The End of Anti-Viral Resistance?

[Billy T]

Mod note:

The first two posts copied/moved from here for interest in discussion


If I am to participate significantly the papers discussed need to be much more detailed in facts I can learn, not broad generalities, such as "methodology."

For example, I found the following very interesting:

"Peregrine-pharmaceuticals...is developing a monoclonal antibody bavituximab, which targets phosphatidylserine molecules [PS] presented on the outer side of cancer blood vessel cells. PS is only a side-effect, a characteristic of cancerous tissues from which cancer does not benefit. In normal, healthy vascular cells, PS is tightly segregated to the internal side of the cell. This segregation appears to be impaired in many kinds of tumor blood vessels, where PS becomes present on the external side of the cells. This phenomenon was observed in lung, breast, prostate and pancreatic cancer, among others. Monoclonal antibodies that are injected into the blood stream can recognize only targets that are presented on the external side of cells, healthy cells that have PS exclusively on their inner side will be unaffected, while cancer blood vessels would be targeted by the antibody exclusively. ..."

I.e. unlike VEGF drugs (such as very succesful Avastin now being sold) that only arrest the growth of solid tumors (by inhibiting new blood supply) this approach may kill the exisiting tumor. ("chemical surgery" to selectively remove it.) I have learned of at least a dozen other clever ideas for developing "magic bullets" for cancer and other diseases. One for viral infections "works" by keeping the newly made viral particles inside an infected cells "folded up" - to exit thru the cell wall and infect other cells, most viral particles need to "unfold" and become more linear, or spear like. I.e.they are trapped in the jail of the cell they were born in, greatly reducing their rate of infection and adding the body's defenses get the upper hand to eliminate them. Also many great idea for heart and arterial problems are now in the labs. Humans are about to enter an exciting new age of medicine and not only because of the new understanding of DNA etc.

Summary: If I am to actively particiapte, the papers will need to be about exploitable facts which can help in major medical problem areas. (I love to learn in any scientific area, but it can also be useful economically to recognize some things before everyone dose.) Do not take the above as a recommendation to invest in PPHM - they will may never get their developmental drug, bavituximab, to market. (Most early stage drugs fail to be profitable even if they do get thru the FDA.)

 

[Billy T]

The day after my post 9 results of Phase 1 trial were released. (I think the text I made bold very significant as it implies that the virus can not mutate to escape control.) Here are the highlights:

"... Results indicate that bavituximab was generally safe and well tolerated, with no dose limiting toxicities or serious adverse events reported. Anti-viral activity (decline of greater than or equal to 0.5 log10 reduction in HCV RNA) was observed at all dose levels and was most consistent in patients receiving 3 mg/kg of bavituximab. In this cohort, 83% of the patients demonstrated anti-viral activity. An assessment of the cytokine profile in this cohort also suggests bavituximab induces a pro-inflammatory cytokine profile, defined as an increase in the ratio of TNF alpha and TGF beta. Stimulating an immune response is a key proposed anti-viral mechanism of action of bavituximab.
...
Twenty-four patients received bavituximab twice weekly for two weeks at escalating dose levels ... More than half of the patients had genotype 1 HCV, the most difficult-to-treat strain.
...
Bavituximab is the first investigational agent in a new class of anti-phosphotidylserine (PS) monoclonal antibody immunotherapeutics that target and bind to cellular components that are normally not present on the outside of cells, but which become exposed on certain virally infected cells {See post 9 for some potential cancer tragets also} and on the surface of enveloped viruses. ... Since bavituximab's PS target comes from the host and not the virus, bavituximab is expected to be less susceptible to the development of anti-viral resistance than many other therapies. ..."

Billy T comment:
Having cleared the toxic failure mode and a novel mechanism with wide applications (in combination with other drugs perhaps) it is beginning to look like they may have a winner.

More details at:
http://news.morningstar.com/news/ViewNews.asp?article=/PR/20071105LAM124_univ.xml

 

[S.A.M.]

This is very interesting, since they are targeting specific presentation of phosphatidylserine on the extracellular surface in cancer cells.

Movie link here (look for An Understanding of Bavituximab)
http://www.peregrineinc.com/#

Details:

Bavituximab is a chimeric Anti-PS monoclonal antibody analog which is used to potentially treat cancers and viral infections. It binds to phosphatidylserine and other exposed host cell lipids when induced by cellular stress. Additional analogs in the class include 3G4, 2aG4, 9d2 and Hu3g4.

