It's hard to compare since those are "newly diagnosed patients". Looks like good/hopeful news for the people with newly diagnosed GBM though.

Hey- isn't that the company that said they were getting approval for the approach in some European country, but it was basically not true, and then there was a lawsuit about it?


j

OT: "AIDS Researcher Haynes Tops 2007 NIH Grants List"




AIDS Researcher Haynes Tops 2007 NIH Grants List

http://inside.duke.edu/article.php?id=182§ion=glance&ParentID=17633


" No principal investigator received more grant dollars from the National Institutes of Health in 2007 than Duke’s Barton F. Haynes, M.D., according to a list compiled by Genetic Engineering & Biotechnology News.

Haynes, who is Frederic M. Hanes professor of medicine and immunology at Duke University Medical Center and director of the Center for HIV AIDS Vaccine Immunology (CHAVI), received $46,482,429, putting him atop the 2007 ranking of principal investigators.

In the list of grant-receiving institutions, Duke ranked six in NIH grants, with $372,132,106 coming in during 2007.

Ranking first was Johns Hopkins University, with 2007 NIH grants totaling $566,516,255."


-----------



j

senrex,


the post that 'tarvacin' pointed to is a good quick summary.
Also, now that a "Duke paper" is being talked about more often, I'll post this stuff again.

in my opinion- When you see the "Duke paper", besides the name Barton Haynes, you'll see the name David Pisetsky, (among others).

The anti-PS MOA they discuss will have to do with more than virus particles, more than apoptotic cells, and more than virally infected cells.

It will have to do with the shed apoptotic debris, (originally called "cell dust" when it was first discussed a few decades ago).

I believe that Haynes, Pisetsky, and the others will put forth the hypothesis that the shed microparticles from apoptotic cells, (which wear exposed PS), are what is responsible for the immune escape / weakened/unsuccessful immune response, seen in HIV infection, (and cancer and other viral infections but I don't know how 'broad' the Duke paper's discussion will be).

I believe that Peregrine's anti-PS antibodies can affect this 'pathway', (a pathway that Pisetsky calls "a novel amplification loop of cell death").

I think anti-PS can turn the tide, reconstitute/refortify the immune response against cancer and chronic viral infections, and I think it does so via cleaning up / covering the PS on this shed debris.

I think that's what we'll be reading about in the "Duke paper", and it has implications for potential therapy of all cancers, viral infections, malaria and other parasitic diseases, atherosclerosis, and other diseases.


that's my opinion based on my reading.

j


------------------------------------



Pisetsky of Duke 2005 -









Pisetsky of Duke 2006 -








Haynes and Pisetsky 2007 -












Haynes CHAVI presentation 2007 -

Yes,


and I like how he mentioned it a few times. I think he also mentioned an antiviral paper out of UTSW as well?

So one out of UTSW and one out of Duke?

If that's indeed what was said, (and I'll go back and listen to the replay later), then I'd assume that the viral paper out of UTSW would probably cover what "we" already know, but has yet to be published:

* binding to all enveloped viruses,
* the in vitro CMV experiments,
* the in vitro RSV experiments,
* the Lassa fever guinea pig experiments,
* the CMV mouse experiments, etc.


A paper out of Duke would be covering all the things we haven't heard yet, (and you know my thoughts on what it will likely be about):



Haynes hypothesis -




..."Acutely expressed cytokines and apoptotic
microparticles hypothesized to play a key role in AHI pathogenesis....


April 9, 2007


http://72.14.209.104/search?q=cache:BCKueWKqWTIJ:www.chavi.org/wysiwyg/downloads/CHAVI_012_protocol_v1.pdf+%22CHAVI+012%22&hl=en&ct=clnk&cd=1&gl=us&client=firefox-a


-------------------------------


"Their [Haynes group] current hypothesis is that HIV induces a massive apoptosis
before and during viral ramp-up, and that plasma microparticles (fragments of apoptotic CD3
and T cells) have a suppressive effect on Ab generation, thereby amplifying the apoptotic
cascade. "


May 22, 2007

http://www3.niaid.nih.gov/research/topics/HIV/vaccines/advisory/avrs/PDF/AVRS_May07_Summary.pdf


--------------------------------


"we demonstrated the presence of 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 antigen specific
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."

August 20, 2007

http://www.hivvaccineenterprise.org/_dwn/poster_sessions.pdf














j

NICE to see this -


near term value driver - "Duke antiviral paper" :)






------


j

PPHM webcast presentation


Peregrine BIO CEO conf. webcast starting now.
http://www.corporate-ir.net/ireye/confLobby.zhtml?ticker=PPHM&item_id=1752434



j

Clinical / Regulatory / Litigation Calendar

[Please keep entries up to date! See updating procedure at the end of this post.]

NOTE: ANYONE MAY UPDATE THIS FILE


Edits: VRTX (PROVE-3 timing). PPHM (Bavituximab phase II patient dosing begun).


AMGN – Denosumab: Three-year data from phase III PMO trials (vs. alendronate) 1Q08; three-year data from phase III PMO fracture study: 2H08; Presentation of data from phase III HALT trial in breast cancer: 1H08; Data from phase III HALT trial in prostate cancer: 2H08.

AMLN – LAR NDA submission: mid 2009 if bioequivalence study needed; earlier if not needed.

BMY – Apixaban phase-3 in orthopedic surgery: fall 2008; phase-2 in ACS: Dec 2008 at ASH.

CEGE - VITAL1 GVAX prostate phase III interim "1H/'early' 2008. Final analysis ?09
- GVAX + MDX010 P1 results ?08
- oncolytic virus (bladder cancer) P1 results at AUA(5/08)

CYT.TO - Initiated pivotal A-fib trial Oct/06. Complete enrollment 2nd/half 07. Results 2nd half 08.

DDSS – Tramadol NDA: second approvable letter received 5/31/07. New clinical trial likely. Ph III Trazodone results 2nd qtr/08

DNA – Avastin sBLA in breast cancer PDUFA date: 2/23/08 (advisory panel voted 5-4 against on 12/5/07); Avastin adjuvant CRC interim look Q2 08; Rituxan in Primary Progressive MS Ph III Results Q2 08.

DNDN – Provenge 9902b study: interim analysis (~180 deaths) 2H08; final analysis (360 deaths) 2010.

ELN – AAAB001- final phase II data Q3 08
AB-001 phase-3: Interim data 2H09 (est.), final data 2H10 (est.). (First patient dosed 12/21/07.)

ELN – ELND005 for AD phase-2: Interim data mid 2009 (est.), final data 1H10 (est.) (First patient dosed 12/21/07.)

GILD – Viread in HBV: FDA PDUFA date 8/11/08; EMEA action date expected 2Q08. (NDA and MAA submitted 10/11/07.)

GILD – GS9190 polymerase inhibitor for HCV: new phase-1 trial to test QT-prolongation announced 10/18/2007; no start date yet.

GTCB – ATryn in US: positive top-line phase-3 data were reported 2/4/08; BLA submission mid 2008; FDA action: late 2008/early 2009 assuming priority review.

GTCB – US Atryn partnership announcement: 1Q08.

GTCB – ATryn phase-2 DIC trial by Leo Pharma in Europe/Canada: enrollment complete end 2008.

GTCB – Merrimack MM-093 results of phase-2 extension trial in RA: July 2008.

HGSI – Phase-3 Albuferon: report data from genotype-2/3 phase-3 trial: end 2008; report data from genotype-1 phase-3 trial: spring 2009; submit BLA fall 2009.

IDIX – IDX899 phase-1/2 seven-day monotherapy study: additional, lower-dose cohorts to be reported during 1H08 (800mg cohort was reported 2/6/08).

IDIX – IDX899 phase-2 six-week head-to-head vs Sustiva (IDX899+Truvada vs Sustiva+Truvada): start enrollment 1H08.

IDIX – IDX184 nucleotide polymerase inhibitor for HCV: file IND 1H08.

IDIX – Protease inhibitor for HCV: file IND in (late) 2008.

ISA.TO-European psoriasis P3 results 2008. Phase 2B 6&12 month renal results 2008. Phase II/III Uveitis results 2008.

ITMN – ITMN-191 Phase-1b: enrollment of 3rd dosing cohort complete end of Jan 2008. 4th Cohort to be done. After 4th cohort a cohort of non-responders will be done. On 1/7/08 announced advanced to combination study in Q2 2008. Data from all four cohorts to be reported at or before EASL and/or DDW in PR, Poster or both (Yes I know it is very wide range).

ITMN - Pirfenidone - CAPACITY Trials enrollment completed May 2007. Top-line results January 2009 (72 week treatment period).

LBPFF – see DDSS

MCU/MPH.to - Medicure - MC-1 Lead drug candidate for cardiovascular reperfusion is in PH 3 trial /w 3000 patients, one of the largest trials in Canadian History.
Full enrollment completed Sept. 14 with Top Line Data expected by Late February /08 or Mid March at the latest.

