HspE7
Encyclopedia
HspE7 is an investigational therapeutic vaccine
candidate being developed by Nventa Biopharmaceuticals
for the treatment of precancerous
and cancer
ous lesion
s caused by the human papillomavirus (HPV). HspE7 uses recombinant DNA
technology to covalently
fuse a heat shock protein
(Hsp) to a target antigen
, thereby stimulating cellular immune system
responses to specific diseases. HspE7 is a patented construct consisting of the HPV Type 16 E7 protein and heat shock protein 65 (Hsp65) and is currently the only candidate using Hsp technology to target the over 20 million Americans already infected with HPV.
The candidate is being developed with a Toll-like receptor 3 (TLR3
) agonist
adjuvant
for multiple indications, including cervical intraepithelial neoplasia (also known as cervical dysplasia or CIN), genital wart
s, cervical cancer
, and head and neck cancers.
, as well as anal cancer
, vulvar cancer
, and penile cancer. Several types of HPV, particularly type 16, have been found to be associated with oropharyngeal squamous-cell carcinoma, a form of head and neck cancer
. HPV-induced cancers often have viral sequences integrated into the cellular DNA. Some of the HPV "early" genes, such as E6 and E7, are known to act as oncogene
s that promote tumor growth and malignant transformation
.
An infection with one or more high-risk HPV types is believed to be a prerequisite for the development of cervical cancer (the vast majority of HPV infections are not high risk); according to the American Cancer Society
, women with no history of the virus do not develop this type of cancer. However, most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer. Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more.
HPV infection is a necessary factor in the development of nearly all cases of cervical cancer
. A cervical Pap smear
is used to detect cellular abnormalities. This allows targeted surgical removal of condylomatous and/or potentially precancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. HPV vaccine
s Gardasil
and Cervarix
, which block initial infection with some of the most common sexually transmitted HPV types, may lead to further decreases in the incidence of HPV-induced cancer, however, they do not address the millions of people worldwide already infected with the virus.
It is estimated that nearly 10 million women are diagnosed with some form of cervical dysplasia each year in major global markets in the U.S., EU and Japan, many of whom could benefit from a non-surgical treatment. As a result, HspE7 is first being developed for the treatment of CIN.
(RRP). These trials were initiated prior to the discovery that potency could be greatly enhanced by addition of a vaccine adjuvant, and, as a result, Nventa is currently developing HspE7 combined with the adjuvant Poly-ICLC.
A Phase 1b study has been completed assessing the safety and tolerability of HspE7 with Poly-ICLC in four cohorts totaling 17 patients with CIN. All patients were administered 500 mcg of HspE7 with each of the four cohorts receiving escalating doses of adjuvant – 50, 500, 1,000 and 2,000 mcg.
Nventa has indicated that it is currently working with the U.S. Food and Drug Administration (FDA) to finalize the trial design for a Phase 2 clinical study for HspE7 in patients with high grade cervical dysplasia (CIN 2/3).
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
candidate being developed by Nventa Biopharmaceuticals
Nventa Biopharmaceuticals Corporation
Nventa Biopharmaceuticals Corporation was a Canadian incorporated biopharmaceutical company headquartered in San Diego, California developing therapeutics for the treatment of viral infections and cancer, focusing on diseases caused by human papillomavirus...
for the treatment of precancerous
Premalignant condition
A precancerous condition is a disease, syndrome, or finding that, if left untreated, may lead to cancer. It is a generalized state associated with a significantly increased risk of cancer....
and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
ous lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s caused by the human papillomavirus (HPV). HspE7 uses recombinant DNA
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
technology to covalently
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
fuse a heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
(Hsp) to a target antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
, thereby stimulating cellular immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
responses to specific diseases. HspE7 is a patented construct consisting of the HPV Type 16 E7 protein and heat shock protein 65 (Hsp65) and is currently the only candidate using Hsp technology to target the over 20 million Americans already infected with HPV.
TLR 3
Toll-like receptor 3 also known as CD283 is a protein that in humans is encoded by the TLR3 gene...
) agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
adjuvant
Immunologic adjuvant
In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid...
for multiple indications, including cervical intraepithelial neoplasia (also known as cervical dysplasia or CIN), genital wart
Genital wart
Genital warts is a highly contagious sexually transmitted disease caused by some sub-types of human papillomavirus . It is spread through direct skin-to-skin contact during oral, genital, or anal sex with an infected partner...
s, cervical cancer
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
, and head and neck cancers.
