Methods of enhancing antibody-dependent cellular cytotoxicity

a cytotoxicity and antibody technology, applied in the field of enhancing the cytotoxicity of therapeutic monoclonal antibodies, can solve the problems of low antibody activity, increased dosage and cost of treatment, and insufficient therapeutic effects on cancer, so as to increase the efficiency of a therapeutic monoclonal antibody and enhance the therapeutic effect of monoclonal antibodies. , the effect of increasing the efficiency of a therapeutic monoclonal antibody and increasing the ad

Inactive Publication Date: 2013-09-12
VENTIRX PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0038]The ADCC enhancer molecule enhances or improves the effector activity of an antibody. Thus, regardless of the antigen-binding activity, the methods of the present invention can increase the therapeutic effect of an antibody by enhancing the effector activity exhibited by the antibody. The ADCC enhancer molecule may improve ADCC by activating NK cells or CD56+ cells either directly or indirectly. Additionally, having a greater proportion of activated NK cells may help overcome the poor ADCC observed in a subset of patients that have low affinity Fc receptors.
[0041]According to some embodiments, methods are provided for enhancing the killing of NK sensitive target cells. In some embodiments, the method comprises administering to subject a therapeutically effective amount of a therapeutic antibody and an ADCC enhancer molecule in an amount sufficient to increase killing of NK sensitive target cells.
[0044]According to some embodiments, methods are provided for enhancing the therapeutic effectiveness of monoclonal antibodies. According to some embodiments, methods are provided for increasing the efficiency of a therapeutic monoclonal antibody. In some embodiments the method comprises administering to subject a therapeutically effective amount of a therapeutic antibody and an ADCC enhancer molecule in an amount sufficient to increase ADCC. Alternatively, the method of the present invention comprises administering to a subject a therapeutically effective amount of a therapeutic antibody, an ADCC enhancer molecule in an amount sufficient to increase ADCC and one or more chemotherapeutic agents.
[0045]According to some embodiments, methods are provided for increasing the clinical effectiveness of a therapeutic anti-ErbB2 monoclonal antibody comprising administering to a subject in need thereof the therapeutic anti-ErbB2 monoclonal antibody in combination with the ADCC enhancer molecule of the present invention. Alternatively, the method of the present invention comprises administering to a subject in need thereof the therapeutic anti-ErbB 2 monoclonal antibody in combination with the ADCC enhancer molecule of the present invention and one or more chemotherapeutic agents. In preferred embodiments, the anti-ErbB 2 monoclonal is trastuzumab.
[0047]According to some embodiments, methods are provided for increasing the clinical effectiveness of a therapeutic anti-CD20 monoclonal antibody comprising administering to a subject in need thereof the therapeutic anti-CD20 monoclonal antibody in combination with the ADCC enhancer molecule of the present invention. In preferred embodiments, the anti-CD 20 monoclonal is rituximab.
[0049]According to some embodiments, methods are provided for increasing the clinical effectiveness of a therapeutic anti-EGFR monoclonal antibody comprising administering to a subject in need thereof the therapeutic anti-EGFR monoclonal antibody in combination with the ADCC enhancer molecule of the present invention. The methods of the present invention also comprises administering to a subject in need thereof the therapeutic anti-EGFR monoclonal antibody in combination with the ADCC enhancer molecule of the present invention and one or more chemotherapeutic agents. In preferred embodiments, the anti-EGFR monoclonal is panitumumab, cetuximab, necitumumab, or zalutumumab.

Problems solved by technology

However, there are some instances of low antibody activity contributing to insufficient therapeutic effects on cancers, autoimmune diseases, inflammation, and infection.
Such insufficient drug action may lead to increased dosages and cost required for treatment.
Such antibodies bind to antigens on the surface of target cells, via their Fc domain, to Fc receptors on the surface of effector cells such as NK cells and macrophages, thereby exerting damage on target cells.

