# US 10,865,232 B2 · NKG2D-IG fusion protein for cancer immunotherapy

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- Number: US 10,865,232 B2
- Document ID: US10865232B2
- Status: Granted
- Kind: B2
- Application number: 15/775,568
- Filed: 2016-11-11
- Published: 2018-12-13
- Granted: 2020-12-15
- Earliest claimed: 2015-11-13
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Glenn Dranoff; Ryan Sullivan; Matthew Vanneman
- Web page: https://patentgrep.com/patent/US10865232B2

## CPC

- C07K 14/7056: {Lectin superfamily, e.g. CD23, CD72}
- A61K 38/178: {Lectin superfamily, e.g. selectins}
- A61K 38/2086: {IL-13 to IL-16}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07K 14/5443: {IL-15}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- 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

## Abstract

Methods and compositions for cancer immunotherapy are provided. The methods involve the use of a chimeric molecule (e.g., fusion protein) comprising a dimeric NKG2D portion and an Fc portion, which binds one or more NKG2D ligands. In some embodiments, the molecule further comprises a drug moiety (e.g., an IL15/Ra moiety). The methods disclosed herein are useful for the treatment of cancer that is associated with abnormal expression of one or more NKG2D ligands.

## Claims

### Claim 1

A dimeric NKG2D-Fc chimera including two distinct NKG2D ligand binding sites, each NKG2D ligand binding site attached to an Fc fragment, wherein: each NKG2D ligand binding site comprises NKG2D or a ligand binding portion of NKG2D; and the Fc fragment comprises a fragment crystallizable region (Fc) of an immunoglobulin.

### Claim 2 (depends on 1)

The dimeric NKG2D-Fc chimera according to claim 1, further comprising a drug moiety.

### Claim 3 (depends on 2)

The dimeric NKG2D-Fc chimera according to claim 2, wherein the drug moiety is attached to an amino terminus or a carboxy terminus of the chimera.

### Claim 4 (depends on 2)

The dimeric NKG2D-Fc chimera according to claim 2, further comprising at least one linking molecule, wherein the at least one linking molecule is not a contiguous portion of NKG2D, the Fc fragment, or drug moiety and which covalently joins:
(a) an amino acid of the NKG2D or the ligand binding portion of NKG2 to an amino acid of the Fc fragment, or
(b) an amino acid of the Fc fragment to the drug moiety.

### Claim 5 (depends on 4)

The dimeric NKG2D-Fc chimera according to claim 4, wherein the at least one linking molecule is a peptide linker of about 2 to about 25 amino acids in length.

### Claim 6 (depends on 4)

The dimeric NKG2D-Fc chimera according to claim 4, wherein the at least one linking molecule is a glycine-serine linker.

### Claim 7 (depends on 6)

The dimeric NKG2D-Fc chimera according to claim 6, wherein the glycine-serine linker is represented by:
the formula (GS)n, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; or
the formula (GGGGS)n (SEQ ID NO: 2), wherein n is 1, 2, 3, 4, or 5.

### Claim 8 (depends on 7)

The dimeric NKG2D-Fc chimera according to claim 7, wherein the glycine-serine linker is represented by the formula (GS)3 or the formula (GGGGS)4 (SEQ ID NO:3).

### Claim 9 (depends on 1)

The dimeric NKG2D-Fc chimera according to claim 1, wherein the ligand binding portion of NKG2D comprises an extracellular fragment of NKG2D.

### Claim 10 (depends on 1)

The dimeric NKG2D-Fc chimera according to claim 1, wherein the Fc fragment comprises a fragment crystallizable region (Fc) of a human immunoglobulin (IgG).

### Claim 11 (depends on 2)

The dimeric NKG2D-Fc chimera according to claim 2, wherein the drug moiety is selected from the group consisting of: cytokine, chemokine, small molecule, toxin, radionuclide, and an enzyme.

### Claim 12 (depends on 11)

The dimeric NKG2D-Fc chimera according to claim 11, wherein the drug moiety is a cytokine selected from the group consisting of: IL-2, IL-12, IL-15, IL-18, IL-21 and IFN-α.

### Claim 13 (depends on 11)

The dimeric NKG2D-Fc chimera according to claim 11, wherein the drug moiety comprises a heterocomplex of IL-15 and soluble IL-15 receptor alpha chain.

### Claim 14

A composition comprising: a dimeric NKG2D-Fc chimera including two distinct NKG2D ligand binding sites, each NKG2D ligand binding site attached to an Fc fragment, wherein: each NKG2D ligand binding site comprises NKG2D or a ligand binding portion of NKG2D; and the Fc fragment comprises a fragment crystallizable region (Fc) of an immunoglobulin; and a pharmaceutically acceptable carrier.