Toll Like Receptors (TLRs) are pattern recognition receptors localised on the cell surfaces and intracellular membranes of antigen presenting cells (APCs). TLRs recognise certain conserved repeating structural motifs on the surface of pathogens, which are known as pathogen associated molecular patterns (PAMPs). Upon binding to these PAMPs, TLR signaling activates the APCs resulting in cytokine production, increased co-stimulatory molecule expression and enhanced capacity to present antigen. TLR ligands are therefore very potent and specific adjuvants. The selection of specific TLR ligands with a specific vaccine antigen will shape the immune outcome and provide a means of tuning vaccine formulations.
What is PolyMAP
Whilst small synthetic TLR agonists are relatively cheap and simple to manufacture, they poorly reproduce the essential 'pattern' component of the larger natural ligands. We have shown that when these individual ligands are presented in a more natural linear pattern along the length of a biocompatible polymer, the immune response is up to 200 times higher on a per molecule basis. In fact, 1ng of a synthetic TLR agonist presented as polyMAP has an equivalent NfkB stimulating capacity as 100ng of LPS. Furthermore, by adjusting the specific TLR receptor classes targeted by polyMAP, it is also possible to maintain this adjuvant potency but reduce the unwanted toxicities of the non-specific non-synthetic adjuvants.
PolyMAP thus has three key properties that contribute to the enhanced adjuvant activity and safety:
Increased receptor avidity through cooperative, multi-valent interactions
Clustering of receptors through cross-linking
Improved solubility of TLR ligands that are otherwise difficult to use in their free form
The polymer component of the PolyMAP platform is based upon soluble poly-[N-(2-hydroxypropyl) methacrylamide] (poly-HPMA), which has already been investigated in several clinical trials as a biocompatible drug carrier. Poly-HPMA has no known human toxicity and no intrinsic adjuvant activity. A useful property of this polymer is that TLR ligands (or other adjuvants) can be readily incorporated along the entire polymer molecule. It is also possible to incorporate different types of ligands onto the same backbone or to co-link adjuvants and antigens into the same macro-molecule, making it a highly adaptable platform. Large quantities can be produced to cGMP.
PolyMAP thus directly reflects the potent antigenic effects of natural pathogen surfaces and cellular debris but in a synthetic and highly adaptable form that is well suited to low cost cGMP scale-up and production.
PolyMAP data
In vitro The polyMAP platform has been shown to enhance the activation of cytokine production from human dendritic cells and macrophages.In vivo, PolyMAP has demonstrated clear benefit as an adjuvant for the model antigen ovalbumin, producing higher antibody titres more quickly than the non-polymer-displayed form of the same ligand (see the figure below). The same material has also been used to effectively initiate rejection of cancer in syngeneic tumour models.
Market potential
Vaccines continue to be a phenomenal success story for pharmaceutical companies. The world market for preventative vaccines reached over $22 billion in 2009, a 16% increase on 2008 and it is predicted to increase at a compound annual rate of 9.7% during the next five years [1]. The potential for significant growth and uptake of therapeutic vaccines will only add to this significant growth potential in the longer term.
In order to drive growth in the vaccine sector, and in particular in order to enter the demanding therapeutic vaccine sector, it is imperative to have new technologies that will enhance vaccine safety and efficacy. The hunger of the major players to develop new products in this sector is demonstrated particularly by the large corporate deals related to vaccine delivery and adjuvant platforms.
