Nanoparticle systems to stimulate and maintain immune system responsiveness at treatment sites

Patent metadata

Field	Value
Publication number	US-2023331804-A1
Application number	US-202017758296-A
Country	US
Kind code	A1
Filing date	Dec 31, 2020
Priority date	Dec 31, 2019
Publication date	Oct 19, 2023
Grant date	—

Abstract

Nanoparticle systems that genetically modify monocytes/macrophages in vivo to (1) recruit additional immune cells to a treatment site; (2) remain activated at the treatment site providing an on-going stimulatory signal to other immune cells; and (3) secrete bispecific immune-cell engaging antibodies that bind antigens on cells of interest at the treatment site and also bind and activate the recruited immune cells to destroy the bound cell. The systems can also inhibit the activity of transforming growth factor beta (TGFβ).

First claim

What is claimed is:

1 . A nanoparticle comprising:
a targeting ligand that binds to a professional phagocyte; and a nucleic acid that encodes a protein molecule having at least a first binding domain and a second binding domain, wherein the first binding domain is specific to a cell surface protein expressed by an immune cell, and wherein the second binding domain is specific to a cell surface protein expressed by a cancer cell.

2 . The nanoparticle of claim 1 , wherein the targeting ligand binds to a cell surface protein expressed by a monocyte, a macrophage, or both.

3 . The nanoparticle of claim 1 , wherein the targeting ligand comprises di-mannose.

4 . The nanoparticle of claim 1 , wherein the nucleic acid comprises ribonucleic acid (RNA).

5 . The nanoparticle of claim 4 , wherein the RNA comprises messenger RNA (mRNA).

6 . The nanoparticle of claim 5 , wherein the mRNA comprises synthetic RNA or in vitro transcribed RNA (IVT RNA).

7 . The nanoparticle of claim 1 , wherein the first binding domain is specific to a cell surface protein of a lymphocyte.

8 . The nanoparticle of claim 7 , wherein the lymphocyte is selected from the group consisting of a T-cell, a B-cell, a natural killer (NK) cell, and a tumor-infiltrating lymphocyte (TIL) cell.

9 . The nanoparticle of claim 1 , wherein the first binding domain is specific to a cell surface protein of a T-cell selected from the group consisting of a CD8+ T cell, CD4+ T cell, a gamma delta T cell, and an NK T-cell.

10 . The nanoparticle of claim 9 , wherein the first binding domain is specific to CD3.

11 . The nanoparticle of claim 1 , wherein the protein molecule is a bi-specific T-cell engager.

12 . The nanoparticle of claim 11 , wherein the protein molecule is an EpCAM-CD3 bi-specific T-cell engager.

13 . The nanoparticle of claim 1 , wherein the second binding domain is specific to an antigen expressed by the cancer cell.

14 . The nanoparticle of claim 1 , further comprising a second nucleic acid that encodes one or more interferon regulatory factors (IRFs).

15 . The nanoparticle of claim 1 , further comprising a tumor cell proliferation inhibitor or a nucleic acid encoding a tumor cell proliferation inhibitor.

16 . The nanoparticle of claim 15 , wherein the nucleic acid encodes an antibody, or an antigen-binding fragment of an antibody.

17 . The nanoparticle of claim 15 , wherein the nanoparticle comprises a nucleic acid encoding a CD40-CD40L inhibitor or a TGFβ inhibitor.

18 . The nanoparticle of claim 1 , wherein the nanoparticle is a liposome, a liposomal nanoparticle, a lipid nanoparticle, or a solid lipid nanoparticle.

19 . A composition comprising:
a first plurality of nanoparticles, wherein each of the first plurality of nanoparticles comprises:
a targeting ligand that binds to a professional phagocyte; and
a nucleic acid encoding a protein molecule having a first binding domain specific to a cell surface protein expressed by an immune cell, and a second binding domain is specific to a cell surface protein expressed by a cancer cell.

20 . The composition of claim 19 , wherein the targeting ligand binds to a cell surface protein expressed by a monocyte, a macrophage, or both.

