Tag: ISA Pharmaceuticals
Company News: Publication Demonstrates Superior Activity of ISA Pharmaceuticals´ SLP® Vaccines Compared to Whole Protein Vaccines
– Study published in European Journal of Immunology elucidates different, improved antigen presentation and T cell-inducing power of SLP® vaccines
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced the publication of a peer-reviewed paper in the European Journal of Immunology.[1] The article describes a previously unknown mechanism that explains the excellent efficacy of ISA’s Synthetic Long Peptide (SLP®) vaccines. The authors demonstrate that compared to whole protein antigens, SLP®s are processed much more rapidly and efficiently by dendritic cells (DCs), resulting in an increased antigen presentation to CD4+ and CD8+ T cells, and enhanced CD8+ T cell activation. The improved presentation relates to a distinct intracellular localization of SLP®s after uptake by DCs.
Cancer immune therapy requires the induction of potent CD4+ and CD8+ T cell responses to the malignant cells. This is accomplished by DCs, the major antigen-presenting cells of the immune system. So far it has been challenging to induce a sufficiently potent reaction by vaccinating with whole protein antigens. In a number of preclinical and clinical studies, ISA Pharmaceuticals has already observed improved efficacy of its SLP® vaccines as compared to whole protein vaccines.
To study the underlying mechanism, researchers used both mouse and human DCs. They found that after incubation with SLP® vaccines and subsequent uptake by the DCs, the SLP®s are located in the cell, but are largely outside the cells’ endosomes. In contrast, protein antigens are processed inside endosomes, resulting in a much slower and different processing route. In the study, SLP®s were processed far more efficiently and distinctly into both MHC class I and II antigen presentation pathways than whole protein antigens. This lead to a strong activation of both CD4+ and CD8+ T cells, resulting in potent and efficient immune responses to the antigen.
In previously published clinical studies, ISA had already demonstrated the superiority of SLP® vaccines over short peptide vaccines. Short peptide vaccines, which fit precisely into MHC class I molecules, often do not result in a sufficiently long antigen presentation, and also carry the risk of inducing a mix of favorable pro-immunogenic and detrimental tolerogenic signals. Moreover, short peptide vaccines do not instate efficient immunologic memory. ISA also demonstrated that these differences are caused by the highly selective uptake, processing and presentation of SLP®s by professional antigen-presenting cells, and by the presence of both CD4 and CD8 epitopes in the long peptides.
[1] Rosalia et al.; “Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T-cell activation”, DOI: 10.1002/eji.201343324
http://onlinelibrary.wiley.com/doi/10.1002/eji.201343324/abstract;jsessionid=F0FBA5A73F264503207C22EDF313FAB0.d04t03.
Company News: Three Peer-Reviewed Papers by ISA Pharmaceuticals Introduce Strategies to Improve Immunotherapy Against Cancer
– Local Delivery of Checkpoint Control Antibodies Greatly Improve Efficacy and Safety
– Promising Potential for Combinatorial Strategies
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced the publication of three peer-reviewed papers that demonstrate the benefit of local delivery of a checkpoint control antibody targeting CTLA-4 (cytotoxic T lymphocyte antigen-4) for the successful eradication of cancer and the reduction of side effects. The papers include a review that underlines the importance of strategies for combinatorial treatments to improve further the immunotherapy of cancer. ISA Pharmaceuticals is developing cancer immunotherapies along those lines, in particular its Synthetic Long Peptide (SLP®) vaccine ISA101 for the treatment of HPV-induced diseases, such as cervical cancer and head and neck cancer, and ISA203 for the treatment of various tumors including lung cancer, head and neck cancer, breast cancer and melanoma.
In a paper just published in Clinical Cancer Research [1], a team of scientists from Leiden University Medical Center (LUMC) and ISA Pharmaceuticals report that in preclinical mouse models of cancer, the injection of a CTLA-4 blocking antibody in a slow-release formulation close to the tumor is very effective in activating a systemic anti-tumor (CD8+) T cell response. CTLA-4 is a crucial immune checkpoint protein that down-regulates the body’s immune response. The low-dose local treatment (50μg subcutaneously in a slow-release vehicle) eradicates tumors, including distant tumors, as effectively as a high-dose systemic treatment (2×200μg intraperitoneally). The method also leads to a 1000-fold decrease of antibody levels in the serum, thereby reducing adverse events and the risk of autoimmunity.
