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Author Topic: Could this be the holy grail ?  (Read 166146 times)

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Offline Matts

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Re: Could this be the holy grail ?
« Reply #150 on: March 30, 2009, 03:00:32 AM »
Thank You for Your postings about Anti-PS, this topic is very interesting


Let's wait for some results about the Bavi(3g4,2g12,PGN 635,1N11,former Tarvacin) HIV/HCV trial.
Possibly this mAb is not so good against HIV as against cancer or HCV, but there will be better mAbs
in the future.

The Peregrine trials so far are all small, not randomized, uncontrolled and not further than phase II.
Nevertheless Bavituximab has potential against all enveloped viruses (HepC, HIV, Influenza/Avian Flu, CMV, RSV, Lassa Fever), solid tumor types and unenveloped viruses.
Peregrine and DTRA have a biodefence contract of 44Mio$ against viral Hemorrhagic Fevers (Ebola, Marburg, Lassa). Maybe Anti-PS will be the '"Magic bullet" the people are looking for 100 years'. Time will tell.


The Duke/CHAVI/Barton Haynes/Gates/Peregrine/NIH collaboration and their new "SuperBavi" PGN632 [11.31] have even much better results against HIV than all other anti-PS. New Results are expected
within the 1st half of 2009.

-http://www.investorvillage.com/smbd.asp?mb=1773&mn=705&pt=msg&mid=6497373



At the Cowen Conference in Boston (march) they told bavituximab could be used in near future as ' post-exposure- treatment and topical microbizide'. At the moment only Barton Haynes (Duke) knows the possible potential of Mab against HIV. Duke and CHAVI decide what and when they publish something. Peregrine provides the best Mabs, but the HIV/HCP trial and the research is done by Duke. I hope we will hear more soon and Mabs can bring a vaccine and prophylactic treatment in the future.

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=36488065




- A blog about Anti_ps:

http://anti-ps.blogspot.com/search?q=hiv


- News about Peregrine and their mAbs:

http://investorshub.advfn.com/boards/board.aspx?board_id=2076
 







« Last Edit: March 31, 2009, 08:42:47 PM by Matts »
tivicay/kivexa

Offline georgep77

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Re: Could this be the holy grail ?
« Reply #151 on: March 30, 2009, 07:44:11 PM »

-http://www.investorvillage.com/smbd.asp?mb=1773&mn=707&pt=msg&mid=6535688

 
Can somebody explain me the graphs from: Bavi vs. Duke-PPHM mab 11.31

                                 Thanks      ;D
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
+ 2008

Offline Matts

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Re: Could this be the holy grail ?
« Reply #152 on: March 30, 2009, 09:20:00 PM »
sorry this was a wrong link

http://www.investorvillage.com/smbd.asp?mb=1773&mn=705&pt=msg&mid=6497373


Tri-mab are the monoclonal antibodies 2G12(Bavi),2F5 and b12. CL1, P1, IS4 are also mAbs. The newest is Duke's PGN632 a.k.a. 11.31, 1000 times stronger than all other mAbs. But so far not tested in humans.


From Dr Moody’s Abstract, AIDS'08/Capetown 10-14-08 :
“…In contrast, B2GPI-indep. anti-lipid mAbs (PGN632, P1, IS4, CL1) inhibited HIV-1 primary isolate infection of PBMC. The most potent mAb PGN632 inhibited 7/7 B & C clade HIV-1 isolates (IC80s<0.02-0.16 mg/mL) and SHIV-SP162P3. Cell preincubation and virus capture studies showed the mAbs acted at host cell surfaces to inhibit HIV-1 infection. Immunofluorescence of CD4þ T cells showed the mAbs bound to lipid rafts…”

NEUTRALIZING ANTIBODIES TO THWART HIV (NIAID 1-6-09)…
“…they [IS4, CL1, P1, PGN632=’most-potent, aka ‘11.31’] neutralized virus in the PBMC assay, apparently through release of b-chemokines (MIP1a, MIP1b) by monocytes in the culture. Such chemokines interfere with virus entry through the CCR5 receptor. Furthermore, neutralization could be reverted by antibodies against MIP1a & MIP1b. These anti-lipid antibodies stick to the host target cell and not the virus to prevent infection…”
http://www3.niaid.nih.gov/topics/HIVAIDS/Research/vaccines/reports/aidsvac2008.htm

= = = = = = What’s PBMC ?:
DUKE Jan’08: “Peripheral Blood Mononuclear Cells (PBMC’s) such as CD4+ cells are invaluable for HIV research. The levels of CD4+ cells, a primary target of HIV infection, can indicate how the immune system is responding to infection over a specific period of time. Use of PBMC’s for HIV research has dramatically increased in recent years as vaccine discovery efforts and multi-center clinical trial networks have expanded.”

CONCLUSIONS
“The AIDS Vaccine 2008 Conf. 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’, aka ’11.31’] 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.”
See: http://anti-ps.blogspot.com
. . .Specifically, http://anti-ps.blogspot.com/2009/01/cape-town-wrap-up-anti-lipid-antibodies.html
------------------------------------------------------
Some general quotes about PS/ Mabs:

 Barton Haynes' previous big shocker in 2005 that got all the money thrown his way (CHAVI & Gates), which made him the #`1 top govt. funded doc in the country, was in Science. That's where he showed that the few rare broadly neutralizing abs found in people bound to not only viral bits, but also phospholipids. He reasoned that those rare BNAbs were not typically made in most people for reasons I've already discussed...
It's taken two short years to move from (most folks) seeing the lipid-binding characteristics of those now-famous rare mabs as a hindrance, to seing them as the KEY....


Or- to re-phrase that - Haynes' original paper sent a shock-wave through the research community, with his data that the extremely rare BNAbs (Broadly Neutralizing Abs) were polyspecific for viral epitopes AND PHOSPHOLIPIDS. The phospholipid binding was seen negatively, surely, as a likely reason for the abs rarity in people, and also with potential safety problems.

I expect the upcoming paper to change the view of that 180 degrees.

In the upcoming paper:

* I expect them to say/prove that targteting phospholipids alone with antibodies can neutralize HIV.
(That's a shocker with implications for many viruses and other diseases).

* I expect them to say/prove that you don't need to target the virus itself.

* I expect them to say/prove that by targeting phospholipids alone with abs you can prevent fusion of the virus with a cell.

* I expect them to say/prove that targeting certain (host-cell) phospholipids on the virus and on virally infected cells with abs is safe.
(Anyone who understands the long-standing foundations of the immunological paradigm will realize how big a change this is).

* I expect them to discuss various details as to the binding specificities of anti-phospholipid abs which further delineate pathogenic and non-pathogenic abs. (That's still quite a grey area among most scientists. Carl Alving, who heads the vaccine dept at Walter Reed has written on this topic in the past couple years and, along with Haynes' team, Pojen Chen and Schroit/Thorpe & PPHM, is on the forefront of the present understanding of what delineates pathogenic and non-pathogenic autoantibodies, and is a proponent of the concept of SAFE abs to phosppholipids). This grey area (at best, presently), is the reason many scientists and others look funny when you tell them about Bavituximab's target.)

* I expect this paper to sound the bell, most authoratively, which ushers in the concept of phospholipid-targeting as a new promising field of therapy, with implications for treating numerous diseases - viral, cancer, and others. I expect it to change how science views disease and disease therapy in a fundamental way, (a little more on that later).

* I expect them to discuss and lend authority to the fact that PS is immunosuppressive, and that covering PS blocks the immunosuppressive signals INITIATED by exposed PS.

* I expect to see specific cytokine data from experiments which detail this PS-initiated immunosuppressive change.

