ProMIS™

The ProMIS™ target identification technology is an in silico rational selection approach to identify novel Disease Specific Epitopes (DSE) on the molecular surface of misfolded proteins.

Using only partial information about the 3D native structure, the ProMIS™ algorithm can predict the misfolded conformation of the protein including motifs that become exposed (see diagram). In diseases where the misfolded protein, and not the normal structure, is implicated in the pathology, as in the case with SOD1 and ALS, designing antibodies that are specific for the misfolded form is very valuable for both therapeutic and diagnostic purposes.

Misfolded proteins in Cancer:

It is well established that protein misfolding is a central pathological event in many fatal neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recently, intriguing evidence for a role of misfolded proteins in cancer has been identified. Studies in our laboratories and others have confirmed this role. Furthermore, a growing body of published literature on this topic provides additional support for our scientific rationale. The focus on misfolded proteins represents an entirely new approach to the identification of cancer targets and may allow for the development of very selective therapeutics offering greater efficacy with reduced toxicity.

Cancer cells are stressed by uncontrolled growth, rapid cell division and oxidative damage which can induce protein misfolding and unfolding as well as partial loss of native structure. In some cases, the ability of cancer cells to effectively evade the immune system and continue to grow and spread throughout the body may depend on aberrant signaling by incorrectly folded proteins. It appears that misfolded proteins are tolerated more in cancer cells compared to normal cells where they are either refolded into their proper configuration or discarded.

Indirect evidence for the importance of protein misfolding in cancer is demonstrated by the increased sensitivity of cancer cells to proteasome inhibitors, suggesting the production of a larger quantity of unfolded or misfolded protein compared to normal cells. The selective targeting of cancer cells based on expression of misfolded proteins represents an entirely new avenue for therapeutic intervention.

Currently, the primary issues associated with the failure of new therapeutics in the clinic fall into three general categories:

1. The target selected for therapeutic intervention is not causal to the pathogenesis of the disease.
2. The drug being tested fails to effectively neutralize the disease target; and
3. The drug has off target side effects that make it toxic and prevent its use at therapeutic levels.

Amorfix's strategy to identify novel DSE's on well-validated targets using the ProMIS™ technology will attempt to solve these problems by producing highly selective and potent proprietary therapeutics with greater efficacy and safety, thereby greatly reducing the risk of failure.

Amorfix plans to target proteins which may be misfolded in diseases where cells are under stress and/or more likely to produce misfolded proteins as is the case in cancer. Once a protein has been identified, antibodies and vaccines can be developed and assessed for therapeutic and diagnostic use. The Company is establishing strategic alliances to expand its capabilities to develop immunotherapeutics to numerous proteins and is also exploring partnerships with other companies to accelerate the development and expand its program to other proteins of interest.