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

A chorionic gonadotropin, monoclonal antibody technology, used in antibody mimics/scaffolds, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, for targeting specific cell fusion, etc.

Inactive Publication Date: 2007-09-19
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

[0244] Example 1: Production of βhCG-B11

[0245] Vaccine conjugate design: The construct is produced by linking the βhCG antigen with B11, a complete human antibody that binds to the human macrophage mannose receptor on dendritic cells. Through the genetic fusion method, the heavy chain of the antigen and the antibody are covalently bonded to complete the bonding, as shown in Figure 3.

[0246] Recombinant expression of βhCG-B11 vaccine conjugate: As shown in Figure 2, a plasmid containing the neomycin gene and the dihydrofolate reductase gene is generated, which contains the antibody B11 in the heavy chain CH 3 Region-fused βhCG coding sequence (SEQ ID NO: 9 and 10). Using a standardized protocol (Qiagen Inc, Valencia, CA), the resulting plasmid construct was transfected into CHO cells. The transfected cells were selected in a medium containing the antibiotic G418. Let the cells grow in increasing concentrations of methotrexate to further amplify the expression. After expansion,...

Embodiment 2

[0247] Example 2: Production of B11scfv-βhCG

[0248] Vaccine conjugate design: The second construct is produced by linking the βhCG antigen with the B11 single-chain fusion (ScFv). The B11 single-chain fusion (ScFv) is capable of interacting with the mannose receptor of human macrophages on dendritic cells. Body binding and containing intact human B11 antibody V L And V H Fragmented single chain antibody. Through the genetic fusion method, the antigen and the carboxyl end of the B11 ScFv are covalently bonded to complete the bonding, as shown in Figure 1 (referred to as the B11sfv-βhCG construct).

[0249] Recombinant expression of the B11sfv-βhCG vaccine conjugate: As shown in Figure 1, a plasmid containing the B11sfv-βhCG construct (SEQ ID NO: 11 and 12) was generated. Using a standardized protocol (Qiagen Inc, Valencia, CA), the resulting plasmid construct was transfected into mammalian cells. The transfected cells were selected in a medium containing the antibiotic G418. ELIS...

Embodiment 3

[0250] Example 3: Functional characteristics of vaccine conjugates

[0251] The recognition of antibody-targeted vaccines on its associated receptors on the surface of APC is the first step of this drug delivery platform. Flow cytometry studies have confirmed that βhCG-B11 and B11sfv-βhCG constructs specifically bind to MR-expressing cultured human DC (Figure 4).

[0252] The anti-MR antibody was used as a probe to examine the in situ staining of MR on macrophages in human skin DCs and various human tissue sections. Frozen sections of human tissues were stained with anti-MR human antibody B11. The DC present in the epidermal layer of the skin was clearly labeled with the B11 antibody (data not shown). Note that there is a combination with DC in the epidermis of the skin. Furthermore, immunohistochemistry experiments with dendritic cells stained with anti-MR B11 HuMAb in all tissues showed no unexpected cross-reactivity (results not shown). These studies have been repeated with βhC...

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Abstract

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

Description

[0001] Related application [0002] This application claims priority to U.S. Provisional Patent Application No. 10 / 903,191 filed on July 30, 2004. The entire disclosure of the aforementioned application is incorporated herein by reference. Background of the invention [0003] The immune response starts at the level of specialized antigen presenting cells (APC), which include dendritic cells (DC) and macrophages (Mg) that are present in body tissues. DC express high levels of cell surface molecules and complement receptors, which interact with T lymphocytes and therefore can induce an effective immune response. DC also secretes cytokines, chemokines and proteases, which can initiate an immune response and culminate the expansion of cellular and humoral immunity. [0004] DC expresses major histocompatibility complex (MHC) molecules that bind antigen fragments on its surface. T cells expressing T cell receptors (TCR) that recognize such antigen-MHC complexes are activated and initiat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61P37/04A61K39/395A61K39/00C07K14/59C07K16/28
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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