METHODS OF TREATING AGING-RELATED DISORDERS
Provided herein are methods of treating an aging-related disease or condition in a subject in need thereof, killing or reducing the number of senescent cells in a subject in need thereof, improving the texture and/or appearance of skin and/or hair in a subject in need thereof, and assisting in the treatment of obesity in a subject in need thereof, that include administering to the subject a therapeutically effective amount of one or more natural killer (NK) cell activating agent(s) and/or a therapeutically effective number of activated NK cells.
1 . A method of treating liver fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide comprising:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain comprising a sequence that is at least 80% identical to SEQ ID NO: 188;
(ii) a soluble tissue factor domain comprising a sequence that is at least 80% identical to SEQ ID NO: 93; and
(iii) a first domain of a pair of affinity domains, wherein the first domain of the pair of the affinity domains comprises a sequence that is at least 80% identical to SEQ ID NO: 115; and
(b) a second chimeric polypeptide comprising:
(i) a second domain of the pair of affinity domains, wherein the second domain of the pair of affinity domains comprises a sequence that is at least 80% identical to SEQ ID NO: 113; and
(ii) a second target-binding domain comprising a sequence that is at least 80% identical to SEQ ID NO: 188,
wherein the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains.
2 . The method of claim 1 , wherein the multi-chain chimeric polypeptide results in a decrease in the activation of a TGF-β receptor.
3 . The method of claim 1 , wherein the first target-binding domain and the soluble tissue factor domain directly abut each other in the first chimeric polypeptide.
4 . The method of claim 1 , wherein the first chimeric polypeptide further comprises a linker sequence between the first target-binding domain and the soluble tissue factor domain in the first chimeric polypeptide.
5 . The method of claim 1 , wherein the soluble tissue factor domain and the first domain of the pair of affinity domains directly abut each other in the first chimeric polypeptide.
6 . The method of claim 1 , wherein the first chimeric polypeptide further comprises a linker sequence between the soluble tissue factor domain and the first domain of the pair of affinity domains in the first chimeric polypeptide.
7 . The method of claim 1 , wherein the second domain of the pair of affinity domains and the second target-binding domain directly abut each other in the second chimeric polypeptide.
8 . The method of claim 1 , wherein the second chimeric polypeptide further comprises a linker sequence between the second domain of the pair of affinity domains and the second target-binding domain in the second chimeric polypeptide.
9 . The method of claim 1 , wherein the soluble tissue factor domain does not stimulate blood coagulation.
10 . The method of claim 1 , wherein the soluble tissue factor domain comprises or consists of a sequence from a wildtype soluble human tissue factor.
11 . The method of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 188;
the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 93;
the first domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 115;
the second domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 113; and
the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 188.
12 . The method of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 188;
the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 93;
the first domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 115;
the second domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 113; and
the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 188.
13 . The method of claim 1 , wherein:
the first target-binding domain comprises SEQ ID NO: 188;
the soluble tissue factor domain comprises SEQ ID NO: 93;
the first domain of the pair of affinity domains comprises SEQ ID NO: 115;
the second domain of the pair of affinity domains comprises SEQ ID NO: 113; and
the second target-binding domain comprises SEQ ID NO: 188.
14 . The method of claim 1 , wherein:
the first chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 236; and
the second chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 193.
15 . The method of claim 1 , wherein:
the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 236; and
the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 193.
16 . The method of claim 1 , wherein:
the first chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 236; and
the second chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 193.
17 . The method of claim 1 , wherein:
the first chimeric polypeptide comprises SEQ ID NO: 236; and
the second chimeric polypeptide comprises SEQ ID NO: 193.
18 . A method of killing or reducing the number of senescent cells in a subject having liver fibrosis, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide comprising:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain comprising a sequence that is at least 80% identical to SEQ ID NO: 188;
(ii) a soluble tissue factor domain comprising a sequence that is at least 80% identical to SEQ ID NO: 93; and
(iii) a first domain of a pair of affinity domains, wherein the first domain of the pair of the affinity domains comprises a sequence that is at least 80% identical to SEQ ID NO: 115; and
(b) a second chimeric polypeptide comprising:
(i) a second domain of the pair of affinity domains, wherein the second domain of the pair of affinity domains comprises a sequence that is at least 80% identical to SEQ ID NO: 113; and
(ii) a second target-binding domain comprising a sequence that is at least 80% identical to SEQ ID NO: 188,
wherein the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains.
19 . The method of claim 18 , wherein the multi-chain chimeric polypeptide results in a decrease in the activation of a TGF-β receptor.
20 . The method of claim 18 , wherein the first target-binding domain and the soluble tissue factor domain directly abut each other in the first chimeric polypeptide.
21 . The method of claim 18 , wherein the first chimeric polypeptide further comprises a linker sequence between the first target-binding domain and the soluble tissue factor domain in the first chimeric polypeptide.
22 . The method of claim 18 , wherein the soluble tissue factor domain and the first domain of the pair of affinity domains directly abut each other in the first chimeric polypeptide.
23 . The method of claim 18 , wherein the first chimeric polypeptide further comprises a linker sequence between the soluble tissue factor domain and the first domain of the pair of affinity domains in the first chimeric polypeptide.
24 . The method of claim 18 , wherein the second domain of the pair of affinity domains and the second target-binding domain directly abut each other in the second chimeric polypeptide.
25 . The method of claim 18 , wherein the second chimeric polypeptide further comprises a linker sequence between the second domain of the pair of affinity domains and the second target-binding domain in the second chimeric polypeptide.
26 . The method of claim 18 , wherein the soluble tissue factor domain does not stimulate blood coagulation.
27 . The method of claim 18 , wherein the soluble tissue factor domain comprises or consists of a sequence from a wildtype soluble human tissue factor.
28 . The method of claim 18 , wherein:
the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 188;
the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 93;
the first domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 115;
the second domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 113; and
the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 188.
29 . The method of claim 18 , wherein:
the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 188;
the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 93;
the first domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 115;
the second domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 113; and
the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 188.
30 . The method of claim 18 , wherein:
the first target-binding domain comprises SEQ ID NO: 188;
the soluble tissue factor domain comprises SEQ ID NO: 93;
the first domain of the pair of affinity domains comprises SEQ ID NO: 115;
the second domain of the pair of affinity domains comprises SEQ ID NO: 113; and
the second target-binding domain comprises SEQ ID NO: 188.
31 . The method of claim 18 , wherein:
the first chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 236; and
the second chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 193.
32 . The method of claim 18 , wherein:
the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 236; and
the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 193.
33 . The method of claim 18 , wherein:
the first chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 236; and
the second chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 193.
34 . The method of claim 18 , wherein:
the first chimeric polypeptide comprises SEQ ID NO: 236; and
the second chimeric polypeptide comprises SEQ ID NO: 193.