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US 2019/0169289 A1Published application
Optimized pne-based chimeric receptor t cell switches and uses thereof
AssigneeThe California Institute for Biomedical Research
InventorsTravis YOUNG, David T. RODGERS, Ian HARDY, Chanhyuk KIM, Peter G. SCHULTZ, Eric HAMPTON, Eduardo LABORDA, Leonard PRESTA
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Abstract
Disclosed herein are chimeric antigen receptor effector cells (CAR-ECs) and CAR-EC switches. The switchable CAR-ECs are generally T cells. The one or more chimeric antigen receptors may recognize a peptidic antigen on the CAR-EC switch. The CAR-ECs and switches may be used for the treatment of a condition in a subject in need thereof.
Claims36
A chimeric antigen receptor comprising an extracellular domain, a transmembrane domain an intracellular signaling domain, wherein the extracellular domain comprises:
- a. a region that interacts with a chimeric antigen receptor switch;
- and
- b. a hinge domain.
-15. (canceled)
A soluble T cell receptor switch comprising:
- a. a chimeric antigen receptor binding peptide;
- and
- b. a soluble T cell receptor or portion thereof.
-25. (canceled)
A chimeric antigen receptor switch comprising:
- A.
- i. a chimeric antigen receptor binding peptide;
- ii. a targeting moiety;
- iii. and a linker,
- wherein the linker links the chimeric antigen receptor binding peptide to the targeting moiety;
- B.
- i. a fusion antibody comprising:
- a. a chimeric antigen receptor binding peptide;
- and
- b. a light chain of an antibody or antibody fragment;
- wherein the chimeric antigen receptor binding peptide is connected to the light chain of the targeting antibody or antibody fragment, and
- ii. a heavy chain of the targeting antibody or antibody fragment;
- or
- C.
- i. a fusion antibody comprising:
- a. a chimeric antigen receptor binding peptide;
- and
- b. a heavy chain of an antibody or antibody fragment;
- wherein the chimeric antigen receptor binding peptide is connected to the heavy chain of the targeting antibody or antibody fragment, and
- ii. a light chain of the targeting antibody or antibody fragment.
17 more elements
-72. (canceled)
A method of producing an optimal switchable chimeric antigen receptor platform, comprising:
- A.
- i. incorporating a first chimeric antigen receptor binding peptide to a first site of a targeting moiety that binds a first cell surface molecule on a first target cell to produce a first switch;
- ii. incorporating a second chimeric antigen receptor binding peptide to a second site of a second targeting moiety that binds a second cell surface molecule on a second target cell to produce a second switch;
- iii. contacting the first target cell with the first switch and a first chimeric antigen receptor effector cell expressing a first chimeric antigen receptor;
- iv. contacting the second target cell with the second switch and a second chimeric antigen receptor effector cell expressing a second chimeric antigen receptor;
- and
- v. comparing a first cytotoxic effect of the first switch and the first chimeric antigen receptor effector cell on the first target cell to a second cytotoxic effect of the second switch and the second chimeric antigen receptor effector cell on the second target cell;
- and
- vi. selecting the first switch and first chimeric antigen receptor effector cell or the second switch and the second chimeric antigen receptor effector cell as the optimal switchable chimeric antigen receptor platform based on comparing the first cytotoxic effect to the second cytotoxic effect:
- or
- B. modulating a parameter of a first switchable chimeric antigen receptor platform or a second swtichable chimeric antigen receptor platform, and comparing a first outcome of the first switchable chimeric antigen receptor platform in response to modulationg the parameter to a second outcome of the second switchable chimeric antigen receptor platform in response to modulationg the parameter, wherein the parameter is selected from:
- i. affinity of the chimeric antigen receptor for the chimeric antigen receptor-effector cell switch;
- ii. distance between the chimeric antigen receptor-effector cell membrane and a target cell;
- iii. a number of chimeric antigen receptor-effector cell binding peptides on the chimeric antigen receptor-effector cell switch;
- iv. chimeric antigen receptor density on the chimeric antigen receptor-effector cell membrane;
- v. number of engagements between the chimeric antigen receptor-effector cell and the target cell,
- vi. and any combination thereof.
14 more elements
-106. (canceled)
-129. (canceled)
-146. (canceled)
A method of treating relapsed cancer, comprising administering:
- a. a first chimeric antigen receptor switch comprising a first chimeric antigen receptor binding peptide and a first targeting moiety;
- b. a second chimeric antigen receptor switch comprising a second chimeric antigen receptor binding peptide and a second targeting moiety;
- and
- c. a chimeric antigen receptor effector cell that binds the first chimeric antigen receptor binding peptide and the second CAR-BP,
- wherein the first chimeric antigen receptor switch is administered before a relapse of the subject and the second chimeric antigen receptor switch is administered after the relaspe of the subject.
2 more elements
-149. (canceled)
A two-component cancer therapeutic comprising:
- a. chimeric antigen receptor switch comprising a chimeric antigen receptor binding peptide and a targeting moiety, wherein the chimeric antigen receptor binding peptide is a non-endogenous peptide;
- and
- b. a chimeric antigen receptor effector cell that binds the chimeric antigen receptor binding peptide.
-153. (canceled)
A method comprising,
- administering to a subject an optimized first chimeric antigen receptor effector cell (CAR-EC) platform comprising
- a. a first CAR-EC switch comprising
- i. a first chimeric antigen receptor binding peptide (CAR-BP) and
- ii. a targeting moiety that binds a cell surface molecule on a target cell;
- and
- b. a first CAR-EC comprising a first chimeric antigen receptor (CAR) that binds the CAR-BP on the CAR-EC switch;
- wherein one or more parameter of the first CAR and the first CAR-EC switch are modified as compared to a second CAR and a second CAR-EC switch to induce an optimal CAR-EC-mediated cytotoxic effect on the target cell upon the binding of both the targeting moiety of the first CAR-EC switch to the surface molecule on the target cell and the first CAR-BP of the first CAR-EC switch to the first CAR on the first CAR-EC.
4 more elements
A method comprising, administering to a subject
- a) a first CAR-EC switch comprising
- i. a first chimeric antigen receptor binding peptide (CAR-BP) and
- ii. a targeting moiety that binds a cell surface molecule on a target cell;
- and
- b) a first CAR-EC comprising a first chimeric antigen receptor (CAR) that binds the CAR-BP on the CAR-EC switch;
- wherein one or more parameter of the first CAR and the first CAR-EC switch are modified as compared to a second CAR and a second CAR-EC switch to induce an optimal CAR-EC-mediated cytotoxic effect on the target cell upon the binding of both the targeting moiety of the first CAR-EC switch to the surface molecule on the target cell and the first CAR-BP of the first CAR-EC switch to the first CAR on the first CAR-EC.
3 more elements
Dependencies are inferred from the claim text.