JPWO2020176397A5

JPWO2020176397A5 -

Info

Publication number: JPWO2020176397A5
Application number: JP2021549606A
Authority: JP
Publication date: 2023-03-02

Claims

A composition comprising a first population of mesoporous silica particles and a viral vector.

2. The composition of claim 1, wherein the viral vector is conjugated to the first population of mesoporous silica particles.

3. The composition of claim 1 or 2 , wherein the viral vector is electrostatically or covalently conjugated to the first population of mesoporous silica particles.

A composition according to any preceding claim, wherein the first population of mesoporous silica particles is surface-modified.

5. The composition of claim 4 , wherein the surface modification of the first population of mesoporous silica particles comprises primary, secondary, tertiary or quaternary amines.

6. The composition of claim 4 or 5 , wherein the surface modification of the first population of mesoporous silica particles comprises polyethyleneimine.

7. A composition according to claim 5 or 6, wherein the polyethyleneimine or primary, secondary, tertiary or quaternary amine is separated from the silica surface by a linker.

A common structure for surface modification is:

, wherein L is a linker and X is a primary, secondary, tertiary or quaternary amine or polyethyleneimine.

The surface modification of the first population of mesoporous silica particles has the following structure:

The composition according to any one of claims 4 to 8, comprising

surface modification of the first population of mesoporous silica particles comprising:
(i) trimethylammonium;
(ii) N,N,N-trimethylpropane-1-ammonium; or
(iii) —OH (hydroxyl), amine, carboxylic acid, phosphonate, halide, azide, alkyne, epoxide, sulfhydryl, polyethyleneimine, hydrophobic moiety or salt thereof, optionally C ₁ -C ₂₀ alkyl or (- O(CH2-CH ₂ -) _1-25 linker ,
The composition according to any one of claims 4 to 9 , comprising

A composition according to any one of claims 1 to 10, wherein the first population of mesoporous silica particles has its surface covalently modified with a trialkoxysilyl compound or a trihydroxysilyl compound.

The surface modification of the first population of mesoporous silica particles is about 1000-20,000 Da, about 1,200-15,000 Da, about 1,500-12,000 Da, about Polyethylenimine having an average molecular weight of 2,000 Da, about 3,000 Da, about 4,000 Da, about 5,000 Da, about 6,000 Da, about 7,000 Da, about 8,000 Da, about 9,000 Da, or about 10,000 Da A composition according to any one of claims 4 to 11 , comprising

(a) the mesoporous silica particles contain pores with a diameter of 2-50 nm ;
(b) the soporous silica particles have a surface area of at least about 100 m ² /g; or
(c) the composition is suitable for injection;
A composition according to any one of claims 1-12 .

A composition according to any one of claims 1 to 13 , wherein the viral vector is a retrovirus, adenovirus, adeno-associated virus, herpes virus or lentivirus.

15. The composition of any one of claims 1-14 , wherein the viral vector comprises an expression control sequence operably linked to the nucleotide sequence.

the nucleotide sequence is
(i) a chimeric antigen receptor (CAR), an engineered TCR, one or more cytokines, one or more chemokines, shRNAs to block inhibitory molecules , or mRNAs to induce protein expression ; or
(ii) a polypeptide that targets a tumor antigen;
16. The composition of claim 15 , which encodes

17. The composition of claim 16 , wherein the CAR comprises an antigen binding domain, a transmembrane domain, a co-stimulatory signaling region and a signaling domain.

(i) the antigen binding domain binds to a tumor antigen; and/or
(ii) the signaling domain is a CD3 zeta signaling domain;
18. The composition of claim 17 .