21 . The composition of claim 19 , wherein the targeting ligand comprises di-mannose.

22 . The composition of claim 19 , wherein the nucleic acid comprises RNA.

23 . The composition of claim 22 , wherein the RNA comprises mRNA.

24 . The composition of claim 23 , wherein the mRNA comprises synthetic RNA or IVT RNA.

25 . The composition of claim 19 , wherein the first binding domain is specific to a cell surface protein of a lymphocyte.

26 . The composition of claim 25 , wherein the lymphocyte is selected from the group consisting of a T-cell, a B-cell, an NK cell, and a TIL cell.

27 . The composition of claim 19 , wherein the first binding domain is specific to a cell surface protein of a T-cell selected from the group consisting of a CD8+ T cell, CD4+ T cell, a gamma deltaT cell, and an NK T-cell.

28 . The composition of claim 27 , wherein the first binding domain is specific to CD3.

29 . The composition of claim 19 , wherein the protein molecule is a bi-specific T-cell engager.

30 . The composition of claim 29 , wherein the protein molecule is an EpCAM-CD3 bi-specific T-cell engager.

31 . The composition of claim 19 , wherein the second binding domain is specific to an antigen expressed by the cancer cell.

32 . The composition of claim 19 , further comprising a pharmaceutically acceptable carrier.

33 . The composition of any of claim Nos. 19 - 32 , wherein at least a subset of the first plurality of nanoparticles further comprises one or more of (a) a nucleic acid encoding one or more interferon regulatory factors (IRFs), and (b) a nucleic acid encoding IKKβ.

34 . The composition of any of claim Nos. 19 - 32 , further comprising:
a second plurality of nanoparticles, wherein at least a subset of the second plurality of nanoparticles comprise one or more of (a) a nucleic acid encoding one or more interferon regulatory factors (IRFs), and (b) a nucleic acid encoding IKKβ.

35 . The composition of any of claim Nos. 19 - 34 , further comprising a tumor cell proliferation inhibitor.

36 . The composition of any of claim Nos. 19 - 35 , wherein at least a subset of the first or second plurality of nanoparticles further comprise a nucleic acid encoding a tumor cell proliferation inhibitor.

37 . The composition of any of claim 34 , wherein at least a subset of the first or second plurality of nanoparticles further comprise a nucleic acid encoding an antigen-binding fragment of an antibody of a tumor cell proliferation inhibitor.

38 . The composition of any of claim Nos. 19 or 34 - 36 , further comprising a third plurality of nanoparticles, wherein at least a subset of the third plurality of nanoparticles comprise a nucleic acid encoding an antigen-binding fragment of an antibody of a tumor cell proliferation inhibitor.

39 . The composition of any of claim Nos. 35 - 38 , wherein the tumor cell proliferation inhibitor is a CD40-CD40L inhibitor or a TGFβ inhibitor.

40 . The composition of claim 38 , comprising the first plurality of nanoparticles and the third plurality of nanoparticles in the absence of the second plurality of nanoparticles.

41 . The composition of claim 38 , wherein the first, second, and/or third plurality of nanoparticles comprise a liposome, a liposomal nanoparticle, a lipid nanoparticle, or a solid lipid nanoparticle.

42 . A composition for treating cancer in a human subject, the composition comprising:
a first plurality of nanoparticles, wherein each of the plurality of nanoparticles comprises
(i) a targeting ligand that binds to a monocyte, macrophage, or both; and
(ii) an mRNA encoding a protein molecule having at least a first binding domain specific to a cell surface protein expressed by a lymphocyte, and a second binding domain specific to a cell surface protein expressed by a cancer cell;
wherein the first plurality of nanopa

Assignees

• Fred Hutchinson Cancer Center
• Tidal Therapeutics Inc

Inventors

• Stephan Matthias
• Nielsen Ulrik

Classifications

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K40/42

  Cancer antigens · CPC title

• A61K40/15

  Natural-killer [NK] cells; Natural-killer T [NKT] cells · CPC title

• A61K40/17

  Monocytes; Macrophages · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title