# US 2016/0355601 A1 · Methods and Compositions for the Treatment of Pancreatic Cancer

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- Number: US 2016/0355601 A1
- Document ID: US20160355601A1
- Status: Published application
- Kind: A1
- Application number: 14/429,278
- Filed: 2013-10-01
- Published: 2016-12-08
- Earliest claimed: 2012-10-19
- Assignees: Opsona Therapeutics Limited
- Applicants: Opsona Therapeutics Limited
- Inventors: Thorsten Hagemann
- Web page: https://patentgrep.com/patent/US20160355601A1

## CPC

- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- G01N 33/57525: of the liver or pancreas
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- G01N 2500/02: Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

A composition comprising a TLR2 antagonistic antibody or antigen binding fragment thereof for use in the treatment or prophylaxis of pancreatic cancer is provided. The antibody or antigen binding fragment may be provided for simultaneous, separate or sequential administration with a secondary chemotherapeutic agent such as gemcitabine, and optionally a tertiary chemotherapeutic agent such as abraxane for enhanced treatment. Also provided is a screening method for the identification of compounds for use in treatment or prevention of pancreatic cancer.

## Claims

### Claim at position 1

1-22. (canceled)

### Claim 23

A method for treating or preventing pancreatic cancer comprising the step of:
administering a therapeutically effective amount of a Toll-like receptor 2 (TLR2) antagonist to a subject in need thereof wherein the TLR2 antagonist is an antibody that specifically binds to TLR2, or an antigen binding fragment thereof.

### Claim 24

(canceled)

### Claim 25 (depends on 23)

The method as claimed in claim 23 wherein the antibody or antigen binding fragment thereof specifically binds to an epitope comprising leucine rich repeat regions 11 to 14 of TLR2.

### Claim 26 (depends on 23)

The method as claimed in claim 23 wherein the antibody or antigen binding fragment thereof specifically binds to a non-continuous epitope comprising amino acid residues His318, Pro320, Arg321, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of SEQ ID NO: 1.

### Claim 27 (depends on 23)

The method as claimed in claim 23 wherein the antibody or antigen binding fragment thereof specifically binds to a non-continuous epitope comprising amino acid residues His318, Pro320, Gln321, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of SEQ ID NO: 2.

### Claim 28 (depends on 23)

The method as claimed in claim 23 wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising a complementarity determining region (CDR) 1 region comprising the amino acid sequence of SEQ ID NO:3, a CDR2 region comprising the amino acid sequence of SEQ ID NO:4 and a CDR3 region comprising the amino acid sequence of SEQ ID NO:5, and/or a light chain variable region comprising a CDR1 region comprising the amino acid sequence of SEQ ID NO:6, a CDR2 region comprising the amino acid sequence Gly-Ala-Ser and a CDR3 region comprising the amino acid sequence of SEQ ID NO:7.

### Claim 29 (depends on 23)

The method as claimed in claim 23 wherein the antibody or antigen binding fragment comprises a light chain variable domain comprising an amino acid sequence of SEQ ID NO:10, or a sequence which has at least 90% amino acid sequence identity with SEQ ID NO:10, and/or a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO:11, or a sequence which has at least 90% amino acid sequence identity with SEQ ID NO:11.

### Claim 30 (depends on 28)

The method as claimed in claim 28, wherein the antibody or antigen binding fragment antagonises TLR2 function independently of binding of the antibody or antigen binding fragment to CD32.

### Claim 31 (depends on 23)

The method as claimed in claim 23 wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:13, or a sequence which has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:13, and/or a light chain comprising the amino acid sequence of SEQ ID NO:12, or a sequence which has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:12, or an antigen binding fragment thereof.

### Claim 32 (depends on 23)

The method as claimed in claim 23 wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8, or a sequence which has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:8, and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:9, or a sequence which has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:9.

### Claim 33 (depends on 23)

The method as claimed in claim 23 wherein the antibody is a humanised version of anti-TLR2 antibody T2.5, or an antigen binding fragment thereof.

### Claim 34 (depends on 23)

The method as claimed in claim 23 wherein the method further comprises a step of administering sequentially, separately or simultaneously a therapeutically effective amount of a secondary chemotherapeutic agent.

### Claim 35 (depends on 34)

The method as claimed in claim 34 wherein the secondary chemotherapeutic agent is an agent that increases TLR2 expression when administered without a TLR2 antagonist.

### Claim 36 (depends on 34)

The method as claimed in claim 34 wherein the secondary chemotherapeutic agent is an agent that increases the overall percentage of myeloid infiltrate when administered without a TLR2 antagonist.

### Claim 37 (depends on 34)

The method as claimed in claim 34 wherein the secondary chemotherapeutic agent is selected from one or more of the group consisting of gemcitabine, cyclophosphamide, fluorouracil (5FU), oxaliplatin, FolFox, Folfiri and Folfirinox.

