Gone for good.
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This is nonsense. Once inside the cell how does bavi then have any activity?
You don't believe it is an antibody? How do you think they make it????
Here is another paper from a different group which reaches pretty much the same conclusion.
The survival curves are very similar in the two papers.
Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head
Cancer Science Volume 103, Issue 11, pages 2012–2020, November 2012
http://onlinelibrary.wiley.com/doi/10.1111/j.1349-7006.2012.02411.x/abstract
Tumor-associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumor-associated macrophages can be affected by cancer-related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM-related factors and the clinical impact of TAMs. CD68 (a pan-macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease-free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC.
That would be my guess.
Yes, it should be "This paper shows how pancreatic patients with more M1-type have a higher survival
than the patients with more of the M2-type."
Thanks.
This is an interesting paper on pancreatic cancer.
My interest here is the MOA for bavituximab proposed by Dr. Thorpe which involves the switching of
macrophage phenotypes from the immunosuppressive M2-type to the immunostimulatory M1-type.
This paper shows how pancreatic patients with more M2-type have a higher survival than the patients with
more of the M2-type. If this MOA is valid then we might also expect it would be also true in NSCLC.
Significance of M2-Polarized Tumor-Associated Macrophage in Pancreatic Cancer
Journal of Surgical Research 167, e211–e219 (2011)
http://www.sciencedirect.com/science/article/pii/S0022480409002844
-----------------------------------------------------------------------------------
Background. The roles of infiltrating macrophages
within the tumor microenvironment are complex
because of their functional variety. The aim of this
study is to examine the role and prognostic significance
of tumor-associated macrophages (TAMs) that
have an M2 polarized function in pancreatic cancer.
Materials and Methods. Formalin-fixed, paraffinembedded
blocks were obtained from 76 patients
with pancreatic head cancer. All patients underwent
macroscopic curative resection. We assessed the number
of infiltrating macrophages within the tumor invasive
front by not only CD68 but also by CD163 and
CD204, which are specific receptors on M2-polarized
macrophages. Furthermore, to evaluate lymphangiogenesis,
we measured the density of lymphatic vessels
in the tumor invasive front by using D2-40.
Results. High incidence of lymph node metastasis
was shown in cases with a high number of CD163- or
CD204-positive macrophages. Significantly increased
lymphatic vessel density (LVD) was shown in cases
with lymph node metastasis compared with cases without
lymph node metastasis (P[0.0094). Significantly
increased LVD (P[0.0175) and a poor prognosis
(P[0.0171) were shown in cases with a high number
of macrophages that express CD163 or CD204, however,
there was no significant difference according to
the number of CD68-positive macrophages.
Conclusions. M2-polarized TAMs in the invasive
front of pancreatic cancer are associated with a poor
prognosis due to accelerated lymphatic metastasis
and inhibition of the functional interaction between
M2-polarized TAMs and tumor cells may improve the
prognosis
------------------------------------------------------------------------------
Note that this figure shows the markers low CD163/CD204 (M1-type macrophages) have a
significantly better survival then the high CD163/CD204 (M2-type macrophages).
In fact, the figure B shows that the MOS for the M2 type is approximately 9 months and the MOS
for the patients with predominately M1 type is approximately 18 months, or a doubling of MOS.
It also shows that using high and low CD68 as a marker does not work as well.
-----------------------------------------------------------------------------------------------------
INTRODUCTION
Pancreatic cancer is more aggressive than any other
gastrointestinal malignancy due to the propensity for
hematogenous or lymphatic metastasis in its early
stage, which is associated with a poor prognosis [1].
Compelling evidence has emerged in recent years that
the tumor microenvironment plays a critical role in
tumor progression [2, 3]. Solid tumors are comprised of
tumor and nontumor cells, such as resident stromal cells
and migratory hemopoietic cells. Complex crosstalk between
these cells regulates tumor growth, invasion, and
metastasis. Macrophages are one of the major components
of the tumor microenvironment; those are derived
from CD34þ bone marrow progenitors develop into
monocytes, and extravasate into various tissues where
they differentiate into resident macrophages. Macrophages
are a heterogeneous cell population that adapt
and respond to a large variety of microenvironmental
signals. While macrophage activation by T helper 1
(Th1) cytokines, such as interferon-g (IFN- g), interleukin-
1b (IL- b), and lipopolysaccharide was named ‘‘classical’’
activation, that byThelper 2 (Th2) cytokines, such
as IL-4 and IL-13 was named ‘‘alternative’’ activation.
Mirroring the Th1 and Th2 nomenclature, many
researchers refer to polarized macrophages as M1 and
M2 cells [3]. These subpopulations of macrophage have
different types of receptor expression and cytokine and
chemokine production. M1-polarized macrophages
have the IL-12high, IL-23high, IL-10low phenotype and
produce tumor necrosis factor a (TNF-a) and nitric oxide
(NO): M1-polarized macrophages are potent effector
cells that kill microorganisms and tumor cells. In contrast,
M2-polarized macrophages have the IL-12low,
IL-23low, IL-10high phenotype and have high expression
of several receptors, such as class A scavenger receptor
(SR-A, CD204) and mannose receptor (MR, CD163).
