Antibodies for diagnosis and therapeutic treatment of prostate cancer

Jemal

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Got this from the other forum. Looks like a very interesting patent to me. It was published 25 august 2011. It's mainly related to prostate cancer, but ME/CFS is also mentioned. Things are still moving... we are seeing some more positive developments lately I believe.

Inventors:

Kohli, Manu (Dunn Loring, VA, US)
Goldblatt, Michael (McLean, VA, US)
Kinch, Michael (Laytonsville, MD, US)
XMRV appears to be related to both prostate cancer if it infects a male germ cell and chronic fatigue syndrome in both sexes. (If the virus does not infect a germ cell). Prostate cancer cells exhibit TSG101 on the surface only upon infection with a virus like XMRV. Antibodies to TSG101 can be effective diagnostics to identify individuals with a predisposition to prostate. They can also be used in place of current diagnostics to confirm the presence of prostate cancer. TSG101 antibodies, when administered in vivo, exhibit the ability to reduce tumor size, suppress metastatic transformation and extend survival.
BACKGROUND OF THE INVENTION
1. Field of the Invention

This invention pertains to detection of Xenotropic Murine Leukemia-Virus Related virus, or XMRV, as well as detection and possible treatment of disease states associated with that virus, including metastatic prostate cancer and Chronic Fatigue Syndrome, or CFS.

2. Related Art

This invention relates to the detection of the presence of TSG101 protein on the surface of cells of mammalian hosts suspected of being infected with XMRV. In particular, XMRV has recently been found to be associated with malignant prostate cancer cells. Fan, PNAS, Vol. 101, 5, 1449-11450 (2007). TSG101 is a protein ordinary found in the cytoplasm of healthy mammalian cells, and is conserved in mammals. TSG101 is instrumental as a member of the family of ESCRT protein in directing proteinacious material within cell for storage and destruction. In the event of infection by many enveloped viruses, it appears that the normal function of TSG101 is hijacked by the infecting virus. In the event of infection by a variety of viruses, TSG101 is found on the cell surface of the infected cell. This phenomenon, and the ability to bind to the TSG101 and thereby inhibit viral infectivity, is reported in U.S. patent application Ser. No. 11/940,714, the entirety of which is incorporated by reference.

The binding of TSG101 on the cell surface, as well as other ESCRT proteins like Nedd4 is also discussed in U.S. patent application Ser. No. 11/939,122 filed Nov. 30, 2007, also incorporated herein by reference. Interference with the activity of TSG101 in a virally infected cell poses so many potential anti-viral treatments that small molecule binding, which would not be limited to cell surface phenomena, also provides therapeutic treatment, as reported in U.S. patent application Ser. No. 12/261,603 filed Oct. 30, 2008. All of these cases are directed to the identification and treatment of disease states associated with viral infection itself, such as influenza, HIV/AIDS, RSV and related viral diseases.

The recent identification of XMRV as highly associated with aggressive, metastatic prostate cancer presents an opportunity to diagnose and treat this most common of deadly male cancers, if a way to identify the infection of prostate cancer cells by XMRV can be found. Researchers have postulated that perhaps a genetic defect in RNase L, an effector in the interferon induced innate response may provide a favorable opening for the virus. In these individuals, a single aa mutation, R462Q leads to reduced enzyme activity which may be all that is necessary to allow the retrovirus to successfully infect the cell. If the virus manages to infect a germ cell, any oncogene (typically captured) may be integrated into the DNA of the host cell, and passed on as stably inherited elements. This may in fact be the causal link between prostate cancer and XNRV that many are looking for. It is, in any event, clear that XMRV infection is found in a high percentage of prostate tumor cells, particularly aggressive metastatic ones.