Bavituximab binds to various aminophospholipids and is dependent on interaction with plasma protein beta2-glycoprotein 1 to mediate binding.

These target aminophospholipids, usually residing only on the inner leaflet of the plasma membrane of cells are purportedly only exposed in virally infected, damaged or malignant cells.

The drug’s binding to phospholipids, alerts the body’s immune system to attack the tumor endothelial cells, Thrombosing the tumors vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues.

http://en.wikipedia.org/wiki/Bavituximab

 

[S.A.M.]

Some background on the plasma membrane of cells, based on the fluid mosaic model

According to the accepted current theory, known as the fluid mosaic model, the plasma membrane is composed of a double layer (bilayer) of lipids, oily substances found in all cells (see Figure 1). Most of the lipids in the bilayer can be more precisely described as phospholipids, that is, lipids that feature a phosphate group at one end of each molecule. Phospholipids are characteristically hydrophilic ("water-loving") at their phosphate ends and hydrophobic ("water-fearing") along their lipid tail regions. In each layer of a plasma membrane, the hydrophobic lipid tails are oriented inwards and the hydrophilic phosphate groups are aligned so they face outwards, either toward the aqueous cytosol of the cell or the outside environment. Phospholipids tend to spontaneously aggregate by this mechanism whenever they are exposed to water.

Phsophatidylserine belongs to the class of phospholipids.

It is interesting that PS presentation becomes asymmetric in cancer, since this has also been seen in conditions of apoptosis, when the cell is targeted for destruction. I would assume therefore that it is a "signal" of cell damage

The distribution of phospholipids across the two leaflets of the plasma membrane is important for many cellular processes including phagocytosis and hemostasis. In the present study we investigated the in vivo plasma membrane distribution of the aminophospholipid phosphatidylserine in mouse embryos with a novel technique employing Annexin V, a Ca2+ dependent phosphatidylserine binding protein, conjugated to fluorescein isothiocyanate and biotin. Annexin V directly applied to cryostat sections labeled the plasma membrane of all cells at the interface. In contrast, Annexin V injected intracardially into viable mouse embryos labeled almost exclusively apoptotic cells. These apoptotic cells were visible in all tissues and derived from all germ layers. Our experiments demonstrate that phosphatidylserine is asymmetrically distributed between the two leaflets of the plasma membrane in virtually all cell types in vivo and that this asymmetry is lost early during apoptosis.

http://www.nature.com/cdd/journal/v4/n4/abs/4400241a.html

 

[Billy T]

I so seldom search that I had not seen SAM's wiki link. THANKS. I should have realized that since it works by stimulating the immune system what I made bold in wiki's text below:

"... Bavituximab-treated survivors {animal tests, I think} were immune to reinfection. ... Our study demonstrates the promise of anionic phospholipids as targets for new broad-spectrum anti-viral drugs. ..."

There is a lot related that I for one do not understand. Unfortunately SAM I tend to agree with CharonZ that your idea of a "journal club" will not fly, but as You, I and CharonZ did have some success in the thread about lowering cost of DNA "snipping" specific threads may attract some. Unfortunately, even there we are dependant on the good will of the experts to answer questions - I like to teach in physics areas, perhaps some experts will enjoy shairing what they know?

Later by edit - fantastic picture you posted while I was typing the above. - Thanks.

 

[Billy T]

About 99% sure that common detergents are better "grease cutters" than soap becuase they too have one hydrophilic and one hydrophobic end, which binds to molecule of "fat /grease" and the hydrophilic end then "pulls" that molecule into water solution, to ultimately "go down the drain."

Why does not detergent make bipolar "skins"? More impotantly: Why is detergent not extremely toxic by messing up all the cell walls? Any ideas?

 

[S.A.M.]

Depends on what you mean by detergent. Most detergents are more than just plain surfactants and are simply not strong enough. But strong soaps can damage the skin as can repeated washing with no moisturising

Water content, humidity, pH, intracellular lipids, and rates of shedding help retain the protective barrier properties of the skin. When the barrier is compromised (e.g., by hand hygiene practices such as scrubbing), skin dryness, irritation, cracking, and other problems may result. Although the palmar surface of the hand has twice as many cell layers and the cells are [is less than] 30 times thicker than on the rest of the skin (47), palms are quite permeable to water (48).

