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Vaccine conjugate including a human chorionic gonadotropin beta subunit antigen linked to an anti-mannose receptor (mr) antibody

A conjugate and antibody technology, applied in the direction of antibody mimic/scaffold, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, for targeting specific cell fusion, etc.

Inactive Publication Date: 2013-03-27
CELLDEX THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Because existing methods cannot efficiently and specifically target APCs, many therapeutic vaccines require DCs to be purified from a patient, exposed to the antigen, and reinfused back into the patient

Method used

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  • Vaccine conjugate including a human chorionic gonadotropin beta subunit antigen linked to an anti-mannose receptor (mr) antibody
  • Vaccine conjugate including a human chorionic gonadotropin beta subunit antigen linked to an anti-mannose receptor (mr) antibody
  • Vaccine conjugate including a human chorionic gonadotropin beta subunit antigen linked to an anti-mannose receptor (mr) antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] Example 1: Production of βhCG-B11

[0246] Design of vaccine conjugates : This construct was generated by linking the βhCG antigen to B11, a fully human antibody that binds to the human macrophage mannose receptor on dendritic cells. Through the method of genetic fusion, the antigen and the heavy chain of the antibody are bonded through covalent bonding, such as image 3 shown.

[0247] Recombinant Expression of βhCG-B11 Vaccine Conjugate :Such as figure 2 As shown, a plasmid containing the neomycin gene and the dihydrofolate reductase gene containing the antibody B11 in the heavy chain CH 3 βhCG coding sequence (SEQ ID NO: 9 and 10) fused to the region. The resulting plasmid constructs were transfected into CHO cells using standardized protocols (Qiagen Inc, Valencia, CA). Transfected cells were selected in medium containing the antibiotic G418. Expression is further amplified by growing cells in increasing concentrations of methotrexate. After expansion, ce...

Embodiment 2

[0248] Example 2: Production of B11scfv-βhCG

[0249] Design of vaccine conjugates : A second construct was generated by linking the βhCG antigen to a B11 single-chain fusion (ScFv) that binds to the human macrophage mannose receptor on dendritic cells and contains intact human B11 Antibody V L and V H fragments of single-chain antibodies. Through the method of genetic fusion, the antigen is bonded to the carboxyl terminus of B11 ScFv through covalent bonding, such as figure 1 (referred to as B11sfv-βhCG construct).

[0250] Recombinant Expression of B11sfv-βhCG Vaccine Conjugate :Such as figure 1 Plasmids containing the B11sfv-βhCG constructs (SEQ ID NOs: 11 and 12) were generated as indicated. The resulting plasmid constructs were transfected into mammalian cells using standardized protocols (Qiagen Inc, Valencia, CA). Transfected cells were selected in medium containing the antibiotic G418. ELISA was performed to confirm the expression of the B11sfv-βhCG constr...

Embodiment 3

[0251] Example 3: Functional Characteristics of Vaccine Conjugates

[0252] Recognition of antibody-targeted vaccines to their cognate receptors on the surface of APCs is the first step in this drug delivery platform. Flow cytometry studies have demonstrated that the βhCG-B11 and B11sfv-βhCG constructs specifically bind to cultured human DCs expressing MR ( Figure 4 ).

[0253] In situ staining of MR on macrophages in human skin DCs and various human tissue sections was examined using an anti-MR antibody as a probe. Cryosections of human tissue were stained with anti-MR human antibody B11. DCs present in the epidermal layer of the skin were clearly labeled with B11 antibody (data not shown). Binding to DC was noted in the epidermal layer of the skin. Furthermore, immunohistochemical experiments with dendritic cells stained with anti-MR B11 HuMAb in all tissues tested and showed no unexpected cross-reactivity (results not shown). These studies have been repeated with βhCG...

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Abstract

The present invention provides novel antibody vaccine conjugates and methods of using the conjugates to induce cytotoxic T cell (CTL) responses. In a specific embodiment, the vaccine conjugate comprises human chorionic gonadotropin beta subunit (beta hCG) antigen linked to an anti-mannose receptor (MR) antibody.

Description

[0001] related application [0002] This application claims priority to US Provisional Patent Application No. 10 / 903,191, filed July 30,2004. The entire disclosure of the above application is incorporated herein by reference. Background of the invention [0003] The immune response is initiated at the level of specialized antigen-presenting cells (APCs), which include dendritic cells (DCs) and macrophages (Mgs) present in body tissues. DCs express high levels of cell surface molecules and complement receptors that interact with T lymphocytes and are thus able to induce potent immune responses. DCs also secrete cytokines, chemokines, and proteases that are capable of initiating immune responses and culminating in the amplification of cellular and humoral immunity. [0004] DCs express major histocompatibility complex (MHC) molecules on their surface that bind antigen fragments. T cells expressing T cell receptors (TCRs) that recognize such antigen-MHC complexes are activated...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/28A61P37/04A61K39/395A61K39/00C07K14/59
CPCA61K39/0006C07K14/59C07K16/2851C07K2317/622C07K2319/00A61K39/0011C07K2317/77C07K16/28A61K2039/5154A61K2039/6056C07K2318/10C07K2317/73C07K2319/33A61P31/04A61P31/12A61P33/02A61P35/00A61P37/04Y02A50/30A61K2039/572C07K2317/21C07K2317/33C07K2317/56C07K2317/565
Inventor T·克勒M·恩德雷斯L·何V·拉马克里什纳
Owner CELLDEX THERAPEUTICS INC
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