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Author Topic: Could this be the holy grail ?  (Read 167801 times)

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Offline veritas

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Re: Could this be the holy grail ?
« Reply #100 on: January 16, 2009, 06:32:39 AM »
David,

I appreciate your intervention to allow calmer heads to prevail in explaining the potential of anti-ps as a therapeutic and vaccine. Escalation of emotion is never a good thing when discussing science, especially science that has not been proven 100% to date. That being said, I would like to further explain my position and also take issue with a few points. 
 I have been following Dr. Philip Thorpe's research on anti-ps since the late 90s. He is the inventor of the device. The science has been put through its paces in vitro and completed for both viral and cancer indications in the form of the 3g4 antibody.

Subsequently, Phase 1 trials for various cancer indications and HepC  have been completed.
A co-infection trial for HepC and HIV in phase 1 is on going and interim results should be reported soon.
Phase ll cancer trials for various indications have commenced and of course a simple search of clinicaltrials .gov can confirm.

My point here is to show that the science has developed to the point of Phase ll status. Considering the unique moa of this new paradigm, specifically the fact that the antibody attaches to exposed ps and does not go directly after the virus or cancer indication, potentially, gives the antibody broad therapeutic properties. Of course the trials in vivo have to be completed to prove total effectiveness and safety , but results thus far have shown top line safety data and some efficacy.

CHAVI has made Dr. Thope's lab part of their global initiative to find a cure and vaccine for HIV .
 I believe they are using another form of Bavi (2g12) along with other broadly neutralizing antibodies in their pre-clinical efforts, many of which I have reported in this thread.

 Dr. Barton Haynes, Director of CHAVI, explained how exposed ps shields the virus from the immune system (see patents at beginning of this thread) and how any cure or vaccine will have to address this issue.

With the release of the vaccine research study (the shiv re-challenge study by PA Marx,D Montefiore et al.), I believe we will be hearing from CHAVI fairly soon. I certainly hope so. Who knows, Bavi might qualify for the FDA's fairly new Animal Rule.

I've tried to develop this thread,referencing studies and announcements pertinent to the science as it develops . I fully understand the caveats concerning the science and qualified my statements in previous posts addressing that issue (ie: if the science proves itself as it has done in pre-clinicals). What I don't want to see here is mis-information touted as fact without references.

 Bavi , in and of itself might not be the answer. Maybe a second generation Bavi will have to be developed. But I believe that this approach is the most promising and could possibly be the HOLY GRAIL.

I'll be following this science until proven otherwise.

veritas
« Last Edit: January 16, 2009, 09:42:52 AM by veritas »

Offline Ann

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Re: Could this be the holy grail ?
« Reply #101 on: January 16, 2009, 08:02:39 AM »
Veritas,

Have you ever heard of paragraphs? I can't get through your massive blocks of text without going cross-eyed.

Ann
Condoms are a girl's best friend

Condom and Lube Info  



"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline veritas

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Re: Could this be the holy grail ?
« Reply #102 on: January 16, 2009, 08:13:52 AM »

Ann,

Thankyou for correcting my sentence structure. I'll have to watch that in the future.

What did you think of the content?


veritas






























Offline Ann

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Re: Could this be the holy grail ?
« Reply #103 on: January 16, 2009, 08:21:42 AM »
Veritas,

That's just the point. I can't READ the content due to crossed-eyes.

Next time you're in research mode, why not research "writing for the internet"? Most guides will tell you to break your text up into paragraphs of five or so sentences to make what you write readable!

Ann
Condoms are a girl's best friend

Condom and Lube Info  



"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline veritas

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Re: Could this be the holy grail ?
« Reply #104 on: January 16, 2009, 09:01:04 AM »

Ann,

I'll have to checkout those guidelines.

In the meantime, I'd sure like to hear your comments about the post's content since you are a moderator. Can you try to get through the post? If not, I won't pursue it.

veritas

Offline Ann

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Re: Could this be the holy grail ?
« Reply #105 on: January 16, 2009, 09:16:10 AM »
Veritas,

I can't. I already have a headache. You can still edit, why don't you go fix it so it can be read?

Ann
Condoms are a girl's best friend

Condom and Lube Info  



"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline veritas

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Re: Could this be the holy grail ?
« Reply #106 on: January 16, 2009, 09:45:38 AM »

Ann,

Just for you the post is modified.

Anxiously awaiting your remarks!


veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #107 on: January 16, 2009, 10:03:14 AM »

More anti-ps research:




CONCLUSIONS
“The AIDS Vaccine 2008 conference was primarily focused on basic research. Much of this was dealing with broadly-neutralizing anti-HIV antibodies. The few, rare, known familiar suspects: 2F5, 2G12, b12, were the subject of hundreds of experiments presented at the conference. It seemed that "the way forward" was thought to be via insights into these promising antibodies, 2 of which bind a lipid and the virus, and one of which (b12) binds a sugar that coats a viral protein. According to other interesting data presented at the conference, the antibody b12 is apparently the most potent of the three. Along comes Duke University's researcher [Dr. Tony Moody], and presents data from CHAVI 005 experiments, showing that they've got an antibody [PPHM-Duke Collab. mab ‘PGN632’] which only binds a lipid. This particularly potent antibody is orders of magnitude more potent than even b12, and in subtype-C HIV viruses, ( a very common subtype), the anti-lipid antibody was over 1000 times more potent than b12, 2F5, and 2G12. If that is not enough of a surprise to the field, to continue the out-of-the-box theme, it turns out that this unprecedented incredibly powerful antibody works by sticking to a lipid on uninfected T cells, causes an increase in the beta chemokines that block the CCR5 receptor, which prevent HIV from entering a cell in the first place.”

From ‘CAPE TOWN WRAP-UP’ on JBM’s Anti-PS Blog…
“Anti-Lipid Antibodies make their debut at the Cape Town, South Africa AIDS Vaccine 2008 Conference

Offline bimazek

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Re: Could this be the holy grail ?
« Reply #108 on: January 16, 2009, 07:34:08 PM »
Big breakthru by Scientists Create Technique to Screen Antibody Libraries against Large Antigen Libraries
and the did it first with HIV.