Therapeutic rationale
Over 100 different HPV types have been identified and are referred to by number. About a dozen HPV types, including types 16, 18, 31 and 45, are called "high-risk" types because they can lead to cervical cancerCervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
, as well as anal cancer
Anal cancer
Anal cancer is a type of cancer which arises from the anus, the distal orifice of the gastrointestinal tract. It is a distinct entity from the more common colorectal cancer. The etiology, risk factors, clinical progression, staging, and treatment are all different. Anal cancer is typically a...
, vulvar cancer
Vulvar cancer
Vulvar cancer, a malignant invasive growth in the vulva, accounts for about 4 % of all gynecological cancers and typically affects women in later life. It is estimated that in the United States in 2006 about 3,740 new cases will be diagnosed and about 880 women will die as a result of vulvar cancer...
, and penile cancer. Several types of HPV, particularly type 16, have been found to be associated with oropharyngeal squamous-cell carcinoma, a form of head and neck cancer
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
. HPV-induced cancers often have viral sequences integrated into the cellular DNA. Some of the HPV "early" genes, such as E6 and E7, are known to act as oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
s that promote tumor growth and malignant transformation
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
.
An infection with one or more high-risk HPV types is believed to be a prerequisite for the development of cervical cancer (the vast majority of HPV infections are not high risk); according to the American Cancer Society
American Cancer Society
The American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
, women with no history of the virus do not develop this type of cancer. However, most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer. Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more.
HPV infection is a necessary factor in the development of nearly all cases of cervical cancer
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
. A cervical Pap smear
Pap smear
The Papanicolaou test is a screening test used in to detect pre-cancerous and cancerous processes in the endocervical canal of the female reproductive system. Changes can be treated, thus preventing cervical cancer...
is used to detect cellular abnormalities. This allows targeted surgical removal of condylomatous and/or potentially precancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...
s Gardasil
Gardasil
Gardasil , also known as Gardisil or Silgard, is a vaccine for use in the prevention of certain types of human papillomavirus , specifically HPV types 6, 11, 16 and 18. HPV types 16 and 18 cause an estimated 70% of cervical cancers, and are responsible for most HPV-induced anal, vulvar, vaginal,...
and Cervarix
Cervarix
Cervarix is a vaccine against certain types of cancer-causing human papillomavirus .Cervarix is designed to prevent infection from HPV types 16 and 18, that cause about 70% of cervical cancer cases. These types also cause some other genital cancers and some oropharyngeal cancers...
, which block initial infection with some of the most common sexually transmitted HPV types, may lead to further decreases in the incidence of HPV-induced cancer, however, they do not address the millions of people worldwide already infected with the virus.
It is estimated that nearly 10 million women are diagnosed with some form of cervical dysplasia each year in major global markets in the U.S., EU and Japan, many of whom could benefit from a non-surgical treatment. As a result, HspE7 is first being developed for the treatment of CIN.
Clinical progress
Nventa originally advanced HspE7 as a single-agent therapy into multiple Phase 2 clinical trials with positive results, including trials in cervical dysplasia and recurrent respiratory papillomatosisLaryngeal papillomatosis
Laryngeal papillomatosis, also known as recurrent respiratory papillomatosis or glottal papillomatosis, is a rare medical condition , caused by a HPV infection of the throat. Laryngeal papillomatosis causes assorted tumors or papillomas to develop over a period of time...
(RRP). These trials were initiated prior to the discovery that potency could be greatly enhanced by addition of a vaccine adjuvant, and, as a result, Nventa is currently developing HspE7 combined with the adjuvant Poly-ICLC.
A Phase 1b study has been completed assessing the safety and tolerability of HspE7 with Poly-ICLC in four cohorts totaling 17 patients with CIN. All patients were administered 500 mcg of HspE7 with each of the four cohorts receiving escalating doses of adjuvant – 50, 500, 1,000 and 2,000 mcg.
Nventa has indicated that it is currently working with the U.S. Food and Drug Administration (FDA) to finalize the trial design for a Phase 2 clinical study for HspE7 in patients with high grade cervical dysplasia (CIN 2/3).