Thanks entdoc! I think the important thought is distinguishing the normal from the "stressed" cell scenario as stated by Garnick et al. Thanks again for your input.
Thanks bio and dia as well...and mojo and of course cj and FTM and our TA wizard JR as well as all the contributors!
More on Bavi’s MOA and the reasons for its immunostimulatory, anti-cancer capabilities…
2005 article that describes the immunosuppressive effects of exposed Phosphatidylserine (PS) – the underpinning/foundation of Bavituximab’s moa… “Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo” Peter R. Hoffmann, et al The Journal of Immunology, Feb.2005, p.1393–1404 http://www.jimmunol.org/cgi/content/full/174/3/1393 ABSTRACT: Phosphatidylserine (PS) on apoptotic cells promotes their uptake and induces anti-inflammatory responses in phagocytes, including TGF-B 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. There was also a decrease in formation and size of germinal centers in spleen and lymph nodes, accompanied by decreased levels of Ag-specific IgG in blood. Many of these effects were mimicked by an agonistic Ab-specific for the PS receptor. TGF-B appears to play a critical role in this inhibition, as the inhibitory effects of PS were reversed by in vivo administration of anti-TGF-B Ab. PS-containing liposomes did not appear to directly inhibit dendritic cell maturation in vitro in response to a variety of stimuli, nor did it prevent their migration to regional lymph nodes in vivo, suggesting that the inhibitory effects may have resulted from complicated interactions between tissue cells and dendritic cells, subsequently inhibiting their ability to productively activate T lymphocytes. . . . In conclusion, we believe that the interaction of PS receptor with its ligand PS play a critical role in tissue homeostasis, an important part of which is the regulation of inflammation. Our data are most consistent with the hypothesis that PS represses inflammation in tissue in part by inducing secretion of TGF-B, thereby avoiding activation of an immune response perhaps by the generation of regulatory T cells. The anti-inflammatory response to PS on dying cells is likely to provide one of the many ways in which autoimmunity is prevented. Arur and colleagues (64) recently reported that annexin I externalized by apoptotic cells may contribute to the efficient interaction between PS on the apoptotic cell membrane and PS receptor on phagocytes. Given that annexin I (lipocortin) has been recognized as an anti-inflammatory protein for many years, it is tempting to speculate that one way in which it mediates its function is by binding to and enhancing the activation of PS receptor.
The Cliff Notes 7-word synopsis => “Evolution has favored pathogenesis that resembles apoptosis.”
= = = = = = = = = = = = = = = = = = Peregrine’s Bavituximab generates full immune response against cancer by reversing the inhibitory effect of PS on dendritic cells (DC)… AACR/2010 #1919, Mon, 4-19-10, “Immunobiology of the Tumor Microenvironment” “Phosphatidylserine on Dying Tumor Cells Suppresses Dendritic Cell Activation and Inhibits Tumor Immunity: Reversal With PS-Targeting Antibody” Xianming Huang, Dan Ye, Philip E. Thorpe (UTSW-MC, Dallas) ABSTRACT (direct link: http://tinyurl.com/y44n46l ): We recently showed that PS on the surface of apoptotic cancer cells can suppress recognition of tumor antigens by the immune system. It appears from work in several laboratories that dendritic cells (DC) that ingest PS-expressing tumor cells fail to mature in response to external maturation signals. In the present study, we investigated whether masking PS on apoptotic tumor cells with anti-PS antibody (2aG4) [NOTE: “2aG4” is a mouse IgG2a version of murine mab 3G4; bavituximab is chimeric 3G4] can reverse the inhibitory effect of PS on DC. Mouse bone marrow derived DC were cocultured with irradiated (PS-expressing) 4T1 breast tumor cells in the presence or absence of 2aG4. We found that: (i) masking tumor cell PS with 2aG4 increases their phagocytosis by DCs; (ii) masking tumor cell PS with 2aG4 allows DCs to mature and express immunostimulatory molecules (CD40, CD80, CD86 and MHC II); (iii) masking PS with 2aG4 decreases the production of anti-inflammatory cytokines (TGFB and IL-10) and increases the production of inflammatory cytokines (TNFa, CCL5, IL-1B and IL-6), indicating that PS-blockade polarizes DC towards the immunostimulatory type I phenotype; (iv) immunizing mice with 2aG4-treated irradiated 4T1 cells enhances the immunogenicity of the tumor cells, rendering them resistant to rechallenge with syngeneic viable 4T1 tumor cells. These results have important implications for our understanding of the immunosuppressive effects of PS in cancer and could lead to the development of a novel whole cell cancer vaccine strategy in which PS-blocking is used to enhance immunogenicity. *end* FULL PDF: http://www.peregrineinc.com/images/stories/pdfs/2010_AACR_Poster_PS_Reversal.pdf