Method used

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  • Methods of enhancing antibody-dependent cellular cytotoxicity
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  • Methods of enhancing antibody-dependent cellular cytotoxicity

Examples

Experimental program
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Effect test

example 1

Enhancement of the Therapeutic Effectiveness of Monoclonal Antibody Therapy by Enhancing NK Activity and ADCC Including ADCC in Genetically Resistant Populations

[0190]A subcutaneous formulation comprising the ADCC enhancer {2-amino-8-[4-(pyrrolidinylcarbonyl)phenyl]-(3H-benzo[f]azepin-4-yl)}-N,N-dipropylcarboxamide was used for the experiments. The structure for {2-amino-8-[4-(pyrrolidinylcarbonyl)phenyl]-(3H-benzo[f]azepin-4-yl)}-N,N-dipropylcarboxamide is as follows:

[0191]Stimulation of PBMCs:

[0192]Human Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll™ density gradient centrifugation and resuspended in RPMI containing 2% heat-inactivated FBS. PBMCs at a concentration of 1 to 3 million cells per mL were incubated with 10-500 nM ADCC enhancer in a humidified CO2 incubator for 18-72 hrs. Activated PBMCs were then used as effector cells in NK and ADCC assays.

[0193]NK and ADCC Assays:

[0194]PBMCs activated with the ADCC enhancer were tested for the ability to enhance ...

example 2

Polymorphisms of FcγR and Cancer Treatment

[0199]ADCC is mediated through immune effector cells included NK cells that engage the Fc portion of the monoclonal antibody through specific receptors. Patients with single nucleotide polymorphisms in these receptors such as FcRgamma3a position 158 and FcRgamma2a position 131 have a poorer clinical prognosis presumably from poor ADCC due to a lower affinity of the receptor for the monoclonal antibody. Previous studies have found that a polymorphism in the FcγR3A molecule (158F / V) that alters the molecule's affinity for IgG1 is an important factor determining the clinical efficacy seen with some monoclonal antibodies (mAbs) used in the treatment of cancer. To determine if this common polymorphism affects the baseline antibody-dependent cellular cytoxicity (ADCC) response and / or response to the ADCC enhancer molecule of the present invention (Compound VTX-2337), PBMCs from donors were genotyped for the two alleles encoding the F and V isoform...

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Abstract

The application relates to method of increasing antibody-dependent cellular cytotoxicity in a subject receiving therapeutic monoclonal antibody treatment. In some embodiments, methods are provided for administering to subject to a subject in need thereof a therapeutic antibody in conjunction with an ADCC enhancer molecule.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Ser. No. 61 / 326,406, filed Apr. 21, 2010, the contents of which are incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE[0002]Embodiments of the present disclosure are directed to methods of enhancing the cytotoxicity of therapeutic monoclonal antibodies for the treatment of cancer and other cellular diseases.BACKGROUND OF THE DISCLOSURE[0003]Monoclonal antibodies (MAbs) have demonstrated clinical effectiveness in a variety of malignancies. Monoclonal antibodies are now being commonly used as therapeutic agents for the treatment and / or prevention of cancers, autoimmune diseases, thrombosis, inflammation, and infection. However, there are some instances of low antibody activity contributing to insufficient therapeutic effects on cancers, autoimmune diseases, inflammation, and infection. Such insufficient drug action may lead to increased dosages and cost required for treatment....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55A61K45/06A61K39/395
CPCA61K31/55A61K39/395A61K45/06A61K2300/00C07K16/2863A61K39/39558C07K16/32C07K16/2887C07D223/16A61P1/00A61P1/04A61P15/00A61P19/02A61P25/00A61P29/00A61P35/00A61P35/02A61P35/04A61P43/00A61K39/39A61K2039/505C07K16/3046C07K2317/21C07K2317/24C07K2317/732
Inventor HERSHBERG, ROBERT
Owner VENTIRX PHARMA
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