MEDX - Ipilimumab BLA submission sometime in 2008 (phase-3 data reported 12/10/07).

Merrimack: see GTCB

MNTA – Meeting with FDA re Lovenox ANDA: date not specified, but soon.

MNTA — Lovenox patent appeal (Sanofi v Amphastar): oral arguments began 1/8/08.

MNTA – M118 phase-2 data in stable angina to be presented at unspecified medical conference in 2008.

MS.TO - Complete enrollment in pivotal Secondary Progressive MS trial this year, interim results mid 2008, trial results in 2009.

NBIX - NBI-56418 Complete enrollment, 6-month phase 2b endometriosis trial 4Q07
NBIX - NBI-56418 Topline data, 6-month phase 2b endometriosis trial 2Q08

Novocell – see SRDX

NRMX, NRM.TO – European ph-3 Alzhemed trial complete 2008 (N Amer ph-3 failed, as reported 8/26/07).

Pharming – Rhucin in EU: appeal of EMEA rejection to be submitted by 2/11/08;

Pharming – Rhucin in US: phase-3 top-line data 1Q08; BLA submission in 2008 if warranted by data.

PHRM – Satraplatin MAA to EMEA to be filed 2/08 following analysis of final OS data.


PPHM- Bavituximab (cancer): Peregrine dosing patients in phase II breast cancer trial w/docetaxel Feb 08

PPHM- Bavituximab (cancer): Peregrine receives approval to conduct phase II NSC lung cancer trial w/carboplatin/paclitaxel Jan 08

PPHM- Bavituximab (cancer): Peregrine receives approval to conduct phase II breast cancer trial w/carboplatin/paclitaxel Jan 08

PPHM- Bavituximab (cancer): phase 1 monotherapy trial adds site in Charlotte, NC. expect to complete patient enrollment Q2 08

PPHM- Bavituximab (viral): phase 1 trial: HCV / HIV coinfected patients: Johns Hopkins added as additional site Dec 07

PPHM- Cotara: phase 2 glioblastoma multiforme Indian trial patient enrollment initiated 6/07. Interim info in Q1 08

PPHM- Cotara: glioblastoma multiforme US trial sites expanded to include MUSC 6/07. Interim info in Q1 08

RPRX– Proellex
*Initiate US PII Endometriosis trial (Enrollment Oct 2007)
*One year extension data (Q1 2008)
*Initiate Fibroids Pivotal PIII trials (?)
*Initiate Anemia Pivotal PIII trial(s) (? – New IND required)

RPRX – Androxal
*Initiate Pivotal PIII trials (?)

RPRX – Other: select alternate Proellex-class compound for advancement into breast cancer studies via potential partner TBA.

SGP – Boceprevir ph-2 trial in treatment-naïve HCV: 12-week data reported on 10/18/07 (#msg-23788779); end-of-treatment data due in 2008 and SVR data in late 2008 or early 2009.

SRDX - Novocell phase-1/2 trial in type-1 diabetes: top-line data due in 2008 (enrollment complete 8/30/06).

TH.TO -Complete enrollment confirmatory TH9507 HIV Associated Lipodystropy trial 3rd qtr/07, final results 1st qtr/08.

VRTX – PROVE-3 trial in treatment-experienced HCV: EoT data and FDA meeting 2Q08; SVR data 4Q08. Note: there has been no commitment to disclose the EoT data to investors.

VRTX – Interim data from BID-dosing phase-2 Telaprevir trial conducted by Tibotec: 2H08.

--
Procedure For Updating Clinical-Trials List

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1. Copy the complete text from the old list. You can find a pointer to this list in the iBox at the top of the main message-board screen.

2. Make your additions or modifications, inserting any new items in alphabetical order.

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great news- Phase II Bavi Dosing Has Begun.



j

that's interesting, since TNT in China, (named Vivatuxin) is approved for lung cancer, and available in Chinese cities.

Vivatuxin is currently being sold for ~ $4,000 per treatment. (about 30,000 yuan)

They've also got it in a phase II glioma trial over there.

I wonder if Peregrine Beijing Pharmaceuticals Technology Development Ltd will come in handy.


j

PS - FWIW - they cut Epstein out of the picture -
http://www.vivatuxin.com/index.do

Alison Stopeck -


"To Prevent and Cure Breast Cancer"
Alison Stopeck, Team Leader:
http://www.azcc.arizona.edu/docs/ACC%20Talent%20sheets/Breast%20Cancer%20(Done)/Breast_Cancer.pdf



BTW - She's had quite a few (phase I) things at ASCO in the past.

put her name into the author window -
http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts


the "C" in ASCO stands for "Clinical",
j

Clinical / Regulatory / Litigation Calendar

[Please keep entries up to date! See updating procedure at the end of this post.]

NOTE: ANYONE MAY UPDATE THIS FILE


Edits:
IDIX (data from CROI conference already out).
PPHM phase II trial updates


AMGN – Denosumab: Three-year data from phase III PMO trials (vs. alendronate) 1Q08; three-year data from phase III PMO fracture study: 2H08; Presentation of data from phase III HALT trial in breast cancer: 1H08; Data from phase III HALT trial in prostate cancer: 2H08.

AMLN – LAR NDA submission: mid 2009 if bioequivalence study needed; earlier if not needed.

BMY – Apixaban phase-3 in orthopedic surgery: fall 2008; phase-2 in ACS: Dec 2008 at ASH.

CEGE - VITAL1 GVAX prostate phase III interim "1H/'early' 2008. Final analysis ?09
- GVAX + MDX010 P1 results ?08
- oncolytic virus (bladder cancer) P1 results at AUA(5/08)

CYT.TO - Initiated pivotal A-fib trial Oct/06. Complete enrollment 2nd/half 07. Results 2nd half 08.

DDSS – Tramadol NDA: second approvable letter received 5/31/07. New clinical trial likely. Ph III Trazodone results 2nd qtr/08

DNA – Avastin sBLA in breast cancer PDUFA date: 2/23/08 (advisory panel voted 5-4 against on 12/5/07); Avastin adjuvant CRC interim look Q2 08; Rituxan in Primary Progressive MS Ph III Results Q2 08.

DNDN – Provenge 9902b study: interim analysis (~180 deaths) 2H08; final analysis (360 deaths) 2010.

ELN – AAAB001- final phase II data Q3 08
AB-001 phase-3: Interim data 2H09 (est.), final data 2H10 (est.). (First patient dosed 12/21/07.)

ELN – ELND005 for AD phase-2: Interim data mid 2009 (est.), final data 1H10 (est.) (First patient dosed 12/21/07.)

GILD – Viread in HBV: FDA PDUFA date 8/11/08; EMEA action date expected 2Q08. (NDA and MAA submitted 10/11/07.)

GILD – GS9190 polymerase inhibitor for HCV: new phase-1 trial to test QT-prolongation announced 10/18/2007; no start date yet.

GTCB – ATryn in US: positive top-line phase-3 data were reported 2/4/08; BLA submission mid 2008; FDA action: late 2008/early 2009 assuming priority review.

GTCB – US Atryn partnership announcement: 1Q08.

GTCB – ATryn phase-2 DIC trial by Leo Pharma in Europe/Canada: enrollment complete end 2008.

GTCB – Merrimack MM-093 results of phase-2 extension trial in RA: July 2008.

HGSI – Phase-3 Albuferon: report data from genotype-2/3 phase-3 trial: end 2008; report data from genotype-1 phase-3 trial: spring 2009; submit BLA fall 2009.

IDIX – IDX899 phase-1/2 seven-day monotherapy study: additional, lower-dose cohorts to be reported during 1H08 (800mg cohort was reported 2/6/08).

IDIX – IDX899 phase-2 six-week head-to-head vs Sustiva (IDX899+Truvada vs Sustiva+Truvada): start enrollment 1H08.

IDIX – IDX184 nucleotide polymerase inhibitor for HCV: file IND 1H08.

IDIX – Protease inhibitor for HCV: file IND in (late) 2008.

ISA.TO-European psoriasis P3 results 2008. Phase 2B 6&12 month renal results 2008. Phase II/III Uveitis results 2008.

ITMN – ITMN-191 Phase-1b: enrollment of 3rd dosing cohort complete by end of Jan 2008. (Data from first two cohorts reported 1/7/08.)

ITMN - Pirfenidone - CAPACITY Trials enrollment completed May 2007. Top-line results Late 2008 (72 week treatment period). No interim analysis planned, though monitored for safety.

LBPFF – see DDSS

MCU/MPH.to - Medicure - MC-1 Lead drug candidate for cardiovascular reperfusion is in PH 3 trial /w 3000 patients, one of the largest trials in Canadian History.
Full enrollment completed Sept. 14 with Top Line Data expected by Late February /08 or Mid March at the latest.

MEDX - Ipilimumab BLA submission sometime in 2008 (phase-3 data reported 12/10/07).

Merrimack: see GTCB

MNTA – Meeting with FDA re Lovenox ANDA: date not specified, but soon.