Here is the good news, imagine you have every key for every lock in the usa in a pile, perhaps 800 million different keys.   the keys are antibodies, now imagine you have one keyhole, and you have to go thru each one individually and figure out if it will fit in the keyhole

well now scientists can do this screening for the key and keyhole for giant liibraries of keys not one at a time basically

this is a great advance because now the monoclonal antibodies which have a better bio activity and profile and lower toxic profile, cause they are fully human  monoclonal antibodies

can be screen in bulk to see what disease key holes they fit

this part i am extrapolating and anyone who is a brilliant molecular biochem genetisist please refine my concepts (they cant be wrong btw lol) anyway


this part i am extrapolating and anyone who is a brilliant molecular biochem genetisist please refine my concept--  every HIV drug has a target which is a keyhole so to speak, on an hiv enzyme, and the drugs that we use are chemicals that have a shape that fit into the keyholes in hiv, well the problem with a chemical key -- a drug -- is the key also has shapes and parts that do not fit into the keyhole but are part of the shape of the handle of the key,  and this part also has interaction with the delicate biological molecules and dna that make you you, so that is a toxic side effect of a chemical drug

where as a  fully human  monoclonal antibody has a shape that fits into the hiv keyhole, turning enzyme off, but also the handle end of the key --- of the fully human  monoclonal antibody has a fully human  shape it  has been genetically engineered to be so perfectly shaped that mostly it does not interact with with human body that is not the keyhole of hiv enzyme for example

remember also that all fully human  monoclonal antibody shapes as well as all chemical drug molecular shapes have electro magnetic charged regions on them so they have a natural attraction to the key shape for the keyhole shape by electro magnetic attraction

kind of like your favorite dildo just fits right in  lol

anyway

now scientists as of today can screen thousands if not tens of thousands of these fully human  monoclonal antibody shapes to see which fit into which parts of disease molecules enzymes etc.

this will be a great leap forward for Antibody Libraries     Antigen Libraries    fully human  monoclonal antibody medicinal treatments for many many disease targets, and also remember

a year ago harvard discovered all 273 target enzymes in human cell that hiv high jacks so that is some great targets

remember also that it is the tools of science like this that sometimes create the biggest leaps forward

i am so good at making analogies and explaining science that it sometimes scares me, ten point bonus question, what writers did i read extensively in science education in my formative years that influenced my truth of knowing that complex science can be explained in simple language to layman without loosing the deep insights....

i will give you a hint... the technique below as well as the writer love and use robots

Create Technique to Screen Antibody Libraries against Large Antigen Libraries

Jan 14 2009, 10:36 AM EST

Scientists Create Technique to Screen Antibody Libraries against Large Antigen Libraries
GEN News Highlights

Investigators at the Scripps Research Institute report that they have developed a technique that enables antibody screening against massive libraries of targets.

Past attempts to instead screen antibody libraries against antigen libraries have been stymied by a variety of technical challenges. A key aspect to the success of the new technique is the use of yeast cells to display the antibodies for screening and phages for the antigens, the researchers explain. Each display was labeled by a different colored fluorescent protein. Screen results were then determined using flow cytometry. Bound pairs are then filtered out of the mix for identification of the antibody and antigen involved.

“It took us a while to get to the right conditions,” remarks Diana Bowley, Ph.D., a Scripps Research staff scientist, “but now that we have, it’s quite easy to visualize and isolate the antibody-antigen pairs.”

The team focused its initial experiments on a known interaction between a specific antibody and a fragment of a protein found on the outside of HIV particles. The group worked with some 10 million antibodies, but the library was weighted to include a known antibody. The antigen library was of similar size and comparably weighted to include the known HIV antigen. The weighting guaranteed the existence of an antibody-antigen pair, which in turn allowed the group to tweak its initial concept until it could identify pairings at the expected rate.

“Many scientists have long recognized that efficient and sufficient access to the libraries demands an effective technique for also screening target antigens by the millions,” notes Richard A. Lerner, M.D., Scripps Research president. “This work now makes that possible.”

The work is reported in this week’s early edition of Proceedings of the National Academies of Science.  http://www.genengnews.com/news/bnitem.aspx?name=48115389&source=genwire

Offline Ann

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Re: Could this be the holy grail ?
« Reply #109 on: January 17, 2009, 07:06:23 AM »
Veritas,

I think that just because something has entered phase two trials doesn't mean it's not going to run up against major obstacles. Like David mentioned, we've seen too many promising treatments come to nothing to get overly excited about this just yet. This research, despite the time already spent on it, truly is still in its infancy.

Ann
Condoms are a girl's best friend

Condom and Lube Info  



"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline veritas

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Re: Could this be the holy grail ?
« Reply #110 on: January 17, 2009, 10:00:47 AM »
Veritas,

I think that just because something has entered phase two trials doesn't mean it's not going to run up against major obstacles. Like David mentioned, we've seen too many promising treatments come to nothing to get overly excited about this just yet. This research, despite the time already spent on it, truly is still in its infancy.

Ann


Ann,
I'm fully aware that the therapy could possibly run into obstacles as the trials go on, however, the number of patients dosed to date, covering various viral and cancer targets plus re-dosing , number greater than 100. Not a significant number when comparing to Phase lll  trials where there could be thousands. However, in all patients dosed to date there have been no adverse effects and some of the cancer patients in the phase 1 trials were terminal (see clinical trials and company reports).

It's true that we have been disappointed many times in the past but all those therapeutic disappointments had one thing in common. They went after the virus directly. The broad therapeutic value of anti-ps is unique, a new paradigm, that links to a primary function of the host cell without causing cellular stress to those cells where ps has not flipped. The virus seems to be too stealthy for such a direct approach. A Trojan Horse (Bavi) is needed to attach to the virus to alert a strong Spartan  army ( your immune system) to get rid of the invader. That being said, I realize the clinical trials must be completed and time will tell the value of the therapy.

The most respected researchers in the country have embraced anti-ps for both viral and cancer indications. Their findings to date have been positive (see the 40 references inthe post  hiv - anti-ps breakthrough). If someone can find a negative peer review please post. I have not been able to find any.

I guess the definition of infancy is fluid. I don't happen to agree but the point is really not worth debating.

As far as this thread is concerned, no one has to get excited about this research if they don't want to. However, this is the Research News and Studies Forum and I felt that this research would be an appropriate addition.If my excitement for this therapy comes through, it's because I believe that this could be the Holy Grail. No one else need believe it.

veritas







« Last Edit: January 18, 2009, 08:39:20 AM by veritas »

Offline J220

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Re: Could this be the holy grail ?
« Reply #111 on: January 18, 2009, 01:29:49 AM »
I feel very optimistic about bavituximab, but mainly because of the novel method of action. I'll wait for further clinical results before I take it to the next level of confidence. It's possible, after all, that it could work. And wouldn't that be something...