M2-polarized macrophages scavenge debris and
promote angiogenesis, tissue remodeling, and repair
[3, 5]. Circulating monocytes were shown to be recruited
by chemotactic factors produced by tumor cells into the
tumor microenvironment and differentiated to tumorassociated
macrophages (TAMs), which have the polarized
M2 phenotype [5, 6]. TAMs receive signals from
diverse cells within the tumor microenvironment and
release various growth factors and cytokines and promote
tumor cell invasion, induce angiogenesis, suppress
antitumor immunity, and facilitate tumor cell metastasis [3–6].
[snip]
DISCUSSION
A dense, desmoplastic stroma rich in inflammatory
cells, fibroblasts, and extracellular matrix proteins is
a trait of pancreatic cancer [36]. TAMs are important
components of inflammatory cells. Macrophages are
plastic cells: they can switch from an activated M1 state
back to M2, and vice versa, according to specific signals.
Malignant tumors recruit circulating monocytes/macrophages
into their microenvironment and let them
mature and differentiate into TAMs that have the M2
phenotype [3–5]. In this tumor microenvironment,
paracrine interaction between cancer cells and TAMs
promotes tumor invasion, angiogenesis, and metastasis.
[snip]
In conclusion, M2-polarized TAMs in the invasive
front of pancreatic cancer promote lymphangiogenesis,
facilitate lymphatic metastasis, and could be a predictor
of a poor prognosis. It is possible that therapy
aimed at disrupting the functional interactions
between pancreatic cancers cells and infiltrating M2-
polarized macrophages may decrease lymphatic
metastasis and prolong survival.
Yes, it is a public board, and we will all be looking for those facts backing up your theory to be presented on this board.
Will you be submitting your theory for publication? Maybe Thorpe can review it.
And yes FTM, there will be scientific facts to back it up.
The other new paper today. More evidence that bavi is being studied as an anti-viral treatment.
Catheterized guinea pigs infected with Ebola Zaire virus allows safer sequential
sampling to determine the pharmacokinetic profile of a phosphatidylserine-targeting
monoclonal antibody
Antiviral Research http://www.sciencedirect.com/science/article/pii/S0166354212002586?v=s5
The coauthors include three Peregrine employees: Kara Corbin-Lickfett, Cyril Empig, Kyle Schlunegger
Abstract
Sequential sampling from animals challenged with highly pathogenic organisms, such as
haemorrhagic fever viruses, is required for many pharmaceutical studies. Using the guinea pig model
of Ebola virus infection, a catheterized system was used which had the benefits of allowing repeated
sampling of the same cohort of animals, and also a reduction in the use of sharps at high biological
containment. Levels of a PS-targeting antibody (Bavituximab) were measured in Ebola-infected
animals and uninfected controls. Data showed that the pharmacokinetics were similar in both
groups, therefore Ebola virus infection did not have an observable effect on the half-life of the
antibody.
[snip]
Bavituximab (PGN401) is a monoclonal human-mouse chimeric antibody, with the variable region
from the mouse IgG3 monoclonal antibody 3G4 that targets phosphatidylserine (PS) joined to the
human IgG1k constant regions (Thorpe, 2010). Whilst PS resides predominantly in the inner leaflet
of the plasma membrane in healthy cells, it externalizes under certain stress conditions, during cell
activation and in cell death via apoptosis (Hengartner, 2000). During this process, PS becomes
available for antibody binding. Initial work with PGN401 focused on its use to target endothelial cells
in tumor vasculature via their PS surface expression (Huang et al., 2005). Bavituximab has completed
Phase II clinical trials in patients with advanced breast cancer and non-small cell lung cancer (Thorpe,
2010), and other Phase II clinical trials are ongoing.
More recently, the effects of PGN401 have been studied in the context of viral infection. Virus induced
events also result in a loss of lipid asymmetry exposing PS on the plasma membrane (Pai et
al., 2009). Binding of PGN401 to these cells results in their elimination through recognition by cells of
the immune system. To date, many of the antiviral properties of PGN401 have been investigated
with hepatitis C virus infections (Sakamoto and Watanabe, 2009), and this work has progressed to
clinical trials (Tomillero and Moral, 2008; Tomillero and Moral, 2009). Studies have also been
undertaken in other viral infections. In 2008, it was reported that PGN401 showed efficacy in guinea
pigs infected with Pichinde virus, a model that closely resembles Lassa fever in humans (Jahrling et
al., 1981), as well as having effects on cells infected with influenza A, vaccinia, vesicular stomatitis
virus and mouse cytomegalovirus (Soares et al., 2008).
Virus induced externalization of PS raises the possibility that PGN401 has broad spectrum antiviral
activity. The advantages of targeting PS include drug specificity for infected cells, and since PS is a
feature of the host cell, effectiveness would potentially not be susceptible to viral escape mutations
(Mir et al., 2009). One such application for a broad spectrum antiviral would be against biodefense
pathogens, such as Ebola virus (EBOV). In addition to important public health problems stemming
from severe disease outbreaks in rural parts of Africa, EBOV also poses a potential bioterrorism
threat and in the past has been included in weapons development programmes (Borio et al., 2002).
Case-fatality rates of the African EBOV species in man are as high as 90%, with no prophylaxis or
treatment available. EBOV has been classified as a Category A biowarfare agent by the Centers for
Disease Control (Bray, 2003) and the development of new strategies against EBOV infection are
required urgently.