MNTA — Lovenox patent appeal (Sanofi v Amphastar): oral arguments began 1/8/08.

MNTA – M118 phase-2 data in stable angina to be presented at unspecified medical conference in 2008.

MS.TO - Complete enrollment in pivotal Secondary Progressive MS trial this year, interim results mid 2008, trial results in 2009.

NBIX - NBI-56418 Complete enrollment, 6-month phase 2b endometriosis trial 4Q07
NBIX - NBI-56418 Topline data, 6-month phase 2b endometriosis trial 2Q08

Novocell – see SRDX

NRMX, NRM.TO – European ph-3 Alzhemed trial complete 2008 (N Amer ph-3 failed, as reported 8/26/07).

Pharming – Rhucin in EU: appeal of EMEA rejection to be submitted by 2/11/08;

Pharming – Rhucin in US: phase-3 top-line data 1Q08; BLA submission in 2008 if warranted by data.

PHRM – Satraplatin MAA to EMEA to be filed 2/08 following analysis of final OS data.


PPHM- Bavituximab (cancer): Peregrine begins patient enrollment in phase II breast cancer trial w/docetaxel 1/08

PPHM- Bavituximab (cancer): Peregrine receives approval to conduct phase II NSC lung cancer trial w/carboplatin/paclitaxel 1/08

PPHM- Bavituximab (cancer): Peregrine receives approval to conduct phase II breast cancer trial w/carboplatin/paclitaxel 1/08

PPHM- Bavituximab (cancer): clinical update of Bavituximab anti-cancer at 10th Intl. Symp. on Anti-Angiogenic Agents. 2/08/08

PPHM- Bavituximab (cancer): phase 1 monotherapy trial adds site in Charlotte, NC. expect to complete patient enrollment 2nd Q 08

PPHM- Bavituximab (viral): phase 1 trial: HCV / HIV coinfected patients: Johns Hopkins added as additional site 12/07

PPHM- Cotara: phase 2 glioblastoma multiforme Indian trial patient enrollment initiated 6/07. Interim info in 1st Q 08

PPHM- Cotara: glioblastoma multiforme US trial sites expanded to include MUSC 6/07. Interim info in 1st Q 08

RPRX– Proellex
*Initiate US PII Endometriosis trial (Enrollment Oct 2007)
*One year extension data (Q1 2008)
*Initiate Fibroids Pivotal PIII trials (?)
*Initiate Anemia Pivotal PIII trial(s) (? – New IND required)

RPRX – Androxal
*Initiate Pivotal PIII trials (?)

RPRX – Other: select alternate Proellex-class compound for advancement into breast cancer studies via potential partner TBA.

SGP – Boceprevir ph-2 trial in treatment-naïve HCV: 12-week data reported on 10/18/07 (#msg-23788779); end-of-treatment data due in 2008 and SVR data in late 2008 or early 2009.

SRDX - Novocell phase-1/2 trial in type-1 diabetes: top-line data due in 2008 (enrollment complete 8/30/06).

TH.TO -Complete enrollment confirmatory TH9507 HIV Associated Lipodystropy trial 3rd qtr/07, final results 1st qtr/08.

VRTX – Interim data from BID-dosing phase-2 Telaprevir trial conducted by Tibotec: 2H08.

--
Procedure For Updating Clinical-Trials List

When adding or modifying entries, please follow these steps:

1. Copy the complete text from the old list. You can find a pointer to this list in the iBox at the top of the main message-board screen.

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yet another validation of PS-blocking tumor vaccine -----



(ex vivo photodynamic treatment of tumor cells, + annexin V, = potent specific tumor therapy / autologous vaccine).



Br J Cancer. 2007 Nov 19

Photodynamic therapy-generated vaccines: relevance of tumour cell death expression.

Korbelik M, Stott B, Sun J.

Department of Cancer Imaging, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.


Recent investigations have established that tumour cells treated in vitro by photodynamic therapy (PDT) can be used for generating potent vaccines against cancers of the same origin. In the present study, cancer vaccines were prepared by treating mouse SCCVII squamous cell carcinoma cells with photosensitiser chlorin e6-based PDT and used against poorly immunogenic SCCVII tumours growing in syngeneic immunocompetent mice. The vaccine potency increased when cells were post-incubated in culture after PDT treatment for 16 h before they were injected into tumour-bearing mice. Interfering with surface expression of phosphatidylserine (annexin V treatment) and apoptosis (caspase inhibitor treatment) demonstrated that this post-incubation effect is affiliated with the expression of changes associated with vaccine cell death. The cured mice acquired resistance to re-challenge with the same tumour, while the engagement of cytotoxic T lymphocytes was demonstrated by detection of high numbers of degranulating CD8+ cells in vaccinated tumours. The vaccines prepared from ex vivo PDT-treated SCCVII tumour tissue were also highly effective, implying that surgically removed tumour tissue can be directly used for PDT vaccines. This opens attractive prospects for employing PDT vaccines tailored for individual patients targeting specific antigens of the patient's tumour.


http://www.ncbi.nlm.nih.gov/pubmed/17971767?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


------------






j

Haynes hypothesis -




..."Acutely expressed cytokines and apoptotic
microparticles hypothesized to play a key role in AHI pathogenesis....


It is proposed to characterize the
innate effector mechanisms activated in primary HIV infection and explore their
role in control of early virus replication; and to address whether HIV impairs
aspects of innate immunity in AHI to promote its persistence. This will facilitate
the design of vaccination strategies to target key effector pathways and/or
circumvent infection-associated impairments in innate functions."


April 9, 2007


http://72.14.209.104/search?q=cache:BCKueWKqWTIJ:www.chavi.org/wysiwyg/downloads/CHAVI_012_protocol_v1.pdf+%22CHAVI+012%22&hl=en&ct=clnk&cd=1&gl=us&client=firefox-a




-------------------------------




"Their [Haynes group] current hypothesis is that HIV induces a massive apoptosis
before and during viral ramp-up, and that plasma microparticles (fragments of apoptotic CD3
and T cells) have a suppressive effect on Ab generation, thereby amplifying the apoptotic
cascade. "


May 22, 2007

http://www3.niaid.nih.gov/research/topics/HIV/vaccines/advisory/avrs/PDF/AVRS_May07_Summary.pdf




--------------------------------




"we demonstrated the presence of 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 antigen specific
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."

August 20, 2007

http://www.hivvaccineenterprise.org/_dwn/poster_sessions.pdf




-----------------------------------




j

cisplatin-induced stroke, & microparticles


1: Stroke. 2007 May

Are circulating endothelial-derived and platelet-derived microparticles a pathogenic factor in the cisplatin-induced stroke?

Periard D, Boulanger CM, Eyer S, Amabile N, Pugin P, Gerschheimer C, Hayoz D.

Service of Angiology, University Hospital, Lausanne, Switzerland. Daniel.


BACKGROUND AND PURPOSE: To evaluate whether cisplatin-induced stroke is mediated by vascular toxicity with release of prothrombotic endothelial and platelet-derived microparticles (MPs). METHODS: Endothelial (CD31(+)CD41(-)), platelets (CD31(+)CD41(+)) and prothrombotic (Annexin V(+)) circulating MPs were quantified by flow cytometry in 18 patients with cancer, before and 3 days after administration of cisplatin, and compared with 18 healthy controls. Thrombin-antithrombin complex and prothrombin fragments (F(1+2)) were measured as markers of the activation of the coagulation. RESULTS: In patients with cancer, baseline levels of circulating prothrombotic, endothelial and platelet-derived MPs were similar to healthy controls and decreased significantly after administration of cisplatin. High-baseline MPs levels were observed in 5 patients who received cisplatin for a second or third cycle. A high-baseline activation of the coagulation was observed in all patients without further increase after cisplatin infusion. CONCLUSIONS: Cisplatin treatment is immediately followed by a decrease in circulating levels of endothelial and platelet-derived MPs. However, a transient increase in MPs is observed at the second and third infusion, and this may contribute to the cisplatin-induced stroke.



---------


enter Bavituximab.

j

microvesicles interfere with the maturation of dendritic cells -------------




The research is fast & furious now....

What, a couple years ago, used to be a "small but growing body of evidence" that PS alters immune cell function, is now a very popular area of research, with scientists talking about these PS-positive microvesicles being involved with the successful pathogenesis of cancer, HIV infection, malaria, sepsis, atherosclerosis, rheumatoid arthritis...

(You'll note that most of the "immunosuppressive microparticle" papers I post are within the last 12 months.)

The 'apoptotic debris', the small vesicles shed from cell membranes, 'microparticles, 'exosomes', etc., are coming to be seen as an important modulator of the immune system.


There is also recent talk that HCV infection can be BEATEN, if only we could somehow get more functional dendritic cells into the game.......