I can say this however, last week I bought 100 shares of Peregrine stock (PPHM), just in case lol
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline veritas

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Re: Could this be the holy grail ?
« Reply #112 on: January 18, 2009, 04:21:22 AM »

J220,

Barvituximab(the one in clinical trials) is the first anti-ps mab developed. Another name for it is the 3g4 antibody. CHAVI is working with second generation anti-ps antibodies that are stronger. That being said I am anxiously awaiting interim results on the co-infection trial of Hep c/hiv for efficacy. Those results will give us a good indication as to efficacy beyond pre-clinical for HIV. My hope is that the mabs that CHAVI is working on do the trick ( no pun intended). lol

veritas

Offline bimazek

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Re: Could this be the holy grail ?
« Reply #113 on: January 18, 2009, 06:01:53 PM »
more info

To prove the concept, the group focused its initial experiments on a known interaction between a specific antibody and a fragment of a protein found on the outside of HIV particles. The group worked with some 10 million antibodies, but the library was weighted to include a known antibody. The antigen library was of similar size and comparably weighted to include the known HIV antigen. The weighting guaranteed the existence of an antibody-antigen pair, which in turn allowed the group to tweak its initial concept until it could identify pairings at the expected rate.

http://www.sciencedaily.com/releases/2009/01/090115164611.htm

New Technique To Tap Full Potential Of Antibody Libraries Developed
ScienceDaily (Jan. 15, 2009) — In hopes of more fully tapping the libraries' potential, a group of Scripps Research Institute scientists, led by Scripps Research President Richard A. Lerner, M.D., has for the first time developed a new screening technique that enables antibody screening against equally massive libraries of targets. This technique makes it possible to accelerate searches for new treatments against cancer and other diseases.
See also:
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The work was recently reported in the Early Edition of the journal Proceedings of the National Academies of Science (PNAS).
The immune system produces antibodies to immobilize invaders, such as bacteria and viruses, by attaching to proteins referred to as antigens on those invaders. For many years, researchers have been producing huge collections of synthetic antibodies that collectively dwarf the number of antibodies humans produce naturally. These resources are a synthetic immune system with almost limitless potential, but existing techniques have only enabled screening the millions upon millions of available antibodies against handfuls of antigens.
"Many scientists have long recognized that efficient and sufficient access to the libraries demands an effective technique for also screening target antigens by the millions," said Lerner. "This work now makes that possible."
Traditional antibody research has involved developing systems in which the antibodies to be tested are incorporated into yeast cells, bacterial viruses known as phages, or some other form of "display" for testing against a target antigen protein. Past attempts to instead screen antibody libraries against antigen libraries have been stymied by a variety of technical challenges.
A key aspect to the success of the Lerner group's technique is using yeast cells to display the antibodies for screening, while using phages for the antigens, with each display labeled by a different colored fluorescent protein.
Screen results are determined using flow cytometry, a technique that allows the researchers to examine images of the yeast cells and phage particles and manipulate them. Using the differing displays means that antibody-antigen pairs that bind can be easily identified, because they show both fluorescent dye tag colors. Bound pairs are then filtered out of the mix for identification of the antibody and antigen involved, which requires genetic sequencing.
"It took us a while to get to the right conditions," says Diana Bowley, Ph.D., a Scripps Research staff scientist and the paper's first author with Teresa Jones, a Scripps Research scientific associate, "but now that we have, it's quite easy to visualize and isolate the antibody-antigen pairs."
To prove the concept, the group focused its initial experiments on a known interaction between a specific antibody and a fragment of a protein found on the outside of HIV particles. The group worked with some 10 million antibodies, but the library was weighted to include a known antibody. The antigen library was of similar size and comparably weighted to include the known HIV antigen. The weighting guaranteed the existence of an antibody-antigen pair, which in turn allowed the group to tweak its initial concept until it could identify pairings at the expected rate.
The group was able to successfully identify the expected pairings, proving the new technique's potential to enable screening of large antibody and antigen libraries. "We're still deciding where to take it next," says Bowley. One likely direction would be to work with a broad group of cancer proteins, which should identify antibodies with potential as new cancer treatments.
In addition to Bowley, Jones, and Lerner, Scripps Research Professor Dennis Burton was an author of the paper, titled "Libraries against libraries for combinatorial selection of replicating antigen-antibody pairs."
This research was supported by The Scripps Research Institute, the Skaggs Institute for Chemical Biology, and Pfizer Inc.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #114 on: February 04, 2009, 08:26:35 AM »

Anti-ps looking good in lung cancer. the moa is the same for virals:

http://finance.yahoo.com/news/Peregrine-Pharmaceuticals-prnews-14247914.html


Can't wait for interim results of HepC/hiv trial!

Offline veritas

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Re: Could this be the holy grail ?
« Reply #115 on: February 04, 2009, 08:56:01 AM »

more info:


Peregrine Pharmaceuticals has issued a press release with interim data from their phase II NSCLC clinical trial. The Peregrine trial is using their anti-lipid antibody "Bavituximab" which targets exposed phosphatidylserine (PS) in combination with carboplatin and paclitaxel. The Peregrine trial was apparently designed to go head-to-head with the phase II trial of what is currently the standard of care for non small cell lung cancer, (Avastin with carboplatin and paclitaxel). The data released today shows Bavituximab achieving a higher percentage of responses than current SOC.


Offline veritas

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Re: Could this be the holy grail ?
« Reply #116 on: February 08, 2009, 05:10:05 AM »

More broadly neutralizing data with respect to an HIV vaccine:


http://www.ncbi.nlm.nih.gov/pubmed/19193787?dopt=Abstract

Offline veritas

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Re: Could this be the holy grail ?
« Reply #117 on: February 08, 2009, 05:34:38 AM »

More studies ------ X4 vs R5  for vaccine design:


Selective replication of X4 and R5/X4 HIV-1 during the in vitro primary CD4+ T cell response
The ability of R5, X4, and R5/X4 isolates of HIV-1 to replicate in CD4+ T cells during the primary in vitro immune response was determined using a system developed by our group to evaluate the synthesis of anti-viral CCR5 ligands [18], the effects of adjuvants on antigen presentation [19]–[21], and the responses to HIV-1 vaccine candidates [22]. Cultures were initiated and infected with the HIV-1 isolates shown in Figure 1a as described in Materials and Methods. As shown in Figure 1a, five of the six X4 and R5/X4 viruses replicated by day 8 of the culture period. The R5/X4 virus HIV-189.6 replicated poorly, if at all. By contrast, none of the four R5 viruses replicated early in the culture period with only HIV-1SF162 showing a modest increase in p24 by day 11. Since the differences in replication appeared to be greatest during the first 11 days of culture, we compared the day 8 median p24 concentrations of the three groups for statistical significance using Student's t-test. As shown in Figure 1b, the differences between the R5 group and either the X4 or X4/R5 groups were statistically significant (p = 0.02) for X4 viruses, p≤0.05 for X4/R5 viruses). These data show that X4 and X4/R5 viruses selectively replicate during the antigen driven primary CD4+ T cell response in vitro with little or no replication of R5 viruses under these experimental conditions. This conclusion was confirmed in subsequent experiments by analysis of intracellular p24.

http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0003481

The above link is a long read however, the full study shows that both  are able to be controlled in potential vaccine design.

