) 7 —CONH-AAY; and

(vi) HS—(CH 2 ) 10 —(CH 2 OCH 2 ) 7 —CONH-FLAAY,

wherein said second linker is covalently linked to said core via the thiol group of the non-peptide portion of the linker.

6 . The vaccine according to claim 1 , wherein said epitopic peptide is linked via its N-terminus to said peptide portion of said second linker.

7 . The vaccine according to claim 6 , wherein said second ligand is selected from the group consisting of:

(i) HS—(CH 2 ) 2 —CONH-AAYZ 2 ;

(ii) HS—(CH 2 ) 2 —CONH-FLAAYZ 2 ;

(iii) HS—(CH 2 ) 3 —CONH-AAYZ 2 ;

(iv) HS—(CH 2 ) 3 —CONH-FLAAYZ 2 ;

(v) HS—(CH 2 ) 10 —(CH 2 OCH 2 ) 7 —CONH-AAYZ 2 ; and

(vi) HS—(CH 2 ) 10 —(CH 2 OCH 2 ) 7 —CONH-FLAAYZ 2 ,

wherein Z 2 represents said epitopic peptide.

1 . A vaccine for the prophylactic or therapeutic treatment of a tumour in a mammalian subject, said vaccine comprising a plurality of nanoparticles and a pharmaceutically acceptable carrier, salt or diluent, at least one of said nanoparticles comprising:

(i) a core comprising a metal and/or a semiconductor atom;

(ii) a corona comprising a plurality of ligands covalently linked to the core, wherein at least a first ligand of said plurality comprises a carbohydrate moiety that is covalently linked to the core via a first linker or comprises glutathione, and wherein at least a second ligand of said plurality comprises an epitopic peptide that is covalently linked to the core via a second linker, said second linker comprising:

a peptide portion and a non-peptide portion, wherein said peptide portion comprises the sequence X 1 X 2 Z 1 , wherein:

X 1 is an amino acid selected from A and G;

X 2 is an amino acid selected from A and G; and

Z 1 is an amino acid selected from Y and F,

and wherein said epitopic peptide forms at least a portion of or is derived from a Tumour-Associated Antigen (TAA).

2 . The vaccine according to claim 1 , wherein said non-peptide portion of the second linker comprises C2-C15 alkyl and/or C2-C15 glycol.

3 . The vaccine according to claim 1 , wherein said first ligand and/or said second ligand are covalently linked to the core via a sulphur-containing group, an amino-containing group, a phosphate-containing group or an oxygen-containing group.

8 . The vaccine according to claim 1 , wherein said epitopic peptide binds to a class I Major Histocompatibility Complex (MHC) molecule or is capable of being processed so as to bind to a class I MHC molecule.

9 . The vaccine according to claim 8 , wherein said epitopic peptide consists of a sequence of 8 to 40 amino acid residues.

10 . (canceled)

11 . The vaccine according to claim 1 , wherein the epitopic peptide is capable of being presented by a class I MHC molecule so as to stimulate a Cytotoxic T Lymphocyte (CTL) response.

12 . The vaccine according to claim 1 , wherein the TAA is a lung cancer antigen.

13 . (canceled)

14 . The vaccine according to claim 12 , wherein said epitopic peptide comprises or consists of an amino acid sequence selected from SEQ ID NOS: 1 to 86.

15 . The vaccine according to claim 14 , wherein the epitopic peptide comprises or consists of an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 82)

VLVPVLVMV;

(SEQ ID NO: 29)

KIYQWINEL;

(SEQ ID NO: 33)

KLGEFAKVLEL;

(SEQ ID NO: 19)

GMYGKIAVMEL;

(SEQ ID NO: 34)

KLIPFLEKL;

and

(SEQ ID NO: 67)

RLLEVPVML.

16 . The vaccine according to claim 1 wherein:

(i) the carbohydrate moiety of said first ligand comprises a monosaccharide and/or a disaccharide; and/or

(ii) said plurality of ligands comprises at least one glutathione ligand covalently linked to the core of the nanoparticle via the glutathione sulphur atom; and/or

(iii) said plurality of ligands comprises:

(a) glucose;

(b) N-acetylglucosamine;

(c) glutathione;

(d) glucose and N-acetylglucosamine;

(e) glucose and glutathione;

(f) N-acetylglucosamine and glutathionie; or

(g) glucose, N-acetylglucosamine and glutathione.

17 . The vaccine according to claim 16 (i), wherein said carbohydrate moiety comprises glucose, mannose, fucose and/or N-acetylglucosamine.

18 . The vaccine according to claim 1 , wherein said first linker comprises C2-C15 alkyl and/or C2-C15 glycol.

19 . The vaccine according to claim 1 , wherein said first ligand comprises 2′-thioethyl-β-D-glucopyranoside or 2′-thioethyl-α-D-glucopyranoside covalently attached to the core via the thiol sulphur atom.

