Tag: immune-stimulatory potency of vaccines improved by 2-3 orders of magnitude
– 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.