# US 2019/0167709 A1 · Compositions and methods for inducing apoptosis

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- Number: US 2019/0167709 A1
- Document ID: US20190167709A1
- Status: Published application
- Kind: A1
- Application number: 16/276,788
- Filed: 2019-02-15
- Published: 2019-06-06
- Earliest claimed: 2013-03-12
- Assignees: University of Utah Research Foundation
- Applicants: University of Utah Research Foundation
- Inventors: Jindrich Henry Kopecek; Jiyuan Yang; Te-Wei Chu
- Web page: https://patentgrep.com/patent/US20190167709A1

## CPC

- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6897: {Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies}
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 16/2887: {against CD20}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/35: Valency
- C07K 2317/40: characterized by post-translational modification
- C07K 2317/55: Fab or Fab'
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

In an aspect, the invention relates to compositions, method, and kits for inducing apoptosis. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

## Claims

### Claim 1

A method of inducing apoptosis, the method comprising:
(i) contacting a population of cells with a first complex comprising a targeting moiety and a morpholino; and
(ii) contacting a population of cells with a second complex comprising a copolymer carrier and one or more morpholinos;
wherein the contacting of the cells with the first complex and the second complex induces apoptosis of the cells.

### Claim 2 (depends on 1)

The method of claim 1, further comprising repeating step (i) and step (ii).

### Claim 3 (depends on 1)

The method of claim 1, further comprising (iii) confirming apoptosis of the cells.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cells are B-cells.

### Claim 5 (depends on 1)

The method of claim 1, wherein the cells are in a subject.

### Claim 6 (depends on 5)

The method of claim 5, wherein the subject has non-Hodgkin's lymphoma.

### Claim 7 (depends on 1)

The method of claim 1, wherein the targeting moiety is specific for a non-internalizing cell surface molecule or slowly internalizing cell surface molecule.

### Claim 8 (depends on 7)

The method of claim 7, wherein the non-internalizing cell surface molecule or slowly internalizing cell surface molecule is a CD20 receptor, a protein tyrosine phosphatase receptor type C, a cell surface death receptor, a prostate stem cell antigen receptor, or a receptor belonging to the tumor necrosis factor receptor superfamily.

### Claim 9 (depends on 7)

The method of claim 7, wherein the targeting moiety is a polysaccharide, a peptide ligand, an aptamer, a Fab′ fragment, or a single-chain variable fragment.

### Claim 10 (depends on 9)

The method of claim 9, wherein the targeting moiety is a Fab′ fragment.

### Claim 11 (depends on 10)

The method of claim 10, wherein the Fab′ fragment is derived from an anti-CD20 receptor antibody.

### Claim 12 (depends on 11)

The method of claim 11, wherein the anti-CD20 receptor antibody is 1F5, rituximab, tositumomab, ibritumomab, ofatumumab, veltuzumab, ocrelizumab, ocaratuzumab, obinutuzumab, PRO131921, BCD-020, IBI-301, ublituximab, or BLX-301.

### Claim 13 (depends on 1)

The method of claim 1, wherein the morpholino of the first complex and the one or more morpholinos of the second complex are complementary.

### Claim 14 (depends on 1)

The method of claim 1, wherein the morpholino of the first complex is 5′ GAG TAA GCC AAG GAG AAT CAA TAT A 3′ (SEQ ID NO:25) and wherein the one or more morpholinos of the second complex are 5′ TAT ATT GAT TCT CCT TGG CTT ACT C 3′ (SEQ ID NO:26).

### Claim 15

A method of inducing apoptosis, the method comprising:
contacting a population of cells with a composition comprising a first complex comprising a targeting moiety and a morpholino and a second complex comprising a complex comprising a copolymer carrier and one or more morpholinos, wherein the contacting of the cells with the composition induces apoptosis of the cells.

### Claim 16 (depends on 15)

The method of claim 15, further comprising repeating the contacting of the cells with the composition.

### Claim 17 (depends on 15)

The method of claim 15, wherein the cells are B-cells.

### Claim 18 (depends on 15)

The method of claim 15, wherein the cells are in a subject.

### Claim 19 (depends on 18)

The method of claim 18, wherein the subject has non-Hodgkin's lymphoma.