(more on that later..)


j

--------------------------------------------


- the paper:


The Journal of Immunology, 2008

Polymorphonuclear Neutrophil-Derived Ectosomes Interfere with the Maturation of Monocyte-Derived Dendritic Cells1

Ceylan Eken2,*, Olivier Gasser*, Gabriela Zenhaeusern{dagger}, Ineke Oehri{dagger}, Christoph Hess{dagger} and Jürg A. Schifferli*

* Department of Research, Immunonephrology Laboratory; and {dagger} Department of Research, Immunobiology Laboratory, University Hospital Basel, Basel, Switzerland

Polymorphonuclear neutrophils (PMNs) are a key component of the innate immune system. Their activation leads to the release of potent antimicrobial agents through degranulation. Simultaneously, PMNs release cell surface-derived microvesicles, so-called ectosomes (PMN-Ect). PMN-Ect are rightside-out vesicles with a diameter of 50–200 nm. They expose phosphatidylserine in the outer leaflet of their membrane and down-modulate monocyte/macrophage-activation in vitro. In this study, we analyzed the effects of PMN-Ect on maturation of human monocyte-derived dendritic cells (MoDCs). Intriguingly, exposing immature MoDCs to PMN-Ect modified their morphology, reduced their phagocytic activity, and increased the release of TGF-β1. When immature MoDCs were incubated with PMN-Ect and stimulated with the TLR4 ligand LPS, the maturation process was partially inhibited as evidenced by reduced expression of cell surface markers (CD40, CD80, CD83, CD86, and HLA-DP DQ DR), inhibition of cytokine-release (IL-8, IL-10, IL-12, and TNF-{alpha}), and a reduced capacity to induce T cell proliferation. Together these data provide evidence that PMN-Ect have the ability to modify MoDC maturation and function. PMN-Ect may thus represent an as yet unidentified host-factor influencing MoDC maturation at the site of injury, thereby possibly impacting on downstream MoDC-dependent immunity.



-------------



j

Bavi MOA / safer chemo? -



J Thromb Haemost. 2007 Dec;5

Chemotherapy-induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity.

Lechner D, Kollars M, Gleiss A, Kyrle PA, Weltermann A.

Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Cisplatin-based chemotherapy predisposes cancer patients to thromboembolic events. Objectives: To investigate whether endothelial damage, via formation of procoagulant endothelial microparticles (EMPs), contributes to cisplatin-related hypercoagulability. Methods: Cell viability and caspase-3/7 activities were assessed in two endothelial cell (EC) lines [human umbilical vein ECs (HUVECs) and human pulmonary microvascular ECs (HMVEC-Ls)] after exposure to cisplatin (1, 2.5, 5, 10 and 20 mum) for up to 120 h. Counts and procoagulant activity of EMPs were measured by flow cytometry and a thrombin generation assay, respectively. Tissue factor (TF) antigen and TF-dependent procoagulant activity of EMP were determined by enzyme-linked immunosorbent assay and a novel functional assay. Results: By inducing apoptosis, cisplatin dose- and time-dependently decreased the viability of confluent HUVECs and HMVEC-Ls. Progression of EC death was accompanied by an increased release of EMPs (relative increase at 20 mum cisplatin for 48 h vs. control: HUVECs 6.5-fold, P < 0.001; HMVEC-Ls 18.4-fold, P < 0.001). EMPs were highly procoagulant (relative increase at 20 mum cisplatin for 48 h vs. control: HUVECs 2.5-fold, P < 0.001; HMVEC-Ls 5.9-fold, P < 0.001). EMP-driven thrombin generation, however, was not dependent on TF: TF expression and TF procoagulant activity levels on microparticles were only marginal and EMP-associated thrombin generation remained unchanged when the extrinsic pathway was blocked by omission of factor VIIa and/or incubation with an anti-human TF antibody. In contrast, blocking of phospholipids by annexin V markedly diminished EMP-associated procoagulant activity. Conclusions: In vitro, cisplatin induced the release of EMPs that showed TF-independent procoagulant activity.



--------


This could become quite a plus for Bavi....

j

Circulating Microparticles as Therapeutic Targets in Cardiovascular Diseases




What was that?



Circulating Microparticles as Therapeutic Targets in Cardiovascular Diseases


Authors: Azevedo, Luciano C.P.1; Pedro, Marcelo A.1; Laurindo, Francisco R.M.1

Source: Recent Patents on Cardiovascular Drug Discovery, Volume 2, Number 1, January 2007

Publisher: Bentham Science Publishers


Circulating Microparticles as Therapeutic Targets in Cardiovascular Diseases


Abstract:

Microparticles are a heterogeneous population of small membrane-coated vesicles released by several cell lines upon activation or apoptosis. Microparticle generation seems to be a well regulated process, although these vesicles are highly variable in size, composition and function. Despite being previously considered inert debris without specific function, recent data demonstrated important pathophysiologic mechanisms orchestrated by microparticles in vascular diseases associated with endothelial dysfunction. These vesicles have been implicated, among others, in the pathogenesis of thrombosis, diabetes, inflammation, atherosclerosis and vascular cell proliferation. In addition to microparticles, circulating activated cells release smaller vesicles denominated exosomes that can also participate in vascular derangement. This mechanistic role of microparticles and exosomes in mediating vascular dysfunction indicates that they may represent novel pathways in short or long-distance paracrine transcelular signaling in vascular environment. The most recent patents regarding microparticles and exosomes are related to their procoagulant potential (U.S. Pat. No. 7005271), role in immune activation of T or B cells (Eurasian Pat. No. 0002827B1) and role in peptide vaccination (World Pat. No. 9705900A1). These commercial applications of microvesicles will be discussed in this review, as well as mechanisms involved in their origin, composition and participation in the pathogenesis of cardiovascular diseases.

http://www.ncbi.nlm.nih.gov/pubmed/18221102?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum



-----------




j

T.L. Whiteside: microvesicle editorial-


British Journal of Cancer, 2005

It's short, and an easy read,

- and so relevant...


Tumour-derived exosomes or microvesicles: another mechanism
of tumour escape from the host immune system?

full text:
http://www.nature.com/bjc/journal/v92/n2/pdf/6602360a.pdf

- here's his closing paragraph:



MV/exosomes are a perfect example of the efficiency of tumours
in orchestrating their escape from the host immune system. By
adapting a ubiquitous process of membrane shedding, tumours are
able to accomplish the loss of those antigens that may be
immunogenic and capable of signalling to immune cells as well
as induce dysfunction or death of immune effector cells located at
a distance from the tumour microenvironment. A better understanding
of this process, and especially of molecular mechanisms
involved in exosome/MV interactions with immune cells, is likely
to provide significant insights into the phenomenon of tumourrelated
immune tolerance. In addition, insights into the MV/
exosome biology are likely to offer opportunities for the
development of novel approaches to immunotherapy of cancer,
graft rejection and other diseases.



---------


j

two more interesting workshops at the conf -

(who knows)..




Therapeutic Workshop
HCV: "Beyond Coin Toss SVRs"

http://ceo.bio.org/opencms/ceo/2008/program/focusSessionDetails.jsp?id=333



Monday, February 11, 2008
9:30 AM
Jade Room

Several HCV drugs in clinical trials have suffered setbacks this year. Rather than looking at these events in a negative light, they instead could potentially open the door to drugs with new mechanisms of action and new targets. Learn about the companies that are trying to emerge from the ashes by addressing this huge market opportunity of more than 250 million people worldwide.

Moderator

* To be announced

Experts

* To be announced

Panelists

* To be announced



----------------------------------------------------------------






Therapeutic Workshop
Non-Cancer Immunotherapy: "It's not just about cancer anymore"

http://ceo.bio.org/opencms/ceo/2008/program/focusSessionDetails.jsp?id=338


Wednesday, February 13, 2008
9:30 AM
Basildon Room

When we think of immunotherapeutics, we tend to associate them as anti-cancer candidates. However, their utility is much more far-reaching than just oncology. Recent clinical setbacks for cancer immunotherapies may increase visibility and attention on how we can effectively harness and train the immune system to recognize and attack threats such as HIV, HCV, neurodegenerative disorders, asthma and allergies, and even addiction. Panelists will discuss their fascinating use of their unique immunotherapy technologies for indications that you may not expect.

Moderator

* To be announced

Experts

* To be announced

Panelists

* To be announced





--------------------------------------------------------





j

Interesting workshop at the BIO CEO conf -

http://ceo.bio.org/opencms/ceo/2008/program/focusSessionDetails.jsp?id=332


Therapeutic Workshop

Neuro-Oncology: "Breaking Down the Barriers to New Neuro-Oncology Drugs"

Monday, February 11, 2008
9:30 AM
East Foyer

Brain cancers, particular glioblastoma multiforme, the most common and most aggressive, leave patients with a poor prognosis and limited treatment options. The standard of care includes invasive surgery and whole brain radiation, and even with this treatment, the survival rate for these patients remains very low. Beyond effectively killing brain cancer cells, another major challenge for drug developers is developing drugs that can successfully cross the blood-brain barrier in order to reach therapeutic concentrations. What companies are up to the challenge and are developing novel new targeted therapeutics and delivery technologies?