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #118 on: February 11, 2009, 08:14:21 AM »

Anti-ps looking good in breast cancer for interim phase 2. Same moa in viral as in cancer:


http://finance.yahoo.com/news/Peregrine-Pharmaceuticals-prnews-14321025.html


Anxiously awaiting interim results for HepC/Hiv co-infection trial. CHAVI has anti-ps mabs that are a lot more potent than Bavi for their vaccine initiative.

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #119 on: February 11, 2009, 08:40:58 AM »

I wonder what is going to be discussed at this syposium?


http://www.keystonesymposia.org/Meetings/ViewMeetings.cfm?MeetingID=990

Read the entire program for the answer.


veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #120 on: February 11, 2009, 09:25:26 AM »

More info about the Bavi trial:



Anti-PS (Bavituximab)

Phase II Breast Cancer Data:


* seven out of fourteen responses
* including one complete response
* in locally advanced or metastatic breast cancer patients

How early is it?...

* these results after two 28-day treatment cycles
* patients will receive up to six treatment cycles


"Bavituximab Has Now Produced Positive Early Results in All Three Ongoing Phase II Combination Therapy Cancer Trials"

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #121 on: February 16, 2009, 04:19:24 PM »

This study is still enrolling as of 12/08:


http://clinicaltrials.gov/ct/show/NCT00503347


co-infection trial HepC/hiv with Bavituximab (anti-ps).

Offline veritas

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Re: Could this be the holy grail ?
« Reply #122 on: February 18, 2009, 09:47:23 AM »

Chavi determining how quickly a vaccine response will have to be:


Initial B cell Responses
Show Ineffective Control of
Viremia in Acute HIV
Infection
Dr. Georgia Tomaras of Duke
University and colleagues found that the
earliest B cell immune responses to HIV
are ineffective at controlling viral
replication in the earliest stages of
infection. Their study of the earliest
antibody responses in acute HIV
infection was published in the December
issue of the Journal of Virology.
One of CHAVI’s goals is to elucidate
the eclipse phase of HIV infection when
a vaccine has the best chance to clear or
neutralize the virus. This “window of
opportunity” is the period of time from
the point of transmission to the
establishment of the latent pool of
infection. It is approximately 10 days
from transmission when virus can be
detected in blood plasma, but can range
between 7-21 days after transmission. In
this study, Tomaras and colleagues
wanted to determine the antibodies that
respond first to HIV, the time points
when they appear in relation to viral
load, and how well they control viral
replication.
Studying samples from plasma donors
who donated every three days and who
became newly infected with HIV, the
team was able to view the earliest
antibody responses before, during and
after plasma viral load ramp-up in acute
HIV infection. The team found that the
first response came 8 days after
transmission in the form of immune
complexes containing either the antibody
Immunoglobulin G (IgG) or M (IgM)
that bound to virions. The antibodies,
anti-Env IgG and anti-Env IgM, were
detected in plasma 13 days after
transmission. Both IgG and IgM
targeted the glycoprotein, gp41, on the
outer coat of the virus.
Using mathematical modeling, the
team determined whether the initial gp41
antibody response was able to control
viral replication. They found no
relationship between the strength of the
anti-gp41 antibody response and a
decrease in viral load indicating that the
initial antibody response had little
impact on control of viremia.
The team concluded from this study
that the potential window of opportunity
for a vaccine to work appears very short.
They are currently taking a closer look at
the immune complexes that first
appeared 8 days after transmission to see
if they may be manipulated to boost
immunity. A suggested hypothesis is
that a primary boost vaccine would need
to induce antibodies prior to infection
followed by a rapid and robust secondary
response within the first week after
transmission that would be capable of
clearing or neutralizing the virus.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #123 on: February 23, 2009, 01:12:04 PM »

Duke finds potent anti -ps antibody for hiv:

http://insciences.org/article.php?article_id=2626

Successfully neutralizes over 80% of transmitted HIV viruses.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #124 on: February 25, 2009, 05:19:19 AM »

Back-up research on 2F5 and 4E10 mab:


http://www.ncbi.nlm.nih.gov/pubmed/19193787?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Duke has mabs stronger than the above. Anti-ps is becoming more viable !

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #125 on: February 25, 2009, 09:49:41 AM »

For those following this thread, this link is worth repeating. Take particular interest in the neutralizing antibody section and notice the potency of IS4 antibody. This antibody seems to have the potency necessary for therapeutic application as suggested in the world patent application at the very beginning of this thread:

http://www.hivvaccineenterprise.org/conference/archive/2008/Presentations/Thursday/Rapporteurs/1250%20R%20Pantophlet.pdf

The above link is not an easy read.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #126 on: February 25, 2009, 11:37:20 AM »

The most potent mab is PGN632, which neutralized 7/7 hiv clades B and C isolates:


Oct. 14, 2008, Oral Abstracts 03: “Neutralizing Antibodies & Immune Escape”
#OA03-06 ”Anti-lipid Human Monoclonal Antibodies Inhibit HIV-1 Infection of PBMC by Binding to Host Cells”
TONY MOODY [Dir., Laboratory of B cell Immunology, Duke Univ. MC]
MA Moody 1, MK Plonk 1, L Fuller 1, H Liao 1, S Xia 1, MS Drinker 1, TC Gurley 1, RM Scearce 1, GD Tomaras 1, C Chang 2, S King 2, A Kavlie 3, PE Thorpe 4, SM Alam 1, PP Chen 5, DC Montefiori 6, BF Haynes 1
1 Duke University Medical Center, Durham, NC
2 Peregrine Pharmaceuticals, Tustin, CA
3 Affitech AS, Oslo, N-0349, Norway
4 University of Texas Southwestern Medical Center, Dallas, TX
5 UCLA School of Medicine, Los Angeles, CA
6 Dept. of Surgery, Duke University Medical Center, Durham, NC
BACKGROUND:
HIV-1-infected or vaccinated humans rarely make broadly-reactive neutralizing antibodies. Some antibodies against conserved Env epitopes share similarities with autoantibodies; one hypothesis is such antibodies are downregulated by immune tolerance. The observation that AIDS may be rare in primary autoimmune disease patients (1) prompted the hypothesis that autoimmune disease patients with defective tolerance mechanisms may make antibodies that in some manner protect against HIV-1 infection. Methods: We studied a panel of human anti-lipid mAbs from autoimmune disease patients and healthy controls. Mabs IS4, CL1, P1, and PGN632 bind cardiolipin and phosphatidylserine independent of b2-glycoprotein I; mAbs B1, B2, PGN634, and PGN635 require b2-glycoprotein I for lipid binding. Inhibition of HIV-1 infection was studied using HIV-1 Env pseudoviruses in TZM/bl cells and using whole virus assays in peripheral blood mononuclear cells (PBMC). MAb interaction with Env, lipids, and cells was determined by surface plasmon resonance (SPR), flow cytometry, and fluorescent microscopy.
RESULTS:
No mAbs bound HIV-1 wild-type Envs by SPR and none significantly neutralized HIV-1 primary isolate pseudoviruses in the TZM/bl assay. In PBMC, b2-glycoprotein I-dependent mAbs minimally inhibited infection. In contrast, b2-glycoprotein I-independent anti-lipid mAbs (PGN632, P1, IS4, CL1) inhibited HIV-1 primary isolate infection of PBMC (IC80s<0.02 to 45 mg/ mL). The most potent mAb PGN632 inhibited 7/7 B & C clade HIV-1 isolates (IC80s<0.02-0.16 mg/mL) and SHIV-SP162P3 (IC80 0.06 mg/mL). Cell preincubation and virus capture studies showed the mAbs acted at host cell surfaces to inhibit HIV-1 infection. Immunofluorescence of CD4ţ T cells showed the mAbs bound to lipid rafts.
CONCLUSION:
Anti-lipid human mAbs inhibit HIV-1 infection in vitro in PBMC likely by binding CD4ţ T cell lipid rafts. Testing these mAbs in passive therapy trials in vivo in non-human primates will be important to determine their protective effect. Nonpathogenic anti-lipid antibodies may provide a target for HIV-1 vaccine development.
PAGE 57, #OA03-06: http://www.hivvaccineenterprise.org/_dwn/forms/Final%20Abstract%20Book.pdf
*end*