[snip]
The half-life of PGN401 was determined to be 30.1 hours in uninfected animals, and 28.4 hours in
the EBOV-infected group, showing similar decays of the monoclonal antibody in serum of guinea pigs
irrespective of EBOV infection status. This will be important for determining optimum dosing
strategies and concentrations of the compound in order to obtain the levels required for effective
antiviral activity. When tested previously in guinea pigs infected with Pichinde virus, PGN401 was
delivered intraperitoneally (Soares et al., 2008). However, this route will be difficult to apply in
humans, so intravenous delivery is preferable and was the principal reason for studying PGN401
pharmacokinetics following this route of administration.
[snip]
There are two new papers. This one where mch1N11 (mouse version of PGN635) is used to treat Leishmania amazonensis
infected mice, and another which tests PGN401 (bavituximab) in guinea pigs infected with Ebola Zaire virus.
This is a great indication of how anti-PS antibodies have potential in anti-viral and anti-parasite uses.
The authors on the Leishmania paper include Dr. Phil Thorpe and Dr. Lynn Soong, who holds a joint appointment at
Department of Microbiology and Immunology, Institute for Human Infections and Immunity, and
Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Sealy Center for
Vaccine Development, University of Texas Medical Branch, Galveston, TX
Phosphatidylserine exposure on the surface of Leishmania amazonensis amastigotes modulates
in vivo infection and dendritic cell function
Parasite Immunolgy http://onlinelibrary.wiley.com/doi/10.1111/pim.12019/abstract
From the Introduction
[snip]
We have previously reported that amastigotes of L. amazonensis employ a unique strategy to
infect and regulate MF activity via the externalization of phosphatidylserine (PS) molecules (16,
17). PS is a phospholipid located in the inner leaflet of the plasma membrane that is translocated
transiently by some cell types during cell activation and differentiation (18-20) and permanently
during apoptotic cell death (21). Externalized PS molecules become targets for receptors
involved in apoptotic cell clearance and for triggering anti-inflammatory responses by
phagocytes, mainly characterized by the production of TGF-ß1 (19). We found that lesionderived
amastigotes make use of PS molecules in a similar way, maintaining those molecules on
their surface which serve as ligands for parasite endocytosis and MF modulation, in a
mechanism that we termed apoptotic mimicry (16, 17). PS exposure on intracellular pathogens
operates in several different infection models to facilitate infection and avoid the immune
system. Apoptotic mimicry is relevant for the infection of organisms such as Trypanosoma cruzi
and Toxoplasma gondii, in which their respective infective stages expose PS as a strategy to
silently invade host cells (22, 23). Viral particles that carry enveloped membranes from their
previous host cells also make use of exposed PS molecules to invade new cells (24-27). In
addition, by inducing transient PS exposure on the surface of host cells, viral infections can
spread signals derived from PS recognition, such as TGF-ß1 and IL-10 production by
neighboring phagocytes, to avoid full activation of the immune system (24). In fact, in viral
infection models, administration of an PS-targeting monoclonal antibody can cure about 35% of
guinea pigs infected with a lethal dose of Pichinde virus (a model for the human Lassa fever).
The efficiency of cure can reach up to 65% of the animals when PS-targeting mAb is combined
with standard anti-viral drugs. Furthermore, PS-targeting mAb treatment was also effective at
rescuing BALB/c mice with lethal murine cytomegalovirus infections (24).
Now, we demonstrate that PS-targeting treatment of mice infected with L. amazonensis parasites
decreases tissue parasite loads and lesion development. The in vivo effect of the antibody-based
treatment correlates both with increased T cell proliferation and increased DC activation in vitro.
DCs infected with lesion-derived amastigotes treated with PS-targeting mAb become more
efficient APCs, both for exogenous antigens, such as OVA, or for parasite antigens. PS-targeting
treatment could be employed, in co-administration with leishmanicidal drugs, as a therapeutic
strategy for the most severe clinical forms associated with L. amazonensis infection. Our
findings lead us to suggest that PS exposure by intracellular amastigotes of L. amazonensis acts
as a novel mechanism to down-modulate host immune responses
[snip]
From the Discussion section
[snip]
In this cutaneous leishmaniasis model, we found decreased tissue parasite loads and attenuated
lesions in mice receiving PS-targeting mAb, but not control mAb (Fig. 1). In contrast to the viral
infection models, PS-targeting treatment was not sufficient to clear leishmanial infection. Our
findings that PS-targeting treatment was able to restrain the kinetics of lesion progression (Fig.
1B) open a future research possibility for co-administering PS-targeting Ab and anti–leishmanial
drugs (42) for better control of non-healing New World leishmaniasis associated with L.amazonensis infection
[snip]
Just as I thought, a fantasy.
So exactly how does your theory explain how bavi can affect the germline DNA that is
used to create the V(D)J recombinations and how does that relate to your so-called fountain of youth?
If you are going to say you have some new theory explaining something then you need
to back it up with supporting facts.
V(D)J recombination is the way in which it is possible to generate the vast number of possible
variable regions of B cell antibodies and T cell receptors. This happens when the B and T cells
are developing and occurs by recombining the germline genes in the developing lymphocyte.
It is a random process which can generate the immense diversity of antigen specificity encoded
in B cell and T cell receptors. It has nothing to do with Bavi. I suggest you read an immunology
textbook, such as "Immunobiology" by Janeway et al.
This commentary is from Dec 2012 Nature Immunology.
There are some sections relevant to bavituximab.
Immunology beats cancer: a blueprint for successful translation
Drew M Pardoll
Abstract
Immunology offers an unprecedented opportunity for the science-driven development of therapeutics.
