Introduction — Autoimmune Diseases

The vertebrate immune system is composed of two branches — the innate immune system and the adaptive immune system.  The innate immune system is composed of non-specific mechanisms, physical barriers, and cells that respond to pathogens indiscriminately by inducing inflammation, preventing pathogen access to tissues (e.g., the physical barrier of human skin), and clearing pathogens.  The adaptive immune system, in contrast, is specifically generated in each individual during childhood: the cells that are produced, which are B and T cells, are specifically selected to respond to an individual protein present in pathogens.  It is this latter arm of the immune system that results in immunological memory and immunity — the ability to respond rapidly to reinfection by the same pathogen, and prevent symptoms from emerging altogether; however, it is also this arm of the immune system that is most frequently dysregulated in autoimmune diseases.

When B and T cells develop normally, cells that respond over-zealously to the patient’s own tissues are eliminated. The result of this process is a property called “tolerance,” where these cells are simply unable to respond to host tissues. However, cells that respond very weakly to host tissues can escape this elimination process and persist in the periphery as pre-autoimmune cells. In a subset of patients, these cells can become activated after infection or physical trauma, resulting in activated autoimmune cells. If these cells remain active, a chronic or relapsing autoimmune disease can develop. Ultimately, which autoimmune disease develops, and the severity of associated symptoms, are determined by what tissues the T and B cells respond to and by the patient’s genetics. For instance, if T and B cells specific for the collagen in joints become activated chronically, rheumatoid arthritis is the result. Furthermore, among these patients, a subset may exhibit ineffective immune regulation due to a genetic factor, resulting in debilitating rheumatoid arthritis.

During an autoimmune disease, T and B cells play distinct roles, with each contributing to the emergence of symptoms. T cells can respond to tissues bearing the autoantigen—the protein driving an autoimmune response—by directly killing the cell or by perpetuating the immune response. B cells, on the other hand, produce antibodies that bind to whole autoantigens and can indirectly result in cell death or tissue destruction. The Pantid®, described below, is primarily focused on reducing or eliminating this B cell component of the autoimmune response.


Introduction - The Pantid®

Pantids® are specifically designed protein therapeutics that can (1) neutralize autoantibodies produced by B cells and (2) kill autoreactive B cells. Autoantibodies typically bind to a known autoantigen protein, such as CTLA-4, PD-1, PD-L1, collagen, etc. During the design of Pantids®, the protein sequence of the autoantigen is literally copied into the Pantids® scaffold, and it is this autoantigen sequence that determines the specificity of the Pantids® as a therapeutic. As shown in Figure 1, the autoantigen sequence comprises the "binding domain" of the Pantid®. The "effector domain" of the Pantids® are cell-killing (i.e., cytotoxic) protein portions that are fused to the autoantigen "binding domain". Because each autoimmune disease is characterized by a distinct and limited set of autantigens, each Pantids® -- container these autoantigen sequences -- is necessarily a specific therapeutic for that autoimmunce disease. As such, there is no one "Pantid®" therapeutic, but rather a catalog of therapeutics, each of which is tailored for a specific patient or a specific autoimmune disease.

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