Offline veritas

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Re: Could this be the holy grail ?
« Reply #127 on: February 27, 2009, 09:29:17 AM »

Since this thread is getting so long, thought I would post this press release again which reviews anti-ps as a therapeutic and possible vaccine for many viral indications:


http://www.zampbioworld.org/bionews/index.php/2008/11/25/11813

Offline veritas

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Re: Could this be the holy grail ?
« Reply #128 on: February 28, 2009, 03:31:22 PM »

What is allowing HIV to escape the immune system? Could it be exposed ps on infected cells?

http://www.sciencedaily.com/releases/2009/02/090227150549.htm

Sounds like a viable therapy should go after a part of the infected cell that cannot mutate. Anti-ps anyone?

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #129 on: March 02, 2009, 05:40:06 AM »

What else can anti-ps do?  Arsenic anyone?


http://engg-medi.blogspot.com/

Sunday, March 1, 2009

Using arsenic to detect cancers?
An international team led by Texan researchers is using arsenic as a powerful tumor imaging agent. In fact, they are using a drug called bavituximab, 'an antibody that homes in on a specific molecular target on the blood vessels that feed tumors.' By linking this drug to very small doses of arsenic -- about one-millionth of what could be considered as poison -- they think it could allow physicians to detect hard-to-find tumors in a near future. The combination has already successfully tested with rats affected by prostate tumors. And it could soon be used on on humans to image breast tumors. But read more...
The Bavituximab drug is a monoclonal antibody analog which is used to potentially treat cancers and viral infections. (Credit: Wikipedia) It has been licensed by Peregrine Pharmaceuticals, Inc. from UT Southwestern Medical Center. As you can see above on the left, Bavituximab can be used as an anti-cancer drug, "Bavituximab binding to the tumor blood vessel cells alerts the body's immune system to attack the tumor and its blood supply" (Credit: Peregrine). But it also can be used as an anti-viral drug as you can see on the right. "After binding to these infected cells, the drug alerts the body's immune system to attack the infected cells" (Credit: Peregrine).
Binding tiny doses of arsenic to bavituximab is a project led by Dr. Philip Thorpe, professor of pharmacology at the University of Texas Southwestern Medical Center, and by Dr. Ralph Mason, professor of radiology and director of the UT Southwestern Cancer Imaging Program.
So why did these scientists decide to hire arsenic for help? The first reason is because "arsenic-labeled bavituximab appears to be safe." The second one is because it works. "In the study, Dr. Thorpe and his colleagues injected radioarsenic-labeled bavituximab into rats with prostate tumors. When the bavituximab bound to its target on the the tumor blood vessels, the tag-along arsenic created a 'hot spot' that researchers then imaged using positron emission tomography methods. The radioactivity levels produced by the arsenic are comparable to those used in standard, routine imaging procedures in humans. The technique allowed them to locate and capture unusually clear images of the tumors. They also discovered that there was little or no detectable uptake of bavituximab by normal organs, including the liver, a common site where drugs become entrapped."
Here is a quote from Thorpe. "We hope to use this technique to detect early tumor deposits that are not visible using other imaging techniques. The images we obtain are so clear that we may be able to see secondary tumors that have spread from the original tumor mass and lodged in distant organs."
This research work is scheduled to appear in the March 1, 2008 issue of Clinical Cancer Research under the name "Vascular Imaging of Solid Tumors in Rats with a Radioactive Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine." Unfortunately, the journal site gives access to its February 15, 2008 issue and gives a preview of its March 15, 2008 issue, but doesn't show anything about its March 1, 2008 issue.
But for more information, you can read a March 3, 2008 news release from Peregrine Pharmaceuticals, which states that Bavituximab can successfully target tumor blood vessels. Here is a quote. "In the study, researchers administered radiolabeled bavituximab to rats with prostate tumors and then conducted molecular imaging studies of the rats over the next several days. The results showed that radiolabeled bavituximab localized to the tumor blood vessels with great specificity. In these subjects, 22 times as much bavituximab localized to the tumor compared to the liver when measured 72 hours post-injection. The study further showed no specific localization of bavituximab to blood or other tissues including the heart, kidney, intestine, muscle, bone and brain. The tumor blood vessel-selective targeting observed in vivo in the study was confirmed by further bio-distribution analyses and by histology studies."
So are you ready for arsenic? Drop me a note if you think it's a good -- or bad -- idea.
Sources: University of Texas Southwestern Medical Center news release, March 1, 2008; and various websites
You'll find related stories by following the links below.
Chemistry
Future
Medicine
Physics
Science

Offline veritas

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Re: Could this be the holy grail ?
« Reply #130 on: March 03, 2009, 04:00:19 AM »
PS explained:
FYI: Antiviral Drugs: Exposed target for broad-spectrum antivirals

http://www.nature.com/nrd/journal/v8/n1/full/nrd2788.html
Nature Reviews Drug Discovery 8, 19 (January 2009) | doi:10.1038/nrd2788
Man Tsuey Tse

Phosphatidylserine, the most abundant anionic phospholipid of the plasma membrane, has been used as a target to develop a novel broad-spectrum antiviral agent called bavituximab. Strikingly, bavituximab was able to cure overt disease in guinea-pigs infected with a potentially lethal dose of Pichinde virus, a model of Lassa fever virus.