These findings are supported by an increasing number of studies demonstrating that local targets, mainly present in the microenvironment of tumors and draining lymph nodes, are key players in tumor progression. As published in a second paper by researchers from LUMC and ISA, a review in the International Journal of Cancer [2], local immunotherapies have clear advantages over systemic treatments, both in their ability to shift tumor-promoting mechanisms towards effective tumor-eradicating immunity and in terms of reducing the risks of systemic administration.
In the third publication in Seminars in Immunology [3], current cancer immunotherapy approaches are reviewed, concluding that most standalone immunotherapeutic strategies either fail to affect progressive diseases and survival significantly – or only do so in a minority of patients. The authors support combinations of synthetic vaccines that stimulate tumor-specific T cell responses and adjuvants, immune-modulating antibodies, cytokines, or chemotherapy.
[1] Fransen MF et al. (2103), Clin Cancer Res, Published Online First June 20, 2013; doi: 10.1158/1078-0432.CCR-12-0781
[2] Fransen MF et al. (2013), Int. J. Cancer, 132: 1971–1976; doi: 10.1002/ijc.27755
[3] Arens R et al., (2013), Sem Immunol, Published Online First May 21, 2013;
doi: 10.1016/j.bbr.2011.03.031
Company News: ISA Pharmaceuticals Strengthens Management Team
– Company hires Jan Fagerberg as Chief Medical Officer and Jens Hennecke as Chief Business Officer
– Ronald Loggers becomes Acting Chief Executive Officer and Gerard Platenburg Chief Operating Officer
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced that it has appointed Dr. Jan Fagerberg, M.D., Ph.D., as Chief Medical Officer and Dr. Jens Hennecke, Ph.D., as Chief Business Officer and Advisor. Furthermore, Ronald Loggers, M.Sc., MBA, will step down from the Board of Directors and assume the role of Acting Chief Executive Officer, while Gerard Platenburg will become Chief Operating Officer.
Dr. Jan Fagerberg (51) is a board-certified clinical oncologist with more than 20 years of experience in clinical research and the development of oncology drugs. He joins ISA from Amgen where he was Vice President Global Development and Managing Director of Amgen Research (Munich) GmbH. During his career, Dr. Fagerberg has held senior executive positions at Amgen, Micromet, TopoTarget, and F. Hoffmann-La Roche. His responsibilities have included the global clinical development of blinatumomab (AMG 103), belinostat (PXD101), capecitabine (Xeloda), and clinical development programs of bevacizumab (Avastin) outside the U.S.. Dr. Fagerberg has extensive international regulatory experience, and was successful in obtaining 11 FDA and EMA approvals for Xeloda and Avastin. At Micromet, he also initiated the clinical development of several compounds in collaboration with global pharma companies. Jan Fagerberg received his M.D. (1988) and Ph.D. (1995) for work in clinically applied passive and active immunotherapy in cancer from the Karolinska Institute in Stockholm (Sweden).
Dr. Jens Hennecke (45) has a strong track record in business development, corporate development and licensing. He brings extensive experience in the negotiation and closing of corporate alliances. Prior to joining ISA and building his own business development advisory franchise, he was Senior Vice President Business Development at Micromet, Inc., where he managed the company’s business and corporate development, intellectual property and information technology departments. He also played a key role in establishing partnerships with major pharma companies, and in Micromet’s acquisition by Amgen in 2012. Prior to joining Micromet in 2001, Dr. Hennecke was a post-doctoral researcher at Harvard University. He holds a B.Sc. in biology from the University of Göttingen, Germany, and a Ph.D. from the ETH Zurich, Switzerland.
Before becoming Acting Chief Executive Officer, Ronald Loggers (45) had been on the Supervisory Board of ISA since 2009. He is currently also Managing Director at Multifund B.V., a family-owned investment company. Prior to that, he worked seven years for HAL Investments B.V., five years for McKinsey & Company and one year for Fokker Aircraft B.V. He brings extensive managerial, investment and financing experience. Ronald obtained an MBA from INSEAD (France) and an M.Sc. in Chemical Engineering from Delft University of Technology (The Netherlands).