* I expect them to discuss the overwhelming apoptosis in early HIV infection, and that shed vesicles which contain cell membrane phospholipids, expose PS, and that this debris with exposed PS is responsible for blunting the immune system's  response.

* Further, and importantly, I hope they put forth the idea that this way that HIV hides from the immune system, (via exposed PS), is quite possibly a general escape mechanism of disease. I hope to read discussion that, since PS is an early external apoptotic sign, and the cells of the immune system have evolved to recognize it as a fundamental signal for a friendly/homeostasis/pro-growth/repair resonse, that "successful" cancers, viruses, and protozoan parasites seem to have independently evolved to take advantage of this signaling, obviously, because it provides the best advantage allowing them to survive and thrive.

* I expect them to show with compelling data that anti-PS mabs safely deal with this oh so fundamental loop-hole/compromise that has been with us since the dawn of metazoans, (which has been proven to be, as you'd expect, also the dawn of the apoptotic process).

* and I think it'll make the "news" :)

-------------------
we demonstrated the presence of CD3+, CD45+, and
phosphatidylserine (PS)-expressing microparticles in these plasma samples
at the time of viral load ramp-up.

Conclusion: These results demonstrate that at the time of viral load ramp-up
in acute HIV-1 infection, there are elevations in plasma levels of TRAIL, FAS
Ligand, and TNFR2 that were associated with the presence of microparticles
from apoptotic T cells. The presence of these apoptotic markers suggests
apoptosis occurring at the time of initial HIV-1 viral load ramp-up. That PS+
apoptotic cells and microparticles have been reported to suppress antigenspecific
immune responses suggests the hypothesis that immune cell
apoptosis in the very earliest stages of acute HIV-1 infection may delay the
onset of potentially protective anti-HIV-1 immune responses. (CHAVI)

He's (B.Haynes) now recently on record as saying that PS looks to be responsible for a failure of the immune system  to eradicate the HIV virus, or even keep it more in check,
Bavituximab binds the PS exposing microparticles,
(as he showed in the previous CHAVI Admin meeting)....

“We have also been collaborating with researchers at Duke and other institutions to better understand the potential of Bavituximab in an HIV setting. Significant findings of these studies include data supporting Bavituximab binding to mult. strains of HIV and binding to HIV-infected cells


Bavi's MOA - I make that point to further illustrate that recently the general thrust of the overall research into HIV therapy and vaccines, is moving much more in line with Bavi's MOA. It's fascinating, and amazing.


Realize that Haynes is the Director, the top leader, of NIH's whole $300 million CHAVI program, which, along with the Gates $287 million CAVD, both fall under what's called the Global HIV Vaccine Enterprise.

Realize that the reason the money got thrown at Haynes, (crudely put but accurate enough), was due to his MAJOR discovery of the broadly-neutralizing HIV abs found in people naturally stuck to host-cell phospholipids...

and understand that Haynes is the one talking about abundant PS downregulating the immune system's  fight against HIV

and understand that Haynes and others in CHAVI / Gates are working with and generating data on Bavituximab and other PPHM (Peregrine pharmaceuticals)mabs that fall under PPHM's anti-phospholipid platform in his experiments.

Let there be no confusion about that.
------------

in CHAVI 005, they're looking for broadly neutralizing HIV antibodies which target host-cell phospholipids in lupus patients.
in CHAVI 006, they're looking for broadly neutralizing HIV antibodies which target host-cell phospholipids in syphilis patients.
All this is as a model to see if it's worth it to try to design a vaccine that elicits this type of ab in people.
as for "Bavi's MOA" -in CHAVI 012 they're looking into how PS-exposing microparticles may blunt a successful immune response early in HIV infection.
The point of CHAVI & Gates CAVD work is to eventually create a successful VACCINE.
A vaccine is a preventative for something BEFORE your body encounters it.

Bavi and other PPHM mabs are being used to see if it's "worth it" to try to design an immunogen that creates 'natural bavi' in one's body, to stay on the lookout for HIV's potential arrival.
The CHAVI / Gates research may or may not be successful in CREATING A VACCINE. If they are successful, it will take serious time, and serious money.

Any VACCINE work that CHAVI / Gates does with  mabs in their quest to see if they protect from HIV infection, (or alter the immune response in a beneficial way), is IMMEDIATELY applicable  as a THERAPEUTIC.
As I've been saying -
Bavi acts as a therapeutic vaccine for what you've got in ya.

All that data that CHAVI / Gates researchers have been accumulating, has been guiding, and will continue to guide, PPHM's anti-phosphatidylserine antiviral therapeutic (and therapeutic vaccine) research.

Now, it is beyond the scope of the topic of this post, but it is also looking like if and when any HIV vaccine is arrived at, Bavi will again play a role as an ADJUVANT. Due to Bavi's MOA, it should make any vaccine more effective. It should facilitate any immunogen to be 'recognized' more easily.

I hope you realize that Bavi lasts about three days in a person. If you don't have HIV when you get a shot of Bavi, it won't do anything for you down the road. Part of the vaccine research will likely be using combinations of bavi WITH HIV immunogens, much like Thorpes fabulously successful work that so beautifully isolated and illustrated Bavi's immune-modulating vaccination effect against malignant glioma.
This is all well-documented science, illustrated by numerous specific Bavituximab papers and presentations.

I think things will be getting interesting soon,
keep watching! :)













« Last Edit: March 31, 2009, 03:09:22 AM by Matts »
tivicay/kivexa

Offline veritas

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Re: Could this be the holy grail ?
« Reply #153 on: March 31, 2009, 08:29:44 AM »

Matts,

Thanks for your research.

 Anti-ps looks extremely promising and I'm anxiously waiting for interim results on the co-infection trial for Hepc/hiv using 3g4. I realise 3g4 is not the strongest anti-ps mab, however, it should give some indication as to viability with respect to hiv in vivo.

Anti-ps mabs have been dosed in approximately 200 people thus far. The safety data thus far has been incredible----- TOPLINE SAFETY------- in all those dosed. I believe that is due to the targeted aspect of the therapy---- sort of like a smart bomb.

I know CHAVI is going for the homerun---a vaccine. But I believe that will be pretty difficult,due to the incedible viral ramp-up in the first 7to10 days of infection. I do believe that a therapeutic using anti-ps is viable, especially if the immune response can be strong enough to get to the resting infected cd4s.

Lets hope something breaks soon.

v

Offline veritas

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Re: Could this be the holy grail ?
« Reply #154 on: March 31, 2009, 09:43:45 AM »


Anti-PE, another weapon in the arsenal to fight hiv:

http://finance.yahoo.com/news/Peregrine-Pharmaceuticals-prnews-14794329.html


 v

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #155 on: March 31, 2009, 03:56:55 PM »
Veritas (or anyone else who might know):

Is there any way to find out (or estimate) when clinical trials might begin for the use of bavi with respect to HIV? Right now they are in preclinical studies, right?

Offline veritas

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Re: Could this be the holy grail ?
« Reply #156 on: March 31, 2009, 05:12:24 PM »

Inch,

It is in clinical trials right now for co-infection with hepc/hiv. However, I believe you were referring to HIV  directly. I believe those trials will come out of the CHAVI group since they have mabs that are more powerful than the 3g4 antibody in the co-infection trials. As to when those trials will start----- they only have funding from the Gates Foundation for another 3 years so they will have to show progress, which I assume will include clinical trials. My guess is that clinical trials ,hopefully, will begin by next year.

v

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #157 on: March 31, 2009, 06:50:51 PM »
Thanks V, that's good to know. I was getting my info. from your latest link, above, which states:

"PE belongs to the aminophospholipid family that also includes phosphatidylserine (PS), the target for Peregrine's monoclonal antibody bavituximab that is in a clinical trial for hepatitis C virus (HCV) infection and in preclinical studies for HIV and other viral infections."