The successes of antibodies to the immunomodulatory receptor CTLA-4 and blockade of the immunoinhibitory
receptor PD-1 in cancer immunotherapy, from gene discovery to patient benefit, have created a paradigm for
driving such endeavors.
[snip]
Many interesting clinical insights came from
the 12 years of clinical experience with ipilimumab.
First, the kinetics of clinical responses
to anti-CTLA-4 (that is, tumor shrinkage)
tend to be much slower than those of chemotherapy
or tyrosine-kinase inhibitors, and in
some patients, tumor regression is preceded
by apparent progression, as assessed by computerized
tomography or magnetic resonance
imaging. Such findings suggest a mechanism
of action compatible with the original report
by Hodi and Dranoff showing that ultimate
tumor regression is preceded by activation
of the immune system and infiltration of the
tumor by activated lymphocytes. Additionally,
although formal regressions are induced in a
relatively small proportion of patients and
complete responses, as assessed by computerized
tomography or magnetic resonance imaging,
are rare (<5%), roughly 20% of patients
treated with only four doses of ipilimumab
remained alive over 4 years after therapy (in
contrast to ~5% of control patients). Wolchok,
Hoos and colleagues recognized that these
response qualities were different from those of
conventional cancer therapies and developed
the concept of ‘immune-response criteria’ to
help clinicians evaluate the efficacy of this new
class of immunotherapy in their patients. The
durable responses in advanced melanoma suggest
that the dream of cancer immunotherapy—
an appropriately activated endogenous
antitumor immune response that can have
memory and keep cancers at bay long after the
cessation of therapy—may not be so fanciful.
With the approval for the use of ipilimumab
to treat melanoma in hand, analysis of the use
of ipilimumab to treat many other cancers is
being aggressively pursued.
[snip]
http://www.nature.com/ni/journal/v13/n12/abs/ni.2392.html
That caught my eye too because it is very similar to what oncologists used to say about cancer and the immune system.
The dogma was that it was all about genes and finding the mutations would lead to the cure of cancer.
Well, that hasn't worked out so far. It turned out that it is a lot more complicated than any one realized.
They once thought there would be mutations which would explain a lot of things, but most of them only account
for a few percentage of cases. Take Alzheimer's for example, this new discovery still only accounts for 1-2% of Alzheimer's patients.
There have been hints that PS may be involved with Alzheimer's but research has been very limited,
http://www.nytimes.com/2012/11/15/health/gene-mutation-that-hobbles-immune-response-is-linked-to-alzheimers.html?ref=health
You are inferring something that isn't true. See CJ's post, they were both given 30 minutes before, nothing has changed.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79650678
This is all about nothing. CJ posted this on Sept 17th. Nothing about the conference has changed since then.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79650678
I first posted about this on July 11th
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=77421212
The write up in the issue of mAbs was done months ago and is appearing now to coincide with the meeting.
Follow up. Here is a map showing the distribution of Dengue Fever. From Wikipedia.
Map showing the distribution of dengue fever in the world, as of 2006. Map produced by the Agricultural Research Service of the US Department of Agriculture.
Source: Slide #8 of a presentation by Gary G. Clark, PhD, entitled "Dengue: An emerging arboviral disease".
Cyan: Areas infested with Aedes aegypti. Red: Areas with Aedes aegypti and recent epidemic dengue fever.
It infects 50 to 100 million people worldwide a year, leading to half a million hospitalizations, and approximately 12,500–25,000 deaths.
Interesting recent developments with Dengue Virus. Dengue fever sweeps India. Dengue vaccine fails in trial.
Paper shows that the Dengue virus uses receptors for PS on the surface of host cells to gain entry.
Binding the PS on the virions with PGN401 (Bavituximab) or PGN632 might then block the entry of the virus.
The TIM and TAM Families of Phosphatidylserine Receptors Mediate Dengue Virus Entry.
http://www.cell.com/cell-host-microbe/retrieve/pii/S1931312812003046
From the Discussion section
The present study adds significant insights into the molecular
interactions that occur between DV and the host cell during viral
entry. We show that TIM and TAM proteins, two receptor families
involved in apoptotic cell recognition and clearance, mediate DV
infection. TIM- and TAM-mediated enhancement of virus infection
is dependent on PtdSer associated with DV particles. This
supports a model by which DV use a strategy of ‘‘apoptotic
mimicry’’ to infect target cells (Laliberte and Moss, 2009; Mercer
and Helenius, 2008).
[snip]
We reveal an unexpected role for PtdSer during DV infection.
Our data suggest that PtdSer is displayed on the surface of DV.
particles and is important for TIM- and TAM-mediated infection.
[snip]
TIM and TAM proteins mediate the entry of other viruses
(Feigelstock et al., 1998; Kondratowicz et al., 2011; Morizono
et al., 2011; Shimojima et al., 2012, 2006). AXL and TIM-1 are
receptors for Ebola virus, which, like DV, infects a broad range
of cell types and causes hemorrhagic fever (Kondratowicz
et al., 2011; Shimojima et al., 2006). TIM-1-mediated Ebola infection
depends on a direct interaction between the viral glycoprotein
GP through residues outside the MILIBS (Kondratowicz
et al., 2011), indicating that DV and Ebola virus may use distinct
TIM-1 regions. A recent study also identified Gas6 and ProS as
‘‘bridging factors’’ that link PtdSer expressed on the viral envelope
of lentiviral pseudotypes and vaccinia virus to AXL expressed
on the target cell (Morizono et al., 2011). Collectively,
these data suggest that TIM and TAM facilitation of viral infection
may represent a general mechanism exploited by viruses that
incorporate PtdSer in their membrane for optimal infection.