Moderator

* To be announced

Experts

* To be announced

Panelists

* To be announced


------------



j

Jan 15, 2008, Journal of Immunology -


Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells.

Eken C, Gasser O, Zenhaeusern G, Oehri I, Hess C, Schifferli JA.

Department of Research, Immunonephrology Laboratory.

Polymorphonuclear neutrophils (PMNs) are a key component of the innate immune system. Their activation leads to the release of potent antimicrobial agents through degranulation. Simultaneously, PMNs release cell surface-derived microvesicles, so-called ectosomes (PMN-Ect). PMN-Ect are rightside-out vesicles with a diameter of 50-200 nm. They expose phosphatidylserine in the outer leaflet of their membrane and down-modulate monocyte/macrophage-activation in vitro. In this study, we analyzed the effects of PMN-Ect on maturation of human monocyte-derived dendritic cells (MoDCs). Intriguingly, exposing immature MoDCs to PMN-Ect modified their morphology, reduced their phagocytic activity, and increased the release of TGF-beta1. When immature MoDCs were incubated with PMN-Ect and stimulated with the TLR4 ligand LPS, the maturation process was partially inhibited as evidenced by reduced expression of cell surface markers (CD40, CD80, CD83, CD86, and HLA-DP DQ DR), inhibition of cytokine-release (IL-8, IL-10, IL-12, and TNF-alpha), and a reduced capacity to induce T cell proliferation. Together these data provide evidence that PMN-Ect have the ability to modify MoDC maturation and function. PMN-Ect may thus represent an as yet unidentified host-factor influencing MoDC maturation at the site of injury, thereby possibly impacting on downstream MoDC-dependent immunity.



--------



j

re:


---------


Feb9: “10th Intl. Symposium on Anti-Angiogenic Agents”, SanDiego http://tinyurl.com/yreuwd
...Dr. Alison T. Stopeck (Ariz C.C.), “Phase I Clinical Studies of the Anti-Tumor Vasculature Antibody, Bavituximab”
...12-20-07 PR: "The bavituximab cancer clinical pgm will be discussed at an important scientific forum when interim clinical data is presented in Feb'08 at Angio2008"



---------



King quote:

from Dec. 10, 2007

"Now, moving to the Phase I Bavituximab trial in the US [ http://www.clinicaltrials.gov/ct/show/NCT00129337 ], we finally seem to be gathering momentum in this trial. Now that we have reached dosing levels, we expect to have anti-cancer activity based on preclinical studies. As a result, we have seen increased patient screening activity at the current sites. In addition, we are looking at the possibility of adding new sites to the trial just to ensure that we will be able to complete the trial in a timely fashion.

(WHICH BY THE WAY THEY HAVE DONE, RECENTLY ADDING A SITE IN CHARLOTTE, NC. - j)

"Another positive development for this program recently occurred when one of our clinical investigators was invited to present interim results from this study at the prestigious 10th Annual Intl. Symposium on Anti-Angiogenesis Agents in San Diego in February [ 2-8-08: http://tinyurl.com/yreuwd ]. Dr Alison Stopeck of the Arizona Cancer Center in Tucson, Arizona will present data gathered from the US Phase I trial and our other clinical experience with Bavituximab. This is an excellent opportunity to raise the profile of our Bavituximab program with influential scientists and clinicians. It will also give us the opportunity to provide an update to the investment community on progress in the Bavituximab cancer program. "



----------------



"we expect to have anti-cancer activity"

"Dr Alison Stopeck of the Arizona Cancer Center in Tucson, Arizona will present data gathered from the US Phase I trial and our other clinical experience with Bavituximab"

"provide an update to the investment community on progress in the Bavituximab cancer program."


----


I'm looking forward to hearing how the US trial is proceeding.



j

Must read: Dr. Licia Rivoltini -



I've posted a few of Rivoltini's papers lately, - studying shed apoptotic microparticles as they relate to tumor progression and metastasis.

The latest - which just came out, in the journal Apoptosis (Cell Death and Differentiation), is a MUST READ IMO.


In preparation for a possible Duke/Haynes paper, I strongly suggest people reading this entire paper below. As you can probably guess by my posts yesterday, I suspect the pathway suggested for intervention in this paper below, will be similar to what we'll hear about from a "Duke" paper...

j

----------

snip -


"Indeed, by reducing the bioavailability of tumour microvesicles through pharmacological intervention, it could be speculated that multiple functions of cancer immunity could be simultaneously recovered"....




----------------------------------


the full paper -

Tumour-released exosomes and their implications in cancer immunity

http://www.nature.com/cdd/journal/v15/n1/full/4402237a.html


M Iero1, R Valenti1, V Huber1, P Filipazzi1, G Parmiani2, S Fais3 and L Rivoltini1

---------------------------------------


BTW - FYI - here's a photograph from Rivoltini-

Colorectal cancer cells and their shed apoptotic (PS positive) microvesicles -






--------

j


Dr. Licia Rivoltini:

"Indeed, by reducing the bioavailability of tumour microvesicles through pharmacological intervention, it could be speculated that multiple functions of cancer immunity could be simultaneously recovered"....




------------------------------------------------




Dr. Barton Haynes - CHAVI Director:

Tumor-released microvesicles as vehicles of immunosuppression





Cancer Res. 2007 Apr

Tumor-released microvesicles as vehicles of immunosuppression.


Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L.

Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.


Tumor-released microvesicles, or exosomes, which are abundant in the body fluids of patients with cancer, are likely to be involved in tumor progression. We recently showed that microvesicles released by human melanoma and colorectal carcinoma cells can promote the differentiation of monocytes to myeloid-derived suppressor cells which support tumoral growth and immune escape. These findings underscore an important role for these extracellular organelles in remodeling tumor-stromal interactions to promote malignancy.



--------



j

T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor.

J Cell Physiol. 2007 Jul

Zakharova L, Svetlova M, Fomina AF.


Department of Physiology and Membrane Biology, University of California Davis, Davis, California 95616, USA.


Activated T lymphocytes release vesicles, termed exosomes, enriched in cholesterol and exposing phosphatidylserine (PS) at their outer membrane leaflet. Although CD4(+) activated T lymphocytes infiltrate an atherosclerotic plaque, the effects of T cell exosomes on the atheroma-associated cells are not known. We report here that exosomes isolated from the supernatants of activated human CD4(+) T cells enhance cholesterol accumulation in cultured human monocytes and THP-1 cells. Lipid droplets found in the cytosol of exosome-treated monocytes contained both cholesterol ester and free cholesterol. Anti-phosphatidylserine receptor antibodies recognized surface protein on the monocyte plasma membrane and prevented exosome-induced cholesterol accumulation, indicating that exosome internalization is mediated via endogenous phosphatidylserine receptor. The production of proinflammatory cytokine TNF-alpha enhanced in parallel with monocyte cholesterol accumulation. Our data strongly indicate that exosomes released by activated T cells may represent a powerful, previously unknown, atherogenic factor.


--------



I suppose this could have something to do with the increase in atheroslerosis in HIV patients..

(when you consider the devastation wreaked on CD4 T cells in early HIV infection),


j

Yes, that's the classic "hockey stick" graph of increased value in phase 2.

- and other drugs responsible for that typical hockey stick looking increase in value aren't as broad, in terms of potential therapeutic applicability, as Bavituximab...







--------



j

Jan 2008 - cerebral malaria protection via PS sequestration -

different method, but again via inhibition of PS exposure
(prevention of microparticle release/accumulation) -



-------------



Proc Natl Acad Sci U S A. 2008 Jan 14

Protection against cerebral malaria by the low-molecular-weight thiol pantethine.

Penet MF, Abou-Hamdan M, Coltel N, Cornille E, Grau GE, de Reggi M, Gharib B.

Centre de Résonance Magnétique Biologique et Médicale, Unite Mixte de Recherche Centre National de la Recherche Scientifique 6612.

We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood-brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation-coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.


--------------


j

additional Malaria microparticle inhibition ----

(via inhibition of PS exposure)

Cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier.

Combes V, Coltel N, Faille D, Wassmer SC, Grau GE.

University of Sydney, Department of Pathology, Medical Foundation Building (K25), 92-94 Parramatta Road, Camperdown, NSW 2042, Australia.


