Bispeciﬁc antibodies function by recognizing and binding to two different targets. In the case of T-cell engagers, one part of the bispeciﬁc binds to the T-cell and another to a target on the tumor cell (tumor antigen) with the goal of activating the T-cell against the tumor cell. Bispeciﬁc T-cell engagers have shown incredible promise in treating cancer. However, the safety proﬁles seen to date in clinical trials leave room for new approaches that can widen the therapeutic window of this exciting class of therapies. We believe therapeutics developed from our highly innovative T-LITE™ platform will overcome these historical challenges, enabling safer and more eﬃcacious treatments through reduced side effects and higher dosing.
Our T-LITE’s bispeciﬁc functionality is selectively switched on through administration of a small-molecule activator. This decouples target binding of the tumor antigen and T-cell (CD3 domain) from the induction of cell-cell interactions and activation of the T-cells. This switchable activity enables precise on/off control over the timing and magnitude of T-cell redirection and cytotoxic activity. Unlike conventional half-life extended bispeciﬁc T-cell engaging antibodies, whose effects can last for days, causing potential side effects such as cytokine release syndrome, the activity of our T-LITE therapies is dependent on the oral administration of our small molecule activator and can be turned off within hours. This process is non-destructive to the antibodies, leaving them engaged with target cells and ready for reactivation. This on/off control enables the physician to increase T-cell activity when more eﬃcacy is needed, or to reduce activity if side effects become apparent.
Image 1. T-LITEs enable precise on/off control over the timing and magnitude of T-cell redirection and tumor cytotoxic activity. 1. Long half-life “Dormant” T-LITEs are dosed to the patient in the absence of the small molecule activator. Each T-LITE molecule is given time to biodistribute and bind its intended cell type, without resulting in immediate immune activation; 2. The small molecule activator is orally dosed to the patient to induce T-cell redirection and tumor cytotoxicity. This process is titratable and reversible; 3. Dosing of the small-molecule activator results in the formation of the active T-LITE complex, recruiting T-cells to target tumor cells and inducing T-cell mediated killing.
Soteria’s T-LITE platform is enabled by our proprietary LITE Switch® chemically induced dimerization (CID) technology. LITE Switches utilize FDA approved small molecules to induce dimerization of two protein domains, which are based on human proteins for reduced risk of immunogenicity. These properties make LITE Switches the optimal CID technology for therapeutic application.
- Human antibody-based chemically induced dimerizers for cell therapeutic applications
- December 4, 2017
- Publication: Nature Chemical Biology
- Authors: Zachary B Hill, Alexander J Martinko, Duy P Nguyen & James A Wells
- Abstract: Chemically induced dimerizers (CIDs) have emerged as one of the most powerful tools for artiﬁcially regulating signaling pathways in cells; however, currently available CID systems lack the properties desired for use in regulating cellular therapies. Here, we report the development of human antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule–protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. We demonstrate this concept by generating three antibodies that are highly selective for the BCL-xL–ABT-737 complex compared to BCL-xL alone. We show the potential of AbCIDs for application in regulating human cell therapies by using them to induce CRISPRa-mediated gene expression and to regulate CAR T-cell activation. We believe that the AbCIDs generated in this study will ﬁnd application in regulating cell therapies and that the general method of AbCID development may lead to the creation of many new and orthogonal CIDs.