-------------------------------------------------------------------------------------------------------
Remember the Nature Medicine paper from Dec 2008 which showed how bavi could cure guinea pigs
infected with Pichinde virus. I suggest this may also be possible for Dengue fever, for which there is no treatment.
http://www.nature.com/nm/journal/v14/n12/abs/nm.1885.html
As Dengue Fever Sweeps India, a Slow Response Stirs Experts’ Fears
http://www.nytimes.com/2012/11/07/world/asia/alarm-over-indias-dengue-fever-epidemic.html?ref=health
In a Setback, Sanofi’s Dengue Fever Vaccine Falls Short of Its Goal
http://www.nytimes.com/2012/09/11/health/a-dengue-vaccine-falls-short-of-expectations.html
http://en.wikipedia.org/wiki/Dengue_fever
You got that right.
I am talking about how the FDA views this, not some internet analysts. The FDA has not said anything about this.
Just go back to days of the fiasco and you will find articles.
No, the point is that CSM, a usually reliable and FDA approved CRO, made mistakes that affected
Peregrine's trial. That is why Peregrine immediately filed the lawsuit against them.
Are you speaking for the FDA? Clearly investors saw the problems as a risk they did not want to bear,
but I don't think you, or anyone, can say how the FDA is viewing this.
FDA, analysts, institution buyers, and the lender did not buy the story that PPHM have no responsibility over this botched trial.
...and that includes finding reliable testing vendor, manufacturer, and verifying their reliable processes.
Your analogy is not true. The car maker has control over the making of the car and can inspect the components
from the supplier before they are installed. In a double blinded trial Peregrine would have no way of knowing that
CSM had made mistakes until after the trial was run. Peregrine discovered the mistakes exactly when those mistakes
would have been available for inspection, and announced the facts as they should have and were required to do so.
For those of you that are interested in the APS angle here is a more readable summary,
written by the senior authors, of the research published in the Ramesh et al paper.
This is freely available and has the picture I posted.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389810/
Here is the last paragraph of the Conclusions section.
Currently patients with APS are treated chronically with anticoagulation medications such as
heparin or warfarin. Despite long-term use of the anticoagulants, recurrent thrombosis can
occur in APS patients. Furthermore, use of anticoagulants is fraught with complications
including bleeding episodes and osteopenia. With the recent new knowledge that has
been gained regarding the processes that underlie aPL actions on endothelium, we anticipate
that novel interventions can be developed that directly target the pathogenetic mechanisms,
thereby affording greater efficacy and fewer complications in the management of this
potentially life-threatening disorder
I assume so. This was arranged well in advance of Sept 24th.
You can access this about the meeting from the journal "mAbs".
http://www.landesbioscience.com/journals/mabs/article/22221/?show_full_text=true&
Next event Dec 5 at IBC Antibody Therapeutics meeting in San Diego
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79650678
Lets hope that Shan actually has something new to talk about.
Philip Thorpe (Univ. of Texas SW Medical Ctr) will give an update on the mechanism of anti-tumor action of bavituximab, an immunostimulatory chimeric monoclonal antibody that is showing promising activity in clinical trials in patients with various types of cancer. Bavituximab targets the immunosuppressive lipid phosphatidylserine (PS) that becomes exposed on tumor blood vessels and tumor cells. Tumors externalize PS and secrete PS-expressing exosomes that impose quiescence on immune cells, thereby creating a tumor microenvironment that supports tumor growth. Bavituximab causes myeloid-derived suppressor cells in tumors to differentiate into tumoricidal M1 macrophages that destroy tumor vasculature and tumor cells by antibody-dependent cell-mediated cytotoxicity. It also causes immature dendritic cells in tumors to mature and present tumor antigens that result in the generation of tumor-specific cytotoxic T cells. Thus, bavituximab reactivates innate & adaptive tumor immunity, and induces an immune cell-mediated shutdown of tumor vasculature. Joseph Shan (Peregrine Pharm.) will then give an update on the performance of bavituximab in clinical trials in patients with cancer. Bavituximab has been shown to be well-tolerated both as a single agent and in combination with approved therapies. Bavituximab has demonstrated promising anti-tumor activity as an adjunct to std. chemotherapy, and is advancing to late stage clinical development in NSCLC.
There is more to this APS story then what I have posted so far.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81225196
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81239853
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81241148
The research presented in last year's Ramesh et al paper and in yesterday's presentation at the AHA
meeting is an explanation of why the side-effects of using Bavi for cancer treatment have not included increased
thrombosis. If you remember when the trials first started this was a concern because of the increase
of thrombosis seen in APS and since Bavi also binds to beta2-GPI. Now we can understand at least one
of the mechanisms for why this does not happen.
Here is info on apoER2. You can see why the approach of reducing this to block the chain of events in APS is not a good idea.
http://en.wikipedia.org/wiki/ApoER2
CJ's post pulling together the pieces.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81227620
The Ramesh et al 2011 paper freely available:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3007129/
The difference in this case is that bavi is used to prevent the reduction of NO produced by the enzyme eNOS (endothelial NO synthase),
and not to increase the production of NO by macrophages. The figure below shows how bavi switches the macrophage
phenotype from M2 to M1. The M1 macrophages increase their production of NO by another form of NOS, iNOS (inducible NOS).
