Cell
AssigneeUCL Business PLC
InventorsMartin Pulé, Khai Kong, Shaun Cordoba
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Abstract
The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising: (i) an antigen-binding domain; (ii) a spacer (iii) a trans-membrane domain; and (iv) an endodomain wherein the antigen binding domains of the first and second CARs bind to different antigens, and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain.
Claims17
A T cell or natural killer (NK) cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising:
- (i) an antigen-binding domain;
- (ii) a spacer
- (iii) a trans-membrane domain;
- and
- (iv) an endodomain,
- wherein the antigen binding domains of the first and second CARs bind to different antigens;
- wherein one of the first or second CARs is an activating CAR comprising an Immunoreceptor Tyrosine-based Activation motif (ITAM)-containing activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-on inhibitory endodomain comprising a tyrosine phosphatase domain from a Src homolog (SH2) domain-containing protein tyrosine phosphatase which is recruited by a phosphorylated Immunoreceptor Tyrosine-based Activation motif (ITIM);
- and wherein the spacer of the first CAR and the spacer of the second CAR co-localise upon ligation of the first CAR and the second CAR.
A nucleic acid sequence encoding a first chimeric receptor (CAR) and second CAR, each CAR comprising:
- (i) an antigen-binding domain,
- (ii) a spacer,
- (iii) a trans-membrane domain and
- (iv) an endomain,
- wherein the antigen binding domains of the first and the second CARs bind to different antigens, and
- wherein one of the first or second CARs is an activating CAR comprising an Immunoreceptor Tyrosine-based Activation motif (ITAM)-containing activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-on inhibitory endodomain comprising a tyrosine phosphatase domain from a Src homolog (SH2) domain-containing protein tyrosine phosphatase which is recruited by a phosphorylated Immunoreceptor Tyrosine-based Activation motif (ITIM);
- and wherein the spacer of the first CAR and the spacer of the second CAR co-localise upon ligation of the first CAR and the second CAR.
A kit which comprises
- a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR) and a second nucleic acid encoding a second CAR, each CAR comprising
- (i) an antigen-binding domain,
- (ii) a spacer,
- (iii) a trans-membrane domain and
- (iv) an endodomain,
- wherein the antigen binding domains of the first and second CARs bind to different antigens,
- wherein one of the first or second CARs is an activating CAR comprising an Immunoreceptor Tyrosine-based Activation motif (ITAM)-containing activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-on inhibitory endodomain comprising a tyrosine phosphatase domain from a Src homolog (SH2) domain-containing protein tyrosine phosphatase which is recruited by a phosphorylated Immunoreceptor Tyrosine-based Activation motif (ITIM);
- and wherein the spacer of the first CAR and the spacer of the second CAR co-localise upon ligation of the first CAR and the second CAR,
- wherein the first nucleic acid sequence has the following structure:
- AgB1-spacer1-TM1-endo1
- in which AgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR;
- spacer 1 is a nucleic acid sequence encoding the spacer of the first CAR;
- TM1 is a nucleic acid sequence encoding the transmembrane domain of the first CAR;
- endo 1 is a nucleic acid sequence encoding the endodomain of the first CAR;
- and
- wherein the second nucleic acid sequence encoding the second CAR has the following structure:
- AgB2-spacer2-TM2-endo2
- in which AgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR;
- spacer 2 is a nucleic acid sequence encoding the spacer of the second CAR;
- TM2 is a a nucleic acid sequence encoding the transmembrane domain of the second CAR;
- endo 2 is a nucleic acid sequence encoding the endodomain of the second CAR.
Dependencies are inferred from the claim text.