Long-term changes in skin pH associated with handwashing may pose a concern since some of the antibacterial characteristics of skin are associated with its normally acidic pH (49). In one report, pH increased 0.6 to 1.8 units after handwashing with plain soap for 1 to 2 min and then gradually declined to baseline levels over a period of 45 min to 2 hr (50). Some soaps can be associated with long-standing changes in skin pH, reduction in fatty acids, and subsequent changes in resident flora such as propionibacter (51).

In an investigation of the effect on skin of repeated use of two washing agents, all skin function tests (stratum corneum capacitative resistance, lipids, transepidermal water loss, pH, laser Doppler flow, and skin reddening) were markedly changed after a single wash, and after 1 week further damage was noted (52). In a study of irritant skin reactions induced by three surfactants, damage lasted for several days; complete skin repair was not achieved for 17 days (53).

http://findarticles.com/p/articles/mi_m0GVK/is_2_7/ai_73889933/pg_3

 

[S.A.M.]

I so seldom search that I had not seen SAM's wiki link. THANKS. I should have realized that since it works by stimulating the immune system what I made bold in wiki's text below:

"... Bavituximab-treated survivors {animal tests, I think} were immune to reinfection. ... Our study demonstrates the promise of anionic phospholipids as targets for new broad-spectrum anti-viral drugs. ..."

There is a lot related that I for one do not understand. Unfortunately SAM I tend to agree with CharonZ that your idea of a "journal club" will not fly, but as You, I and CharonZ did have some success in the thread about lowering cost of DNA "snipping" specific threads may attract some. Unfortunately, even there we are dependant on the good will of the experts to answer questions - I like to teach in physics areas, perhaps some experts will enjoy shairing what they know?

Later by edit - fantastic picture you posted while I was typing the above. - Thanks.

I know a little bit more about biochemistry and physiology as that is more closely related to nutrition than pure biology. If I can, I will definitely answer your questions.

This is a great topic!

 

[CharonZ]

I have to admit that I have not read the whole of this thread (am taking a break from writing a paper that I do not like too much myself ). But just to respond to this:

Why does not detergent make bipolar "skins"? More impotantly: Why is detergent not extremely toxic by messing up all the cell walls? Any ideas?

Detergents usually have a hydrophilic head and a longer, hydrophobic tail. This makes the molecule somewhat wedge-shaped. As a result they tend to layer together to form round micelles (a bit like narrow slices of a cake) rather than large bilayers.
Or in other words, this form is thermodynamically more stable.

As regarding toxicity, SAM already answered to it. One just have to add that the outer epidermis of the skin consists of dead ceratinized cells that are somewhat resistant to detergents, and of course it depends on the strength and concentration of the detergent in question.
Essentially comparatively little of any solution will permeate the skin and reach living cells. Even then a high enough detergent/lipid membrane ratio has to be reached before the cells get seriously damaged. This can be easily achieved in vitro (e.g. by resuspending cells in a somewhat concentrated detergent solution, but it is not easy to achieve merely by washing hands.
Rather effects as described by SAM will happen.

If you are interested in the thermodynamics behind it, I can advise to a number of papers e.g.:

J. Phys. Chem., 100 (16), 6764 -6774
H. Heerklotz et al.
http://pubs.acs.org/cgi-bin/article.cgi/jpchax/1996/100/i16/html/jp9523534.html

I am sure the formulas, though chemically inspired, should be pleasing for the physicist

 

[S.A.M.]

Why does not detergent make bipolar "skins"?

Ah sorry I misunderstood this; I assumed you meant why the detergents don't affect the skin.

 

[Exhumed]

Sounds almost too good to be true. Any skeptics?

Do not take the above as a recommendation to invest in PPHM - they will may never get their developmental drug, bavituximab, to market. (Most early stage drugs fail to be profitable even if they do get thru the FDA.)

Can you elaborate as to why?

 

[S.A.M.]

Usually humans are a bit more variable in their reactions than suggested by cell culture, animal models and double-blinded randomised placebo-controlled clinical trials.

 

[Billy T]

Sounds almost too good to be true. Any skeptics?
Can you elaborate as to why?

Yes I am a skeptic to some extent, but I do like their general approach and fact that they also have further along system of delivery of I131 to brain tumors that "kills from the inside out" as it binds to some of the interior tumor cells and thus keeps the radiation most intense in tumor tissue.

See all about the company in less than week old presentation at:
http://www.wsw.com/webcast/rrshq12/pphm/