IP Library › Granted Patent US 12,721,901
Granted Patent B2
US 12,721,901 · App. 17/641,495 · Granted Sep 1, 2026

Antigen-binding protein constructs and uses thereof

Inventors: Alexander J. Nichols (Lincoln, MA); Brian P. Fiske (Cambridge, MA); Nimish Gera (Waltham, MA)
A61K47/6849A61K47/68031A61K47/68035A61P35/00C07K16/2866A61K2039/505C07K2317/33C07K2317/73C07K2317/77C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 12,721,901
App. No.
17/641,495
Granted
Sep 1, 2026
Kind
B2
Abstract

Provided herein are antigen-binding protein constructs and uses of the same.

Claims (67)

1 . A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding CD123 or an epitope of CD123 presented on the surface of a target mammalian cell,

wherein the first antigen-binding domain comprises:

a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 64, SEQ ID NO: 70, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 78, or SEQ ID NO: 79; or

a heavy chain variable domain of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 40, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, or SEQ ID NO: 100 and a light chain variable domain of SEQ ID NO: 2;

and wherein:

(i) the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or

(ii) the dissociation constant (K D ) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the Kp at a pH of about 7.0 to about 8.0.

2 . The pharmaceutical composition of claim 1 , wherein the ABPC is degraded in the target mammalian cell following internalization of the ABPC by the target mammalian cell.

3 . The pharmaceutical composition of claim 1 , wherein the ABPC further comprises a conjugated toxin, radioisotope, drug, or small molecule.

4 . A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding CD123 or an epitope of CD123 presented on the surface of a target mammalian cell; and

a conjugated toxin, radioisotope, drug, or small molecule,

wherein the first antigen-binding domain comprises:

a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 64, SEQ ID NO: 70, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 78, or SEQ ID NO: 79; or

a heavy chain variable domain of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 40, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, or SEQ ID NO: 100 and a light chain variable domain of SEQ ID NO: 2;

and wherein:

(i) the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or

the dissociation constant (K D ) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the K D at a pH of about 7.0 to about 8.0; and

(ii) the composition provides for one or more of:

an increase in toxin liberation in the target mammalian cell as compared to a composition comprising the same amount of a control ABPC comprising a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2;

an increase in target mammalian cell killing as compared to a composition comprising the same amount of the control ABPC; and

an increase in endolysosomal delivery in the target mammalian cell as compared to a composition comprising the same amount of the control ABPC.

5 . The pharmaceutical composition of claim 4 , wherein the composition provides for:

an increase in toxin liberation in the target mammalian cell as compared to a composition comprising the same amount of the control ABPC; and/or

an increase in target mammalian cell killing as compared to a composition comprising the same amount of the control ABPC.

6 . The pharmaceutical composition of claim 1 , wherein the composition provides for an increase in endolysosomal delivery in the target mammalian cell as compared to a composition comprising the same amount of a control ABPC.

7 . The pharmaceutical composition of claim 1 , wherein the composition:

results in less of a reduction in the level of CD123 presented on the surface of the target mammalian cell as compared to a composition comprising the same amount of a control ABPC comprising a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2; or

does not result in a detectable reduction in the level of CD123 presented on the surface of the target mammalian cell.

8 . The pharmaceutical composition of claim 1 , wherein the target mammalian cell is a cancer cell.

9 . The pharmaceutical composition of claim 1 , wherein the ABPC is cytotoxic or cytostatic to the target mammalian cell.

10 . The pharmaceutical composition of claim 1 , wherein the ABPC comprises a single polypeptide.

11 . The pharmaceutical composition of claim 10 , wherein the antigen-binding domain is an scFv.

12 . The pharmaceutical composition of claim 1 , wherein the ABPC comprises two or more polypeptides.

13 . The pharmaceutical composition of claim 12 , wherein the ABPC is an antibody.

14 . The pharmaceutical composition of claim 1 , wherein the ABPC further comprises a second antigen-binding domain.

15 . An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding CD123 or an epitope of CD123 presented on the surface of a target mammalian cell,

wherein the first antigen-binding domain comprises:

a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 64, SEQ ID NO: 70, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 78, or SEQ ID NO: 79; or

a heavy chain variable domain of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 40, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, or SEQ ID NO: 100 and a light chain variable domain of SEQ ID NO: 2;

and wherein:

(i) the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or

(ii) the dissociation constant (K D ) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the Kp at a pH of about 7.0 to about 8.0.

16 . An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding CD123 or an epitope of CD123 presented on the surface of a target mammalian cell; and

a conjugated toxin, radioisotope, drug, or small molecule,

wherein the first antigen-binding domain comprises:

a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 64, SEQ ID NO: 70, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 78, or SEQ ID NO: 79; or

a heavy chain variable domain of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 40, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, or SEQ ID NO: 100 and a light chain variable domain of SEQ ID NO: 2;

and wherein:

(i) the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or

the dissociation constant (K D ) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the K D at a pH of about 7.0 to about 8.0; and

(ii) the composition provides for one or more of:

an increase in toxin liberation in the target mammalian cell as compared to a composition comprising the same amount of a control ABPC comprising a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2;

an increase in target mammalian cell killing as compared to a composition comprising the same amount of the control ABPC; and

an increase in endolysosomal delivery in the target mammalian cell as compared to a composition comprising the same amount of the control ABPC.

17 . A kit comprising at least one dose of the pharmaceutical composition of claim 1 .

18 . A method of treating a cancer characterized by having a population of cancer cells that have CD123 or an epitope of CD123 presented on their surface, the method comprising:

administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a subject identified as having a cancer characterized by having the population of cancer cells.

19 . A method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that have CD123 or an epitope of CD123 presented on their surface, the method comprising:

administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a subject identified as having a cancer characterized by having the population of cancer cells.

20 . A method of inducing cell death in a cancer cell in a subject, wherein the cancer cell has CD123 or an epitope of CD123 presented on its surface, wherein the method comprises:

administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a subject identified as having a cancer characterized by having a population of the cancer cells.

21 . A method of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that have CD123 or an epitope of CD123 presented on their surface the method comprising:

administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a subject identified as having a cancer characterized by having the population of cancer cells.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2022
From: NICHOLS, ALEXANDER J.; FISKE, BRIAN P.; GERA, NIMISH
To: MYTHIC THERAPEUTICS, INC.
Reel/Frame 059477/0001 →
Continuity (2)
Provisional Application 62900113 · Sep 13, 2019
Related Publication 20220306751A1 · Sep 29, 2022
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