This figure was shown in Thorpe's NYAS symposium talk.
CJ, thanks for putting all that together. One difference between the Ramesh et al JCI paper and what was reported on
in the AHA abstract is that in the JCI paper 2aG4 (mouse bavi) was used, and in the AHA abstract PGN635 (fully human bavi)
was used. In the AHA abstract they report on testing their three hypotheses developed from the JCI paper.
See the figure shown again below.
1) Block the chain of events in the pathway at the first step (ii in the figure below) from occurring by using PGN635,
this prevents the interaction between domain V of beta2-GPI and the end domain of apoER2.
2) Add more NO (nitric oxide) since the pathway results in a reduction of NO production. They did this by adding the NO
donor S-nitroso-N-acetylpenicillamine.
3) Block the production of apoER2 which would also block the first step. They did this by using a short interfering RNA
(siRNA) to destroy the messenger RNA that codes for the gene for apoER2.
I believe the endothelial migration which is restored by these three methods is part of the normal endothelial
repair mechanisms. VEGF (vascular endothelial growth factor) is part of this process.
So what does all this mean? My guess is that PGN635 could be given to patients with APS to reduce thrombosis.
It would work by competing with the pathogenic autoantibodies for binding to beta2-GPI. Enough bavi would
saturate the binding to beta2-GPI using domain II and thus block any attempts by the autoantibodies to bind via domain I.
The other two mechanisms, adding NO, and blocking apoER2 production, might have more systemic side effects.
It is late so this will be short. The literature on antiphospholipid syndrome (APS) and its associated antiphospholipid
antibodies (aPL), and on the target of these antibodies, beta2-glycoprotein I (beta2-GPI), is vast.
The following is from the introduction in last year's paper by Ramesh et al.
The antiphospholipid syndrome (APS) is an autoimmune disorder
characterized by the presence of circulating antiphospholipid antibodies
(aPL) and recurrent thrombosis (1). A link between APS and
greater risk of atherosclerosis in peripheral and coronary arteries
has also been established (2). aPL are directed not against phospholipids,
but rather against plasma proteins with affinity for anionic
cell surface phospholipids, and a pathogenetically important major
subset of aPL is directed against ß2-glycoprotein I (ß2GPI) (3–7).
Binding of aPL to phospholipid-bound ß2GPI causes its dimerization,
which further increases its affinity for negatively charged phospholipids
and cell surfaces (8). The endothelium is a primary target
of aPL, and pathogenic autoantibody binding to ß2GPI causes the
upregulation of adhesion molecule expression and a proinflammatory
and prothrombotic endothelial cell phenotype (9). How aPL
binding to ß2GPI on the endothelial cell surface induces a transmembrane
signal to modify endothelial cell behavior is unknown.
NO generated by the endothelial isoform of NOS (eNOS) is a key
determinant of vascular health that regulates several physiological
processes, including leukocyte adhesion, thrombosis, endothelial
cell migration and proliferation, vascular permeability, and vascular
smooth muscle cell growth and migration (10). The eNOS
enzyme, which generates NO upon the conversion of l-arginine to
l-citrulline, is activated by numerous extracellular stimuli and is
promoted primarily by increases in the phosphorylation of S1179
(in bovine eNOS; S1177 in human eNOS) by PI3 kinase/Akt kinase
and also by dephosphorylation of T497 (11–13). Whether aPL alter
eNOS function is unknown.
To better understand the molecular basis of APS, we designed
the present study to test the hypothesis that aPL-induced increases
in leukocyte–endothelial cell adhesion and thrombus formation
are caused by eNOS antagonism. In addition, we determined
whether aPL-induced eNOS inhibition involves ß2GPI, and if the
process also requires an LDL receptor (LDLR) family member, particularly
apoER2, which has the capacity to directly bind ß2GPI
(14, 15).
I will have time later this evening to try to explain.
This was a follow up to this paper published last year. Looks like a way to treat APS.
J Clin Invest. 2011 Jan;121(1):120-31. doi: 10.1172/JCI39828. Epub 2010 Dec 1.
Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via ß2GPI and apoER2.
Ramesh S, Morrell CN, Tarango C, Thomas GD, Yuhanna IS, Girardi G, Herz J, Urbanus RT, de Groot PG, Thorpe PE, Salmon JE, Shaul PW, Mineo C.
Source
Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract
In antiphospholipid syndrome (APS), antiphospholipid antibodies (aPL) binding to ß2 glycoprotein I (ß2GPI) induce endothelial cell-leukocyte adhesion and thrombus formation via unknown mechanisms. Here we show that in mice both of these processes are caused by the inhibition of eNOS. In studies of cultured human, bovine, and mouse endothelial cells, the promotion of monocyte adhesion by aPL entailed decreased bioavailable NO, and aPL fully antagonized eNOS activation by diverse agonists. Similarly, NO-dependent, acetylcholine-induced increases in carotid vascular conductance were impaired in aPL-treated mice. The inhibition of eNOS was caused by antibody recognition of domain I of ß2GPI and ß2GPI dimerization, and it was due to attenuated eNOS S1179 phosphorylation mediated by protein phosphatase 2A (PP2A). Furthermore, LDL receptor family member antagonism with receptor-associated protein (RAP) prevented aPL inhibition of eNOS in cell culture, and ApoER2-/- mice were protected from aPL inhibition of eNOS in vivo. Moreover, both aPL-induced increases in leukocyte-endothelial cell adhesion and thrombus formation were absent in eNOS-/- and in ApoER2-/- mice. Thus, aPL-induced leukocyte-endothelial cell adhesion and thrombosis are caused by eNOS antagonism, which is due to impaired S1179 phosphorylation mediated by ß2GPI, apoER2, and PP2A. Our results suggest that novel therapies for APS can now be developed targeting these mechanisms.
