Cancer - Mechanism of Action
Biothera’s lead drug candidate, Imprime PGG® (Imprime PGG), is an immune modulator that is being developed as a combination immunotherapy to be administered with certain cancer drugs to improve treatment efficacy. Imprime PGG specifically activates to Complement Receptor 3 (CR3, also known as CD11b/CD18 or Mac-1) on innate immune cells. Although CR3 is expressed on the surface of several innate immune cells including macrophages, dendritic cells, and natural killer cells, Biothera has identified a very specific effect that Imprime PGG has on neutrophils.
The CR3 receptor on innate immune cells is involved with a number of immune functions against pathogens. This receptor is a “dual occupancy” receptor that has two binding sites. One site binds a PAMP found on pathogens. The second binding site of CR3 can bind complement, a soluble protein that is part of the immune system. Complement obtained its name because it “complements” the immune response by binding to the surface of foreign pathogens, and targeting them for immune cell recognition. When the CR3 receptor on neutrophils, binds both the complement on the pathogen and the PAMP, simultaneously, it triggers a signal that initiates a immune cell killing mechanism against the pathogen.
Biothera has developed a method by which Imprime PGG can direct this primary killing mechanism against multiple targets including cancer cells. Neutrophils are generally thought not to be involved in cancer killing activity. Monoclonal Antibody drugs have become the “state of the art” cancer therapy, because they can selectively target and bind to cancer cells. Certain on them can also activate complement to also bind to the surface of the cancer cell. When Imprime PGG is administered, it binds to one of sites on the CR3 of neutrophils and “primes” this innate immune cell for enhanced activity.
When Imprime PGG is administered in combination with a complement activating anti-cancer monoclonal antibodies, there is a significant enhancement in efficacy. When the primed neutrophil binds to the complement on surface of the antibody targeted cancer cell, both sites on CR3 are occupied (one site bound to the complement and one to Imprime PGG) and the killing mechanism is triggered against the cancer cell. These white blood cells represent the largest population of innate immune system and are perhaps the most proficient killer of all the immune cells.
Monoclonal antibody drugs have dramatically changed the therapeutic options for cancer patients. Cancer cells, however, are often able to evade the killing mechanisms normally induced by these monoclonal antibody drugs, namely Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicity (ADCC) resulting in relatively low response rates to the drugs. Biothera, however, has demonstrated in numerous preclinical models that when Imprime PGG is administered in combination with these anti-cancer monoclonal antibodies, there is a significant enhancement in cancer cell killing. This synergistic effect does not result from enhancing the known killing mechanisms of ADCC and CDC. Instead, this synergistic effect relies on the antibody’s ability to target the cancer cells and activate complement on the surface of the tumor cells. Imprime PGG does not reduce the activity of existing monoclonal antibody killing mechanisms (ADCC/CDC), it simply adds another new mechanism that directs neutrophils to kill cancer cells targeted by monoclonal antibodies. The potential of Imprime PGG as a combination immunotherapy to enhance drug efficacy is not limited only to cancer applications since antigen-targeting drugs, like monoclonal antibodies, are being developed for many other disease indications.