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Immunomodulation by Anti-cd3 immunotoxins to treat cancers not uniformly bearing surface cd3

an immunotoxin and immunomodulation technology, applied in the field of immunomodulation by anticd3 immunotoxins to treat cancers not, can solve the problems of individual immune system not being able to destroy, affecting the survival rate of patients, and taking a few months or even years to achieve the maximum level, etc., to achieve the effect of prolonging the survival tim

Inactive Publication Date: 2015-06-18
ANGIMMUNE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides methods for improving the lives of patients with certain cancers that don't have certain proteins on their surface. These methods involve giving the patient an antibody that targets a specific protein, which helps to reduce the number of certain immune cells in the patient. This allows new and mature immune cells to grow in the patient, while still targeting the cancer cells.

Problems solved by technology

In cases of full-blown cancer, an individual's immune system has not been able to destroy cancer cells, possibly because they arise from pre-existing cells of the body and are thus recognized as innocuous “self” cells rather than as potentially dangerous “foreign” invaders.
The effects are usually delayed and can take a few months or even years to achieve their maximum levels.
However, given the many types of cancers, the complexity of the disease, and the limited and variable efficacies of existing agents, this strategy is not always successful, and there remains an ongoing need to identify new anti-cancer agents and / or a need for new ways of using existing agents.
In addition, currently known immunomodulatory agents typically have adverse side effects such as the development of autoimmune diseases.
This likely results from the breaking of tolerance to self antigens during repopulation, which, in addition to the cancer cells, the immune system then “sees” as abnormal.
However, these patents do not describe the use of these immunotoxins as immunodulatory agents.

Method used

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  • Immunomodulation by Anti-cd3 immunotoxins to treat cancers not uniformly bearing surface cd3
  • Immunomodulation by Anti-cd3 immunotoxins to treat cancers not uniformly bearing surface cd3
  • Immunomodulation by Anti-cd3 immunotoxins to treat cancers not uniformly bearing surface cd3

Examples

Experimental program
Comparison scheme
Effect test

example 1

of Cutaneous T Cell Lymphoma with A-dmDT390-bisFv(UCHT1)

[0033]A number of immunomodulators have been used to treat solid cancers such as renal cell cancer and melanoma. Among these are infusions of IL-2 and antibodies directed at the activating lymphocyte epitopes CTLA-4 and the inhibitory lymphocyte epitope PD1 as well as its ligand PD1-L The response rates for anti-CTLA-4, ipilimumab; have been low, around 10-15%. Immunomodulators such as anti-CTLA-4 or IL-2 May have a higher response rate on solid tumors when combined with local radiation therapy of metastatic lesions, likely by increasing the pool of presentable tumor antigen (abscopal effect).

[0034]An unfortunate side effect of the immunomodulators IL-2, anti-CTLA-4, anti-PD1 and anti-PD1-L is an increased incidence of autoimmune diseases, presumably because of enhanced T cell activity that breaks tolerance toward self antigens.

[0035]A-dmDT390-bisFv (UCHT1), an anti-T cell immunotoxin, is being studied as a treatment for cutane...

example 2

Study of A-dmDT390-bisFv (UCHT1) Fusion Protein in Patients with Surface CD3+ Malignant T Cell Disease: Summary of Patients # 2 & 7

[0037]Patient #2 is an 82-year-old Caucasian male who developed cutaneous T cell lymphoma (CTCL) with a maculopapular rash on his buttocks and a groin mass. Biopsy of both lesions showed lymphoblastoid T-cell lymphoma. A computed tomography (CT) scan showed diffuse adenopathy. He received six cycles of CHOP chemotherapy (i.e., cyclophosphamide, doxorubcin, vincristine, and methylprednisolone), but after several years the rash recurred. Biopsy again showed CTCL. He did not have node or marrow involvement based on CT scans and bone marrow biopsies and was staged as IB. He was treated with A-dmDT390-bisFv(UCHT1) and achieved a response lasting 17 months, which included partial remission (PR) of 11 months duration and complete remission (CR) of 6 months duration. Patient #2 was then removed from the study due to return of buttock lesions that responded to na...

example 3

dmDT390-bisFv (UCHT1) as an Immunomodulator

[0041]Based on the results obtained in Examples 1 and 2, A-dmDT390-bisFv (UCHT1) is administered as an immunomodulator of late stage metastatic melanoma or renal cell cancer in combination with palliative radiation to induce the priming of activated T cells by releasing tumor antigens. The safety of combining the immunotixin with palliative radiation therapy in patients with stage IV melanoma or renal cell cancer is determined. The tumor response and duration of response at non-irradiated sites (abscopal effect) is documented. T cell activation occurring after administration of A-dmDT390-bisFv(UCHT1) and local radiation to a metastatic lesion of melanoma or renal cell cancer is assessed by following CD4+ T cells for HLA-DR and ICOShigh T cells using flow cytometry.

[0042]20 μg / kg dose (see Example 1) is chosen for immunomodulation. The A-dmDT390-bisFv (UCHT1) dose of 20 μg / kg total is given as 2.5 μg / kg / injection twice a day at 4-6 hours int...

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Abstract

Methods of modulating the immune systems of patients suffering from cancers that do not hear, or do not uniformly bear, surface CD3 are provided. The methods involve administering an anti-CD3 immunotoxin (e.g. A-dmDT390-bisFv(UCHT1)), to the patient so a to cause the patient's Immune system to recognize and destroy non-CD3 cancer cells.

Description

BACKGROUND OP THE INVENTION[0001]1. Field of the Invention[0002]The invention generally relates to methods of treating patients suffering from cancers that do not bear, or do not uniformly bear, surface CD3 epitopes. In particular, the methods involve administering anti-CD3 immunotoxins to modulate the immune systems of such patient and achieve long-term immune protection against non-CD3 cancers.[0003]2. Background of the Invention[0004]Two important tools in the treatment of cancer are immunotoxins and immunomodulatory agents. Immunotoxins are anti-human recombinant fusion proteins that target and kill specific types of cancer mils. Targeting is typically mediated via a targeting portion of the protein (e.g. a modified antibody or antibody fragment specific for binding to a particular epitope of interest), and killing is typically carried out by a toxin moiety that is attached to the targeting portion. Upon administration, immunotoxins thus directly target and bind to cancer cells ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28A61K39/00A61K39/395
CPCC07K16/2809A61K2039/505A61K39/0011A61K39/3955A61K38/164C07K16/30A61K2039/545C07K2317/35C07K2317/622C07K2319/00A61P35/00Y02A50/30C07K2317/73A61K47/6829A61K47/6849A61K47/6879
Inventor NEVILLE, JR., DAVID M.
Owner ANGIMMUNE