Peregrine Pharmaceuticals, Inc. has reported that two preclinical studies presented during the AACR 100th Annual Meeting 2009 provided further confirmation of the immunomodulatory mechanisms contributing to the anti-tumor activity of its phosphatidylserine (PS) targeting antibodies.
One study confirms the anti-tumor effects and immune stimulating ability of a fully human anti-PS antibody and the other demonstrates the ability of a second fully human anti-PS antibody to stimulate development of a critical component of the adaptive immune system.
These human PS-targeting antibodies, which are currently being evaluated for both anti-cancer and anti-viral applications, increase the number of product candidates in Peregrine's anti-PS pipeline. Peregrine's lead anti-PS antibody bavituximab is currently in Phase II clinical trials in advanced breast and lung cancers.
"These preclinical studies further elucidate the unique immunomodulatory mechanisms contributing to the observed anti-tumor activity of anti-PS antibodies in preclinical and clinical studies," said Dr. Philip Thorpe, professor of pharmacology at UT Southwestern Medical Center in Dallas, a scientific advisor to Peregrine and co-author of one of the AACR presentations. "These presentations provide additional insight into the mechanisms that act to selectively destroy the blood vessels supporting tumor growth and spread and also to reverse the ability of tumors to suppress the body's natural immune response, resulting in the mobilization of important inflammatory and other anti-tumor components of the immune system. Together, the studies provide compelling evidence suggesting that PS-targeting antibodies facilitate an important cytokine shift in the tumor environment that subsequently encourages multiple types of immune system cells to mount anti-tumor responses."
In a presentation1 on Monday, a series of preclinical studies by a team of scientists from Peregrine Pharmaceuticals and Affitech A/S used a fully human anti-PS antibody, PGN635, to confirm previous observations that in vitro, anti-PS antibodies stimulate the tumor microenvironment to recruit monocytes and other immune cells to the tumor with resulting anti-tumor effects, most likely via cell-mediated mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). Their data further define the role of anti-PS antibodies in mediating tumor cell cytotoxicity and the tumor microenvironment, showing that the anti-PS antibody induced a sequential release of cytokines and beta-chemokines and stimulated enhanced macrophage recruitment to tumors. Furthermore, the researchers showed that in vitro, PGN635 induced antibody-dependent death of endothelial cells, the same cell type found in the tumor vasculature, a key target of anti-PS cancer therapy. The studies also demonstrated the anti-tumor potential of PGN635 in vitro and in a number of animal cancer models.
"Data from our experiments has helped to clarify details regarding the mechanisms responsible for the anti-tumor results observed with Peregrine's PS-targeting antibodies," said Dr. Monica Friedrich, a Peregrine research scientist and lead author of the study. "In data presented at this conference last year, we demonstrated that our fully human antibody PGN635 localizes to tumors and causes an increase in several inflammatory cytokines while decreasing an important anti-inflammatory cytokine. The new data we present confirms that PGN635 also triggers immune cells to produce other chemokines and cytokines that have the potential to alter the suppressed immune environment commonly found in tumors, attracting additional immune cells and stimulating more aggressive anti-tumor responses. We believe this upregulation of the immune response contributes to the encouraging anti-tumor effects demonstrated by PGN635 and other anti-PS antibodies."
A second study2 presented on Monday by researchers from UT Southwestern Medical Center and Affitech demonstrated the ability of Peregrine's fully human PS-targeting antibody PGN632 to promote the maturation of dendritic cells, important antigen-presenting cells of the immune system. In the in vitro studies, immature dendritic cells cultured in the presence of PGN632 exhibited a significant increase in the production of inflammatory cytokines and chemokines. PGN632 also induced an increase in the expression of cell-surface molecules that are indicative of mature dendritic cells and that assist in antigen presentation functions, as well as in stimulating T-cell proliferation.
Dr. Xianming Huang, assistant professor of pharmacology at UT Southwestern Medical Center and lead author of the study, noted, "Dendritic cells are the professional antigen-presenting cells of the immune system and they play a crucial role in initiating adaptive immune responses. Dendritic cells must be mature, or activated, to be effective, yet tumors and other pathogens such as viruses often possess the ability to undermine this maturation, thereby suppressing the immune response. The results presented today suggest that by blocking exposed PS, anti-PS antibodies have the potential to promote dendritic cell maturation in the body and thereby stimulate a more effective immune response."
The fully human PS-targeting antibodies in these studies were developed through Peregrine's collaboration with Affitech A/S. The study by Dr. Huang, et al. was partly supported by the Gillson Longenbaugh and Meredith D. Chesler Foundations.
Peregrine president and CEO Steven King commented, "It is noteworthy that these studies were primarily conducted using our new fully human antibodies, which could serve as the basis for the next generation of anti-PS therapies. Our PS-targeting antibody platform now includes several promising antibodies in preclinical evaluation that vary in their binding profile and in their specific immunomodulatory activity. The unique functional characteristics of these different antibodies open the door to new product candidates and extended applications for our anti-PS technology. We are more encouraged than ever that our anti-PS platform has very broad potential, and we look forward to further development of our growing preclinical pipeline of PS-targeting candidates both through internal efforts and collaborations with partners."