I guess apart from being in clinical trial for HCV (as stated above) it's also in clinical trials for HCV/HIV co-infection? From the sound of the above quote it seems Peregrine is planning clinical trials of Bavi and HIV?

Offline Matts

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Re: Could this be the holy grail ?
« Reply #158 on: March 31, 2009, 10:35:57 PM »
 Thank You Veritas for the info about the new Anti-PE


The New PPHM PE-Targeting Agent (this one is totally human like PNG635 ,BAVI is chimeric):

...The spectrum of viral treatment for the present invention extends to any virus, whether enveloped or not, DNA or RNA. ....of the invention at least in part block viral replication inside the cell, and/or prevent escape of virus from cells, the invention is not limited to the treatment of enveloped viruses alone, nor to any particular virus, which is an important advantage....
The invention is suitable for treating all viruses that infect vertebrates, particularly humans, and particularly viruses that are pathogenic in animals and humans. The viral infections and associated and resultant diseases that can be treated by the invention include those viruses and diseases set forth in Table J, as exemplified by treating CMV, RSV, arenavirus and HIV infections, and the diseases hepatitis, influenza, pneumonia, Lassa fever and AIDS.

( P.S. Hard to believe)


*http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7,511,124.PN.&OS=PN/7,511,124&RS=PN/7,511,124
« Last Edit: April 02, 2009, 04:37:37 AM by Matts »
tivicay/kivexa

Offline Matts

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Re: Could this be the holy grail ?
« Reply #159 on: March 31, 2009, 10:47:41 PM »


HIV - Phosphatidylserine  - Haynes - Multicomponent vaccine - therapeutic Mab for treatment

 August 20, 2008
The announcement by NIAID Director Dr. Anthony Fauci to scrap the upcoming “PAVE-100″ HIV vaccine clinical trial, (following on the heels of the failed Merck “STEP” HIV vaccine trial), showed yet again how difficult and elusive the goal of an effective HIV vaccine remains.

In the midst of these sobering developments, an important new insight was gained into why experimental HIV vaccines have failed to elicit an adequate immune response. The discovery, published in the August issue of the Journal of Virology (1), came from the leader of NIAID’s “CHAVI” organization, Dr. Barton Haynes of Duke University, who is also a principle investigator of the Gates Foundation HIV vaccine effort.

In their paper, Haynes and colleagues discuss experiments showing that HIV weakens the immune system much faster than previously thought. The primary mechanism responsible for this immunosuppression is an overwhelming amount of what Haynes terms “microparticles”, which are tiny particles shed from the outer membranes of infected and dying cells. This cellular debris accumulates during early HIV infection, and circulates throughout the body blunting the functions of the immune cells that would ideally fight the virus. Popular news articles have discussed this aspect of the Duke researchers’ findings, but the details and broader implications of the team’s discovery have yet to be elucidated in the media.

The paper explains that the microparticles contain the molecule phosphatidylserine (PS) exposed on their surface. PS is a lipid that normally lines the interior of the cell membranes of every cell in our body. As a cell dies, it loses the ability to maintain PS on the inside of the cell membrane. The PS flips to the exterior, where it is perceived by immune cells as a sign of a dying native cell. The Haynes team cite recent data showing how exposed PS appears to be the fundamental signal that shifts the behavior of immune cells into not mounting an antigen-specific attack, since PS is interpreted as a sign of “self” rather than a foreign invader (2). Other researchers have also recently illustrated the suppressive effects of PS on macrophages, the resulting cytokine environment, dendritic cells, and T cells (3-7). It is thus no surprise that recent research has also revealed exposed PS as a feature common to many diverse pathogens (8-22), as if they independently evolved to exploit a similar mechanism of evasion, since it provides the crucial advantage of triggering an inappropriate immune response, facilitating the pathogen’s survival and proliferation.

A review of Haynes’ recent patent applications provides further details that have yet to be published in the journals. In one application, titled “Multicomponent Vaccine” (23), Haynes explains that any future successful HIV vaccine must interrupt this PS-mediated immunosuppressive signaling. A specific goal mentioned is for a vaccine to induce antibodies to PS (anti-PS), thereby blocking the overwhelming immune suppression seen in the Duke research, allowing the viral immunogen in the vaccine the chance to evoke T and B cells which effectively fight the virus.

In yet another recent patent application, Haynes proposes using anti-PS as a promising treatment for people already infected with the virus (24). He discusses the ability of anti-PS monoclonal antibodies to bind to HIV and HIV-infected cells, saying anti-PS “can be safely used as a therapeutic Mab for treatment of HIV infected subjects”, and that it can “broadly neutralize HIV in an unprecedented manner”.

Perhaps the most fascinating comment found in one of Haynes’ many recent patent applications is his suggestion that HIV’s method of immune evasion may be a general escape mechanism utilized by other pathogens (24), and that similar means of therapy may be effective against other diseases. Indeed, a review of the recent major journals corroborates this concept.*


In April, the journal Science published experiments showing that the pox family of viruses, (vaccinia), utilize exposed PS to gain entry into cells (25).

In the March issue of the journal Clinical Cancer Research, scientists from Harvard University discuss experiments in which blocking PS signaling helped facilitate complete melanoma tumor regressions (26).

The protozoan parasites responsible for many of the deadly diseases affecting much of the developing world have been found to rely on exposed PS to successfully avoid the immune system of their host (16-22).

Several cancer researchers have recently published data which bears a striking resemblance to the new findings of the Haynes HIV group, showing a very similar method of systemic immune suppression caused by PS-exposing microparticles shed from tumor cells (29-34), (see also 27, 28).

In another recent Haynes patent application he also discusses PS-exposing microparticles as playing a role in the pathogenesis of several auto-immune diseases as well as atherosclerosis (35), (see also 36-40).

Taken together, these discoveries suggest a new immunological perspective of pathogenesis in general. A paradigm appears to be emerging in which the necessary and admirable flexibility of the immune system has been exploited precisely where it is most vulnerable – when it must commit to a ‘friendly’ response. The recent HIV research by Haynes and colleagues, focusing on PS-induced immune suppression, and the safe therapeutic targeting of exposed PS with antibodies, carries implications of unprecedented broad therapeutic potential.

*http://www.iayork.com/MysteryRays/2008/08/18/quality-and-quantity-once-again-with-vaccination/



Sources:http://www.iayork.com/MysteryRays/2008/08/18/quality-and-quantity-once-again-with-vaccination/#comments
« Last Edit: April 01, 2009, 10:37:49 PM by Matts »
tivicay/kivexa

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #160 on: March 31, 2009, 11:48:44 PM »
Matts: Thanks for the above. Just curious: what's the date of the article you cut and pasted?
Thanks ;)

Offline veritas

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Re: Could this be the holy grail ?
« Reply #161 on: April 01, 2009, 06:00:54 AM »

 Matts,

  I thought you would like that anti-pe patent.

  I trust you read the world patents submitted by Duke at the beginning of this thread ------- one for the multi-component vaccine and the other for a therapeutic using is4.  Since most of the pre-clinical work is being done by CHAVI for HIV, I'm sure they will be involved in the clinical trials when they come up with their final "mix".

  Inch,

  It wouldn't surprise me if CHAVI is trying to incorporate anti-pe in their quest for the cure. Thorpe's lab is part of the CHAVI group.

  v


Offline Matts

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Re: Could this be the holy grail ?
« Reply #162 on: April 01, 2009, 11:50:52 PM »
These 2 patents look really good, especially the multicomponent vaccine.

targeted at overcoming: i) HIV diversity, ii) tolerance constraints of neutralizing antibody induction, and iii) apoptotic  induced immunosuppression (FAS, TRAIL,TNF).

