Engineered antibody-interferon mutant fusion molecules

• US 8,980,267 B2
• Filed: 03/04/2013
• Issued: 03/17/2015
• Est. Priority Date: 03/03/2012
• Status: Active Grant

• Current Assignee: ImmunGene Inc.
• Original Assignee: ImmunGene Inc.
• Inventors: Grewal, Iqbal, Khare, Sanjay, Gresser, Michael, Syed, Rashid
• Primary Examiner(s): Landsman, Robert
• Assistant Examiner(s): Hissong, Bruce D
• Application Number:
  US13/784,049
• Publication Number:
  US 20130230517A1
• Time in Patent Office: 743 Days
• Field of Search: None
• US Class Current: 424/134.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: 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
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2851 against the lectin superfamily, e.g. CD23, CD72
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/90 characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• 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
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Abstract

The field of the present invention relates to genetically engineered fusion molecules, methods of making said fusion molecules, and uses thereof in anti-tumor immunotherapies. More specifically, the present invention relates to fusion molecule constructs wherein a tumor associated antigen (TAA) antibody (Ab) serves as a targeting moiety to selectively deliver a cytokine to a tumor cell for purposes of killing or inhibiting the growth or proliferation of said tumor cell. In various embodiments, the engineered fusion molecules comprise a TAA Ab fused to an interferon-alpha (IFN-α) mutant molecule. The engineered Ab-IFN-α mutant fusion molecules of the present invention demonstrate improved therapeutic index and preserved or increased efficacy as compared to Ab-wildtype IFN-α fusion molecules, and/or demonstrate improved PK properties as compared to Ab-wildtype IFN-α fusion molecules.

Claims

1. A genetically engineered fusion molecule comprising a tumor-associated antigen (TAA) antibody (Ab) attached to an interferon alpha (IFN-α

) mutant molecule, wherein said antibody is attached directly to said IFN-α

mutant molecule, wherein said IFN-α

mutant molecule is a mutated human IFN-α

2 molecule comprising at least one mutation in SEQ ID NO;

13, wherein said mutation is selected from H57A, E58A, L30A, and F27A, and wherein the TAA antibody is an IgG antibody.

2. A fusion molecule of claim 1, wherein said fusion molecule demonstrates improved pharmacokinetics (PK) properties as compared to a TAA Ab-wildtype_IFN-α

fusion molecule.

3. A fusion molecule of claim 1, wherein said fusion molecule when contacted to a tumor cell results in the killing or inhibition of growth or proliferation of said tumor cell.

4. A fusion molecule of claim 1, wherein said TAA antibody is an antibody selected from the group consisting of anti-HER2/neu, anti-HER3, anti-HER4, anti-CD4, anti-CD19, anti-CD20, anti-CD22, anti-CD25, anti-CD33, anti-CD138, anti-CD200, anti-CD276, anti-CXCR3, anti-CXCR5, anti-CCR3, anti-CCR4, anti-CCR9, anti-CRTH2, anti-PMCH, and anti-endoplasmin antibody.

5. A fusion molecule of claim 1, wherein the TAA antibody is an anti-HER2/neu antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation F27A in SEQ ID NO;

13.

6. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD20 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation F27A in SEQ ID NO;

13.

7. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD138 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation F27A in SEQ ID NO;

13.

8. A fusion molecule of claim 1, wherein the TAA antibody is an anti-endoplasmin antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation F27A in SEQ ID NO;

13.

9. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD33 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation F27A in SEQ ID NO;

13.

10. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD276 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation F27A in SEQ ID NO;

13.

11. A fusion molecule of claim 1, wherein the TAA antibody is an anti-HER2/neu antibody and wherein the mutated human IFN-α

2 molecule comprises the two mutations R149A and R162A in SEQ ID NO;

13.

12. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD20 antibody and wherein the mutated human IFN-α

2 molecule comprises the two mutations R149A and R162A in SEQ ID NO;

13.

13. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD138 antibody and wherein the mutated human IFN-α

2 molecule comprises the two mutations R149A and R162A in SEQ ID NO;

13.

14. A fusion molecule of claim 1, wherein the TAA antibody is an anti-endoplasmin antibody and wherein the mutated human IFN-α

2 molecule comprises the two mutations R149A and R162A in SEQ ID NO;

13.

15. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD33 antibody and wherein the mutated human IFN-α

2 molecule comprises the two mutations R149A and R162A in SEQ ID NO;

13.

16. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD276 antibody and wherein the mutated human IFN-α

2 molecule comprises the two mutations R149A and R162A in SEQ ID NO;

13.

17. A fusion molecule of claim 1, wherein the TAA antibody is an anti-HER2/neu antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation R162A in SEQ ID NO;

13.

18. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD20 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation R162A in SEQ ID NO;

13.

19. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD138 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation R162A in SEQ ID NO;

13.

20. A fusion molecule of claim 1, wherein the TAA antibody is an anti-endoplasmin antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation R162A in SEQ ID NO;

13.

21. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD33 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation R162A in SEQ ID NO;

13.

22. A fusion molecule of claim 1, wherein the TAA antibody is an anti-CD276 antibody and wherein the mutated human IFN-α

2 molecule comprises the mutation R162A in SEQ ID NO;

13.

23. A fusion molecule of claim 1, wherein said antibody is directly joined attached to said interferon mutant molecule with a peptide linker, wherein said peptide linker is selected from SEQ ID NO:

14 and SEQ ID NO;

15.

24. A pharmaceutical composition comprising a fusion molecule of claim 1 in a pharmaceutically acceptable carrier.