20 .- 21 . (canceled)

22 . The vaccine according to claim 1 , wherein the molar ratio of arbohydrate-containing ligands and/or glutathione ligands to epitopic peptide-containing ligands is in the range 5:1 to 100:1.

23 . (canceled)

24 . The vaccine according to claim 1 , wherein the diameter of the core of the nanoparticle is in the range 1 nm to 5 nm.

25 . (canceled)

26 . The vaccine according to claim 1 , wherein the core comprises a metal selected from the group consisting of: Au, Ag, Cu, Pt, Pd, Fe, Co, Gd and Zn, or any combination thereof.

27 .- 28 . (canceled)

29 . The vaccine according to claim 1 , wherein the core is magnetic.

30 . The vaccine according to claim 1 , wherein the core further comprises an NMR active atom selected from the group consisting of: Mn 2+ , Gd 3+ , Eu 2+ , Cu 2+ , V 2+ , Co 2+ , Ni 2+ , Fe 2+ , Fe 3+ and lanthanides 3+ .

31 . The vaccine according to claim 1 , wherein the core comprises a semiconductor.

32 . (canceled)

33 . The vaccine according to claim 31 , wherein the core is capable of acting as a quantum dot.

34 . The vaccine according to claim 1 , wherein the at least one nanoparticle comprises at least two epitopic peptide-containing ligands, and wherein the epitopic peptide of each of the at least two epitopic peptide-containing ligands differ.

35 . (canceled)

36 . A vaccine according to claim 1 , wherein the vaccine comprises a first species of said nanoparticle having a first epitopic peptide-containing ligand and a second species of said nanoparticle having a second epitopic peptide-containing ligand, wherein the epitopic peptides of said first and second species differ.

37 .- 38 . (canceled)

39 . The vaccine according to claim 1 , further comprising at least one adjuvant.

40 . (canceled)

41 . The vaccine according to claim 39 , wherein the adjuvant comprises (S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys 4 -OH (“Pam 3 Cys”).

42 . The vaccine according to claim 1 , wherein the vaccine is substantially free of adjuvant or wherein the only adjuvant effect is provided by the nanoparticles.

43 .- 50 . (canceled)

51 . A method of prophylactic or therapeutic treatment of a cancer, comprising administering a prophylactically or therapeutically sufficient amount of a vaccine as defined in claim 1 to a mammalian subject in need thereof.

52 . A method according to claim 51 , wherein said cancer is a lung cancer.

53 . (canceled)

54 . A method according to claim 51 , wherein said vaccine is administered at a site for lymphatic uptake.

55 . An in vitro or in vivo method for generating a Cytotoxic T Lymphocyte (CTL) response, comprising:

(i) contacting at least one antigen presenting cell (APC) with a vaccine as defined in claim 1 , such that said epitopic peptide is presented on a class I MHC molecule of said APC; and

(ii) contacting said at least one APC of (i) with at least one CTL cell, such that said CTL cell is activated by said APC to generate a CTL response that is specific for said epitopic peptide.

56 . An in vitro method according to claim 55 , wherein the APC is cultured in the presence of said vaccine, and, simultaneously or sequentially, co-cultured with said CTL cell.

57 .- 58 . (canceled)

59 . An in vivo method according to claim 55 , wherein said vaccine is delivered by a route of administration selected from the group consisting of:

injection into an organ or tissue of a mammalian subject at, or in the vicinity of, a site of lymphatic uptake;

nasal delivery via a spray or gel;

buccal delivery via a spray or gel or orally dissolvable film;

oral delivery via a dissolvable film

transdermal delivery via a patch incorporating the vaccine; and

inhalation delivery of a composition comprising the vaccine.

60 . A method according to claim 55 , wherein said vaccine comprises a pool of nanoparticles having different epitoptic peptides.

61 . A method according to claim 55 , wherein said CTL response comprises production of one or more cytokines.

62 . A method according to claim 61 , wherein said one or more cytokines comprise interferon gamma (IFN-gamma).

63 . A method according to claim 55 , wherein said at least one CTL cell exhibits higher avidity for an MHC-peptide complex that comprises said epitopic peptide displayed on a class I MHC molecule, wherein said higher avidity is higher compared with the avidity for said MHC-peptide complex exhibited by a CTL cell activated by an APC that has been contacted with the same epitopic peptide in free peptide form not linked to a nanoparticle.

Assignments (2)
RELEASE OF SECURITY INTEREST Recorded Nov 5, 2018
From: MIDCAP FINANCIAL TRUST, AS AGENT
To: MIDATECH PHARMA PLC
Reel/Frame 047420/0300 →
SECURITY INTEREST Recorded Jan 2, 2018
From: MIDATECH PHARMA PLC
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 044970/0892 →