Current CAR-T Approaches
Numerous variations of human CAR-T cells are being studied, results have been very impressive, and the first pioneer CAR-T products targeting CD19 in B cell malignancies have been approved by the US FDA in 2017 and European Medicines Agency in 2018. However, as with all new technologies, especially innovative medical interventions, there are frequent and critical problems concurrent with the remarkable success.
Single antigen targeting: Each CAR can target only one antigen. Consequently, if and when a tumor escapes treatment by jettisoning it original target, patients are likely to relapse. Targeting new antigens requires production and administration of a new CAR cell for every new target.
Always on – lacks control: CAR-T cells are supercharged effector lymphocytes and can attack with a vengeance the targeted tumor cells. Aggressive attacks frequently cause a “cytokine storm” and neurotoxicity, life-threatening adverse events.
Mouse-derived scFv receptors: pioneer CAR-T cells contain foreign, usually mouse-derived, antibody targeting domains which will elicit anti-drug antibody (ADA) responses in patients, thereby limiting the durability and efficacy 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, T cells, and some macrophages. There are eight natural ligands, MHC-class I-like Complex (MIC) proteins, for human NKG2D receptors that are rarely expressed on healthy cells. However, when stressed by any one of several provocations, otherwise healthy cells may decorate their surfaces with one or more MIC-ligands 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 activating the NK-cell machinery to mount an attack to kill the decorated, stressed 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, otherwise inert iNKG2D. Next, we fused intact human antibodies to the modified ligands to direct these “orthogonal ligands” to a specific target site, for example, on a cancer cell. This orthogonal ligand fused to the antibody (a MicAbody) can thereby bind both the iNKG2D on an engineered T-cell and the targeted cancer cell.
Using the inert NKG2D 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 target and bind a cancer cell with, for example, its tumor-associated antigen.
When MicAbody™ proteins targeting the tumor-associated antigen are introduced in an appropriate dose, they decorate the surface of the target cell plus bind the iNKG2D on the convertibleCAR-T cells. This bridging effects clustering of the iNKG2D receptors on the convertibleCAR-T cell, activates the T-cell, and the target cell to which the convertibleCAR-T cell is now bound is aggressively attacked and destroyed.
Multi-antigen targeting: convertibleCAR-T cells are targeted to tumor associated antigen through MicAbody dosing. The ability to multiplex or sequentially switch the targeting with MicAbodies allows the targeting of multiple antigens while avoiding the need for new CAR-T cells.
MicAbody dose controlled: The activity of the convertibleCAR-T cells is controlled by dose titration of the proprietary bispecific MicAbodies, thereby providing a means of preventing or managing the adverse events, such as “cytokine storm”.
Human-derived iNKG2D and MicAbodies: Both the engineered iNKG2D immune receptor and the MicAbodies are human-derived and therefore minimize the anti-drug antibody (ADA) response of the patient often seen with the typical mouse-derived receptors on current CAR-T therapies.
MicAdaptor modulation: We constructed a novel class of bispecific fusion proteins, called MicAdaptors, which specifically bind only to our convertibleCAR-T cells to modulate their cellular function. For example, we have designed MicAdaptors that deliver interleukins exclusively to our convertibleCAR-T cells.
In summary, our ACCEL™ platform enables precise control of convertibleCAR-T cells by a family of bi-specific molecules that direct the convertibleCAR-T cells to cancerous cells and modulate the function of the convertibleCAR-T cells: