SUMMARY OF INVENTION
Cellular therapies are engineered using foreign and synthetic protein sequences, such as chimeric antigen receptors (CARs). The frequently observed humoral responses to CAR T-cells result in rapid clearance, especially after re-infusions. There is an unmet need to protect engineered cells from the host immune system, particularly for the advancement of allogeneic cell therapies. By utilizing the IgG-degrading enzyme of S. pyogenes (IdeS), MSK scientists programmed CAR T-cells to defeat humoral immune attacks. IdeS cleavage of host IgG avert Fc-dependent phagocytosis and lysis, and the residual F(ab’)2 remained on the surface, providing cells with an inert “shield” from additional IgG deposition. “Shield” CAR T-cells efficiently cleaved cytotoxic IgG, including anti-CAR antibodies, detected in patient samples and provided effective anti-tumor activity in the presence of anti-cell IgG in vivo.
- This technology may be useful for expanding widespread use of “off-the-shelf” allogeneic cellular therapies as well as for repeated human infusions of engineered cells and more complex engineered cells.
Shield cells may have other important applications beyond the cancer indications traditionally addressed by CAR T-cell therapies. For example, MSK investigators showed elimination of anti-HLA antibodies, which are responsible for acute renal allograft rejection. Shield CAR T-cells could be used to provide local suppression of the host anti-graft response, without systemic effects.
In addition, engineered cell therapies also are being tested against autoimmune diseases, such as for the treatment of pemphigus vulgaris and systemic lupus erythematosus. IdeS has been shown to have positive therapeutic outcomes in animal models of idiopathic thrombocytopenia, Goodpasture’s disease, and arthritis. Therefore, localized use of IgG depleting Shield cells might have advantages in these IgG-mediated autoimmune diseases as well, by provided long-term highly targeted cell protection or depletion of pathogenic IgG.
AREAS OF APPLICATION
- Cancer indications addressed by CAR T-cell therapy, in particular allogeneic cell therapies
- Autoimmune diseases, including IgG-mediated autoimmune diseases (pemphigus vulgaris and systemic lupus erythematosus)
- Renal allograft rejection, suppression of the host anti-graft response, idiopathic thrombocytopenia, Goodpasture’s disease, and arthritis.
PCT application PCT/US2020/44159 (filed Jul 30, 2020)
David A. Scheinberg, MD, PhD, Chair, Molecular Pharmacology Program, SKI; Director, Center for Experimental Therapeutics, MSK
Eileen Flowers, Ph.D.