Maybe CHAVI can be successfull in some years.
« Last Edit: April 02, 2009, 08:31:30 PM by Matts »
tivicay/kivexa

Offline veritas

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Re: Could this be the holy grail ?
« Reply #163 on: April 08, 2009, 05:08:27 AM »

Fauci believes vaccine possible:


http://www.msnbc.msn.com/id/29898087/

Rapid viral buildup in early infection biggest obstacle to preventative vaccine.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #164 on: April 11, 2009, 05:20:25 AM »



CCR5 LIGAND CCL3 (MIP-1-ALPHA)
UP-REGULATES APOBEC3G



"It has been established that the HIV-1-inhibitory activity of A3G is neutralized by Vif (9, 10, 11, 12). This interaction has raised therapeutic potentials, by either inhibiting Vif activity or boosting A3G levels above the neutralizing capacity of Vif to inhibit virus replication (5, 26)."



"Stimulation of primary human CD4+ T cells or immature DC with CCL3 [aka: mip-1-alpha] showed a dose-dependent increase in A3G mRNA expression"



"These findings suggest that CCL3 may not only block and down-regulate CCR5, thereby inhibiting pre-entry of HIV-1 (27, 28), but also stimulate A3G expression, which inhibits postentry replication of HIV-1."



"Thus, stimulation of the CCR5 molecule, which is the major coreceptor of R5 strains of HIV-1 (38, 39), or the CD40 (25) molecule, which is part of a major costimulatory pathway, up-regulates A3G and results in postentry inhibition of HIV-1 replication. This novel finding may be important in enhancing the innate intracellular anti-HIV-1 response and provides a complementary strategy in protective and therapeutic immunization against HIV-1."


http://www.jimmunol.org/cgi/content/full/178/3/1671

Offline Matts

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Re: Could this be the holy grail ?
« Reply #165 on: April 11, 2009, 08:50:03 AM »
Maybe zinc could help to inhibit vif :) Link

Thomas Lehner has developed a trimolecular construct for microbizides and vaccines: http://ec.europa.eu/research/health/poverty-diseases/projects/134_en.htm

T.Lehner and B.Haynes as part CAVD: p.13  Link
« Last Edit: April 13, 2009, 06:44:54 AM by Matts »
tivicay/kivexa

Offline veritas

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Re: Could this be the holy grail ?
« Reply #166 on: April 12, 2009, 05:21:34 AM »

Matts,

Kings college is part of the CHAVI group --- nice find !


https://chavi.org/modules/chavi_sites/index.php?id=18

From your link:

Coordinator:
Thomas Lehner, MD, FRCPath, F Med Sci
Professor of Basic & Applied Immunology, Mucosal Immunology Unit, Guy’s,
King’s & St. Thomas’ Medical & Dental School, Guy’s Hospital, Guy’s Tower
Floor 28
London SE1 9RT
United Kingdom
Phone: 44 207 188 3072
Fax: 44 207 188 4375
Email : thomas.lehner@kcl.ac.uk
Website: www.kcl.ac.uk
 

Offline veritas

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Re: Could this be the holy grail ?
« Reply #167 on: April 13, 2009, 12:46:38 PM »
CAVD Feb 1, 2009

 Annual and Interim Progress Report Summaries
Principal Investigator: Thomas Lehner
Project: Allogeneic – HIV Mucosal Vaccine Strategy Against HIV, Utilizing Innate and Adaptive Immunity
 
Submitted February 1, 2009 (Interim Report)
The aim of the project is to establish if xeno-immunization and allo-immunization of macaques can prevent or contain infection after challenge with SHIVSF162.  In the xeno-immunization experiment the vaccine consisting of HLA-class I and HLA-class II and/or HIVgp140, SIVp27 and HSP70 formulated with dextran into Dextramers was prepared, mixed with a co-adjuvant (Titermax Gold) and administered subcutaneously (x4) to 4 groups (one without Titermax) and 1 control group, each consisting of 8 macaques, over a period of 16 weeks.  The macaques were challenged IV with SHIVSF162P4, 4 weeks after the last immunization and the viral load was monitored.  The results showed significant decrease in viral load or total prevention of infection against the heterologous SHIVSF162P4 in one group of macaques compared with the unimmunized control group over the post-challenge period of 10 weeks (p<0.001 to p<0.05).  Importantly, the protected group of macaques was the one immunized with both HLA-class I + II and HIVgp140 + SIVp27 linked to HSP70 given in the Titermax adjuvant.  Sterilizing protection was not achieved in the other 3 immunized groups, suggesting that excluding any HLA or SHIV antigens fails in eliciting significant protection.

These promising results were then evaluated by examining a number of immune functions.  High titres of complement-dependent neutralizing antibodies were elicited in 3 of the immunized groups with the co-adjuvant compared to pre-immunization (p<0.0001).  Indeed, significant inverse correlation was found between the cumulative viral load (over the 10 weeks of post-viral challenge) and neutralizing antibodies (p<0.05).  High levels of antibodies were induced to the immunizing HLA-class I (A1, A2, A3 and A11) and HLA-class II (DR4) antigens (p<0.01), demonstrating that the recombinant HLA antigens are potent immunogens. As with the neutralizing antibodies, a significant inverse correlation was found between cumulative viral load and the HLA-I antibodies and this appeared to be specific to the protected group of macaques (p<0.001-p<0.05).  Surprisingly, CCR5 antibodies were also elicited in the protected group of macaques and this was associated with a significantly decrease in CCR5 expression in CD4+ T cells (p<0.01), consistent with a decreased infectivity of the primary cell target.  Among the innate anti-viral factors APOBEC3G was investigated and found to be significantly increased in the immunized groups, again with an inverse correlation with the cumulative viral load (p<0.0001). Thus, both antibodies and innate cellular factors were identified in immunized macaques and further cellular parameters are being analysed.

Allogeneic immunization with recombinant macaque MHC class-I and class-II antigens and the other components has also been completed and the immune responses are in the process of being evaluated.  The animals have been challenged and the viral load is being monitored. 

 
 

 
 

Offline Tower311

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Re: Could this be the holy grail ?
« Reply #168 on: April 15, 2009, 03:44:30 PM »
I just read the whole thing.  Man, did that make my heart smile.  It's so exciting to think that something like this COULD happen.  I know it's not done.  But, man, can you imagine if humans figured out how to defeat viruses?  Not just this one, but all of 'em?  That's major.  MAJOR.

It's really far out there, but why not?  It's possible.  We're smart.  We can do it.  I just feel great right now.  Just great.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #169 on: April 16, 2009, 05:45:30 AM »

 Tower311,

  The research is compelling and amazing. As if retro-virus weren't enough, the therapy seems to work well against cancer. Bavituximab is entering phase ll cancer trials against many cancer indications (including lung cancer).

   I'm glad you took the time to read the entire thread. I believe one can see how cautiously the research is being unfolded and how so many of the top researchers in both immunology and oncology are researching anti-ps.

   I also have not been able to find a dissenting paper concerning the therapy. If anyone can find one please post.

