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Bivalent antibody directed against NKG2D and tumor associated antigens

A tumor-related antigen and antibody technology, applied in the direction of antibodies, anti-tumor drugs, antibody medical components, etc.

Inactive Publication Date: 2018-01-02
OHIO STATE INNOVATION FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, no bispecific adapter protein has been designed to cross-trigger all killer immune cells, including CD8+ T cells, NK cells, NKT cells, and γδ T cells, etc.

Method used

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  • Bivalent antibody directed against NKG2D and tumor associated antigens
  • Bivalent antibody directed against NKG2D and tumor associated antigens
  • Bivalent antibody directed against NKG2D and tumor associated antigens

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1: Preparation and properties of anti-CS-1 TriCLE

[0122] Materials and methods

[0123] Cloning of anti-CS1 and anti-EGFRvIII TriCLE. TriCLE was designed in silico and synthesized as a gene fragment (Invitrogen). This gene fragment was cloned into expression vectors (eg, pGEX6p-1 and pET21d). SEQ ID NO: 1 and SEQ ID NO: 2 provide the nucleotide sequences of pET21d-TriCLE and pGEX6p-1-TriCLE, respectively.

[0124] Protein preparation: Protein expression was induced by adding 100 μM IPTG and maintaining overnight at 30°C. Bacterial cells were then harvested and lysed by sonication in lysis buffer containing Tris pH 7.4 and protease inhibitors. TriCLE protein was purified on a HisTRAP column (GE Health Science), refolded and dialyzed against PBS / glycerol using a centrifugal filter unit. The concentration of TriCLE was measured and diluted for use in the experiment.

[0125] Flow Cytometry: The binding affinity of TriCLE was tested by using flow cytomet...

Embodiment 2

[0176] Example 2: Cytotoxicity of NK cells activated by anti-CS-1 Tri-CLE to multiple myeloma (MM) cells

[0177] image 3 is a graph of the cytotoxicity of the NK cell line NKL against the multiple myeloma (MM) cell line H929 in the presence of anti-CS-1 Tri-CLE. Increasing doses of Tri-CLE ranging from 50 pg / mL to 10 μg / mL were added to co-cultures of NKL:H929 at an effector ratio of 20:1.

Embodiment 3

[0178] Example 3: Anti-CS-1 TriCLE effectively stains multiple myeloma cells

[0179] When anti-CS-1 TriCLE was used as a staining reagent for flow cytometry, it stained 80% of MM1.s, a typical cell line isolated from multiple myeloma patients ( Figure 4A ). Mean fluorescence intensity was significantly enhanced when compared to isotype controls. This indicates that the CS1 scFv is functional ( Figure 4B ).

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Abstract

A polypeptide is disclosed that binds tumor-associated antigens (TAA) on the surface of cancer cells and a NKG2D receptor. The NKG2D receptor is expressed on the surfaces of killer cells such as natural killer cells, T cells, natural killer T cells, and gamma delta T cells. In some cases, the TAA is CS-1 or EGFRvIII. Also disclosed are polynucleotides encoding the disclosed polypeptides, vectors comprising the disclosed polynucleotides, and host cells comprising the disclosed vectors. Also disclosed are bivalent antibodies comprising the disclosed polypeptides. Also disclosed are pharmaceutical compositions comprising the disclosed antibodies. Also disclosed are methods of treating cancer in a subject using the disclosed bi-specific antibodies.

Description

[0001] Cross references to related patent applications [0002] This application claims the benefit of U.S. Provisional Application 62 / 118,561, filed February 20, 2015, and U.S. Provisional Application 62 / 119,645, filed February 23, 2015, both of which are hereby incorporated by reference in their entirety This article. Background technique [0003] In 2014, 1.6 million new cancer cases were diagnosed and 585,720 deaths were reported. Current treatment relies heavily on chemotherapy, radiation, surgery and bone marrow transplantation. However, these treatments can be associated with serious side effects, and in some cases, the cancer does not respond to these treatments. Therefore, novel therapies are urgently needed. Cancer immunotherapies are promising because they are highly specific and efficiently induce tumor-lytic activity from lymphocytes. Fusion proteins such as bispecific T cell engagers or bispecific killer cell engagers (BiTE and BiKE) are cancer immunotherapie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/18C07H21/00C12N15/63C12N1/21C12N1/19C12N1/15
CPCC07K16/2851C07K16/2863C07K2317/31C07K2317/622C07K2317/73C07K16/2803A61P35/00A61K38/1774A61K39/39558
Inventor 迈克尔·卡利朱里陈永强余建华
Owner OHIO STATE INNOVATION FOUND
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