Switch costimulatory receptors
Inventors
June, Carl H. • Zhao, Yangbing
Assignees
University of Pennsylvania Penn
Publication Number
US-12404314-B2
Publication Date
2025-09-02
Expiration Date
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Abstract
The present invention relates generally to a fusion protein that when displayed on a cell can convert a negative signal into a positive signal in the cell. The fusion protein is a chimeric protein in that the protein comprises at least two domains, wherein the first domain is a polypeptide that is associated with a negative signal and the second domain is a polypeptide that is associated with a positive signal. Thus, the invention encompasses switch receptors that are able to switch negative signals to positive signals for enhancement of an immune response.
Core Innovation
The present invention provides a fusion protein comprising a first domain and a second domain, wherein the first domain is a polypeptide that is associated with a negative signal and the second domain is a polypeptide that is associated with a positive signal. In one embodiment, the first domain is at least a portion of the extracellular domain of the polypeptide that is associated with a negative signal and the second domain is at least a portion of the intracellular domain of the polypeptide that is associated with a positive signal. The fusion protein can further comprise a transmembrane domain, and examples of polypeptides associated with a negative signal include CTLA4, PD-1 and BTLA while examples of polypeptides associated with a positive signal include CD28 and ICOS.
The background describes that T cells sense their microenvironment and that engagement of inhibitory ligands in the tumor microenvironment can lead to T cell inactivation, and that current systemic approaches to prevent negative signals delivered by PD-1 or BTLA ligands involve antagonistic antibodies or fusion proteins which can prevent inactivation systemically and are expected to lead to autoimmunity or systemic inflammatory syndromes. The invention addresses this need by providing switch receptors that convert negative signals to positive signals to enhance an immune response, and by providing engineered cells that express such fusion proteins and optionally chimeric antigen receptors (CARs) to provide an improved therapeutic index with less toxicity, the ability to provide a one-time treatment that is effective and to avoid the need for the continuing administration of antibodies.
Claims Coverage
Two independent claims were identified. Six main inventive features are extracted from the first independent claim and five main inventive features are extracted from the twelfth independent claim.
Fusion protein comprising inhibitory extracellular domain and stimulatory intracellular domain
A fusion protein comprising an extracellular domain of an inhibitory polypeptide that is associated with a negative signal, a transmembrane domain, and an intracellular domain of a stimulatory polypeptide that is associated with a positive signal, wherein the inhibitory polypeptide is selected from PD-1 and BTLA and the stimulatory polypeptide is selected from CD28 and ICOS.
Chimeric antigen receptor comprising antigen recognition domain and CD3-zeta intracellular domain
A chimeric antigen receptor (CAR) comprising an antigen recognition domain that specifically targets a cancer antigen and an intracellular domain of a CD3-zeta chain.
Enhanced IL-2 and IFN-γ secretion upon ligand binding
When the fusion protein and the CAR are bound to their respective ligands, IL-2 and IFN-γ secretion is enhanced at least three times as compared to IL-2 and IFN-γ secretion in (i) a modified immune cell only expressing the CAR or (ii) a modified immune cell expressing a CAR comprising the antigen recognition domain that specifically targets a cancer antigen, a costimulatory domain, and an intracellular domain of a CD3-zeta chain.
Polarization to secrete IL-17 and IFN-γ
The modified immune cell is polarized to secrete IL-17 and IFN-γ.
Modified immune cell is a modified T cell
The modified immune cell is a modified T cell.
Fusion protein with PD-1 extracellular and CD28 intracellular domains in a cell population
A population of modified immune cells engineered to express a fusion protein comprising an extracellular domain of PD-1 and an intracellular domain of CD28, and to express a CAR comprising an antigen recognition domain that specifically targets a cancer antigen and an intracellular domain of a CD3-zeta chain.
Enhanced cytokine secretion in modified cell population upon ligand binding
When the fusion protein and the CAR are bound to their respective ligands, IL-2 and IFN-γ secretion is enhanced at least three times as compared to IL-2 and IFN-γ secretion in modified immune cells only expressing the CAR.
Population comprises modified CD4+ and CD8+ T cells
The population of modified immune cells comprise modified CD4+ T cells and modified CD8+ T cells.
Fusion protein enhances TNFα, IL2 and IFNγ secretion in CD4+ T cells
The fusion protein enhances TNFα, IL2 and IFNγ secretion in CD4+ T cells, thereby enhancing the CD4+ T cells antitumor response.
CAR comprising antigen recognition domain targeting CD19
The CAR can comprise an antigen recognition domain that specifically targets CD19 (as recited in dependent claims).
Autologous modified immune cell
The modified immune cell can be autologous (as recited in dependent claims).
The independent claims cover modified immune cells and populations engineered to express a fusion 'switch' protein with an inhibitory extracellular domain and an activating intracellular domain together with a CAR comprising a CD3-zeta intracellular domain, wherein ligand binding enhances IL-2 and IFN-γ secretion at least three-fold and the modified cells are polarized to secrete IL-17 and IFN-γ; specific recitations include PD-1 or BTLA extracellular domains, CD28 or ICOS intracellular domains, and populations comprising CD4+ and CD8+ T cells with enhanced CD4+ cytokine responses.
Stated Advantages
Convert negative signals to positive signals for enhancement of an immune response.
Provide an improved therapeutic index with less toxicity and the ability to provide a one-time treatment that is effective, avoiding the need for the continuing administration of antibodies.
Engineered cells are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control.
Engineered cells expressing switch receptors and CARs exhibit enhanced IL-2 and IFN-γ production and can be polarized to secrete IL-17.
Documented Applications
Treatment of cancer, including but not limited to ovarian carcinoma, breast carcinoma, colon carcinoma, glioblastoma multiforme, prostate carcinoma and leukemia.
Treatment of viral infections, including chronic viral infections with HBV, HCV, HTLV-1, HTLV-II, EBV, HSV-I, HSV-II, and KSHV.
Treatment of autoimmune diseases, including but not limited to arthritis, asthma, graft-versus-host disease, organ rejection, psoriasis, systemic lupus erythematosis, atopic allergy, inflammatory bowel disease, multiple sclerosis and others listed in the specification.
Adoptive cellular therapy using T cells or NK cells genetically modified to express switch receptors and optionally chimeric antigen receptors (CARs) for tumor immunotherapy.
Vaccine therapy and application to chronic viral infections, including HIV and other viruses such as EBV, HCV or CMV.
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