Presentation at the American Heart Association annual meeting in LA.
Session: AOS.703.02a-Novel Signaling Pathways in the Regulation of Endothelial Function
Presentation: 13186 - Development of Novel, Mechanism-Based Therapies to Prevent the Cardiovascular Complications of the Antiphospholipid Syndrome
Pres Time: Wednesday, Nov 07, 2012, 10:00 AM -10:15 AM
Location: Hall A-8
Pres. Time: Wednesday, Nov 07, 2012, 10:00 AM -10:15 AM
Specialty: +703. Endothelium, Vascular Tone and Nitric Oxide
Keywords: Endothelial function; Nitric oxide; Cardiovascular therapeutics; Thrombosis; Angiogenesis
Authors: Victoria Ulrich, Philip Shaul, Philip Thorpe, Chieko Mineo, UT Southwestern, Dallas, TX
Abstract: Patients with antiphospholipid syndrome (APS) have circulating antiphospholipid antibodies (aPL) and increased risk of thrombosis as well as non-thrombotic vascular disease. Current APS treatment is limited to anticoagulation, which targets only a portion of APS-related disease and has modest efficacy and serious potential complications. We previously showed that aPL antagonism of endothelial NO synthase (eNOS) underlies APS-associated thrombosis. Seeking to develop therapies directed at the initiating processes for both APS-related thrombosis and non-thrombotic vascular disease, we studied the basis for eNOS antagonism by aPL and also determined how aPL impact endothelial repair. In scratch assays with bovine aortic endothelial cells (BAEC), we found that in contrast to IgG from normal healthy subjects (NHIgG) which had no effect, polyclonal aPL from APS patients inhibited migration stimulated by VEGF. The migratory response was restored by the NO donor S-nitroso-N-acetylpenicillamine, a monoclonal antibody (mAb) to the cell surface protein ß2GPI had effects identical to aPL, and aPL antagonism of migration was prevented by siRNA knockdown of apolipoprotein E receptor 2 (apoER2). Thus, the ß2GPI/apoER2-mediated eNOS antagonism that we previously discovered underlies aPL-induced thrombosis also antagonizes endothelial cell migration. Mimicking the cell culture findings, in C57BL/6 male mice carotid artery reendothelialization was attenuated by aPL treatment, and this was fully prevented by the NO donor molsidomine. We then screened a series of mAb to ß2GPI in assays of eNOS activation in BAEC. Whereas many mirrored aPL and antagonized eNOS, one anti-ß2GPI mAb designated 1N11 had no effect when tested alone and it fully prevented aPL action. 1N11 also prevented aPL inhibition of endothelial cell migration, and it rescued normal carotid artery reendothelialization in aPL-treated mice. Thus, by bypassing or disrupting how aPL antagonize eNOS, an NO donor or a select mAb to ß2GPI can afford protection from the endothelial actions of aPL that underlie the vascular manifestations of APS. Such mechanism-based therapies offer the promise of greater efficacy and fewer complications in patients with this often life-threatening disorder.
Disclosures: V. Ulrich, None; P. Shaul, None; P. Thorpe, Peregrine Pharmaceuticals, Inc., Significant,Other Research Support; Peregrine Pharmaceuticals, Inc., Significant,Ownership Interest; Peregrine Pharmaceuticals, Inc., Significant,Consultant/Advisory Board; C. Mineo, None.
Note that 1N11 = PGN635 the fully human version of bavi
I think the arguments about bavi working inside, or outside, or whatever, is a matter of semantics.
I would define the tumor microenvironment as the tumor mass itself, and the space inside of it, and the
surrounding tissue which is under the influence of the chemokines and cytokines released by the tumor
cells and the leukocytes which have infiltrated the tumor and the surrounding tissue in response to the
tumor. Bavi will bind to PS expressed on the endothelial cells of the tumor vasculature, which are inside the
tumor, and to any PS expressed on the tumor cells themselves, or to PS on exosomes and ectosomes
which can be both inside and outside of the tumor. I think of the tumor microenvironment as the tumor
and its "sphere of influence" surrounding the tumor. Bavi can modify the characteristics of that environment
from one which is immunosuppressive and tumorigenic, to one which is immunostimulatory and tumoricidal.
Here is another one
http://www.uctv.tv/shows/Basic-Immunology-Nuts-and-Bolts-of-the-Immune-System-21376
This is a follow-on to the one you just watched.
You're welcome. I think the "Harnessing the Immune System for Cancer Treatment" video is pretty good.
