MULTISPECIFIC AGENTS FOR TREATMENT OF CANCER
The invention provides multispecific agents having one arm binding CD47, and a second arm binding to CD24. The invention also provides multispecific agents having one arm binding to SIRPα and a second arm binding to siglec-10.
1 . A multispecific agent comprising a first binding arm that specifically binds CD47 and a second binding arm that specifically binds to CD24.
2 . The multispecific agent of claim 1 , wherein the first binding arm antagonizes CD47 binding to SIRPα and the second binding arm antagonizes CD24 binding to siglec-10.
3 . The multispecific agent of any preceding claim, wherein the first binding arm is an antibody VH-VL pair or a SIRPα extracellular domain, and second binding arm is an antibody VH-VL pair or a siglec-10 extracellular domain.
4 . The multispecific agent of any preceding claim having a single first binding arm and a single second binding arm.
5 . The multispecific agent of any one of claims 1 - 3 having two copies of a first binding arm and two copies of a second binding arm.
6 . The multispecific agent of any preceding claim, further comprising a third binding arm specifically binding to a cancer antigen
7 . The multispecific agent of claim 6 , wherein the cancer antigen is CD20.
8 . The multispecific agent of any preceding claim, wherein the first and second binding arms have affinities for CD47 and CD24 within a factor of four for one another.
9 . The multispecific agent of any one of claims 1 - 7 , wherein the second binding arm has a higher affinity for CD24 by at least a factor of five than the first binding arm has for CD47.
10 . The multispecific agent of any preceding claim, further comprising an Fc domain.
11 . The multispecific agent of claim 10 , wherein the Fc domain is of human IgG4 isotype.
12 . The multispecific agent of claim 10 , wherein the Fc domain of human IgG1 or IgG4 isotype.
13 . The multispecific agent of claim 10 , which is of human IgG1 isotype mutated to reduce effector functions.
14 . A method of treating a patient having a cancer, comprising administering a multispecific agent of any preceding claim to the patient.
15 . The method of claim 14 , wherein the cancer expresses CD24 and CD47.
16 . The method of claim 13 or 15 , wherein the multispecific agent further comprises a third binding arm specifically binding to a cancer antigen, wherein the cancer expresses the cancer specific antigen.
17 . The method of any one of claims 14 - 16 , wherein the cancer is adenocarcinoma.
18 . The method of any one of claims 14 - 16 , wherein the cancer is a lymphoma.
19 . The method of any one of claims 14 - 18 , further comprising detecting expression of CD24 and CD47 on cells of the cancer.
20 . A multispecific agent comprising a first binding arm that specifically binds to SIRPα and a second binding arm that specifically binds to siglec-10.
21 . The multispecific agent of claim 20 , wherein the first binding arm antagonizes CD47 binding to SIRPα and the second binding arm antagonizes CD24 binding to siglec-10.
22 . The multispecific agent of claim 20 or 21 , wherein the first binding arm is an antibody VH-VL pair or a SIRPα extracellular domain, and second binding arm is an antibody VH-VL pair or a siglec-10 binding domain.
23 . The multispecific agent of any one of claims 20 - 22 having a single first binding arm and a single second binding arm.
24 . The multispecific agent of any one of claims 20 - 22 having two copies of a first binding arm and two copies of a second binding arm
25 . The multispecific agent of any one of claims 20 - 24 , wherein the first and second binding arms have affinities for SIRPα and siglec-10 within a factor of four for one another.
26 . The multispecific agent of any one of claims 20 - 24 , wherein the second binding arm has at least five fold higher affinity for siglec-10 than the first binding arm has for SIRPα.
27 . The multispecific agent of any one of claims 20 - 27 , further comprising an Fc domain.
28 . The multispecific agent of claim 27 , wherein the Fc domain is of human IgG4 isotype.
29 . The multispecific agent of claim 27 , wherein the Fc domain of human IgG1 or IgG4 isotype.
30 . The multispecific agent of claim 27 , wherein the Fc domain is of human IgG1 isotype mutated to reduce effector functions.
31 . A method of treating a patient having a cancer, comprising administering a multispecific agent of any one of claims 20 - 30 to the patient.
32 . The method of claim 31 , wherein the multispecific agent further comprises a third binding arm specifically binding to a cancer antigen, wherein the cancer expresses the cancer specific antigen.