CHIMERIC ANTIGEN RECEPTORS AGAINST SENESCENT CELLS AND USES THEREOF
The invention relates to a chimeric antigen receptor (CAR) comprising directed to at least one senescent cell-associated antigen, preferably to DEP1 and/or DPP4; including bispecific CAR, bispecific antibodies, and isolated immune cell population expressing the same. It also relates to uses and methods for treating, preventing or alleviating senescence-related diseases or disorders, or for depleting and/or killing senescent cells.
1 . A chimeric antigen receptor (CAR) comprising:
(i) at least one extracellular binding domain, comprising at least one antigen-binding domain directed to a senescent cell-associated antigen, preferably to DEP1 and/or DPP4,
(ii) an extracellular spacer domain,
(iii) a transmembrane domain,
(iv) optionally at least one costimulatory domain, and
(v) at least one intracellular signaling domain.
2 . The CAR according to claim 1 , wherein said at least one antigen-binding domain is directed to DEP1.
3 . The CAR according to claim 1 , wherein said at least one antigen-binding domain is directed to DPP4.
4 . The CAR according to claim 1 , wherein said CAR is a bispecific CAR comprising two antigen-binding domains.
5 . The CAR according to claim 4 , wherein each of the at least two antigen-binding domains binds to a different antigen.
6 . The CAR according to claim 4 , wherein each of the at least two antigen-binding domains binds to DEP1 and DPP4.
7 . An isolated immune cell population expressing at least one CAR according to claim 1 .
8 . The isolated immune cell population according to claim 7 , wherein said isolated immune cell population expresses at least one CAR according to claim 2 and at least one CAR according to claim 3 .
9 . The isolated immune cell population according to claim 7 , wherein said isolated immune cell population expresses at least one CAR according to claim 4 .
10 . The isolated immune cell population according to claim 7 , comprising immune cells selected from the group consisting of T cells, natural killer (NK) cells, or a combination thereof.
11 . An isolated bispecific antibody or a fragment thereof, comprising at least two antigen binding domains directed to at least two senescent cell-associated antigens, preferably the at least two senescent cell-associated antigens are DEP1 and DPP4.
12 . The isolated bispecific antibody or fragment thereof according to claim 11 , comprising:
(i) an antigen-binding domain of an anti-human DEP1 antibody or a fragment thereof; and
(ii) an antigen-binding domain of an anti-human DPP4 antibody or a fragment thereof.
13 . A composition comprising:
the isolated immune cell population according to claim 7 ;
the isolated bispecific antibody or fragment thereof according to claim 11 ; or
a mixture of an isolated anti-human DEP1 antibody or a fragment thereof and an isolated anti-human DPP4 antibody or a fragment thereof.
14 . The composition according to claim 13 , being a pharmaceutical composition and further comprising at least one pharmaceutically acceptable excipient.
15 . A method for treating, preventing or alleviating senescence-related diseases or disorders in a subject in need thereof, comprising administering to said subject the composition according to claim 13 .
16 . The method according to claim 15 , wherein senescence-related diseases or disorders are selected from the group consisting of fibrotic diseases, premalignant disorders, inflammatory diseases and cancers.
17 . A method for depleting and/or killing senescent cells in a subject in need thereof, comprising administering to said subject the composition according to claim 13 .