### Claim 20 (depends on 15)

The method of claim 15, wherein the targeting moiety is specific for a non-internalizing cell surface molecule or slowly internalizing cell surface molecule.

### Claim 21 (depends on 20)

The method of claim 20, wherein the non-internalizing cell surface molecule or slowly internalizing cell surface molecule is a CD20 receptor, a protein tyrosine phosphatase receptor type C, a cell surface death receptor, a prostate stem cell antigen receptor, or a receptor belonging to the tumor necrosis factor receptor superfamily.

### Claim 22 (depends on 15)

The method of claim 15, wherein the targeting moiety is a polysaccharide, a peptide ligand, an aptamer, a Fab′ fragment, or a single-chain variable fragment.

### Claim 23 (depends on 22)

The method of claim 22, wherein the targeting moiety is a Fab′ fragment.

### Claim 24 (depends on 23)

The method of claim 23, wherein the Fab′ fragment is derived from an anti-CD20 receptor antibody.

### Claim 25 (depends on 24)

The method of claim 24, wherein the anti-CD20 receptor antibody is 1F5, rituximab, tositumomab, ibritumomab, ofatumumab, veltuzumab, ocrelizumab, ocaratuzumab, obinutuzumab, PRO131921, BCD-020, IBI-301, ublituximab, or BLX-301.

### Claim 26 (depends on 15)

The method of claim 15, wherein the morpholino of the first complex and the one or more morpholinos of the second complex are complementary.

### Claim 27 (depends on 15)

The method of claim 15, wherein the morpholino of the first complex is 5′ GAG TAA GCC AAG GAG AAT CAA TAT A 3′ (SEQ ID NO:25) and wherein the one or more morpholinos of the second complex are 5′ TAT ATT GAT TCT CCT TGG CTT ACT C 3′ (SEQ ID NO:26).

### Claim 28

A kit comprising (i) a first complex comprising a targeting moiety and a morpholino, and (ii) a second complex comprising a copolymer carrier and one or more morpholinos.

### Claim 29 (depends on 28)

The kit of claim 28, further comprising (iii) instructions for administering the complex of (i) and the complex of (ii).

### Claim 30 (depends on 28)

The kit of claim 28, wherein the first complex and the second complex are co-formulated.

### Claim 31 (depends on 28)

The kit of claim 28, wherein the targeting moiety is specific for a non-internalizing cell surface molecule or slowly internalizing cell surface molecule.

### Claim 32 (depends on 31)

The kit of claim 31, wherein the non-internalizing cell surface molecule or slowly internalizing cell surface molecule is on a cell.

### Claim 33 (depends on 32)

The kit of claim 32, wherein the cell is a B cell.

### Claim 34 (depends on 31)

The kit of claim 31, wherein the non-internalizing cell surface molecule or slowly internalizing cell surface molecule is a CD20 receptor, a protein tyrosine phosphatase receptor type C, a cell surface death receptor, a prostate stem cell antigen receptor, or a receptor belonging to the tumor necrosis factor receptor superfamily.

### Claim 35 (depends on 28)

The kit of claim 28, wherein the targeting moiety is a polysaccharide, a peptide ligand, an aptamer, a Fab′ fragment, or a single-chain variable fragment.

### Claim 36 (depends on 35)

The kit of claim 35, wherein the Fab′ fragment is derived from an anti-CD20 receptor antibody.

### Claim 37 (depends on 36)

The kit of claim 36, wherein the anti-CD20 receptor antibody is 1F5, rituximab, tositumomab, ibritumomab, ofatumumab, veltuzumab, ocrelizumab, ocaratuzumab, obinutuzumab, PRO131921, BCD-020, IBI-301, ublituximab, or BLX-301.

### Claim 38 (depends on 28)

The kit of claim 28, wherein the morpholino of the first complex and the one or more morpholinos of the second complex are complementary.

### Claim 39 (depends on 28)

The kit of claim 28, wherein the morpholino of the first complex is 5′ GAG TAA GCC AAG GAG AAT CAA TAT A 3′ (SEQ ID NO:25) and wherein the one or more morpholinos of the second complex are 5′ TAT ATT GAT TCT CCT TGG CTT ACT C 3′ (SEQ ID NO:26).