Modulation of TIM receptor activity in combination with cytoreductive therapy

• US 8,709,412 B2
• Filed: 07/05/2011
• Issued: 04/29/2014
• Est. Priority Date: 06/29/2001
• Status: Expired due to Fees

• Current Assignee: Children's Medical Center Corporation, Dana-Farber Cancer Institute, Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Dana-Farber Cancer Institute, The Children's Hospital Corporation (Harvard University), Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Jones, Jennifer, Dekruyff, Rosemarie, Umetsu, Dale T., Freeman, Gordon J., Knox, Susan Jane
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US13/176,651
• Publication Number:
  US 20120156224A1
• Time in Patent Office: 1,029 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 39/001102 Receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen

Abstract

A genetic locus and corresponding family of proteins associated with regulation of immune function and cell survival are provided. These genes encode cell surface molecules with conserved IgV and mucin domains. The locus comprising the TIM family is genetically associated with immune dysfunction, including asthma. Furthermore, the TIM gene family is located within a region of human chromosome 5 that is commonly deleted in malignancies and myelodysplastic syndrome. Polymorphisms in the gene sequences are associated with the development of airway hyperreactivity and allergic inflammation, and T cell production of IL-4 and IL-13. The proteins include the human hepatitis A cellular receptor, hHAVcr-1.

Claims

1. A method for the treatment of malignancy in an individual, the method comprising:

administering to said individual an agonistic antibody or fragment thereof that specifically binds to a human T cell/transmembrane, immunoglobulin, and mucin (TIM) encoded polypeptide selected from TIM-1 polypeptide and human TIM-4 polypeptide, in combination with radiation therapy.

2. The method according to claim 1, wherein said TIM polypeptide is TIM-1.

3. The method according to claim 1, wherein said TIM polypeptide is TIM-4.

4. The method of claim 1, wherein distribution of phosphatidylserine (PS) in the individual is determined prior to or in conjunction with administering said antibody or fragment thereof, wherein an individual in which the PS is bound to a tumor cell of the malignancy is selected for administration of the antibody or fragment thereof.

5. The method of claim 4, wherein the distribution of phosphatidylserine is determined by in vivo imaging with a labeled phosphatidylserine binding agent.

6. A method for the treatment of malignancy in an individual, the method comprising:

administering to said individual an antagonistic antibody or fragment thereof that specifically binds to human T cell/transmembrane, immunoglobulin, and mucin (TIM) encoded polypeptide TIM-3 in combination with radiation therapy to a local irradiation field, wherein the antagonistic antibody is provided at a dose that boosts immune responsiveness after radiation therapy to generate a response to sites of metastatic disease outside of the irradiation field.