### Claim 38 (depends on 37)

The method as claimed in claim 37 wherein the secondary chemotherapeutic agent is gemcitabine.

### Claim 39 (depends on 37)

The method as claimed in claim 37 wherein the secondary chemotherapeutic agent comprises fluorouracil (5FU) and oxaliplatin.

### Claim 40 (depends on 34)

The method as claimed in claim 34 wherein the method further comprises a step of administering sequentially, separately or simultaneously a therapeutically effective amount of tertiary chemotherapeutic agent

### Claim 41 (depends on 40)

The method as claimed in claim 40 wherein the tertiary chemotherapeutic agent is abraxane.

### Claim 42 (depends on 40)

The method as claimed in claim 40 wherein the secondary chemotherapeutic agent is gemcitabine and the tertiary chemotherapeutic agent is abraxane.

### Claim at position 22

43-66. (canceled)

### Claim 67

A pharmaceutical composition comprising a TLR2 antagonistic antibody or an antigen binding fragment thereof, a pharmaceutically acceptable carrier, a secondary chemotherapeutic agent that increases TLR2 expression when administered without a TLR2 antagonist and abraxane.

### Claim 68 (depends on 67)

The pharmaceutical composition as claimed in claim 67 wherein the secondary chemotherapeutic agent that increases TLR2 expression when administered without a TLR2 antagonist is gemcitabine.

### Claim 69 (depends on 67)

The pharmaceutical composition as claimed in claim 67 wherein the secondary chemotherapeutic agent that increases TLR2 expression when administered without a TLR2 antagonist comprises fluorouracil (5FU) and oxaliplatin.

### Claim 70

A pharmaceutical composition comprising a TLR2 antagonistic antibody or an antigen binding fragment thereof, a pharmaceutically acceptable carrier and a secondary chemotherapeutic agent that increases TLR2 expression when administered without a TLR2 antagonist, wherein the TLR2 antagonistic antibody or antigen binding fragment comprises a heavy chain variable region comprising a complementarity determining region (CDR) 1 region comprising the amino acid sequence of SEQ ID NO:3, a CDR2 region comprising the amino acid sequence of SEQ ID NO:4 and a CDR3 region comprising the amino acid sequence of SEQ ID NO:5, and/or a light chain variable region comprising a CDR1 region comprising the amino acid sequence of SEQ ID NO:6, a CDR2 region comprising the amino acid sequence Gly-Ala-Ser and a CDR3 region comprising the amino acid sequence of SEQ ID NO:7.

### Claim 71 (depends on 70)

The pharmaceutical composition as claimed in claim 70 wherein the secondary chemotherapeutic agent that increases TLR2 expression when administered without a TLR2 antagonist is gemcitabine.

### Claim 72 (depends on 70)

The pharmaceutical composition as claimed in claim 70 wherein the secondary chemotherapeutic agent that increases TLR2 expression when administered without a TLR2 antagonist comprises fluorouracil (5FU) and oxaliplatin.

### Claim 73 (depends on 70)

The pharmaceutical composition as claimed in claim 70 wherein the pharmaceutical composition further comprises abraxane.

### Claim 74

A screening method for the identification of antibodies or antigen binding fragments thereof for use in treatment or prevention of pancreatic cancer, the method comprising the steps of:
(a) providing candidate antibodies or antigen binding fragments thereof having binding specificity for TLR2;
(b) contacting the candidate antibodies or antigen binding fragments thereof with TLR2; and
(c) identifying antibodies or antigen binding fragments thereof which antagonise TLR2 function;
wherein antagonism of TLR2 function is indicative of utility of the antibody or antigen binding fragment thereof in the treatment or prevention of pancreatic cancer.

### Claim 75 (depends on 74)

The screening method as claimed in claim 74 wherein the method includes a step of identifying antibodies or antigen binding fragments thereof which bind to TLR2 within the region of amino acid residues His318, Pro320, Arg321 or Gln321, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of SEQ ID NO: 1 or SEQ ID NO:2; wherein binding in this region is further indicative of utility of the antibodies or antigen binding fragments thereof in the treatment or prevention of pancreatic cancer.

### Claim 76

A screening method for the identification of secondary therapeutic compounds for use with an antagonistic TLR2 antibody or antigen binding fragment thereof in treatment or prevention of pancreatic cancer, the method comprising the steps of:
(a) screening chemotherapeutic agents for their ability to increase TLR2 expression when administered without a TLR2 antagonist;
wherein an increase in TLR2 expression is indicative of utility of the compound as a secondary therapeutic compound for use with an antagonistic TLR2 antibody or antigen binding fragment thereof in treatment or prevention of pancreatic cancer.