Jennerex Biotherapeutics, Inc. (now owned by SillaJen) was an American

private Private or privates may refer to: Music * " In Private", by Dusty Springfield from the 1990 album ''Reputation'' * Private (band), a Denmark-based band * "Private" (Ryōko Hirosue song), from the 1999 album ''Private'', written and also recorde ...

biopharmaceutical A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...

company that developed the

oncolytic virus An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by lysis#Oncolysis, oncolysis, they release new infectious virus particles or virus, virions to help destroy the remaining ...

es JX-594 and JX-929 among others. By creating oncolytic viruses that can (1) kill tumor cells directly through

lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...

, (2) activate the immune system by delivering genes that encode

immunostimulant Immunostimulants, also known as immunostimulators, are substances (drugs and nutrients) that stimulate the immune system by inducing activation or increasing activity of any of its components. One notable example is the granulocyte macrophage colon ...

s and by overcoming tumor cell-induced

immunological tolerance Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...

, and (3) reduce tumor nutrient supply through the destruction of blood vessels, Jennerex aimed to create a novel approach to treating and possibly curing cancer.

Company

Jennerex received its name in honor of

Edward Jenner Edward Jenner, (17 May 1749 – 26 January 1823) was a British physician and scientist who pioneered the concept of vaccines, and created the smallpox vaccine, the world's first vaccine. The terms ''vaccine'' and ''vaccination'' are derived f ...

, the pioneer of the

smallpox vaccine The smallpox vaccine is the first vaccine to be developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox ...

and "the father of immunology".

Locations

Headquarters are located in the

Financial District, San Francisco The Financial District is a neighborhood in San Francisco, California, United States, that serves as its main central business district and had 372,829 jobs according to U.S. census tracts as of 2012-2016. It is home to the city's largest concen ...

. R&D and manufacturing operations are located at the

UCSF The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California. It is part of the University of California system and is dedicated entirely to health science and life science. It condu ...

Mission Bay campus in San Francisco, at the

Ottawa Hospital Research Institute The Ottawa Hospital Research Institute (OHRI), formerly Ottawa Health Research Institute, is a non-profit academic health research institute located in the city of Ottawa. It was formed in 2001 following the merger of three Ottawa hospitals. The O ...

(OHRI) in

Ottawa Ottawa (, ; Canadian French: ) is the capital city of Canada. It is located at the confluence of the Ottawa River and the Rideau River in the southern portion of the province of Ontario. Ottawa borders Gatineau, Quebec, and forms the core ...

Ontario Ontario ( ; ) is one of the thirteen provinces and territories of Canada.Ontario is located in the geographic eastern half of Canada, but it has historically and politically been considered to be part of Central Canada. Located in Central Ca ...

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

, and at SillaJen, Inc. in

Busan Busan (), officially known as is South Korea's most populous city after Seoul, with a population of over 3.4 million inhabitants. Formerly romanized as Pusan, it is the economic, cultural and educational center of southeastern South Korea, w ...

South Korea South Korea, officially the Republic of Korea (ROK), is a country in East Asia, constituting the southern part of the Korea, Korean Peninsula and sharing a Korean Demilitarized Zone, land border with North Korea. Its western border is formed ...

Company History

2003. Jennerex, Inc. (

San Francisco San Francisco (; Spanish language, Spanish for "Francis of Assisi, Saint Francis"), officially the City and County of San Francisco, is the commercial, financial, and cultural center of Northern California. The city proper is the List of Ca ...

, USA) was established. 2007. Jennerex completed Pexa-Vec Phase 1 clinical trial (HEP001). 2008. Jennerex initiated Pexa-Vec Phase 2a clinical trial (HEP007). 2009.

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) designated Pexa-Vec as an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

for Live Cancer. 2011. Jennerex initiated Pexa-Vec Phase 2b clinical trial (HEP018) for Liver Cancer. 2013. US

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

designated Pexa-Vec as an

. 2014. SillaJen acquires Jennerex, Inc. SillaJen changed its name after the acquisition to SillaJen Biotherapeutics.