Writing in Nature Medicine, Thorpe and colleagues proposed that the effects of a wide range of viruses on host cells could lead to normally intracellular anionic phospholipids being exposed on the surface of infected cells. To test this hypothesis, they used bavituximab — a chimeric antibody that binds to complexes of the phosphatidylserine-binding plasma protein 2-glycoprotein 1 and anionic phospholipids. These experiments showed that infection of mouse cells by Pichinde virus led to phosphatidylserine exposure, and that bavituximab binds to virus-infected cells and infectious virions.

Treatment of guinea-pigs infected with a normally lethal dose of Pichinde virus with bavituximab 6–7 days after infection led to 50% of the animals surviving, and clearance of the virus was observed by day 135. In addition, combination of bavituximab with ribavirin (the current drug of choice for treating Lassa fever) had an additive effect.

The authors also provided evidence for two mechanisms that seem to underlie these effects. First, bavituximab treatment clears infectious virus from the bloodstream. Second, it induces antibody-dependent cellular cytotoxicity of virus-infected cells. As the authors propose, it seems that phosphatidylserine on virions and infected cells might enable viruses to evade immune recognition and dampen inflammatory responses, and that bavituximab interferes with this 'masking' process.


Finally, the authors explored phosphatidylserine exposure in other viral infections. Exposure was also observed in cells infected with influenza virus, vaccinia, vesicular stomatitis virus and mouse cytomegalovirus (CMV). This indicates that this process is a common feature of enveloped viruses; exposure could also extend to non-enveloped viruses. Furthermore, tests in mice infected with an almost lethal dose of CMV showed that all treated mice survived, in contrast to untreated mice, of which only 25% were alive after 96 days.

In both animal models, bavituximab was well tolerated, and no toxicity was observed histologically. Therefore, targeting phosphatidylserine shows promise as an antiviral strategy. In addition, as phosphatidylserine is a host-derived target, the development of resistance could be limited. Clinical trials of bavituximab are currently underway in patients with hepatitis C co-infected with HIV.

***********

Inside-out antivirals
Phosphatidylserine is actively maintained in the inner leaflet of the membranes of healthy cells, but 'flips' and becomes exposed on the cell's exterior during apoptosis. Having first shown that this phenomenon is triggered by infection with a range of viruses in vitro, Soares et al. exploit the loss of asymmetry in the membranes of virally infected cells and enveloped virions by demonstrating the potential of aminophospholipids as antiviral targets. Inspired by studies suggesting the immunosuppressive and anti-inflammatory potential of exposed phosphatidylserine, they show that a chimeric antibody (bavituximab) against complexes comprising a phosphatidylserine-binding plasma protein and anionic phospholipids enhances the robustness of the immune response to viral infection. Treatment with bavituximab not only cured guinea pigs lethally infected with Pichinde virus (a model for Lassa fever virus, a potential bioterrorism agent), but also rescued mice with lethal cytomegalovirus infections. The antiviral effects can primarily be attributed to direct virus clearance from the bloodstream and antibody-dependent cellular cytotoxicity. Bavituximab treatment appears to be well tolerated and augments the antiviral effect of ribavirin, the drug of choice for treating Lassa fever. (Nat. Med. 14, 1357–1362)



References and links
ORIGINAL RESEARCH PAPER
Soares, M. M., King, S. W. & Thorpe, P. E. Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases. Nature Med. 23 Nov 2008 (doi: 10.1038/nm.1885)




 

Offline carpediem98

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Re: Could this be the holy grail ?
« Reply #131 on: March 12, 2009, 02:23:20 PM »
Great work in this thread, Veritas!

I referenced you and the research you've highlighted in a DailyKos thread.  It gave OTHERS hope, as well.  :) 

http://www.dailykos.com/story/2009/3/7/141053/0717/16/705776


Keep spreading the hope - and I hope our optimism is well-placed!

Offline veritas

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Re: Could this be the holy grail ?
« Reply #132 on: March 12, 2009, 05:16:21 PM »

carpediem98,

I started this thread with the intention of giving others hope. If, by referencing this thread, some of your readers were the recipients of that hope then I feel as though I've been successful.

I know anti-ps is a new paradigm in the fight against HIV (and other diseases) and I also understand that being a new paradigm, its value will have to be tested vigorously to prove its merit. However ,what i find fascinating about this therapy is that I have not found any negative papers with respect to this research.
Also. peer review has thus far reinforced Dr. Thorpe's research. Early clinical trials seem to be leaning in that direction also (especially with respect to cancer).

My only complaint is the seemingly snail's pace with respect to the anti viral. Alas, you can't rush science!
 
I will be following this research to its conclusion. Please feel free to reference this thread if you find it has merit.

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #133 on: March 14, 2009, 05:09:38 AM »

Does anti-ps aid in the production of dendritic cells and Il2s ?  It looks that way!



2009 AACR Annual Meeting
April 18-22, 2009
Denver, CO


  Print this Page for Your Records  Close Window 

Abstract Number: 2407
Session Title: Immune Modulating Antibodies and Lymphocyte Transfer
Presentation Title: A novel anti-phosphatidylserine antibody that promotes dendritic cell maturation
Presentation Start/End Time: Monday, Apr 20, 2009, 1:00 PM - 5:00 PM
Location: Hall B-F, Poster Section 16
Poster Section: 16
Poster Board Number: 1
Author Block: Xianming Huang, Dan Ye, Philip Thorpe, Anita Kavlie. UT Southwestern Medical Ctr., Dallas, TX, Affitech AS, Oslo, Norway
11.31 is a fully human anti-phosphatidylserine (PS) antibody that binds to PS directly, as determined by ELISA and by cell staining. In the present study, the effects of 11.31 on bone marrow-derived immature dendritic cells were examined. Bone marrow monocytes were harvested from the femur and tibia of BALB/c mice. Immature dendritic cells were derived by growing bone marrow monocytes in the presence of mouse GM-CSF (20 ng/ml) for 7 days, and the medium replaced with fresh medium containing GM-CSF every other day. Immature dendritic cells were then harvested and cultured in the presence of 11.31 or control human IgG for 48 hours. Cytokine production in the supernatant was measured by ELISA. Maturation of dendritic cells was examined by FACS analysis. We found that 11.31 significantly increased the expression of maturation markers CD40, CD80, CD86 and MHC II on the surface of dendritic cells. 11.31 also significantly increased production of IL-2, IL-6, TNFα, GM-CSF and MIP-1β by immature dendritic cells. Taken together, our results indicate that 11.31 promotes maturation of dendritic cells. 11.31 has the potential to enhance cancer immunotherapy.
 