Brain lesions of cerebral malaria (CM) are characterised by a sequestration of Plasmodium falciparum-parasitised red blood cells (PRBC), leucocytes and platelets within brain microvessels, by an excessive release of pro-inflammatory cytokines as well as by disruption of the blood-brain barrier (BBB). We evaluated the possibility that PRBC and platelets interact and induce functional alterations in brain endothelium. Using an in vitro model of endothelial lesion, we showed that platelets can act as bridges between PRBC and endothelial cells (EC) allowing the binding of PRBC to endothelium devoid of cytoadherence receptors. Furthermore, platelets potentiated the cytotoxicity of PRBC for brain EC by inducing an alteration of the integrity of their monolayer and increasing their apoptosis. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM. Another aspect of inflammatory and infectious diseases is that they often lead to activation of vascular and blood cells. Such activation results in an enhanced vesiculation, i.e. the release of circulating microparticles (MP). We thus explored plasma levels of endothelial MP in Malawian children with malaria. Plasma MP numbers were markedly increased on admission only in patients with severe malaria complicated with coma. Using the experimental mouse model of CM, we evaluated the pathogenic implications of MP using genetically deficient mice in which the capacity to vesiculate is impaired. Such mice, lacking the ABCA-1 gene, upon infection by Plasmodium berghei ANKA, showed complete resistance to CM. When purified from infected susceptible animals, MP were able to reduce normal plasma clotting time and to significantly enhance tumour necrosis factor release from naïve macrophages. Altogether these data provide a novel insight into the pathogenic mechanisms leading to the neurological syndrome. The finding that ABCA-1 gene deletion confers complete protection against cerebral pathology, linked to an impaired MP production, provides new potential targets for therapeutic amelioration of severe malaria.



----------



j

Malaria / microparticle inhibition....

Inhibiting PS exposure (inhibiting microparticles) protects from cerebral malaria complications



------------------



ABCA1 gene deletion protects against cerebral malaria: potential pathogenic role of microparticles in neuropathology.

Combes V, Coltel N, Alibert M, van Eck M, Raymond C, Juhan-Vague I, Grau GE, Chimini G.

Laboratory of Immunopathology, Faculty of Medicine, IFR48, Université de la Méditerranée, 27, Bd Jean Moulin, F-13385 Marseille Cedex 05, France.

The ATP-binding cassette transporter A1 (ABCA1) modulates the transbilayer distribution of phosphatidylserine at the outer leaflet of the plasma membrane. This external exposure of phosphatidylserine is a hallmark of microparticle production and is impaired in ABCA1(-/-) mice. In this study, we report about the complete resistance to cerebral malaria of these mice. On analysis of histological and systemic parameters we evidenced an impairment of cellular responses to Plasmodium berghei ANKA infection in ABCA1(-/-) mice, as shown by lower plasma tumor necrosis factor levels, a weaker up-regulation of endothelial adhesion molecules in brain microvessels, a reduced leukocyte sequestration, as well as an ablated platelet accumulation. Besides, the number and the procoagulant activity of microparticles were dramatically reduced in the plasma of ABCA1(-/-) compared to ABCA1(+/+) mice. Moreover, microparticles derived from Plasmodium berghei ANKA-infected ABCA1(+/+) mice induced a significant increase of tumor necrosis factor release by noninfected macrophages. In ABCA1(-/-) mice platelet and macrophage responses to vesiculation agonists were ablated and reduced, respectively. Altogether, by pointing out the ABCA1 transporter as a major element controlling cerebral malaria susceptibility, these data provide a novel insight into its pathophysiological mechanisms and are consistent with a pathogenic role of microparticles in this neurological syndrome.



----------


j

Malaria -





Cytoadherence of Malaria-Infected Red Blood
Cells Involves Exposure of Phosphatidylserine

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=224332&Ausgabe=228865&ArtikelNr=67908&filename=67908.pdf


Introduction

Malaria, one of the most life-threatening infectious
diseases in the world, causes 1.5-2.7 million deaths
annually [1]. Of the four species of human malaria
parasites, Plasmodium falciparum causes the severest of
symptoms and the greatest number of deaths. Adherence
of red cells infected with the mature stages of the parasite
to endothelial cells (EC) lining the postcapillary venules,
especially in the deep tissues, enables the parasites to
avoid splenic clearance and parasite growth is favored
by an hypoxic microenvironment. The adherence of
P. falciparum-infected red cells also results in the
occlusion of microvessels and can lead to
unconsciousness, coma, and in some cases, death. The
virulent nature of P. falciparum has been attributed to
mechanical obstruction by adherent infected red cells [2].
In this context, an understanding of the mechanisms of
the adherence of malaria-infected red cells may lead to
the development of anti-adhesive reagents and new
therapies.

......

The asymmetry of phospholipids in the lipid bilayer
of the plasma membrane is maintained by several membrane
enzymes such as scramblase, translocase and
flippase [28]. Disruption of phospholipid asymmetry
results in the exposure of phosphatidylserine (PS)
molecules, which are normally located in the inner leaflet
of the phospholipid bilayer. We and other investigators
have shown that PS is exposed on the malaria-infected
red cell surface coincident with parasite development [29-
31]. PS liposomes or PS-exposed cells bind to CD36 [32]
and TSP [33] both of which serve as receptors for the
adherence of P. falciparum-infected red cells [34, 35].
Here, we demonstrate that PS exposure on the exofacial
surface of the P. falciparum -infected cell is involved in
the binding to CD36 and TSP.

.......

Discussion
Drastic changes in the red blood cell membrane are
induced during the intracellular maturation of the malarial
parasite, P. falciparum. These include visible changes in
the shape of the red cell, the appearance of electron-dense
protrusions (called knobs) [3, 49], increased membrane
permeability [50, 51], decreased deformability [52],
insertion of parasite-derived proteins [8-10], changes in
the composition and oxidative damage of membrane
lipids [53, 54], a reduction in cholesterol content [30],
as well as degradation of membrane proteins [55].

........

Further,
Facer et al. [63] detected elevated levels of antiphospholipid
antibodies in the serum of P. falciparuminfected
patients using an ELISA method, and found the
highest IgG and IgM binding was to PS and other anionic
phospholipids, indicating that infected red cells expose
PS on their surface in vivo. In that report, the percentage
of anti-PS IgG or IgM positive serum of P. falciparuminfected
patients as 89% and 79%, respectively. Thus,
the accumulating data support PS exposure in P.
falciparum infected red cells.

.......

The precise mechanism of PS exposure on
P.falciparum-infected red cells remains undefined.
Several investigators have demonstrated that treatment
of red cells with various oxidants, such as
phenylhydrazine [64], hydrogen peroxide [65], or
diamide [66], also results in PS exposure. And, PS
exposure has been demonstrated in red cells from patients
with sickle cell anemia [36, 67, 68], thalassemia [69],
diabetes [70], all of which may be under oxidative stress
[71-73]. The erythrocytic stages of Plasmodium as they
mature, digest hemoglobin, and release highly oxidative
iron-containing products. And, oxidized membrane lipids
have been detected in trophozoite- or schizont-infected
red cell membranes [54], coincident with the time we
and other investigators have detected PS exposure [29-
31]. It seems plausible that oxidative stress could act as
a trigger for PS exposure on the surface of the malariainfected
red cell.

.......

Since PS exposure was detected in the various strains of
falciparum malaria we tested, as well as strains used by
other workers, we contend that PS exposure can
contribute to the universal binding of infected cells to
CD36 and TSP. Our findings (i.e., PS exposure and PSmediated
infected-cell binding to TSP) is also compatible
with the suggestion that PS is involved in abnormal sickle
red cell binding to TSP [76, 77].

.......

Further investigation of the structural requirement of
inhibition of PS-mediated infected-cell binding, as well
as a determination of the relative contributions of PfEMP-
1, band 3 and PS to cytoadherence, may assist in the
development of novel and effective anti-adhesive agents.

In conclusion, PS exposure, modification in band 3
protein, and PfEMP-1 all contribute to cytoadherence/
sequestration and disease pathogenesis in P. falciparum
malaria.




-------


j

BTW odd sod - Here's some snips from Thorpe's patent,


---------------------------------------



[0169] The methods and uses of the present invention are particularly intended for use in animals and patients that have, or are at risk for developing, any form of vascularized tumor; macular degeneration, including age-related macular degeneration; arthritis, including rheumatoid arthritis; atherosclerosis and atherosclerotic plaques; diabetic retinopathy and other retinopathies; thyroid hyperplasias, including Grave's disease; hemangioma; neovascular glaucoma; and psoriasis.


[0685] The in vivo imaging compositions and methods of the invention can be used in imaging per se, or in pre-imaging a site in the body to form a reliable image prior to treatment. Preferably, the imaging is tumor imaging. These compositions and methods can also be applied to imaging and diagnosis of other diseases or conditions associated with aminophospholipids and anionic phospholipids, such those involving cell activation and/or apoptosis, including angiogenic diseases, atherosclerosis, viral infections, and other such conditions in which an internal image is desired for diagnostic or prognostic purposes or to design treatment.



[0806] Whether based upon anti-angiogenesis, prothrombotic vasculature or other anti-vascular mechanisms, the present invention may thus be used to treat prevalent and/or clinically important diseases outside the field of cancer, including arthritis, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic retinopathy, age-related macular degeneration, Grave's disease, vascular restenosis, including restenosis following angioplasty, arteriovenous malformations (AVM), meningioma, hemangioma and neovascular glaucoma. Other targets for intervention include angiofibroma, atherosclerotic plaques, corneal graft neovascularization, hemophilic joints, hypertrophic scars, osler-weber syndrome, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, various other inflammatory diseases and disorders, and even endometriosis. Further diseases and disorders that are treatable by the invention, and the unifying basis of such disorders, are set forth below.

etc.