   Let's hope development picks up speed so anti-ps can start saving lives and relieving the suffering of many people. We need a Holy Grail!

   v


Offline veritas

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Re: Could this be the holy grail ?
« Reply #170 on: April 19, 2009, 04:08:47 PM »

anti-ps (Bavituximab) is a targeted cancer therapy:

http://therpmreport.com/Free/f27af8ed-2215-474b-9700-fcc71e01193d.aspx?utm_source=RPMel

Let's hope they fast track Bavi -------

v

Offline veritas

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Re: Could this be the holy grail ?
« Reply #171 on: April 20, 2009, 08:23:14 AM »

11 of 17 evaluable  patients respond to Bavituximab in phase ll lung cancer trial out of 25 say preliminary results.  Dosing to go on:

http://finance.yahoo.com/news/Peregrine-Pharmaceuticals-prnews-14969179.html?.v=1

Anti-ps (Bavituximab) uses the same moa for viral disease. Anxiously awaiting preliminary data from co=infection trial for HIV/HEPC.

FAST TRACK ANTI-PS NOW !

v


Offline veritas

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Re: Could this be the holy grail ?
« Reply #172 on: April 21, 2009, 08:23:52 AM »

 "Dendritic cells are the professional antigen-presenting cells of the immune system and they play a crucial role in initiating adaptive immune responses. Dendritic cells must be mature, or activated, to be effective, yet tumors and other pathogens such as viruses often possess the ability to undermine this maturation, thereby suppressing the immune response. The results presented today suggest that by blocking exposed PS, anti-PS antibodies have the potential to promote dendritic cell maturation in the body and thereby stimulate a more effective immune response."

http://finance.yahoo.com/news/Studies-Presented-at-AACR-prnews-14981130.html?.v=1

ANTI-PS SHOULD BE FAST TRACKED NOW!

How does the above relate to HIV?

http://jvi.asm.org/cgi/content/abstract/83/8/3486

"Dendritic cells (DCs) are the first in vivo targets of MMTV infection. In this study, we demonstrate that mA3 expressed in target cells restricts MMTV infection in DCs ex vivo and in vivo. By comparing infection of DCs from mA3+/+ and mA3–/– mice with one-hit viruses, we show that mA3 expression in target cells blocked MMTV infection at a postentry step and acted together with virion-packaged mA3 to inhibit infection."

ANTI-PS IS WORKING AND SHOULD BE FAST TRACKED NOW!

v

Offline veritas

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Re: Could this be the holy grail ?
« Reply #173 on: April 21, 2009, 01:59:42 PM »

DCs and hiv ---- another study:

http://jem.rupress.org/cgi/content/full/203/13/2887

Ralph Steinman, Rockefella University, is part of the CHAVI Group.


JBM Blog

v


Offline Matts

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Re: Could this be the holy grail ?
« Reply #174 on: April 21, 2009, 03:32:56 PM »
I'm glad that You mention R. Steinman. The  DEC205-VAC Project is very promising and will possibly go into human trials still in this year.

A lot of information from Rockefeller University: Link

Prof. Klaus Überla DEC-VAC "Why are we still waiting
for the HIV vaccine?" :Link PDF

Ralph M. Steinman: "Dendritic cells and vaccines" :Link


"DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes" : Link Pubmed


"Dendritic Cells In Vivo: A Key Target
for a New Vaccine Science" by R. Steinman:Link PDF   Celldex Therapeutics (Steinamn, Nussenzweig): Link

Sarah Schlesinger, Rockefeller about dendritic vaccine:Link Videopage

"Improved Vaccine Efficacy via Dendritic Cells and Flavivirus Vectors"- Bill&M. Gates Foundation:Link Project Description
« Last Edit: April 21, 2009, 06:25:03 PM by Matts »
tivicay/kivexa

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #175 on: April 21, 2009, 05:23:36 PM »
One of the links above from Matts, says "The aim of vaccines must therefore be to
counteract this fatal development at an early stage."

I hope this does not mean that these vaccines targeting dendritic cells are mant only as preventve or very ealry and not as therapeutic vaccines. I wonder how they define "early stage."

Offline John2038

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Offline veritas

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Re: Could this be the holy grail ?
« Reply #177 on: April 22, 2009, 05:07:40 PM »
How does anti-lipid mab and dendritic cells interact to inhibit hiv? Please read below:


The Potential of Anti-Lipid Mab Induced Dendritic Cell Maturation


An antibody that targets a plasma membrane lipid has shown to be the most potent and most broadly HIV-neutralizing antibody yet found. Duke University researchers, led by Dr. Bart Haynes, funded by the Gates Foundation and the NIH's CHAVI, in work from the CHAVI 005 protocol which seeks to understand why auto-immune patients are statistically less prone to HIV infection and AIDS, presented data at the AIDS Vaccine 2008 conference in Cape Town, SA (which has yet to be published in a peer reviewed journal, but was chosen as a highlight by the conference rapporteur and is summarized on the Global HIV Vaccine Enterprise website) illustrating the exceptionally powerful HIV-inhibiting properties of this non-pathogenic monoclonal 'auto-antibody', currently named 11.31, aka: PGN632.

As illustrated in the rapporteur session of the Gates-funded AIDS Vaccine 2008 conference, the mab was more broadly-neutralizing, and was much more potent than the well-known rare broadly neutralizing mabs 2F5, 2G12, b12 combined.

Like the well-known rare BNAb's 2F5 and 4E10, 11.31/PGN632 binds host-cell lipids. But while 2F5 and 4E10 bind lipids and a viral epitope, 11.31/PGN632 strictly binds lipid. It turns out that the mab binds to exposed anionic lipids on lipid rafts of uninfected CD4+ T cells. Via mechanisms as yet still vague, (possibly via monocytes as discussed in the NIAID review of the mab), the Duke researchers led by Tony Moody found that this mab causes an increase in the beta chemokines MIP-1-alpha and MIP-1-beta, (aka: CCL3 & CCL4), which bind the CCR5 receptor, blocking HIV from entering its target cells.

The role of beta chemokines with regard to HIV infection have been researched by many scientists in the past decade, including of course Robert Gallo's group, who have published extensive data pointing to the chemokines as potential correlates of immune protection to HIV.

Interestingly, Tom Lehner & team at King's College, London, have recently published data illustrating that the CCR5 ligand MIP-1-alpha (as well as HSP70) cause an increase in intracellular APOBEC3G, with the potential to affect HIV post-entry.

Last fall, NIH researchers also surprisingly found that APOBEC3 affects antibody responses.

In short, according to Duke scientists funded by the Bill and Melinda Gates Foundation, this anti-lipid antibody 11.31 / PGN632 causes an increase in CCR5 ligands which potently inhibits HIV entry, and according to research at King's College, CCR5-tickling in turn up-regulates intracellular APOBEC3, which could potentially mutate existing intracellular virus to death.


Other recent data points to protection of mature dendritic cells from HIV, again via increased APOBEC3. Indeed, none other than Dr. Ralph Steinman, co-discoverer of dendritic cells and now a CHAVI Scientific Advisor as well as Global Vaccine Enterprise Science Committee member, has suggested that somehow facilitating an increase in mature dendritic cells at the mucosal point of HIV entry may protect from infection. This makes recent data on 11.31/PGN632 all the more interesting.

The most recent data on antibody 11.31 aka:PGN632 was presented this week, (April 20th, 2009), at the 100th AACR annual conference in Denver. The antibody has been found to facilitate dendritic cell maturation. The mab was found to increase costimulatory molecules on DC's and also increase inflammatory cytokines and chemokines. To quote the abstract,

"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, TNFa, GM-CSF and MIP-1B by immature dendritic cells."

These mechanisms strongly imply the mab's potential as an adjuvant in vaccines against viruses and tumors. Or in the case of HIV, perhaps a combination microbicide / mucosal vaccine, somewhat similar to Lehner's work which includes mucosal vaccination with CCR5 ligands, and Steinman's suggested goal of mature dendritic cells at the mucosal point of viral introduction.

