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Antibody vaccine conjugates and uses therefor

A technology of conjugates and antibodies, applied in the field of antibody vaccine conjugates and their applications, can solve the problems of no effective

Inactive Publication Date: 2006-05-03
CELLDEX THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Because existing methods do not 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 same patient

Method used

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  • Antibody vaccine conjugates and uses therefor
  • Antibody vaccine conjugates and uses therefor
  • Antibody vaccine conjugates and uses therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0228] Example 1: Production of βhCG-B11

[0229] 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 gene fusion method, the antigen and the heavy chain of the antibody are bonded through covalent bonding, as shown in FIG. 3 .

[0230] Recombinant Expression of βhCG-B11 Vaccine Conjugate : As shown in Figure 2, 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, cells are cloned b...

Embodiment 2

[0231] Example 2: Production of B11scfv-βhCG

[0232] Design of vaccine conjugates : A second construct was created 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 a fully human B11 antibody V L and V H fragments of single-chain antibodies. Through the method of gene fusion, the antigen is bonded to the carboxyl terminus of B11ScFv through covalent bonding, as shown in FIG. 1 (referred to as B11sfv-βhCG construct).

[0233] Recombinant Expression of B11sfv-βhCG Vaccine Conjugate : As shown in Figure 1, a plasmid containing the B11sfv-βhCG construct (SEQ ID NO: 11 and 12) was generated. 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 construct.

Embodiment 3

[0234]Example 3: Functional Characteristics of Vaccine Conjugates

[0235] 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 were used to confirm specific binding of the βhCG-B11 and B11sfv-βhCG constructs to cultured human DC expressing MR ( FIG. 4 ).

[0236] 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, immunohistochemistry 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-B11 ...

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Abstract

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

Description

[0001] related application [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 443,979, filed January 31,2003. The entire contents of the aforementioned applications are incorporated herein by reference. Background of the invention [0003] The immune response is initiated at the level of professional 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, thereby inducing potent immune responses. DCs also secrete cytokines, chemokines, and proteases that initiate the immune response and culminate in the amplification of both 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 become activat...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K39/38A61K39/395A61K39/42C07K14/59C07K16/00C07K16/28C07K17/00C12P21/08
CPCA61K39/0006A61K39/0011A61K2039/6056C07K14/59C07K16/28C07K2317/622C07K2317/77C07K2319/00A61K47/646A61K47/6811A61K47/6849C07K16/2851A61P31/12A61P35/00Y02A50/30A61K39/4615A61K39/464444A61K39/4622A61K2039/5154
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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