-----------


and a few Pisetsky of Duke, then Haynes & Pisetsky -



Pisetsky of Duke 2005 -









Pisetsky of Duke 2006 -








Haynes and Pisetsky 2007 -












------------



It seems to me like Haynes wants to clean up the microparticles to see if it will facilitate a more robust immune response.



Will he be successful?????????????????????









j

Bob, it's been an interesting topic the past couple years.


(It's also interesting to see Haynes now working closely with David Pisetsky).


anyway..


here's one for you, from dozens -


Cholesterol Enrichment of Human Monocyte/Macrophages Induces Surface Exposure of Phosphatidylserine and the Release of Biologically-Active Tissue Factor–Positive Microvesicles


Abstract


Objective— Biologically significant amounts of two procoagulant molecules, phosphatidylserine (PS) and tissue factor (TF), are transported by monocyte/macrophage-derived microvesicles (MVs). Because cellular cholesterol accumulation is an important feature of atherosclerotic vascular disease, we now examined effects of cholesterol enrichment on MV release from human monocytes and macrophages.

Methods and Results— Cholesterol enrichment of human THP-1 monocytes, alone or in combination with lipopolysaccharide (LPS), tripled their total MV generation, as quantified by flow cytometry based on particle size and PS exposure. The subset of these MVs that were also TF-positive was likewise increased by cellular cholesterol enrichment, and these TF-positive MVs exhibited a striking 10-fold increase in procoagulant activity. Moreover, cholesterol enrichment of primary human monocyte-derived macrophages also increased their total as well as TF-positive MV release, and these TF-positive MVs exhibited a similar 10-fold increase in procoagulant activity. To explore the mechanisms of enhanced MV release, we found that cholesterol enrichment of monocytes caused PS exposure on the cell surface by as early as 2 hours and genomic DNA fragmentation in a minority of cells by 20 hours. Addition of a caspase inhibitor at the beginning of these incubations blunted both cholesterol-induced apoptosis and MV release.

Conclusions— Cholesterol enrichment of human monocyte/macrophages induces the generation of highly biologically active, PS-positive MVs, at least in part through induction of apoptosis. Cholesterol-induced monocyte/macrophage MVs, both TF-positive and TF-negative, may be novel contributors to atherothrombosis.

Cellular cholesterol accumulation is an important feature of atherosclerosis. In the current study, we found that cholesterol enrichment of human monocytes and macrophages substantially induced the generation of biologically-active microvesicles, including a subset that is tissue factor–positive and highly procoagulant. We conclude that cholesterol-induced monocyte/macrophage microvesicles may be novel contributors to atherothrombosis.


-----------


those PS positive little microparticles contribute to the development of, and accumulate in, atherosclerotic plaque.


BTW - if that interests you, wait til you learn about the pathogenesis of cerebral malaria.



j

Brief Reviews: Procoagulant Microparticles

Disrupting the Vascular Homeostasis Equation?

Olivier Morel; Florence Toti; Bénédicte Hugel; Babé Bakouboula; Laurence Camoin-Jau; Françoise Dignat-George; Jean-Marie Freyssinet

From Université Louis Pasteur (O.M., F.T., B.H., B.B., J.-M.F.), Faculté de Médecine, Institut d’Hématologie et d’Immunologie, Strasbourg, France; Hôpitaux Universitaires de Strasbourg (O.M., B.B.), Fédération de Cardiologie, Strasbourg, France; INSERM (O.M., F.T., B.H., B.B., J.-M.F.), U.770, Le Kremlin-Bicêtre, France; Université Paris-Sud 11 (F.T.), Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM (L.C.-J., F.D.-G.), U.608, Marseille, France; Université de la Méditerranée (L.C.-J., F.D.-G.), Faculté de Pharmacie, Marseille, France; Hôpital de la Conception (L.C.-J., F.D.-G.), Laboratoire d’Hématologie, Marseille, France.
http://atvb.ahajournals.org/cgi/content/abstract/26/12/2594


Apoptosis and vascular cell activation are main contributors to the release of procoagulant microparticles (MPs), deleterious partners in atherothrombosis. Elevated levels of circulating platelet, monocyte, or endothelial-derived MPs are associated with most of the cardiovascular risk factors and appear indicative of poor clinical outcome. In addition to being a valuable hallmark of vascular cell damage, MPs are at the crossroad of atherothrombosis processes by exerting direct effects on vascular or blood cells. Under pathological circumstances, circulating MPs would support cellular cross-talk leading to vascular inflammation and tissue remodeling, endothelial dysfunction, leukocyte adhesion, and stimulation. Exposed membrane phosphatidylserine and functional tissue factor (TF) are 2 procoagulant entities conveyed by circulating MPs. At sites of vascular injury, P-selectin exposure by activated endothelial cells or platelets leads to the rapid recruitment of MPs bearing the P-selectin glycoprotein ligand-1 and blood-borne TF, thereby triggering coagulation. Within the atherosclerotic plaque, sequestered MPs constitute the main reservoir of TF activity, promoting coagulation after plaque erosion or rupture. Lesion-bound MPs, eventually harboring proteolytic and angiogenic effectors are additional actors in plaque vulnerability. Pharmacological strategies aimed at modulating the release of procoagulant MPs appear a promising therapeutic approach of both thrombotic processes and bleeding disorders.

Plasma membrane-derived microparticles are at the crossroad of atherothrombosis processes involving vascular inflammation, remodeling, endothelial dysfunction, and plaque thrombogenicity. After plaque disruption, trapped and circulating microparticles provide the concentration of tissue factor allowing blood coagulation to be triggered. The pharmacological modulation of microparticle release appears a promising preventive approach.




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j

pphmlover,


re:"pr states they will start with 15 patients, and if bavi is working well they will go to 46.wonder if they will announce when and if they go to 46 patients or just do it and leave us wondering."


One of the good things in the way the trials are designed is that it allows for interim PR's.
(In answer to your question, "yes".).

Also realize the details about two-stage (Simon R) phase II trials....

They don't necessarily need to do "all 15" patients to clear the initial hurdle to move on to the larger group....
They need to do around 20% or so better than standard of care- in those 15 patients.
If, say, hypothetically, the chemo SOC results in the cancer they're treating is, for instance- 20% objective responses, (three out of fifteen initial patients), then it may be simply a matter of getting one, or two, more objective responses (four or five out of the initial fifteen patients), to clear the hurdle to move into the larger group.

Now, with just chemo SOC, by definition, it would take all the 15 patients to reach that proven SOC pecentage, whatever it is for the particular indication.

With Bavi, it may (hopefully) not take all fifteen to do 20% (or whatever) better than SOC...

It's possible, in my opinion, with a healthier patient pool, which this is, considering the impressive results in the "pretty far gone" previous Indian patients, that perhaps they can get those 4 or 5 (or whatever) without having to treat 15....

Of course, there's the possibility of 4 out of 4 (the first 4) patients having objective responses.

Remember that 2 out of 2 breast cancer patients in the previous trial, in much weaker patients, achieved objective responses with Bavi plus carboplatin/paclitaxel.

(and that's one of the new trials - Bavi plus carboplatin/paclitaxel against breast cancer).

IMO, once the trials start treating patients, I'd expect to hear the interim update your wondering about, in about three months, tops.



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j

OT: (hopefully :)


Problems force shutdown at disease lab

http://news.galvestondailynews.com/story.lasso?ewcd=fee6b3293a684d92

By Marty Schladen
The Daily News

Published January 25, 2008
GALVESTON — A laboratory used by researchers to study highly infectious organisms is being shut down at the University of Texas Medical Branch after an internal door failed twice.

That door was in a lab containing mice that had been exposed to the virus that causes bird flu. It was between a chemical shower sceintists must walk through before entering the lab, and the lab itself.

Both diseases are highly deadly in humans, but no people were in the two rooms connected by the door when it failed, said university spokeswoman Chris Comer.

In addition, the disease-causing bugs were behind barriers of their own within the lab, so none escaped, Comer said.

“It’s containment within containment within containment and negative air pressure throughout,” Comer said.

Even so, the Robert E. Shope lab is being shut down as a precaution, Comer said.

In addition to the experiments connected by the failed door, there are six other ongoing experiments being conducted in the laboratory.

All will be wrapped up today and the entire laboratory will be fumigated Saturday, Comer said.

Any further experiments will be delayed until the cause of the internal door’s failure is discovered and corrected. Comer said representatives of its manufacturer are being flown in from Germany to investigate. Medical branch engineers believe a defective switching device was responsible for the problem, Comer said.

The door opened twice: at 3 a.m. and again at 2 p.m. Wednesday. Nobody had been in either of the labs it connected since 5 p.m. Tuesday, Comer said.