Offline simpleguy

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Re: Could this be the holy grail ?
« Reply #134 on: March 15, 2009, 02:11:12 PM »
Hi! I'm a 40y hiv+ guy (9 months positive) from Denmark who happened to stumble upon this thread about bavituximab and the science behind using mAbs as a possible therapeutic - Wow! This is very exciting!

One thing that got me a bit worried though, was the thing about the mAbs not neutralizing HIV in a TMZ-bl cell assay. Not being a science person, I didn't really understand what it meant, except I got a feeling of "this doesn't sound very good".

According to the OA03-06 Oral Abstract from the Oct. 2008 AIDS Conference "No mAbs [...] significantly neutralized HIV-1 primary isolate pseudoviruses in the TZM/bl assay". According to the paper in the following link, that can be explained by TMZ-bl cell lines having been "engineered" to have an unusual high concentration of CCR5 on the cell surface[1], compared to the (unengineered) PBMC cells. In other words: a TMZ-bl cell assay doesn't reflect in vivo conditions, whereas PBMC does  :-X (the good thing being that the mAbs neutralized hiv in the PBMC cell assays).

Published August 4, 2006
Increased Efficacy of HIV-1 Neutralization by Antibodies at Low CCR5 Surface Concentration
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16904645

There's a lot of stuff about the science of hiv I don't understand. More science-knowlegdeable people on this board are welcome to correct me, if I got something wrong. Anyway .. I really hope this Duke-PPHM-Affitech et. al. research about mAbs will lead to a more bearable life with hiv (a shift away from HAART and side effects).

[1] https://www.aidsreagent.org/reagentdetail.cfm?t=cell_lines&id=119

See also
http://en.wikipedia.org/wiki/PBMC
http://en.wikipedia.org/wiki/HeLa

2008 JUL: Sustiva OCT: Rayataz DEC: Kaletra • 2009 Off meds • 2011 Intelence • 2012+ Complera

Offline veritas

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Re: Could this be the holy grail ?
« Reply #135 on: March 15, 2009, 03:53:57 PM »

simpleguy,

We are all in the same boat with respect to the understanding of HIV. The science is complicated. If it wasn't complicated the powers that be would have come up with a cure.

I am optimistic about anti-ps therapy because it is a new paradigm in the fight against HIV. We know that trying to attack the virus directly(via HAART) does not and will not eradicate hiv from the body. By attaching to a non-mutateable part of the virus,anti-ps allows our immune system to attack the virus and those cells infected with the virus. The problem is trying to get a strong enough immune response to do the job and that's why I agree with you 100% when you said:

"I really hope this Duke-PPHM-Affitech et. al. research about mAbs will lead to a more bearable life with

hiv (a shift away from HAART and side effects)."

Time will tell. Let's hope it is the holy grail.

veritas

ps: so far, anti-ps is working wonderfully in phase ll cancer trials.




Offline veritas

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Re: Could this be the holy grail ?
« Reply #136 on: March 16, 2009, 08:37:17 AM »

What do we need for a vaccine? B-cells anyone?

http://www3.niaid.nih.gov/news/newsreleases/2009/hiv_antibodies.htm

And what interacts with B-cells to give them the necessary ability for an adaptive immune response to fight a virus ? Dendritic cells anyone?

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

And as we saw in an earlier post, what stimulates the production of Dendritic Cells?

ANTI-PS !!!!!!!!!!

Can we connect the dots?

veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #137 on: March 17, 2009, 09:53:39 AM »

Interesting read even though a bit dated. Bavituximab mentioned using its' former name Tarvacin:

http://www.aapspharmaceutica.com/StudentCenter/SPODCommittee/imagespdfs/Pharmaceutical_Discovery_in_21st_century-GK.pdf

Offline veritas

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Re: Could this be the holy grail ?
« Reply #138 on: March 18, 2009, 05:49:09 AM »

Update on vaccine design. Take particular notice of the remarks by Barton Haynes of Duke University and how anti-ps should play a major part.... Long read:

http://www.cavd.org/SiteCollectionDocuments/CAVD%20Report_%202006-2008%20In%20Review.pdf


veritas

Offline veritas

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Re: Could this be the holy grail ?
« Reply #139 on: March 19, 2009, 12:54:39 PM »

Why anti-ps should work:

 HIV/AIDS
A viral cause of APS has been proposed.[318] HIV infection carries a high frequency of aPL[34,319] but here, too, the aPL in HIV were considered to be of the infection-related type and non-pathogenic. Haynes et al[46] point out that anti-HIV antibodies mounted by most patients fail to neutralize the virus, but a rare few do mount neutralizing responses, and those studied turned out to be polyspecific aCL, similar to the aPL profile seen in lupus (SLE). Indeed, they cite references indicating that SLE patients appear to be protected against contracting HIV, and argue that the general population fails to make such aPL because they have been deleted from the repertoire as self-reactive. In support of their contention, one of the neutralizing anti-HIV they studied was autoreactive with dsDNA, centromere B, histones and other self targets.[46] Relatedly, Zhang et al[320] investigated why most people fail to mount effective immune responses to HIV envelope proteins (Env), and suggested that Env suppresses CD40L expression, which in turn blunts the T cell ability to activate DCs. However, we feel that findings of Zhang et al[320] are consistent with the scenario given by Haynes et al.[46] Specifically, the aPL seen in the context of HIV and other infections may be more than epiphenomena and could offer important clues to immune function.

medscape

Offline veritas

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Re: Could this be the holy grail ?
« Reply #140 on: March 21, 2009, 12:24:22 PM »


IN VIVO:

In Vivo gp41 Antibodies Targeting the 2F5 Monoclonal Antibody Epitope Mediate
Human Immunodeficiency Virus Type 1 Neutralization Breadth

Xiaoying Shen,1,2 Robert J. Parks,1,4 David C. Montefiori,1,2 Jennifer L.
Kirchherr,1,4 Brandon F. Keele,6 Julie M. Decker,6 William A. Blattner,5 Feng
Gao,1,4 Kent J. Weinhold,1,2,3 Charles B. Hicks,4 Michael L. Greenberg,2,
Beatrice H. Hahn,6 George M. Shaw,6 Barton F. Haynes,1,3,4 and Georgia D.
Tomaras1,2,3*

Duke Human Vaccine Institute,1 Departments of Surgery,2 Immunology,3 Medicine,
Duke University Medicine Center, Durham, North Carolina 27710,4 Division of
Epidemiology and Prevention, Institute of Human Virology, University of
Maryland, Baltimore, Maryland 21201,5 Department of Medicine, University of
Alabama at Birmingham, Birmingham, Alabama 35294-00246

Received 20 December 2008/ Accepted 27 January 2009

The broadly neutralizing human monoclonal antibodies (MAbs) 2F5 and 4E10, both
targeting the highly conserved human immunodeficiency virus type 1 (HIV-1)
envelope membrane proximal external region (MPER), are among the MAbs with the
broadest heterologous neutralizing activity and are of considerable interest for
HIV-1 vaccine development. We have identified serum antibodies from an
HIV-infected subject that both were broadly neutralizing and specifically
targeted MPER epitopes that overlap the 2F5 epitope. These MPER-specific
antibodies were made 15 to 20 months following transmission and concomitantly
with the development of autoantibodies. Our findings suggest that multiple
events (i.e., genetic predisposition and HIV-1 immune dysregulation) may be
required for induction of broadly reactive gp41 MPER antibodies in natural
infection.



