The TILAC™ platform is a transformative tolerance induction technology that is completely unlike all previous attempts to induce tolerance. Furthermore, it surpasses current developmental approaches in its elegant simplicity, perfectly personal operation, and universal application.
This technology is differentiated from past attempts by the binding of two powerful adjuvant constituents that make it possible to utilize the pool of endogenous pathogenic antigens to down-regulate the immune response associated with a particular disease, and to do so across the range of targeted autoimmune diseases. The immune system possesses remarkable restorative power that can be harnessed through the creation and maintenance of a particularly robust tolerogenic microenvironment that results in directional modulation of the immune response by regulatory T cells to achieve desired disease remediation.
SHIFTING THE PARADIGM
Tolerogenic approaches using disease-associated antigens have been studied for decades. The emphasis, historically, has been to identify the immunodominant pathogenic antigen or antigens (the antigens responsible for causing the immune response) and then to deliver it (or them) to the immune system in an appropriate formulation. These historic approaches have fallen short of expectations, and all have yielded disappointing results.
As a result of these experiences, many biopharma research efforts in antigen specific approaches have been de-prioritized pending a breakthrough. Researchers across the world are investigating different paths as possible means to induce tolerance, but no approach to the highly sought-after objective of tolerance induction has demonstrated outcomes that are comparable to those expected from the TILAC platform.
- The TILAC therapeutic approach utilizes a formulation comprised of two primary components, a vaccine adjuvant and an anti-inflammatory cytokine, that have been linked to form a unique conjugate. In its first product, TREG 101, both of these components are FDA-approved and have been safely used clinically for decades.
- The approach is highly personalized. It targets pathogenic self-antigens perpetrating the disease only, and yet it requires no antigen to be included in the treatment formulation. It accomplishes this with no no biological contribution from the patient, i.e., blood, cells, etc., of any kind.
- The approach a simple and elegant intervention. It requires no extracorporeal manipulation of tissue or cellular components, no autographs or allographs expanded and transferred out of and into the patient; no transplants or cell transfers at all, no genetic or cellular or TCR manipulation, no injection of esoteric micro-carriers, and no need for global immunosuppression.
- The approach is considered to be, potentially, a universal therapy. Although at this stage, not sufficiently evaluated across the scope of immune-inflammatory conditions, including the range of autoimmune disease, to make broad claims, the approach is designed to take advantage of commonality found in all these disease states, and, consequently, anticipated to be broadly and effectively applied, affecting the lives of millions of people around the world.
It is not possible to elaborate further in a one-page description, but the mechanism of action (Moa) behind this technology makes that assertion perfectly clear. Our research strongly suggests that the TregTherapeutics approach is that breakthrough. The paradigm shift it represents is one that moves away from the identification and delivery of a specific pathogenic antigen in recognition of the fact that the necessary antigens are present within the patient and they do not have to be identified at all – the body knows they are pathogenic. Our approach shifts attention to creating a specific environment that fosters a robust and durable sustained signal that is able to establish a powerful Treg repertoire capable of down-regulating the pathogenic inflammatory response and re-establishing immune homeostasis.
TILAC™ PLATFORM OVERVIEW
The TregTherapeutics tolerogenic approach has been developed over the past two decades, primarily using various models of experimental autoimmune encephalopathy (EAE) in laboratory animals.
These models are typical of investigational research centered on multiple sclerosis. The TregTherapeutics approach was INITIALLY developed as a possible application for MS, and its treatment and cure remain a core objective for the company. Despite this fact, it as the underlying mechanism was elucidated during development, it was discovered that the underlying principles governing the technology are equally applicable to the induction of tolerance in a wide range of disease states that have chronic inflammation as a common denominator.
The initial key research objective was to discover a way to generate a powerful, sustained tolerogenic signal on a cellular level that would translate into strong, clinically significant, disease remediation. Superb research design and execution provided important insights into various linkage mechanisms that included fusion proteins, as well as, various combinations of cytokines, antigens, and adjuvants. This work included the examination of ways to modify conventional fusion proteins to achieve the benefits of linkage but without covalent bonding, a way to link numerous proteins without the complexity of conventional restrictions, a way to convert a tolerogenic cytokine into a super-tolerogenic agent without functionally modifying its structure.
As this research continued over the years it was learned that the research objective, defined above, could indeed be achieved. Furthermore, it was discovered that by varying the linked components, a range of inflammatory conditions could be addressed. The culmination of decades of research was the discovery that under the right conditions, certain anti-inflammatory cytokines could be linked with certain adjuvants in such a way that tolerogenic induced disease remediation could be achieved, regardless of the underlying pathogenic antigens eliciting the immune response. Thus, was born the TILAC platform that creates an in-situ microenvironment that does indeed produce a powerful, sustained tolerogenic signal that has enormous downstream implications. This signal is directed towards endogenous self-antigens, pathogenic autoantigens that are driving the disease process; these are commandeered to direct that tolerogenic signal in a very specific way that initiates and maintains disease remediation. The outcome of the therapy, then, is immune tolerance and re-established immune homeostasis.
Mechanism of Action:
The target for the TregTherapeutics tolerogenic induction therapy is a particular antigen presenting cell (APC) located in peripheral tissue known as the dendritic cell (DC). The DCs normal job is to surveil the blood and lymph for antigen that then to present that antigen to T cells in order to mount an inflammatory immune response to destroy a threat. Under the right conditions, however, the DC can be induced to generate a regulatory T cell instead. The TILAC platform is designed to elicit this transformation in the DC as it interacts with self-antigens without interfering with its normal response to foreign antigens.
The operative principle of the TILAC platform is that the cytokine in the formulation will interact with cytokine receptors on the DC. As a result, this DC will now act as a tolerogenic DC that will induce a regulatory phenotype downstream. The pathogenic endogenous self-antigen is phagocytosed by the DC, undergoes processing, is complexed with the DC’s MHC II molecules, and subsequently is presented on the DC’s surface. The activated DC migrates to the draining lymph node where it comes into contact with the body’s repertoire of antigen-specific naïve CD4 T cells. Once the DC comes into contact with its cognate T cell receptor (TCR), that T cell becomes polarized to express a tolerogenic Treg phenotype marked by FOXP3. This Treg undergoes clonal expansion and migrates to the inflammatory disease site to dominate the immune response to this specific endogenous antigen. The same phenomenon is occurring with every pathogenic epitope associated with the disease, resulting in a repertoire of epitope-targeted Tregs to insure the desired therapeutic impact.
To summarize, there are several expected outcomes from the therapeutic application of the TILAC platform:
- Regulatory T (Treg) cells are clonally expanded to down-regulate the inflammatory immune response
- Pathogenic effector T cells are eliminated via anergy and apoptosis
- Inflammation is quailed and immune homeostasis is reestablished
- Long-term antigen-specific Treg memory cells are generated for a durable outcome
- Future flare-ups caused by intrinsic genetic factors can be treated with remedial boosters to address neo-antigens