# US 8,771,679 B2 · Prodrug activation in cancer cells using molecular switches

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- Number: US 8,771,679 B2
- Document ID: US8771679B2
- Status: Granted
- Kind: B2
- Application number: 13/059,014
- Filed: 2009-08-13
- Published: 2011-06-09
- Granted: 2014-07-08
- Earliest claimed: 2008-08-13
- Assignees: The John Hopkins University
- Applicants: Marc Alan Ostermeier; Chapman M. Wright
- Inventors: Marc Alan Ostermeier; Chapman M. Wright
- Web page: https://patentgrep.com/patent/US8771679B2

## CPC

- C12N 5/0693: {Tumour cells; Cancer cells}
- A61P 35/00: Antineoplastic agents
- C07K 14/47: from mammals
- C12N 9/0036: {acting on NADH or NADPH (1.6)}
- C12N 9/0077: {with a reduced iron-sulfur protein as one donor (1.14.15)}
- C12N 9/1211: {Thymidine kinase (2.7.1.21)}
- C12N 9/2445: {Beta-glucosidase (3.2.1.21)}
- C12N 9/48: acting on peptide bonds (3.4)
- C12N 9/78: acting on carbon to nitrogen bonds other than peptide bonds (3.5)
- C12N 9/86: acting on amide bonds in cyclic amides, e.g. penicillinase {(3.5.2)}
- C12Y 101/01284: S-(hydroxymethyl)glutathione dehydrogenase (1.1.1.284), i.e. nitroreductase
- C12Y 207/01021: Thymidine kinase (2.7.1.21)
- C12Y 302/01021: Beta-glucosidase (3.2.1.21)
- C12Y 305/02006: Beta-lactamase (3.5.2.6)
- C12Y 305/04001: Cytosine deaminase (3.5.4.1)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)
- C12Y: ENZYMES
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention features a novel protein engineering strategy by combining the domains of two independent proteins into a molecular switch. The invention features polypeptides comprising a prodrug activating enzyme and a protein that binds a cancer specific marker, polynucleotides encoding the polypeptides, and molecular switches for converting a prodrug into a toxin, comprising the polypeptides. The invention also features methods for converting a prodrug into a toxin, methods for treating cancer, and methods for making the molecular switches, as well as kits.

## Claims

### Claim 1

A polypeptide encoding a molecular switch comprising a cytosine deaminase and a CH1 domain from p300, comprising the amino acid sequence of SEQ ID NO: 1.

### Claim 2

A polypeptide encoding a molecular switch comprising a cytosine deaminase and a CH1 domain from p300, comprising the amino acid sequence of SEQ ID NO: 2.

### Claim 3

A molecular switch for converting a prodrug into a toxin, comprising a cytosine deaminase and a CH1 domain corresponding to the amino acid sequence of SEQ ID NO: 1.

### Claim 4

A molecular switch for converting a prodrug into a toxin, comprising a cytosine deaminase and a CH1 domain corresponding to the amino acid sequence of SEQ ID NO: 2.