Multispecific chimeric receptors
First Claim
1. A DNA molecule encoding a chimeric membrane bound protein, said protein comprising in the N-terminal to C-terminal direction:
- at least two extracellular inducer-responsive clustering domains in tandem to form a multispecific extracellular inducer-responsive clustering domain that binds specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain;
a transmembrane domain; and
a cytoplasmic signaling domain comprising a ζ
or η
chain of the T-cell receptor, or a Janus kinase,wherein when said membrane bound protein is expressed in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal in said host cell on binding to said at least one inducer molecule.
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Abstract
Novel multispecific chimeric receptor DNA sequences, expression cassettes and vectors containing these sequences as well as cells containing the chimeric DNA and novel chimeric receptor proteins expressed from the sequences are provided in the present invention. The novel multispecific chimeric receptor DNA and amino acid sequences comprise at least three domains that do not naturally exist together: (1) a multispecific binding domain comprising at least two extracellular inducer-responsive clustering domains which serves to bind at least one specific inducer molecule, (2) a transmembrane domain, which crosses the plasma membrane, and (3) either a proliferation signaling domain that signals the cell to divide, or an effector function signaling domain which directs a host cell to perform its specialized function. Optionally, all the multispecific chimeric receptors may contain one or more intracellular inducer-responsive clustering domains attached to one or more of the cytoplasmic signaling domains or the transmembrane domain. The present invention also relates to novel hybrid multispecific chimeric receptors comprising at least one proliferation signaling domain and at least one effector function signaling domain together on the multispecific receptor molecule. The present invention further relates to therapeutic methods and strategies that employ the cells expressing these novel chimeric receptors for the treatment of cancer, infectious disease and autoimmune disease which may have greater therapeutic benefit over a combination of drug therapies.
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Citations
47 Claims
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1. A DNA molecule encoding a chimeric membrane bound protein, said protein comprising in the N-terminal to C-terminal direction:
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at least two extracellular inducer-responsive clustering domains in tandem to form a multispecific extracellular inducer-responsive clustering domain that binds specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; and a cytoplasmic signaling domain comprising a ζ
or η
chain of the T-cell receptor, or a Janus kinase,wherein when said membrane bound protein is expressed in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal in said host cell on binding to said at least one inducer molecule. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 25, 30, 31, 36, 41, 42)
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9. A DNA molecule encoding a chimeric membrane bound protein, said chimeric protein comprising in the N-terminal to C-terminal direction:
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at least two extracellular inducer-responsive clustering domains in tandem to form a multispecific extracellular inducer-responsive clustering domain that binds specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising a Janus kinase; and a cytoplasmic domain comprising ζ
or η
chain of the T-cell receptor;wherein when said membrane bound protein is expressed in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal for proliferation and effector function in said host cell on binding to said at least one inducer molecule. - View Dependent Claims (15, 17, 26, 32, 37)
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10. A DNA molecule encoding a chimeric membrane bound protein, said chimeric protein comprising in the N-terminal to C-terminal direction:
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at least two extracellular inducer-responsive clustering domains in tandem to form a multispecific extracellular inducer-responsive clustering domain that binds specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising ζ
or η
chain of the T-cell receptor; anda cytoplasmic domain comprising a Janus kinase; wherein when said membrane bound protein is expressed in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal for proliferation and effector function in said host cell on binding to said at least one inducer molecule. - View Dependent Claims (11, 12, 13, 14, 16, 27, 33, 38)
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18. A DNA molecule encoding a hybrid extracellular and intracellular multispecific chimeric receptor protein, said chimeric protein comprising in the N-terminal to C-terminal direction:
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at least two extracellular inducer-responsive clustering domains in tandem to form a multispecific extracellular inducer-responsive clustering domain that binds specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising a Janus kinase; and an intracellular inducer-responsive clustering domain comprising an immunophilin or a cyclophilin; wherein when said chimeric receptor protein is expressed in a selected host cell under conditions suitable for expression, said receptor protein initiates a signal for proliferation in said host cell on binding to said at least one inducer molecule. - View Dependent Claims (19, 20, 24, 28, 34, 39)
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21. A DNA molecule encoding a hybrid multispecific chimeric receptor protein, said protein comprising in the N-terminal to C-terminal direction:
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at least two extracellular inducer-responsive clustering domains in tandem to form a multispecific extracellular inducer-responsive clustering domain that binds specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising a Janus kinase; a cytoplasmic domain comprising a ζ
or η
chain of the T-cell receptor; andan intracellular inducer-responsive clustering domain comprising an immunophilin or a cyclophilin; wherein when said hybrid multispecific chimeric receptor is expressed in a selected host cell under conditions suitable for expression, said receptor protein initiates a signal for proliferation and effector function in said host cell on binding to said at least one inducer molecule. - View Dependent Claims (22, 23, 29, 35, 40)
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43. A chimeric protein comprising in the N-terminal to C-terminal direction:
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a multispecific extracellular inducer-responsive clustering domain comprising at least two domains in tandem that bind specifically to at least one inducer-molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; and a cytoplasmic domain comprising a ζ
or η
chain of the T-cell receptor, or a Janus kinase;wherein when said chimeric protein is expressed as a membrane bound protein in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal in said host cell on binding to said at least one inducer molecule.
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44. A chimeric protein comprising in the N-terminal to C-terminal direction:
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a multispecific extracellular inducer-responsive clustering domain comprising at least two domains in tandem that bind specifically to at least one inducer-molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising a Janus kinase; and a cytoplasmic domain comprising ζ
or η
;wherein when said chimeric protein is expressed as a membrane bound protein in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal for proliferation and effector function in said host cell on binding to said at least one inducer molecule.
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45. A chimeric protein comprising in the N-terminal to C-terminal direction:
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a multispecific extracellular inducer-responsive clustering domain comprising at least two domains in tandem that bind specifically to at least one inducer-molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising ζ
or η
chain of the T-cell receptor; anda cytoplasmic domain comprising a Janus kinase; wherein when said chimeric protein is expressed as a membrane bound protein in a selected host cell under conditions suitable for expression, said membrane bound protein initiates a signal for proliferation and effector function in said host cell on binding to said at least one inducer molecule.
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46. A chimeric hybrid binding protein comprising in the N-terminal to C-terminal direction:
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a multispecific extracellular inducer-responsive clustering domain comprising at least two domains in tandem that bind specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising a Janus kinase; and an intracellular inducer-responsive clustering domain comprising an immunophilin or a cyclophilin; wherein when said chimeric hybrid binding protein is expressed as a protein receptor in a selected host cell under conditions suitable for expression, said protein receptor initiates a signal for proliferation in said host cell on binding to either said inducer molecule or combinations thereof.
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47. A chimeric hybrid binding protein comprising in the N-terminal to C-terminal direction:
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a multispecific extracellular inducer-responsive clustering domain comprising at least two domains in tandem that bind specifically to at least one inducer molecule which results in the dimerization or oligomerization of said multispecific extracellular domain; a transmembrane domain; a cytoplasmic domain comprising a Janus kinase; a cytoplasmic domain comprising ζ
or η
chain of the T-cell receptor; andan intracellular inducer-responsive clustering domain comprising an immunophilin or a cyclophilin; wherein when said chimeric hybrid binding protein is expressed as a protein receptor in a selected host cell under conditions suitable for expression, said protein receptor initiates a signal for proliferation in said host cell on binding to either said inducer molecule or combinations thereof.
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Specification