Current CAR-T Approaches
Numerous variations of human CAR-T cells are being studied in hundreds of patients to which CAR-T cells have been transplanted in order to specifically target and treat their malignancies. Results have been very impressive, and this modality of therapy is rapidly expanding with commercialization of the early generation CAR-T cell anticipated this year. However, as with all new technologies, especially innovative medical interventions, there are frequent and very critical problems concurrent with the remarkable success.
Single antigen targeting: Each CAR target only one antigen, if and when a tumor recurs by jettisoning it original target patients are vulnerable to relapse. Targeting new antigens requires production of a new CAR cell for every target.
Always on – lacks control: CAR-T cells are supercharged effector lymphocytes and can attack with a vengeance the targeted tumor cells. CAR-T cells also attack other non-intended cells that happen to exhibit the same target recognized by the antibody domain. Aggressive attacks frequently cause a “cytokine storm”, a life-threatening adverse event.
Mouse-derived scFv receptors: CAR-T cells contain foreign, usually mouse-derived antibody targeting domains which will elicit anti-drug antibody (ADA) responses in patients, thereby limiting the persistence of CAR-T therapies.
Xyphos convertibleCAR Technology Platform
Xyphos’ convertibleCAR technology exploits a powerful immune surveillance pathway involving NKG2D receptors that are present on Natural Killer – (NK-) cells, other lymphocytes such as T-cells, and some macrophages. There are 6 distinct natural ligands for human NKG2D receptors, and these ligands are rarely expressed on healthy cells. However, when stressed by any one of several provocations, otherwise healthy cells may decorate their surfaces with a ligand for NKG2D. The α1-α2 domain of the natural ligands provides the binding site for the NKG2D receptor. The NKG2D receptors then bind their ligands and cluster on the NK-cell surface, thereby activating the NK-cell machinery to mount an attack to kill the decorated cell.
Through protein engineering, Xyphos has gained precise control of this immune surveillance pathway. We have mutated the natural NKG2D receptor so that it no longer binds any of its natural ligands; this become an inert NKG2D (iNKG2D). In addition, we have created mutant ligands that no longer bind the natural NKG2D receptor but do bind specifically to the engineered iNKG2D. Next, to direct and control the target site at which these “orthogonal ligands” can be recognized by the iNKG2D, we fused intact human antibodies to the modified ligands in order to decorate with ligand the intended target cells, e.g. cancer cells, expressing the cognate tumor antigen of the fused antibody.
Using these convertibleCAR “parts” plus natural signaling and activating components of T-cells, we assembled a convertibleCAR-T cell. These inert resting convertibleCAR-T cells remain inactive in the absence of a means to recognize a threatening cell with, for example, its tumor-associated antigen. In addition, the iNKG2D receptor on the convertibleCAR-T cell is human derived, thereby, minimizing any potential ADA response from the patient.
When a tumor-targeted MicAbody Protein targeting the antigen is introduced in an appropriate dose, they decorate the target cell and bind the iNKG2D on the convertibleCAR-T cells. The clustering of the iNKG2D receptors of the CAR activates the convertibleCAR-T cell, and the target cell is aggressively attacked and destroyed.
Multi-antigen targeting: convertibleCAR-T cells are targeted to any tumor associated antigen through MicAbody dosing. The ability to switch or multiplex targeting with the MicAbody Proteins simplifies production by avoiding the need for new CAR-T cells.
MicAbody dose controlled: The activity of the convertibleCAR-T cells and their specific targeting is controlled by dosing with the proprietary bispecific MicAbody Proteins, thereby providing a means of preventing or managing the adverse events, such as “cytokine storm”, that are often associated with CAR-T cells.
human-derived iNKG2D: The iNKG2D engineered immune receptor is human-derived and therefore minimizes the anti-drug antibody response of the patient often seen with the more typical mouse-derived receptors on current CAR-T therapies. The iNKG2D receptor allows for the production of a single, universal CAR-T cell and is compatible with CAR-T persistence.