# US 10,370,422 B2 · Membrane-anchoring and apoptosis-inducing fusion protein comprising a fragment of TRAIL and CD40L and encoding polynucleotides

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- Number: US 10,370,422 B2
- Document ID: US10370422B2
- Status: Granted
- Kind: B2
- Application number: 15/304,282
- Filed: 2015-04-15
- Published: 2017-02-16
- Granted: 2019-08-06
- Earliest claimed: 2014-04-15
- Assignees: The University of Liverpool
- Applicants: The University of Liverpool
- Inventors: Daniel Palmer; Taha Elmitwalli
- Web page: https://patentgrep.com/patent/US10370422B2

## CPC

- C07K 14/4747: {Apoptosis related proteins}
- C07K 14/70575: {NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 (NGF C07K14/48, TNF C07K14/525)}
- C07K 2319/00: Fusion polypeptide
- C07K 2319/03: containing a transmembrane segment
- 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

Provided are compositions comprising fusion proteins, polynucleotides and/or expression vectors with therapeutic utility for suppressing and/or treating cancer, as well as medical uses of these agents, and methods of treatment in which they are used. A fusion protein of the invention comprises an amino acid sequence that provides the apoptosis-inducing activity of TRAIL, and a membrane-anchoring amino acid sequence. The amino acid sequence that provides the apoptosis-inducing activity of TRAIL comprises the extracellular domain of TRAIL, or a fragment or variant thereof. A fusion protein comprising an amino acid sequence from TRAIL that is able to induce apoptosis, and a second sequence that anchors the first sequence to the cell membrane, is markedly more effective at reducing viability of TRAIL receptor positive cells than the naturally occurring (“wild type”) TRAIL protein itself.

## Claims

### Claim 1

A fusion protein comprising an apoptosis-inducing amino acid sequence comprising the extracellular domain of TRAIT or an apoptosis-inducing fragment thereof, and a membrane-anchoring amino acid sequence comprising the transmembrane domain of CD40L or a membrane-anchoring fragment thereof,
wherein the apoptosis-inducing amino acid sequence and the membrane-anchoring amino acid sequence are each in orientation such that the fusion protein is capable of anchoring in a cell membrane and inducing apoptosis.

### Claim 2 (depends on 1)

The fusion protein according to claim 1, wherein the apoptosis-inducing amino acid sequence consists of the extracellular domain of TRAIL.

### Claim 3 (depends on 1)

The fusion protein according to claim 1, wherein the fragment comprises about 165, 160, 155, or 150 contiguous amino acid residues of the native TRAIL sequence.

### Claim 4 (depends on 1)

The fusion protein according to claim 1, wherein the fusion protein comprises amino acid residues from 109 to 276 of SEQ ID NO: 3.

### Claim 5 (depends on 1)

The fusion protein according to claim 1, comprising amino acids residues 1 to 108 of SEQ ID NO: 3.

### Claim 6 (depends on 1)

The fusion protein according to claim 1, comprising or consisting of the amino acid sequence set out in SEQ ID NO: 3.

### Claim 7 (depends on 1)

A polynucleotide encoding a fusion protein according to claim 1.

### Claim 8 (depends on 7)

The polynucleotide according to claim 7, wherein the polynucleotide comprises the sequence set out in SEQ ID NO: 4.