Chimeric Antigen Receptor
The present invention provides a chimeric antigen receptor (CAR) comprising an antigen-binding domain with an affinity in the range of 50 nM to 500 nM, wherein said affinity comprises component kinetics such that the association rate constant (k on ) is greater than or equal to 1×10 5 M −1 S −1 , and/or the dissociation rate constant (k off ) is greater than or equal to 0.01 s −1 .
1 - 28 . (canceled)
29 . A method of treating a cancer which comprises the step of administering a cell which comprises a chimeric antigen receptor (CAR) to a subject, wherein the CAR comprises an antigen-binding domain with an affinity in the range of 50 nM to 500 nM, wherein said affinity comprises component kinetics such that the association rate constant (k on ) is greater than or equal to 1×10 5 M −1 s −1 , and the dissociation rate constant (k off ) is greater than or equal to 0.01 s −1 .
30 . The method according to claim 29 , wherein the affinity comprises component kinetics such that the association rate constant (k on ) is from 1×10 5 M −1 s −1 to 1×10 7 M −1 s −1 , and the dissociation rate constant (k off ) is from 0.01 s −1 to 0.5 s −1 .
31 . The method according to claim 29 , wherein the antigen-binding domain is a scFv.
32 . The method according to claim 29 , wherein the antigen is CD19.
33 . The method according to claim 29 , wherein the cancer is associated with CD19 expression
34 . The method according to claim 29 , wherein the cancer associated with CD19 expression is a B cell lymphoma or leukemia.
35 . The method according to claim 29 , wherein the cell is a T cell or a natural killer (NK) cell.
36 . The method according to claim 29 , which comprises the following steps:
i) transducing or transfecting cells from the subject ex vivo with a vector which comprises a polynucleotide which encodes a CAR as defined in claim 29 , and
ii) administering transfected cells back to the subject.
37 . A method for selecting an antigen-binding domain for use in a chimeric antigen receptor (CAR), the method comprising:
a) determining the affinity and affinity component kinetics of the antigen-binding domain; and
b) selecting the antigen-binding domain for use in a CAR if it has an affinity in the range of 50 nM to 200 nM,
wherein said affinity comprises component kinetics such that the association rate constant (k on ) is greater than or equal to 1×10 5 M −1 s −1 , and the dissociation rate constant (k off ) is greater than or equal to 0.01 s −1 .
38 . The method according to claim 37 , wherein the affinity comprises component kinetics such that the association rate constant (k on ) is from 1×10 5 M −1 s −1 to 1×10 7 M −1 s −1 , and the dissociation rate constant (k off ) is from 0.01 s −1 to 0.5 s −1 .
39 . The method according to claim 37 , wherein the antigen-binding domain is a scFv.
40 . The method according to claim 37 , wherein the antigen is CD19.