Vaccines based on Fibronectin Extra Domain A (EDA) or Extra Domain B (EDB)
Extra domain A and B from fibronectin are capable of binding to toll-like receptor 4 (TLR4) and stimulating dendritic cells to produce pro-inflammatory cytokines. Therefore EDA/EDB could be used as an excellent target for vaccine development. Creative Biolabs is currently developing several EDA-based candidate vaccines for the treatment of malignant tumors including breast cancer, cervical cancer, and colorectal cancer.
Fibronectin Extra Domain A and Extra Domain B
As a ubiquitous multidomain extracellular matrix (ECM) component, fibronectin (FN) contains a number of fibronectin type III (FNIII) repeats with different functions. This is critical in many ECM-dependent processes such as cell adhesion, migration, growth and differentiation. Certain functions of fibronectin depend on the presence of the alternatively spliced type III repeats extra domains A (FNIII EDA) and B (FNIII EDB). These additional domains are expressed near the developing blood vessels during embryogenesis and are expressed under specific conditions (after tissue damage, etc.), within tumors, and at sites of chronic inflammation (psoriasis lesions, etc.). Although not fully understood, FNIII EDA and EDB are known to stimulate Toll-like receptor 4 (TLR4).
Fig.1 FNIII EDA-containing FN fragments produced and of full-length FN with some of its interaction sites displayed. (Julier Z. 2015)
Therapeutic Vaccination against EDA and EDB
The alternatively spliced extra domain A (EDA) and B (EDB) of fibronectin are expressed during embryonic angiogenesis, but are essentially undetectable in adults under normal conditions. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, making them excellent targets for cancer therapy. EDA immunization increases macrophage infiltration and impairs tumor vascular function. Both EDA and EDB are highly expressed around the angiogenic vessels of various tumor types and exhibit strong conservation between species. After tumorigenesis, anti-EDA or anti-EDB immunity can be induced, thereby significantly reducing tumor burden. This is accompanied by an increase in the infiltration of macrophages into the tumor and a decrease in the function of the tumor vasculature in terms of leakage and perfusion.
Fig.2 Generation of domain-specific vaccine proteins and anti-sera against ED-A and ED-B. (Femel J. 2014)
TLR4 Agonist EDA and EDB Expression Service
- E. coli expression system. E. coli expression system is the primary choice of the bacterial expression systems and is commonly used for laboratory research and commercial activities. Methods for producing proteins in E. coli are well-established and the yields are high.
- Chloroplasts expression system. In recent years, the plant expression system has received much attention for their low cost and with the compatibility, safety and oral delivery characteristics of inexpensive, simple, well-defined industrial media. Creative Biolabs has successfully expressed recombinant EDA and EDB in tobacco chloroplasts, which retain their proinflammatory properties of the EDA produced in E. coli.
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References
- Julier Z, et al. The TLR4 agonist fibronectin extra domain A is cryptic, exposed by elastase-2; use in a fibrin matrix cancer vaccine. J Immunol. 2015, 5: 8569.
- Femel J, et al. Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. Oncotarget. 2014, 5(23): 12418-27.
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