The Shope lab is a Biolevel Safety Containment 4 laboratory. Scientists study highly infectious organisms in the secure labs.

The organisms under study in the labs separated by the failed door are both potentially extremely dangerous.

In one, about 10 mice had been infected with the H5N1 influenza virus. The bug, which initially attacks the respiratory system, has killed multitudes of birds, pigs and other animals, primarily in the Far East. It also has killed hundreds of humans, but it doesn’t pass easily between them.

Public health officials are very worried that the virus will change genetically so that it is easily communicable between humans and cause a flu pandemic like the one in 1918. That outbreak is estimated to have killed between 50 and 100 million people worldwide.

Comer, of the medical branch, emphasized that neither pathogen escaped its containment. The medical branch plans to post details of that containment and its safety procedures on the Web today.



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j

one more must read from the same folks -


Cancer Res. 2006 Sep 15

Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes.


Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L.

Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Milan, Italy.



Human tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR(-/low) cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dose-dependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14+ monocytes, skewing their differentiation toward CD14+HLA-DR-/low cells with TGF-beta-mediated suppressive activity on T-cell-functions. Interestingly, a subset of TGF-beta-secreting CD14+HLA-DR- cells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell-mediated control of tumor growth in cancer patients.



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Bavi phase 2 cancer trials should be interesting.
So should Haynes paper...


j

Tumour-released exosomes and their implications in cancer immunity.

Cell Death Differ. 2008 Jan;15

Iero M, Valenti R, Huber V, Filipazzi P, Parmiani G, Fais S, Rivoltini L.

1Unit of Immunotherapy of Human Tumours, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.


Tumour-released exosomes and their implications in cancer immunity.


Tumour cells release vesicular structures, defined as microvesicles or exosomes, carrying a large array of proteins from their originating cell. The expression of antigenic molecules recognized by T cells has originally suggested a role for these organelles as a cell-free antigen source for anticancer vaccines. However, recent evidence shows that tumour exosomes may also exert a broad array of detrimental effects on the immune system, ranging from apoptosis in activated antitumour T cells to impairment of monocyte differentiation into dendritic cells and induction of myeloid suppressive cells. Immunosuppressive exosomes of tumour origin can be found in neoplastic lesions and sera from cancer patients, implying a potential role of this pathway in in vivo tumour progression. Through the expression of molecules involved in angiogenesis promotion, stromal remodelling, delivery of signalling pathways through growth factor/receptor transfer, chemoresistance and genetic intercellular exchange, tumour exosomes could represent a versatile tool for moulding host environment. Hence, their secretion by neoplastic cells may in the future become a novel pathway to target for therapeutic intervention in cancer patients.Cell Death and Differentiation (2008)



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Read that a few times!
and keep that in mind!
with respect to HIV infection as well!

j

Nature Reviews Molecular Cell Biology - February 2008

Interesting issue this month -
http://www.nature.com/nrm/index.html



j

CD4+ T cells / PS / Letvin / Henson / Haynes / King






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It has long been appreciated that CD4+ T lymphocytes are dysfunctional in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV)-infected individuals, and it has recently been shown that HIV/SIV infections are associated with a dramatic early destruction of memory CD4+ T lymphocytes. However, the relative contributions of CD4+ T-lymphocyte dysfunction and loss to immune dysregulation during primary HIV/SIV infection have not been fully elucidated. In the current study, we evaluated CD4+ T lymphocytes and their functional repertoire during primary SIVmac251 infection in rhesus monkeys. We show that the extent of loss of memory CD4+ T lymphocytes and staphylococcal enterotoxin B-stimulated cytokine production by total CD4+ T lymphocytes during primary SIVmac251 infection is tightly linked in a cohort of six rhesus monkeys to set point plasma viral RNA levels, with greater loss and dysfunction being associated with higher steady-state viral replication. Moreover, in exploring the mechanism underlying this phenomenon, we demonstrate that the loss of functional CD4+ T lymphocytes during primary SIVmac251 infection is associated with both a selective depletion of memory CD4+ T cells and a loss of the functional capacity of the memory CD4+ T lymphocytes that escape viral destruction.

Norm Letvin, August 2007
Memory CD4+ T-lymphocyte loss and dysfunction during primary simian immunodeficiency virus infection.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17522197&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum



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Phosphatidylserine (PS) on apoptotic cells promotes their uptake and induces anti-inflammatory responses in phagocytes, including TGF-{beta} release. Little is known regarding the effects of PS on adaptive immune responses. We therefore investigated the effects of PS-containing liposomes on immune responses in mice in vivo. PS liposomes specifically inhibited responses to Ags as determined by decreased draining lymph node tissue mass, with reduced numbers of total leukocytes and Ag-specific CD4+ T cells.


Peter Henson, 2005
Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo
http://www.jimmunol.org/cgi/content/full/174/3/1393


------------


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

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.


Barton Haynes, 2007
http://www.hivvaccineenterprise.org/_dwn/poster_sessions.pdf



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Steve King, Peregrine CEO:


3-12-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/2dtmca

SK: “Expanding the patient population we are treating to potentially include HCV/HIV co-infected individuals is a 3rd focus area… Our interest in this patient population has been further stimulated by solid evidence, thru our collab’s at Duke, that Bavi binds to HIV virus, binds to HIV-infected cells, and may have potent neutralizing effects on the virus.




3-12-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/2dtmca

SK: “ the funding that's coming out of there [Duke] is actually funding a lot of studies that are being done with bavituximab as a model..."

"The collaboration is going extremely well, the data we're generating is really helping us in the way we think about our development of bavituximab for HCV & HIV,"




7-11-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/2c9kwr

SK: “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



9-10-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/38lky9

SK: “Our collab. with HIV researchers at Duke remains strong and is making good progress. The collab. is providing exciting, new insights into the potential of Bavituximab.."

"we are happy with the collaboration and are getting a lot of data from the studies they are doing,"

"Our role in the studies is primarily to provide materials that are then being tested"..

"We are working with a group at Duke. In particular, we participated in a pgm that has been funded through the Gates Foundation [CAVD]. The CHAVI pgm is actually a separate pgm. They are both studying phospholipids as potential targets for the dev. of vaccines. So, in order to pursue that, they’ve been testing Bavituximab.."


There are add’l studies being planned. It’s a very large pgm that’s being run, again, simultaneously through these 2 different pgms – the CHAVI and then the Gates pgm [CAVD]. We are as anxious as anyone else to be able to get some of this info. out there. I know the guys at Duke will want to get it out there at the appropriate time. We are getting a lot of insight into, not just Bavituximab, but other antibodies that we have generated through our various collaborations. Over the long run, that’s going to be some extremely valuable info. that is only going to strengthen our overall antiviral pgm.”



2-10-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/393mau

SK: DUKE – “In addition to the clinical study, we are continuing a significant amount of preclinical work in the antiviral area. Our leading collaboration is with researchers at Duke University and a number of other institutions, including Harvard. This collaboration is progressing very nicely and we are highly encouraged by the results we have seen. As a reminder, we are exploring the potential of Bavituximab and several other anti-PS antibodies for their potential in the treatment and prevention of HIV infections. This collaboration is particularly important because without the collaboration we would not be able to conduct this informative research into the potential of our anti-PS platform for the treatment of HIV. Both we and our collaborators believe we are getting close to being able to share results of these studies either through publications or presentations in the upcoming months.”



Also - Steve King, general anti-PS / viral statement, on Dec 14- 07:
"Based on recent data from our collaborators, we are more enthusiastic than ever about the potential of our anti-PS technology platform for the treatment of viral infections, and we see many potential applications in this area."




j

Memory CD4+ T cells ( & PS ): Letvin / Henson / Haynes / King




Memory CD4+ T cells are needed to fight HIV.

Memory CD4+ T cells disappear early in HIV infection.

Their loss is directly related to the viral set point. (the fewer CD4+ T cells, the higher level of virus).

The viral set point is directly related to time to progression to AIDS, and risk of transfer.

exposed PS is responsible for the loss of Memory CD4+ T cell function and quantity.

Apoptosis is overwhelming in early HIV infection.

Shed apoptotic debris, (microvesivles / 'microparticles') expose PS, and are abundant in early HIV infection.

anti-PS binds PS exposing microvesicles.

Bavituximab and other anti-PS mabs developed by Peregrine Pharmaceuticals are in testing at Duke, under Bart Haynes, and Harvard, to see if they protect from HIV infection, or if they can be successful in lowering the viral set point.

The funding for the work is from the Gates Foundation.

The last time Bart Haynes presented at a Gates Foundation sponsored HIV conference, his abstract stated,

"we demonstrated the presence of phosphatidylserine (PS)-expressing microparticles
in these plasma samples at the time of viral load ramp-up.

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."


Barton Haynes, 2007
http://www.hivvaccineenterprise.org/_dwn/poster_sessions.pdf


The next Gates sponsored HIV conference is late March.


j