The critical scientific rationale for the Amplimmune technology is based on the notion that a balance of positive and negative signals determines the amplitude of T cell responses to their cognate antigens (foreign, self, tumor or pathogen). T cells are initially activated through engagement of their T cell receptor. However, this single recognition event is insufficient to activate the T cell. Additional molecular interactions provide a second signal referred to as co-stimulation, which effectively amplifies the T-cell positive signal. Effective T cell activation requires a combination of T cell receptor engagement and co-stimulation. T cell activation via co-stimulation is in turn balanced by specific inhibitory negative signals referred to as immune checkpoints. Engagement of immune checkpoints is absolutely critical to maintain self-tolerance so that the immune system does not typically attack our own cells and, additionally, to down-modulate natural immune responses once an infection has been cleared.



The primary set of molecules that mediate co-stimulation or act as immune checkpoints of T cell responses is the B7 receptor family. B7 family molecules are cell membrane-associated proteins that interact with various receptors on T cells to transmit either positive (co-stimulatory) or negative (co-inhibitory/immune checkpoint) signals to the T cell. The originally described members of the B7 family are CD80 (B7-1) and CD86 (B7-2). Since 1999, seven additional B7 family members have been identified - 6 of these in the laboratories of Amplimmune founders Dr. Lieping Chen and Dr. Drew Pardoll. Amplimmune technology is based on recent discoveries of specific costimulatory and co-inhibitory pathways in the immune system. The elucidation of these pathways has shaped our understanding of how immunity is regulated.



Cancer and chronic infection can be viewed as pathophysiologic states characterized by hypoactive T cell responses. Cancer patients contain T cells specific for their tumor. Under normal circumstances, these T cells exist in an inactivated or tolerant state. However, if properly activated, they can induce regressions of even large tumor masses. Similar mechanisms of T cell inactivation appear to be operative in chronic infectious diseases such as Hepatitis C virus, Hepatitis B virus and HIV, where T cells specific for the pathogen can be readily demonstrated but do not eliminate the infection. In contrast, autoimmune disease represents a clinical disease state characterized by hyperactive T cell responses that target self-antigens leading to inflammation and targeted destruction of "self" tissues and organs. Similarly, transplant rejection is mediated by immune recognition of alloantigens expressed on the transplanted organ which is viewed as "non-self".



Amplimmune's vision to develop drugs active in the treatment cancer and infectious disease would therefore involve selectively activating T cell populations to eradicate tumor or infection via either increasing T cell co-stimulation agonists and/or blocking immune checkpoints. In contrast, the treatment of autoimmunity would involve development of drugs that block co-stimulatory signals and/or enhance immune checkpoints, which dampen the hyperactive T cell responses to self-antigens or alloantigens expressed on the transplanted organ.