The lead drug candidate, MIS416, is a construct of the microparticle and naturally occurring, non-immunogenic, cytosolically-active TLR-9 and NOD-2 ligands. When administered, these microparticle/ligand complexes are readily absorbed by the cells of the reticulo-endothelial system, with cellular activation occurring only after microparticle internalization and subsequent biodegradation of the microparticle and release of the ligands. Signal transduction pathways activated by these ligands act in concert to activate a broad range of innate immune cell subsets that are central to the development of innate and adaptive anti-tumour responses. In vitro studies have shown that MIS416 has specific immunomodulatory effects on dendritic cell, monocyte / macrophage, Natural Killer (NK) and NKT-cell cytokine secretion patterns, in parallel with enhancement of a broad range of soluble and cellular tumouricidal mechanisms such as granule, Fas, TRAIL and TNF-a.
When administered as a distinct agent, MIS416 is a potent activator of broad but well characterized innate immune responses.
Schematic of TLR9 and NOD-2 activation of signal transduction pathways
Activation of both of these pathways correlates with the early production of NFkB-dependant inflammatory cytokines and chemokines that act locally, serving to recruit cells and act as immune maturation stimuli. These mechanisms underpin the co-ordinated activation of a range of innate immune responses.
Animal toxicology studies have demonstrated that acute, twice weekly (for 4 weeks), and once weekly (for 26 weeks) i.v. administration of MIS416 is well tolerated and at doses up to 20 times the target human dose, observed effects were not explicity adverse and were the result of the drug's extended pharmacological effects.
New Zealand medicines regulator, Medsafe, approved the manufacturing of MIS416 as a medicine in early 2008. This approval means that MIS416 is being made in accordance with the internationally agreed rules of Good Manufacturing Practice ("GMP"). As part of the GMP licensing process, formal stability studies have been performed on samples of MIS416 subjected to multiple freeze-thaw cycles, cold storage (36 months at 2-8 degrees C), and room temperature storage. These studies have confirmed that the bioactivity of MIS416 is stable across the whole range of storage temperature tested for periods in excess of 24 months.
Proof-of-principle studies have demonstrated the immunomodulator microparticle technology to have efficacy in diseases or applications including: autoimmune conditions - specifically Multiple Sclerosis; cancer - examples include metastatic breast, lung, and melanoma disease; infectious disease - examples include influenza and plague and as an adjuvant in an experimental anthrax vaccine; and, radiation injury induced neutropenia. In addition, the microparticle as a vaccine carrier and adjuvant has been evaluated in both malaria and tuberculosis vaccine development programs and in the development of cancer treatment vaccines.