= = = = = = = = = = = = = = = = = = CEO Steve King gave this more layman explanation of Bavi’s MOA on 8-15-12 at Wedbush/NYC: Steve King 8-15-12 Wedbush/Slide7 ( http://tinyurl.com/8mhrtld ): “A very novel MOA - it turns out that PS is not simply a marker of disease, but is actually involved in controlling the immune response to disease. By blocking that immunosuppressive signal, we actually allow the immune system to turn on and fight the disease. The concept is, Phosphatidylserine (PS) itself is a normal component of cellular membranes, present in every cell of the body, only very-tightly regulated to internal side of the cell. So, essentially, if you inject PS-finding agents, such as is done in our Imaging pgm, the agents simply float around and eventually clear the body if there’s no sign of disease. What our scientists discovered, is that as cancer develops, you get a very unique environment, you have poor blood flow, reactive oxygen species, hypoxia – as a result of all these insults, the mechanisms that keep PS inside of cells become disrupted, and the PS becomes exposed on the outside of the cell. It turns out that this exposed PS in the tumor microenvironment is very important in controlling the immune response. The only normal time which you have PS exposure is when cells undergo normal programmed cell death, or apoptosis. So, as cells die, you see the same phenomenon of PS becoming expressed or exposed on the outside of the cell. What happens then is, as the immune system is undergoing its daily routine of removing dead & dying cells, those macrophages & dendritic cells, whose responsibility it is to remove the cells, interact with the dead & dying cells, and actually have a PS-receptor on their surface. As the exposed PS binds to the receptor on the immune cells, it actually sends specific signals to down-regulate the immune response, because when you’re removing dead & dying cells you don’t need a robust immune response, obviously. It turns out that cancer, as well as a number of other diseases, have taken advantage of this fact, and by simply causing PS-exposure during the tumor microenvironment, you now do not get an adequate immune-response to the disease, allowing the tumors to outgrow the poor immune-response that’s being given. Bavituximab is injected, it goes to the site of the disease, so it accumulates on the PS inside the tumor environment, blocks the PS that’s exposed in that environment, and now those immune cells - you can actually detect a significant change in there phenotypes, as they go from a non-inflammatory to a pro-inflammatory state and really begin the fight the disease. And over time, you see development of a full adaptive immune response. As at fully adaptive immune response happens, you then have this full immune response, which includes ADCC, mediated by the antibody itself, normal cell-killing, mediated by the antibody, as well as activation and down-stream effects of the immune response.”
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = By Freethemice 9-11-12 iHub #92820 http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79459776 The doubters all seem to be basing their red flags on the old paradigm. They think of bavituximab as if it were a small molecule drug. So when the MOS is much better than the old rule MOS = 2 X PFS they don't understand how it could be true, so there must be something wrong, or worse. They fail to take the time to learn anything about the unique MOA that bavi has. They understand that it is an antibody and the target is PS, but fail to understand anything else about it. For example, that by targeting the tumor vasculature the effects of the antibody are greatly magnified when each blood vessel feeds hundreds, or thousands, of tumor cells downstream. The fact that bavi can both block the immunosuppressive effects of PS, and at the same time switch the tumor associated macrophages (TAMs) from type M2 to M1, and cause dendritic cells to mature, and reduce the numbers of myeloid-derived suppressor cells (MDSCs), and allow adaptive immunity to work again, is totally lost on them. There is plenty of info out there if they would care to make the effort to learn something new. For example: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=78445110
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