ENGINEERED ANTIBODY-INTERFERON MUTANT FUSION MOLECULES

• US 20150139951A1
• Filed: 02/02/2015
• Published: 05/21/2015
• Est. Priority Date: 03/03/2012
• Status: Active Grant

• Current Assignee: ImmunGene Inc.
• Original Assignee: ImmunGene Inc.
• Inventors: Khare, Sanjay, Gresser, Michael, Syed, Rashid, Grewal, Iqbal
• Granted Patent: US 9,534,057 B2
• Time in Patent Office: Days
• US Class Current: 424/85.7
• 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 method of treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a genetically engineered fusion molecule comprising a tumor associated antigen (TAA) antibody attached to an interferon alpha (IFN-α

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

mutant molecule.

2. The method of claim 1, wherein the TAA antibody is selected from an 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.

3. The method of claim 2, wherein the IFN-α

mutant molecule is a mutated human IFN-α

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

13, wherein the mutation is selected from H57A, E58A, R162A, L30A, and F27A.

4. The method of claim 1, wherein the antibody is directly attached to the interferon mutant molecule with a peptide linker, wherein the peptide linker is selected from SEQ ID NO:

14 and SEQ ID NO;

15.

5. The method of claim 1, further comprising administering to the patient a therapeutically effective amount of a second therapeutic agent, wherein the second agent is selected from an alkylating agent, antimetabolite, immunomodulator, anti-neoplastic agent, anti-tumor agent, anti-angiogenic agent and chemotherapeutic agent.