Interleukin-12 targeted to oncofoetal fibronectin

• US 8,420,087 B2
• Filed: 01/05/2005
• Issued: 04/16/2013
• Est. Priority Date: 01/05/2004
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.), Antisoma Research Limited (Sarossa Plc)
• Original Assignee: EMD Serono Research Center, Inc., Antisoma Research Limited (Sarossa Plc)
• Inventors: Gillies, Stephen, Lo, Kin-Ming, Lan, Yan, Verma, Rakesh
• Primary Examiner(s): STOICA, ELLY GERALD
• Application Number:
  US10/596,997
• Publication Number:
  US 20070202103A1
• Time in Patent Office: 3,023 Days
• Field of Search: None
• US Class Current: 424/134.1
• CPC Class Codes: A61K 47/6813 the drug being a peptidic cytokine, e.g. an interleukin or interferon
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/5434 IL-12
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The invention provides a compound comprising a target specific portion and an effector portion wherein the target specific portion comprises or consists of a monoclonal antibody having specificity for oncofoetal fibronectin, or a fragment or variant thereof which retains the antigen binding specificity of the parent monoclonal antibody and the effector portion comprises or consists of interleukin-12, or a functional fragment or variant thereof, characterized in the monoclonal antibody having specificity for oncofoetal fibronectin binds to a region of oncofoetal fibronectin other than the ED-B region. The invention further provides nucleic acids encoding the compounds of the invention, and the use of such compounds in medicine, e.g. in the treatment of cancer.

Claims

1. A compound comprising a target specific portion and an effector portion wherein:

(i) the target specific portion comprises a monoclonal antibody having specificity for oncofoetal fibronectin, or a fragment or variant thereof which retains the binding specificity for oncofoetal fibronectin of the parent monoclonal antibody; and

(ii) the effector portion comprises interleukin-12, or a functional fragment or variant thereof;

wherein the target specific portion is capable of binding an amino acid sequence within the repeat 7 domain of fibronectin,

wherein the compound comprises one or more polypeptides selected from the group consisting of the polypeptide of SEQ ID NO;

6 and the polypeptide of SEQ ID NO;

7, and wherein

SEQ ID NO;

6 includes SEQ ID NO;

1 and SEQ ID NO;

3; and

SEQ ID NO;

7 includes SEQ ID NO;

2.

2. A compound according to claim 1 wherein the compound comprises the polypeptide of SEQ ID NO:

6 and the polypeptide of SEQ ID NO;

7.

3. A compound according to claim 1 further comprising the polypeptide of SEQ ID NO:

4 linked by at least one disulphide bond to the polypeptide of SEQ ID NO;

6.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition according to claim 4 wherein the composition is suitable for parenteral administration.

6. A compound according to claim 1,

wherein the compound comprises the polypeptide of SEQ ID NO:

6, and further wherein;

the target specific portion further includes the polypeptide of SEQ ID NO;

2; and

the effector portion further includes the polypeptide of SEQ ID NO;

4 conjugated to SEQ ID NO;

3 by at least one disulphide bond;

and wherein the target specific portion is fused to the effector portion via the linker sequence that comprises the amino acid sequence ATATPGAA (SEQ ID NO;

     5).

7. A compound according to claim 1, comprising:

the polypeptide of SEQ ID NO;

6;

the polypeptide of SEQ ID NO;

7 conjugated to the polypeptide SEQ ID NO;

6 by at least one disulphide bond; and

the polypeptide of SEQ ID NO;

4 conjugated to the polypeptide SEQ ID NO;

6 by a disulphide bond.

10. The compound of claim 1, wherein the compound comprises the polypeptide of SEQ ID NO:

7, and further wherein;

the target specific portion further includes includes;

the polypeptide of SEQ ID NO;

1; and

the effector portion comprises;

the polypeptide of SEQ ID NO;

3; and

the polypeptide of SEQ ID NO;

4 conjugated to SEQ ID NO;

3 by at least one disulphide bond;

and wherein the target specific portion is fused to the effector portion via the linker sequence that comprises the amino acid sequence ATATPGAA (SEQ ID NO;

     5).

8. A compound comprising a target specific portion and an effector portion wherein:

(i) the target specific portion comprises a monoclonal antibody having specificity for oncofoetal fibronectin, or a fragment or variant thereof which retains the binding specificity for oncofoetal fibronectin of the parent monoclonal antibody; and

(ii) the effector portion comprises interleukin-12, or a functional fragment or variant thereof;

wherein the target specific portion is capable of binding an amino acid sequence within the repeat 7 domain of fibronectin, wherein;

the target specific portion comprises;

the polypeptide of SEQ ID NO;

1; and

;

the polypeptide of SEQ ID NO;

2; and

the effector portion comprises;

an IL12p35 domain; and

an IL12p40 domain conjugated to the IL12p35 domain by at least one disulphide bond;

and wherein the target specific portion is fused to the effector portion via the linker sequence that comprises the amino acid sequence ATATPGAA (SEQ ID NO;

     5).

9. The compound of claim 8, wherein the compound comprises a polypeptide selected from the group consisting of the polypeptide of SEQ ID NO:

6 and the polypeptide of SEQ ID NO;

7.