With the data presented at the AIDS Vaccine 2008 conference outlining the antibody's unprecedented potency of HIV inhibition, combined with details presented this week clarifying the mechanisms involved - specifically up-regulating costimulatory molecules on dendritic cells as well as expression of inflammatory cytokines and chemokines, could this phosphatidylserine (PS) targeting antibody 11.31 / PGN632 which binds lipid rafts on uninfected T cells, besides preventing HIV cell entry via beta chemokines as shown by Duke scientists, could it increase efficient antigen presentation by DC's, and stimulate activation of CD8+ T cells? Both of these actions are clearly implied by the mab's DC maturation details listed above.

Finally, could these same mechanisms induce the activation of latent cells harboring the HIV reservoir, waking up the dormant virus and directing it's self-destruction via beta chemokine-induced increased intracellular APOBEC3?

jbm/blog

ANTI-PS SHOULD BE FAST TRACKED!

v



.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #178 on: April 22, 2009, 05:12:17 PM »


Anti-ps takes on prostate cancer model and reduces tumors by 90%:

http://finance.yahoo.com/news/Data-Presented-at-AACR-Annual-prnews-14997163.html?.v=1


ANTI-PS SHOULD BE FAST TRACKED!

v

Offline georgep77

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Re: Could this be the holy grail ?
« Reply #179 on: April 22, 2009, 05:59:33 PM »

Anti-ps takes on prostate cancer model and reduces tumors by 90%:

Even in an mouse model, 90% is awesome    :o
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
+ 2008

Offline hotguyinTX

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Re: Could this be the holy grail ?
« Reply #180 on: April 24, 2009, 01:46:26 AM »
"Via mechanisms as yet still vague, (possibly via monocytes as discussed in the NIAID review of the mab), the Duke researchers led by Tony Moody found that this mab causes an increase in the beta chemokines MIP-1-alpha and MIP-1-beta, (aka: CCL3 & CCL4), which bind the CCR5 receptor, blocking HIV from entering its target cells.

The role of beta chemokines with regard to HIV infection have been researched by many scientists in the past decade, including of course Robert Gallo's group, who have published extensive data pointing to the chemokines as potential correlates of immune protection to HIV."

This is quite troubling to me because there are studies showing otherwise, showing no evidence that it suppresses HIV or worse, even promote HIV replication. How do they determined that beta chemokines work?

Here are a few studies:


Offline veritas

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Re: Could this be the holy grail ?
« Reply #181 on: April 24, 2009, 05:46:13 AM »
hotguyinTX,

I believe you will find your answer here, as reported by NIAID:

http://www3.niaid.nih.gov/topics/HIVAIDS/Research/vaccines/reports/aidsvac2008.htm

'Neutralizing antibodies to thwart HIV
Dennis Burton of the Scripps Research Institute discussed how administering neutralizing antibodies can safeguard monkeys against infection with an HIV–SIV chimeric virus (SHIV). IgG1b12, a broadly neutralizing antibody competes for the same niche on the HIV shell glycoprotein, gp120 that serves as the initial contact point for CD4, thereby blocking viral entry into cells bearing CD4 on their surface. High concentration of b12 infused intravenously into monkeys prevents SHIV infection through the vaginal route (Nature 449: 101, 2007). Studies with another broadly neutralizing, 2G12 that binds to a dense cluster of carbohydrates on gp120, revealed that 2G12 protected monkeys at 100 fold lower concentration than b12, thus implying that the epitope targeted by 2G12 may be more beneficial or 2G12 is a more effective antibody. In addition, multiple low dose challenge experiments in monkeys to more closely mimic human HIV infection showed that b12 provided passive protection effectively at much lower concentrations that those employed in previous experiments.


Tony Moody of Duke University School of Medicine established a panel of b2-glycoprotein I independent anti-lipid monoclonal antibodies from auto-immune disease patients. These antibodies failed to neutralize HIV in the standardized TZM-bl reporter cell line assay. However, they neutralized virus in the PBMC assay, apparently through release of b-chemokines (MIP1a, MIP1b) by monocytes in the culture. Such chemokines interfere with virus entry through the CCR5 receptor. Furthermore, neutralization could be reverted by antibodies against MIP1a and MIP1b. These anti-lipid antibodies stick to the host target cell and not the virus to prevent infection. A vaccine that induces such antibodies may not be able to directly neutralize HIV but it may reduce virus spreading."

Could you repost the studies you found, it looks like they didn't take. Thanks.

v
« Last Edit: April 24, 2009, 05:48:42 AM by veritas »

Offline veritas

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Re: Could this be the holy grail ?
« Reply #182 on: April 24, 2009, 09:26:49 AM »

More info as to why anti-ps will get around that problem of short mabs:

"With the Caltech discovery in mind, it's important to note the fundamental difference of a lipid-targeting approach to virus neutralization. Until quite recently, all attempts by scientists to develop powerful neutralizing antibodies against viruses were aiming at the virus, which of course seems logical. Rather than targeting the traditional common-sense target of the virus spikes poking up through the ocean of host-cell lipid goop, anti-lipid antibodies do not aim for the viral spikes or anything directly to do with viral proteins at all. Anti-lipid antibodies target the goop. There's no need for antibody stretches. That "goop" is made up of lipids from our own cell membranes which get stuck to the virus as it exits one of our cells. It was traditionally considered a waste of time, or possibly worse, to deliberately target lipids with antibodies. That opinion is quickly changing. It turns out that the host-cell lipids exposed on viruses may play a powerful role in inhibiting a successful immune response, as well as an active role in viral entry into cells."


http://1.bp.blogspot.com/_ekJ44PA8pQc/SfG06j17ocI/AAAAAAAAAQw/tNqtG2PvfB4/s1600-h/hiv+virion+cartoon+labeled.JPG

jbm/blog


v























Offline hotguyinTX

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Re: Could this be the holy grail ?
« Reply #183 on: April 25, 2009, 12:51:19 AM »
Hi! Not sure why the links were missing.. I probably forgot to copy and paste the links!

While I am extremely excited, remember that antibodies can be extremely toxic and can cause long term damage to our immune systems. Take this for an example:

"TGN1412 (also known as CD28-SuperMAB) is the working name of an immunomodulatory drug which was withdrawn from development, originally intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis.[1] It is a humanised monoclonal antibody that not only binds, but is a strong agonist for the CD28 receptor of the immune system's T cells."

http://en.wikipedia.org/wiki/TGN1412

Result? It made them deathly ill even tho it was administrated at a subclinical dose (500 times lower than the safe dose in animals).

Apparently, there's a lot about our immune system that we have not fully understand. What's so difficult is that we know for a fact that we have people who seem to be resistent to HIV infection despite repeated exposure and we are STILL NOT sure about their resistence.. is that possible that they simply got lucky? Or is there immune system difference involved? I am sure you have heard of delta32... but we have reports of them getting infected with HIV anyway... are we REALLY confident that it was that isolated gene mutation that made them mroe resistent or is that genetic mutation having some interesting effects on immune system which in turn makes them more resistent to hiv infection or if infected, progress much slower?

HIV is a fascinating virus because it has puzzled scientists and it doesn't seem to behave like a typical retrovirus... we get flu and if we get it, we either get sick or die... but a lot of people are immune to infection... and when we DO get sick, we usually get rid of the flu virus and we're just fine afterwards. That's not the case with HIV yet we know for a fact, there are two documented cases where a person who got transplant have been "cured" of HIV - no traces of HIV left. Why? Even more puzzling, if delta32 was supposed to protect you from one strain of HIV, why did it "cure" those HIV+ patients even tho they have at least two different strains and one of them does not need the um... let me think.. CR5 receptors (not recalling right off). And why do some people with delta32 still get infected with HIV?