Tumor antigen is TSHR, CD19, CD123, CD22, CD30, CD171, CS-1, CLL-1, CD33, EGFRvIII, GD2, GD3, BCMA, Tn Ag, PSMA, ROR1, FLT3, FAP, TAG72, CD38, CD44v6 , CEA, EPCAM, B7H3, KIT, IL-13Ra2, mesothelin, IL-11Ra, PSCA, PRSS21, VEGFR2, Lewis Y, CD24, PDGFR-beta, SSEA-4, CD20, folate receptor alpha, ERBB2 (Her2/neu ), MUC1, EGFR, NCAM, Prostase, PAP, ELF2M, EphrinB2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, Tyrosinase, EphA2, Fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o- Acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE A1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1 , MAD-CT-2, Fos-related antigen 1, p53, p53 mutants, prostein, survivin and telomerase, PCTA-1/Galectin 8, MelanA/MART1, Ras mutants, hTERT, sarcoma translocation breakpoints, ML- IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, TRP-2, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE -1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxylesterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1 or A composition according to any one of claims 16 to 18, selected from any combination thereof.

(i) a T cell stimulating compound or tumor antigen ; and/or
(ii) cytokines;
The composition of any one of claims 1-19 , further comprising:

The T cell stimulating compound or tumor antigen is IL -2, IL-15, anti-CD2 mAb, anti-CD3 mAb, anti-CD28 mAb, neoantigen peptides, peptides from common antigens such as TRP2, gp100, tumor cell lysates, CD19, CD20 , CD22, ROR1, Mesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD - 2, NY-ESO-1 TCR, MAGE A3 TCR, or a combination thereof. thing.

A composition according to any preceding claim, further comprising a second population of mesoporous silica particles.

a T cell stimulating compound or tumor antigen ,
(i) a first population of mesoporous silica particles or a second population of mesoporous silica particles ; or
(ii) a lipid envelope on the surface of the second population of mesoporous silica particles;
23. The composition of claim 22 , which is conjugated or adsorbed to.

Cytokines are
(i) conjugated or adsorbed to a first or second population of mesoporous silica particles; and/or
(ii) IL-1, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-15, IL-17, IL-21 or transforming growth factor beta (TGF) -β), or agonists thereof, mimetics thereof, variants thereof, functional fragments thereof or combinations thereof;
A composition according to any one of claims 20-23 .

A method comprising contacting a T lymphocyte with the composition of any one of claims 1-24 .

26. The method of claim 25 , further comprising contacting the T lymphocytes with a T cell stimulating compound or tumor antigen.

27. The method of claim 25 or 26 , wherein the contacting step occurs in vitro or in vivo .

28. The method of any one of claims 25-27 , further comprising activating the T lymphocytes by contacting the T lymphocytes with a T cell stimulating compound or tumor antigen.

( a) contacting the T lymphocyte population with a composition according to any one of claims 1-24 ; and (b ) contacting the T lymphocyte population with a T cell stimulating composition or a tumor antigen . ,
A method of expanding a T cell population comprising :

The T cell stimulatory compound or tumor antigen is IL -2, IL-15, anti-CD2 mAb, anti-CD3 mAb, anti-CD28 mAb, neoantigenic peptides, CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA , glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR or a combination thereof.

a T cell stimulating compound or tumor antigen ,
(i) a first population of mesoporous silica particles or a second population of mesoporous silica particles; and/or
(ii) a lipid envelope on the surface of the second population of mesoporous silica particles;
The method of any one of claims 28-30 , wherein the method is conjugated or adsorbed to

further comprising contacting the T lymphocytes with a cytokine, optionally wherein the cytokine is IL-1, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-15, IL-17, IL-21 or transforming growth factor beta (TGF-β), or agonists thereof, mimetics thereof, variants thereof, functional fragments thereof or combinations thereof, claims 25-31 The method according to any one of .

A pharmaceutical composition comprising a composition according to any one of claims 1-24 and a pharmaceutically acceptable excipient.

A composition according to any one of claims 1 to 24 or a medicament according to claim 33 for use in a method of treating a subject having a disease, disorder or condition associated with elevated expression of a tumor antigen A composition or pharmaceutical composition, optionally wherein the disease, disorder or condition associated with elevated expression of a tumor antigen is cancer.

A composition according to any one of claims 1 to 24 or a medicament according to claim 33 for the manufacture of a medicament for treating a subject with a disease, disorder or condition associated with elevated expression of tumor antigens Use of the composition, optionally wherein the disease, disorder or condition associated with elevated expression of tumor antigens is cancer.