Pipeline

Oncolytic viruses developed by Jennerex are based on the

vaccinia virus ''Vaccinia virus'' (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...

Pexa-Vec (Jx-594)

Pexa-Vec is an engineered oncolytic virus that selectively destroys cancer cells and induces tumor immune response. Uncontrolled cell division, inactivation of the

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

pathway that is necessary to defend against viral infections, and constitutively active EGFR-

Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...

signaling pathway, are common features of

cancer cell Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...

s. These features enable rapid replication of the JX-594 virus and lysis of the host cancer cells. Deletion of

thymidine kinase Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...

(TK) from the JX-594 genome prevents virus replication in normal cells. The immunostimulatory cytokine

GM-CSF Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

is produced from the JX-594 genome following infection, inducing immune response against both the virus and the tumor and enabling lasting tumor immunity. Finally, JX-594 reduces nutrient supply to tumors through blood vessel destruction. Because JX-594 is based on the Wyeth strain vaccinia virus that is commonly used for vaccination, it is well tolerated by rats, rabbits, and humans.

Design

To engineer JX-594, human ''GMCSF'' gene (encoding

granulocyte macrophage colony-stimulating factor Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts th ...

or GM-CSF; driven by a synthetic early/late promoter) and ''lacZ'' gene (encoding

β-galactosidase β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyst, catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosi ...

or β-gal; driven by the p7.5 early/late promoter) were inserted into the ''TK'' gene (encoding

or TK) in the J segment of the Wyeth strain

. Elimination of TK from the JX-594 genome restricts viral replication to tumor cells, whereas

production facilitates tumor immune response against, and β-gal is included for virus tracking purposes.

Efficacy

Initially, it was demonstrated that patients with refractory melanomas who received intratumoral injection of JX-594 (10⁴-2x10⁷ PFU/lesion; 10⁴-8x10⁷ PFU/session for 6 weeks) had mixed (3/7), partial (1/7), or complete (1/7) responses. Upon comparison of

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

(i.v.) delivery of JX-594 (10⁹ PFU) to intratumoral (i.t.) injection in immunocompetent liver cancer model in rabbits over 7 weeks, it was found that the i.t. treatment reduced the average primary tumor volume from 425 cm³ in control animals to 20 cm³ in i.t.-treated animals, and to 35 cm³ in the i.v. treatment group. Furthermore, the average number of lung metastases was reduced from 17 in control animals to 0.5 in i.t.-treated animals and none in the i.v.-treated animals.

Immune response

Dense infiltration of with CD4⁺ and CD8⁺

T lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

into the tumor was observed following intratumoral injection of JX-594. Despite the presence of anti-vaccinia antibodies, virally encoded GM-CSF mRNA was detected at injection sites up to 31 weeks following the intratumoral JX-594 inoculation and was not present in the serum. Systemic GM-CSF was detected up to 7 weeks following both intratumoral and intravenous injection of JX-594.

Safety

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s following intratumoral injection are limited to

flu-like symptoms Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss o ...

and resolve within 24 hours. Toxicology studies in New Zealand White rabbits (3 weekly i.v. doses of 10¹⁰ PFU) showed that JX-594 was well tolerated, and no toxicologically significant effects were observed. There were no overt clinical signs, with the exception of ~5% of body weight loss by day 6 that was followed by a recovery by day 33.

JX-929

JX-Next Generation

Novel oncolytic viruses in Jennerex pipeline are engineered through the Selective Oncolytic Vaccinia Engineering (SOLVE) platform. This platform is used to optimize virus targeting to specific cancer types, to select

transgene A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

s to include into the viral genome, and to optimize viral infection and/or replication selectivity through targeted mutations.

Partnerships

Jennerex has partnered with Transgene, Green Cross, Lee's Pharmaceuticals, Rex Medical, and SillaJen for JX-594 development and commercialization. As of October 9, 2012, Jennerex has not licensed rights for JX-594 in either the United States or Japan.

References

{{reflist, 2

External links

Jennerex
homepage Companies based in San Francisco Biotechnology companies of the United States Defunct pharmaceutical companies of the United States Technology companies based in the San Francisco Bay Area