Remember the vaccine failure when vaccinated people were more likely to get infected? Why? Is priming our immune system actually more dangerous than making our immune less active? And now I am hearing that a systemic autoimmune disease may "protect" patients from getting HIV.

Hopefully we'll get to the point where we will have a coherent theory on HIV and its effect on immune system AND also on how immune system really work. But I sure hope as hell that we have SOMETHING to treat and possibly cure HIV/AIDS!

Offline veritas

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Re: Could this be the holy grail ?
« Reply #184 on: April 25, 2009, 04:44:52 AM »
I'm familiar with the TGN1412 problem. I believe the mab was tested in the UK. The reaction occured within hrs of the patients being dosed, causing a cytokine storm in the patients bodies. Such a reaction has not occured with Bavituximab. As a matter of fact quite the opposite. All the safety data so far has been top line in all patients  dosed(over 200) some of which were terminal cancer patients.

How about those links?

v

« Last Edit: April 25, 2009, 04:47:20 AM by veritas »

Offline veritas

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Re: Could this be the holy grail ?
« Reply #185 on: April 27, 2009, 08:27:54 AM »

Anti-ps now attacks breast cancer, see phase ll results:


http://finance.yahoo.com/news/Peregrine-Pharmaceuticals-prnews-15038173.html?.v=1

same moa for viral -------

ANTI-PS SHOULD BE FAST TRACKED NOW!

v

Offline veritas

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Re: Could this be the holy grail ?
« Reply #186 on: April 28, 2009, 08:59:51 AM »






 
The strongest anti-ps mabs to date:




 
From the Wires
Affitech-Discovered Anti-PS Antibodies in Development by Peregrine Pharmaceuticals Show Excellent Functionality in Preclinical Studies

By: PR Newswire
Apr. 28, 2009 06:00 AM
 
   

 

OSLO, Norway, April 28 /PRNewswire/ -- Affitech AS, the human antibody therapeutics company, announced today that preclinical data on two fully human anti-PS (phosphatidylserine) antibodies were presented by its collaboration partner Peregrine Pharmaceuticals at the 100th Annual Meeting of the American Association for Cancer Research (AACR) 2009 held during April 18 - 22, 2009 in Denver, CO. The preclinical studies of PGN635 and PGN632 provided further confirmatory evidence that the anti-tumor effects observed with anti-PS antibodies reflect their immunomodulatory mechanism of action, including their ability to stimulate the immune system. Additionally, PGN635 demonstrated encouraging signs of efficacy in a preclinical model of prostate cancer. Both antibodies were isolated using Affitech's unique MBAS (Molecule Based Antibody Screening) method for selection and improvement of fully human antibodies from large libraries.

The researchers from Peregrine, Affitech and UT Southwestern Medical Center confirmed previous observations that in vitro, anti-PS antibodies stimulate the tumor microenvironment to recruit monocytes and other immune cells to the tumor with resulting anti-tumor effects, most likely via cell-mediated mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). Their data further defined the role of anti-PS antibodies in mediating tumor cell cytotoxicity and the tumor microenvironment, showing that the anti-PS antibody induced a sequential release of cytokines and beta-chemokines and stimulated enhanced macrophage recruitment to tumors. Furthermore, the researchers showed that in vitro, PGN635 induced antibody-dependent death of endothelial cells, the same cell type found in the tumor vasculature, a key target of anti-PS cancer therapy. The studies also demonstrated the anti-tumor potential of PGN635 in vitro and in a number of animal cancer models. Specifically, in a mouse model of prostate cancer, treatment with a mouse equivalent of PGN635 significantly retarded the growth of tumors by more than 90%.

In a separate study, researchers from UT Southwestern Medical Center (Peregrine's academic collaborators) and Affitech demonstrated in in vitro studies that immature dendritic cells cultured in the presence of PGN632 exhibited a significant increase in the production of inflammatory cytokines and chemokines. PGN632 also induced an increase in the expression of cell-surface molecules that are indicative of mature dendritic cells and that assist in antigen presentation functions, as well as in stimulating T-cell proliferation.

"These results demonstrate the efficiency and robustness of Affitech's range of antibody discovery platforms which include CBAS (Cell Based Antibody Screening) in addition to MBAS. They are being applied with increasing success to build proprietary oncology pipelines for both collaborators such as Peregrine and for ourselves," said Dr Martin Welschof, CEO of Affitech AS.

Commenting on the research progress of the antibodies and Peregrine's collaboration with Affitech, Steven King, President and CEO of Peregrine Pharmaceuticals said, "As leaders in the development of anti-PS antibodies for both oncology and anti-viral applications, we are delighted with these promising data for our fully human anti-PS antibodies from Affitech. They are the result of our well-established and highly productive collaboration and we look forward to continuing success in this and other projects."

For more information on Peregrine's anti-PS programs, visit http://www.peregrineinc.com
 



Offline veritas

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Re: Could this be the holy grail ?
« Reply #187 on: April 30, 2009, 05:19:24 AM »

Anti-ps takes aim at melanoma:

Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner


Luize G. Lima, Roger Chammas, Robson Q. Monteiro, Maria Elisabete C. Moreira, Marcello A. Barcinski


Division of Experimental Medicine, National Cancer Institute, RJ, Brazil
Institute of Medical Biochemistry, Federal University of Rio de Janeiro, RJ, Brazil
Laboratory of Experimental Oncology, School of Medicine, University of São Paulo, SP, Brazil
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil


L.G. Lima et al., Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner, Cancer Lett. (2009), doi:10.1016/j.canlet.2009.03.041


ABSTRACT:
Exposure of phosphatidylserine (PS) on cellular membranes and membrane-derived microvesicles stimulates a number of anti-inflammatory responses involved in malignant processes. Herein we show that B16F10 cells, a highly metastatic melanoma cell line, produce large quantities of PS-containing microvesicles in vitro. Tumor microvesicles increased TGF-b1 production by cultured macrophages and, in vivo, enhanced the metastatic potential of B16F10 cells in C57BL/6 mice, both effects being reversed by annexin V. Most strikingly, microvesicles induced melanoma metastasis in BALB/c mice, which are normally resistant to this tumor cell line. Altogether, this is the first demonstration that tumor derived microvesicles favor the establishment of melanoma metastasis in a PS-dependent manner, possibly by down-regulating the host’s inflammatory and/or anti-tumoral immune responses.

v


Offline veritas

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Re: Could this be the holy grail ?
« Reply #188 on: May 02, 2009, 05:50:57 AM »

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #189 on: May 02, 2009, 12:14:44 PM »
From the link above:

"Following the failure of the STEP Trial in 2008, this year has been an affirmation of the original mandate for the Center for HIV/AIDS Vaccine Immunology (CHAVI) that was to perform the basic and translational research to promote the development of a safe and effective preventive HIV-1 vaccine"

So their mandate is specifically the development of a preventive vaccine not a therapeutic one?

Offline veritas

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Re: Could this be the holy grail ?
« Reply #190 on: May 02, 2009, 02:55:17 PM »
Inch,

The absolute way to end the hiv pandemic is to have a preventative vaccine, so yes, their mandate is to find a preventative vaccine. However, what if the vaccine was both a preventative and a therapeutic?