Gerard Platenburg (48) joined ISA Pharmaceuticals in an executive role in 2009 and helped to mature ISA’s organization into its current form. He has over 20 years of experience as an executive in the biotech industry. He gained experience in several innovative biotech companies, amongst others Pharming and Prosensa, which he co-founded and grew into a clinical-stage company. Gerard holds a degree as a chemist/molecular biologist from the University of Leiden, The Netherlands.
The management team will consist of Ronald Loggers (Acting Chief Executive Officer), Gerard Platenburg (Chief Operating Officer), Prof. Kees Melief (Chief Scientific Officer), Jan Fagerberg (Chief Medical Officer) and Jens Hennecke (Chief Business Officer).
Company News: Novel AMPLIVANT™ Technology Introduced at AACR Annual Meeting 2013
– AMPLIVANT™ TLR-ligand adjuvant to improve immunotherapies –
ISA Pharmaceuticals B.V., a clinical-stage biopharmaceutical company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, announces that Cornelis Melief, Professor at Leiden University and Chief Scientific Officer of ISA, presented details on the company’s novel AMPLIVANT™ technology at the American Association for Cancer Research (AACR) 2013 Annual Meeting. AMPLIVANT™ is based on a powerful, proprietary toll-like receptor (TLR) ligand designed to improve immunotherapies. This promotes direct dendritic cell targeting of the antigen as well as antigen processing, resulting in long-term activation of dendritic cells and antigen presentation.
Toll-like receptors (TLRs) expressed by immune cells such as dendritic cells (DCs) or macrophages, play a key role in innate immunity by recognizing characteristic molecular structures present on the surface of bacteria and other microorganisms. Once these TLR ligands bind to the receptors, a signaling cascade is triggered which, among other effects, activates cells initiating immune responses. Thereby, they have the capacity to generate a robust acquired immune response.
Together with other scientists at Leiden University, the ISA team had observed that adding known strong TLR ligands to a vaccine consisting of synthetic long peptides resulted in a greatly improved immune response.
“Our rationale then was to link the peptide antigen chemically to the TLR ligands in order to obtain an even more efficient antigen delivery into the dendritic cells and additional activation stimuli from the TLR ligand,” said Melief. “In addition, we found that the AMPLIVANTTM-SLP conjugate is ingested more efficiently and leads to the creation of an antigen depot in the dendritic cells. This in turn results in long-lived antigen processing and presentation at the cell surface of the DCs.”
In tumor mouse models, conjugates of TLR ligands and synthetic long peptides resulted in much greater anti-tumor activity, long-term tumor protection and increased survival as compared to vaccines consisting of mixtures of peptides or peptides plus free TLR ligands.
To improve the TLR ligand performance further and to maximize clinical benefit, a synthetic TLR2-activating ligand was modified by rational molecular design, following a crystal structure analysis of the interaction between the ligand and its receptor.
“These efforts led to the AMPLIVANT™ technology, which had already yielded a number of proprietary agonists with enhanced receptor activation and DC maturation,” Melief added. “Our AMPLIVANTTM adjuvants are 100-fold more effective in terms of receptor stimulation than existing reference adjuvants, and we have also shown that they result in enhanced priming of CD8 T-cells in vivo.”
ISA is now planning a Phase I/II study to demonstrate safety and immunogenicity. “In this study, we will validate the AMPLIVANT™-SLP conjugate concept along the lines of our ISA101 vaccine, which has demonstrated clinical efficacy against pre-malignant disease,” said Gerard Platenburg, Managing Director of ISA Pharmaceuticals. “AMPLIVANT™ conjugates are based on two synthetic long peptides chosen from the 13 SLPs of the ISA101 vaccine. The trial in patients with HPV16-positive head and neck cancer is expected to start in early 2014.”
A Phase II trial of ISA101 in vulvar intra-epithelial neoplasia has established clinical proof-of-concept. In cervical cancer, ISA101 has completed a phase I/II trial and will enter into a randomized phase II trial later this year. ISA is also about to enter a phase I/II study in anal intra-epithelial neoplasia (AIN) with ISA101.