More videos from the UCSF Osher Mini Medical School for the Public
Cancer Biology 101
http://www.uctv.tv/shows/Cancer-Biology-101-22574
Your Immune System 101
http://www.uctv.tv/shows/Your-Immune-System-101-Introduction-to-Clinical-Immunology-21375
A good video on immunotherapy from UCSF
http://www.uctv.tv/shows/Harnessing-the-Immune-System-for-Cancer-Treatment-22577
From The Guardian. Sunday 28 October 2012. Sarah Boseley
Cancer fight stalls amid push for profits, doctors say.
Newer drugs fall short of hopes and cost too much, say experts who pledge to improve care in poorer countries
Progress against cancer is stalling, with the latest targeted cancer drugs failing to live up to expectations and priced so high that treatment is becoming unaffordable even in rich countries, according to experts at a meeting of nearly 100 eminent cancer specialists from around the world.
At the two-day meeting in Lugano, Switzerland, the doctors agreed a 10-point declaration, to be published early next year, which will chart the way forward for cancer care around the globe. Much needs to be done, they believe, to improve treatment, care and prevention both in the developed world and in poor countries, where cancer rates are rising even faster. They agreed to embark on an ambitious plan to get essential cancer care to those who are dying early in developing countries, in the same way that Aids doctors took on the fight to get HIV treatment into hard-hit Africa.
The meeting of the World Oncology Forum, organised by the European School of Oncology and attended by experts such as epidemiologists Sir Richard Peto and Prof Michel Coleman as well as the government's national cancer director, Sir Mike Richards, agreed urgent action was needed on many fronts.
Only a few years ago, many cancer experts thought the arrival of targeted medicines, designed to attack the genetic makeup of the tumour, would make dramatic inroads into cancer deaths. That has not happened. Instead, these therapies have only bought a few extra months of life. If the question was whether the world was winning the war on cancer, said Douglas Hanahan of the Swiss Institute for Experimental Cancer Research, who outlined the latest state of drug research, "in general, for most forms of human cancer, the answer is clearly no".
The excitement generated by targeted drugs, which interfere with specific molecules involved in tumour growth and suppression, has been short-lived.
Doctors reported apparently miraculous results from the use of the BRAF-inhibitor vemurafenib in advanced malignant melanoma, a usually fatal form of skin cancer. Within two weeks, the tumours had melted away.
"But six months later, [the cancer] is back with a vengeance," he said.
Other drugs working in a similar way – including erlotinib (Tarceva) for a form of lung cancer, bevacizumab (Avastin) for breast, colorectal and other cancers, and sunitinib (Sutent) for renal cell carcinoma and gastrointestinal sarcoma – have also not done so well, said Hanahan. Resistance to the drugs builds up, sometimes very quickly. "All came on line with great expectations. The reality check is they are all working in the important first step, but we have a long way to go in terms of winning the war."
The future is probably using these drugs together or in combination with other, older types of drugs, but the price is likely to be prohibitive.
A year's treatment with vemurafenib alone would cost £91,000. Even though the manufacturer, Roche, has offered an undisclosed discount to the Department of Health, the National Institute for Health and Clinical Excellence said in June it was too much for the NHS to pay. No health service will be able to afford to put a patient on two or three such drugs at the same time.
Doctors at the meeting said pharmaceutical industry prices were unsustainable – and the pursuit of profits stopped companies taking part in trials of combinations of their drugs with those of their competitors, which might help patients. They were also said to be not interested in testing their drugs combined with older drugs that are out of patent.
Prof Alexander Eggermont, general director of the Gustave Roussy Cancer Institute in France, said the "economic models of molecular medicine are very uncertain, because if you don't produce cures, you don't know if it is going to sell".
Decades ago, genuine breakthrough drugs were discovered which continue to have a huge impact on the disease. Peto, an epidemiologist at Oxford University, pointed out that five years of tamoxifen reduces mortality in most breast cancers by a third and the benefits continue even after a woman stops taking it. It now appears that taking it for 10 years is even more effective. Nobody knows why resistance does not develop, as it does with the new drugs.
But the meeting agreed that while changes are needed in research, regulation and funding to speed progress on new drugs for intractable cancers, a great deal could and must be done now to tackle cancer in less well-off countries where children and women, in particular, are dying of preventable and curable diseases.
"The divide is such that in Canada almost 90% [of children with leukaemia] can hope to survive while in the poorest countries of the world, 90% are expected to die," said Prof Felicia Knaul, director of the Harvard University global equity initiative.
Between a third and a half of all cancers – 2.4m to 3.7m a year – are preventable, said Knaul, and 80% of those are in lower- and middle-income countries. Preventing and treating them would offer potential productivity savings globally of more than $130bn (£80bn) a year – far more than the cost of treatment.
Cheap vaccines and basic screening can prevent and detect cervical cancer, which kills young women and mothers; cheap hepatitis B vaccination protects against liver cancer; and screening picks up breast cancer early. The dire shortage of morphine and other opioid drugs in developing countries to relieve suffering from cancer pain must be addressed, the doctors said.
Rifat Atun, professor of international health management at Imperial College Business School, called on doctors and scientists to have "bold ambition" and follow the lead of clinicians involved in the Aids response.
"Prevention is important and we need to do it. That does not mean we should not be providing treatment," he said. A decade ago, people said it was not possible to get antiretroviral drugs to patients with HIV in Africa. There are now more than 8 million people in lower-income countries on them.
The forum agreed to a 10-point plan including a goal to cut deaths globally, oppose tobacco – possibly by a tax on manufacturers' profits – accelerate research and get an essential package of cancer care to poor countries.
Thank you.