From the above link: 

New discoveries and progress of the B Cell Discovery Team include:

• Completed enrollement in CHAVI 005 protocol of study of protective antibodies in autoimmune diseases and defined a class of anti-lipid antibodies with breadth of protection the in vitro PBMC assay for R5 transmitted/founder strains (Nature Medicine, submitted 2009)

http://chavi.org/modules/chavi_reports/index.php?id=30

The above jumped out at me.

v

ps: I have a feeling a lot of hiv info will be coming out soon from CHAVI.
« Last Edit: May 02, 2009, 02:59:32 PM by veritas »

Offline Inchlingblue

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Re: Could this be the holy grail ?
« Reply #191 on: May 02, 2009, 04:08:37 PM »
Inch,

The absolute way to end the hiv pandemic is to have a preventative vaccine, so yes, their mandate is to find a preventative vaccine. 

Believe me, I have nothing against a preventive vaccine, it would be amazing, I just did not realize that their mandate was specifically that. I thought they were also working specifically on therapeutic vaccines (and, yes, some of the vaccine candidates have potential to act as both, which is a consolation).

Not to get into a debate about it, because it's academic at this point, but I do think a therapeutic vaccine, one that essentially conferred a functional cure, would also end the HIV pandemic.

Offline veritas

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Re: Could this be the holy grail ?
« Reply #192 on: May 04, 2009, 03:41:30 PM »

Lets follow what CHAVI been doing with lipid mabs:


FROM HAYNES’ 5-1-09 CHAVI UPDATE:
“…The (CHAVI) B Cell Discovery Team has defined a class of anti-lipid antibodies with breadth of protection in vitro PBMC assay for R5 transmitted/founder strains. (Nature Medicine, submitted 2009)”

INTERESTING:
“Acute HIV infection almost always involves virus that homes to the CCR5 coreceptor ("R5-tropic virus"). During advanced HIV disease the viral swarm may shift its focus to the alternate CXCR4 receptor ("X4-tropic virus"), but that happens in only about half of people with advanced disease.”
http://www.natap.org/2005/Euro/euro_4.htm

FROM THE HAYNES/MOODY AIDS-VACCINE’08/CAPETOWN PRESENTATION:
“We studied a panel of human anti-lipid mAbs from autoimmune disease patients & healthy controls. Mabs IS4, CL1, P1, and PGN632 bind cardiolipin and PS indep. of B2GP1… In PBMC, …B2GP1-indep. anti-lipid mAbs (PGN632, P1, IS4, CL1) inhibited HIV-1 primary isolate infection of PBMC… The most potent mAb, PGN632 [aka “11.31”], inhibited 7/7 B & C clade HIV-1 isolates and SHIV-SP162P3.
CONCLUSION: Anti-lipid human mAbs inhibit HIV-1 infection in vitro in PBMC likely by binding CD4þ 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://tinyurl.com/7dnmpe

FROM THE 1-6-09 NIAID REVIEW OF THE MOODY/HAYNES AIDS’08 TALK:
“NEUTRALIZING ANTIBODIES TO THWART HIV”
Tony Moody of Duke Univ. School of Medicine established a panel of B2GP1 indep. anti-lipid mabs from auto-immune disease patients. These antibodies failed to neutralize HIV in the standardized TZM-bl reporter cell line assay. However, they neutralized virus in the PBMC assay, apparently through release of b-chemokines (MIP1a, MIP1b) by monocytes in the culture. Such chemokines interfere with virus entry through the CCR5 receptor. Furthermore, neutralization could be reverted by antibodies against MIP1a and MIP1b. These anti-lipid antibodies stick to the host target cell and not the virus to prevent infection. A vaccine that induces such antibodies may not be able to directly neutralize HIV but it may reduce virus spreading.
http://www3.niaid.nih.gov/topics/HIVAIDS/Research/vaccines/reports/aidsvac2008.htm

I think its happening.

v


Offline veritas

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Re: Could this be the holy grail ?
« Reply #193 on: May 05, 2009, 05:42:47 AM »

Anti-ps will be presented at ASCO:

ASCO’09 Ph.2 Bavi/BREAST-GA: Oral Presentation
Nice to see the revelation in today’s PR that updated prelim. data from the Ph.2 Bavi+Doce/BREAST trial [GA.] was selected to be given at ASCO’09 as an oral presentation.

SK: “…we look forward to reporting updated preliminary results from the trial at the upcoming ASCO Annual Meeting [May29-June2]."

Same moa for viral !!!

I think its happening.

v

Offline veritas

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Re: Could this be the holy grail ?
« Reply #194 on: May 05, 2009, 10:42:23 AM »

IN VIVO imaging using anti-ps for cancer using arsenic:

Conclusion: For the first time, a radioarsenic labelled
antibody could be studied in vivo. The PET-images show
an impressive tumor enrichment. 74As might not be the
ideal isotope for PET, because of its low positron
emission rate of 29%, but the long half-life of 17.8 days
nevertheless makes it a useful tool for the observation of
long-term pharmacokinetics

http://www.kernchemie.uni-mainz.de/downloads/jb2003/b20.pdf

v

Offline veritas

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Re: Could this be the holy grail ?
« Reply #195 on: May 08, 2009, 07:50:08 AM »

Anti-ps and cancer:

http://www.peregrineinc.com/images/stories/media/siteFiles/Anti-PS%20Technical%20Backgrounder%20-%20Oncology.pdf

Viral has same moa -------- its happening

v

ps: read the references for peer review------- Could this be the Holy Grail for cancer?

Offline freewillie99

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Re: Could this be the holy grail ?
« Reply #196 on: May 08, 2009, 10:19:05 AM »
Beware Romanians bearing strange gifts

Offline J220

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Re: Could this be the holy grail ?
« Reply #197 on: May 08, 2009, 12:12:49 PM »
What's happening?

I think he meant the anti-ps it working, so far, and according to the latest data released by Peregrine. Didn't you read the link he provided?

I must say I'm impressed with the anti-phosphatidylserine concept...so far. If this works as an anti-cancer agent there is a very good chance this will work as an anti-hiv agent, not to mention herpes and hepatitis, as well, because the moa, as veritas stated is the same....ps exposure on the outside of cells allows whatever pathogen they are infected to escape immune suppresion by the body, If Bavituximab can tag the PS on either hiv or cancer infected cells for destruction by the immune system, this could work....can't wait for further data...
"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 Inchlingblue

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Re: Could this be the holy grail ?
« Reply #198 on: May 08, 2009, 12:45:54 PM »
Veritas:  Is there any news on when Bavituximab will be tested specifically for its effect on HIV?

I came across this online:

"Dr. Barton Haynes, director of Duke University's Human Vaccine Institute and the Center for HIV/AIDS Vaccine Immunology (CHAVI) is currently investigating PS as a potential target for preventing HIV infection."

http://www.eurekalert.org/pub_releases/2008-11/bp-nms111808.php

I guess this is all still pre-clinical and very early stages, right? I wonder if anyone is looking at its potential therapeutic value in treating HIV not just preventing it.
« Last Edit: May 08, 2009, 12:49:57 PM by Inchlingblue »

Offline veritas

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Re: Could this be the holy grail ?
« Reply #199 on: May 08, 2009, 04:37:27 PM »
Inch,

They are testing anti-ps as a therapeutic right now in the co-infection trial of Hepc/hiv.The antibody they are using is the 3g4 antibody. This clinical trial is being done by Peregrine Pharm. The antibodies that CHAVI is testing are second generation anti-ps antibodies (pgn835 and IS4 among others). The two patents posted at the very beginning of this thread will give you an understanding as to how they work and what they do. Who knows, they might have a vaccine that works as both a preventative and a therapeutic. The CHAVI group is working on both. Some day ,if you have the time, peruse this thread from the beginning. I think a lot of your questions will be answered.
Anti-ps is in phase ll clinical trials for cancer as a therapeutic, its the same moa for viral!

v
« Last Edit: May 08, 2009, 04:40:20 PM by veritas »

 


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