At the same time, researchers have found that sixty-seven percent (67%) or more of humans suffering from Chronic Fatigue Syndrome (CFS) are infected with XMRV. While the causal relationship is not clear, in fact, the degree of association is so high that XMRV is implicated by many as instrumental in the course of this chronic disease. The probability that the retrovirus is a causative agent is reinforced by the fact that a large majority of CFS patients first exhibit CFS symptoms following a period of illness in which they exhibit flu-like symptoms. XMRV, like HIV, is a retrovirus that has a long resident life, and thus could be causing the initial flu-like infection, followed by a period of residency in which the CFS symptoms are manifested. Typically CFS persists for life. A large proportion of these patients exhibit pain and immune problems and CFS is highly correlated with Fibromyalgia, which may be simply an extreme reaction to the viral infection.

Current methods of diagnosis of prostate cancer are limited. The two diagnostics widely available are a digital rectal exam, where a medical professional palpates the prostate through the rectum to try and detect hard lumps or anomalies. The other is an assay for prostate specific antigen or PSA. Elevated PSA may indicate prostate cancer. Neither diagnostic is complete. Many men with high PSA levels do not have prostate cancer. Many types of prostate cancer, and many aggressive but early stage cancers, are not detectable by digital exam. In either event, a questionable result is followed by biopsy and tissue analysis and MRI or similar imaging.

There are few effective cures for viral infection, and fewer vaccines. Therapeutics tend to be targeted at the specific virus, which will mutate to escape the effectiveness of the therapeutic, and, like HIV, can remain at rest in the body for many years. As of the filing date of this application, there was neither treatment for, nor vaccine to prevent, XMRV infection. When the sequelae of the infection manifest, such as aggressive metastatic prostate cancer, or CFS, treatment is largely limited to tumor attack and patient support.

SUMMARY OF THE INVENTION
Applicants have now demonstrated that cells, in particular, prostate cells, infected with XMRV, can be detected by antibody binding to TSG101 on the surface of the cells, where uninfected cells show no binding (by staining) by the same antibodies. Antibodies, both polyclonal and monoclonal, to TSG101 are widely available. This presents a new, powerful method to detect XMRV infection. Male patients testing positive for XMRV infection should be considered in a higher risk category for development of aggressive prostate cancer, and appropriate diagnostics, behavior modification and therapy initiated.

Cells of mammals, including humans, can also be assayed for the genetic defect in RNase L. Individuals not displaying symptoms of prostate cancer, CFS or XMRV infection may be candidates for vaccination to induce the expression of anti-TSG101 antibodies. An effective circulating titer of such antibodies has been shown to inhibit viral proliferationthe virus cannot escape the infected cell with budding, so that the infection does not spread. Passive protection through the administration of human or humanized anti-TSG101 antibodies may also be effective.
More at:
http://www.freepatentsonline.com/y2011/0206695.html
 

eric_s

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Yes, this sounds very interesting and i must have missed it before. The only thing is that it's "only" a patent application and not a peer-reviewed paper. But still very interesting of course.
 

alex3619

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Hi, I was about to post this article then found it had already been posted. It is very interesting indeed. I wonder if there are other cell lines exhibit TSG101 if they are infected with XMRV. That could be a generalized diagnostic test. If so it might also be the case the anti-TSG101 could then be used to treat ME. Bye, Alex
 

redo

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I am glad to see they are following up on this. Kohli, Kinch (and Cassella, Diaz) had a an abstract where they talked about using monoclonal antibodies against TSG101.

Back then they said "For example, TSG101 is essential for infections caused by all retroviruses tested to date." (my bolds). And "Altogether, these findings suggest potential opportunities for TSG101-directed therapeutic in the treatment or prevention of XMRV-associated diseases."

The quotes are from about 2/3 down on this page:
http://www.mecfsforums.com/wiki/Abstracts_from_1st_International_Workshop_on_XMRV
 

redo

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There are actually more groups whom put a great deal of weight into TSG101's importance in retroviruses. Here's an article where it's described as HIV's "Ticket to ride", and they claim it's essential for the budding of the virus. Here's another one where they describe "tal" (Tsg101-associated ligase) as a regulator for retrovirus' budding.

Hopefully they'll run some trials soon. Some of the studies are almost a decade old, and it's easy to make some monoclonal antibodies to see how that goes.