Offline simpleguy

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Re: Could this be the holy grail ?
« Reply #141 on: March 21, 2009, 03:12:04 PM »
Illustration, showing the size of an antibody compared to the trimer gp41/gp120 and the 2F5 and 4E10 binding sites on the spike of a hiv virion. http://jvi.asm.org/cgi/content-nw/full/75/22/10892/F10

Fascinating...

Taken from a 2001 study on hiv and antibodies
http://jvi.asm.org/cgi/content/full/75/22/10892
2008 JUL: Sustiva OCT: Rayataz DEC: Kaletra • 2009 Off meds • 2011 Intelence • 2012+ Complera


Offline veritas

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Re: Could this be the holy grail ?
« Reply #143 on: March 21, 2009, 04:05:09 PM »
Illustration, showing the size of an antibody compared to the trimer gp41/gp120 and the 2F5 and 4E10 binding sites on the spike of a hiv virion. http://jvi.asm.org/cgi/content-nw/full/75/22/10892/F10

Fascinating...

Taken from a 2001 study on hiv and antibodies
http://jvi.asm.org/cgi/content/full/75/22/10892


Simpleguy,
Your illustration shows how targeted these antibodies are.  Since ps is only exposed on virons, infected cells, and dying cells, side effects, if any, should be minimal. In clinical trials to date, only topline safety data has been reported (see earlier posts). By magnifying the illustration, you can get the full effect of the moa (especially for those of us who need the magnification.)

The work is fascinating !

veritas

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #144 on: March 21, 2009, 05:35:29 PM »
Our findings suggest that multiple events (i.e., genetic predisposition and HIV-1 immune dysregulation) may be
required for induction of broadly reactive gp41 MPER antibodies in natural infection.

I'm trying to figure out this sentence in laymen's terms. Any suggestions?

Offline simpleguy

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Re: Could this be the holy grail ?
« Reply #145 on: March 21, 2009, 07:40:38 PM »
The theory is that broadly reactive antibodies (able to neutralize different clades and/or mutations of hiv) produced by your own body, probably only takes place in a body with a "twisted" immune system, for example in people suffering from the autoimmune disease Lupus; a disease characterized by the body producing antibodies which stick to healthy tissue and signaling the immune system to attack it. Lupus could be the result of "genetic predisposition".

The antibody "overlapping the 2F5 epitope", isolated from the hiv+ subject, was found at a time where autoimmune antibodies were also present, probably because that person is suffering from an autoimmune disease. Research shows that very few people with autoimmune disease are hiv+, and if they are, their hiv doesn't progress.

gp41 MPER = the spikes on the surface of hiv virus
Lupus: http://en.wikipedia.org/wiki/Systemic_lupus_erythematosus
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Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #146 on: March 21, 2009, 08:04:49 PM »
Thanks, Simpleguy, that clears it up. I "get" it.

Offline simpleguy

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Re: Could this be the holy grail ?
« Reply #147 on: March 21, 2009, 09:11:08 PM »
lol ... ;o)

I was quoting from the article that veritas posted (#140)
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Offline veritas

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Re: Could this be the holy grail ?
« Reply #148 on: March 25, 2009, 09:46:22 AM »

More B-cells and hiv:


B cells in HIV infection and disease
Susan Moir1 & Anthony S. Fauci

http://www.nature.com/nri/journal/v9/n4/execsumm/nri2524.html
Nature Reviews Immunology 9, 235-245 (April 2009) | doi:10.1038/nri2524

Summary

HIV infection leads to perturbations of all of the main cell types of the immune system, including B cells. Most B-cell perturbations are associated with indirect effects of ongoing HIV replication, although some perturbations arise regardless of the decrease in viraemia by effective antiretroviral therapy (ART).
Many B-cell defects in HIV infection are associated with alterations in the B-cell subpopulations that circulate in the peripheral blood. Most B cells in healthy individuals comprise resting naive and memory B cells, whereas several minor subpopulations are over-represented in HIV-infected individuals, including immature transitional B cells, exhausted B cells, activated mature B cells and plasmablasts.

In vitro and in vivo studies show that HIV can also interact directly with B cells, although the frequency of these interactions is unlikely to account for the extent of B-cell dysregulation that is observed in infected individuals. HIV virions complexed with complement and antibody can bind B cells through the complement receptor CD21, and HIV virions and proteins, including gp120 and Nef, can also interact directly or indirectly with B cells.
Indirect effects of HIV viraemia on B cells include B-cell hyperactivity (as manifested by hypergammaglobulinaemia), increased B-cell polyclonal activation, increased B-cell turnover, increased expression of activation markers and of markers that are associated with activation-induced apoptosis, increased frequency of B-cell malignancies and increased differentiation of B cells to plasmablasts.
HIV viraemia with CD4+ T-cell lymphopenia is associated with an increased frequency of immature transitional B cells. This increase is also associated with increased serum levels of interleukin-7.
HIV viraemia leads to B-cell exhaustion, as manifested by increased expression of multiple inhibitory receptors, altered expression of homing receptors, decreased cell division and somatic hypermutation in vivo, decreased proliferative and effector properties in vitro and enrichment of HIV-specific responses in the exhausted B-cell compartment.
Although most B-cell perturbations in HIV-infected individuals are attributed to viraemia and are reversible by ART, one important exception is the loss of memory B cells. All stages of HIV infection are associated with a decrease both in the frequency of resting memory B cells and of B-cell responses against T-cell-dependent and T-cell-independent antigens.
Many B-cell perturbations observed in HIV infection also arise in various infectious and non-infectious disease settings that involve immune dysfunction. Several human diseases that affect B cells show dysregulation of immature transitional B cells, whereas others show dysregulation of memory B cells, with alterations that are similar to B-cell exhaustion and activation-induced terminal differentiation.

Author affiliations
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
Correspondence to: Susan Moir1 Email: smoir

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