IP Library › Granted Patent US 12,673,989
Granted Patent B2
US 12,673,989 · App. 17/616,745 · Granted Jul 7, 2026

pH-dependent antigen-binding constructs specific to FOLR 1

Inventors: Alexander J. Nichols (Lincoln, MA); Brian P. Fiske (Cambridge, MA); Nimish Gera (Waltham, MA)
Assignee: Mythic Therapeutics, Inc.
C07K16/28A61K47/68031A61K47/68035A61P35/00C07K16/30C07K2317/31C07K2317/565C07K2317/77C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 12,673,989
App. No.
17/616,745
Filed
Dec 6, 2021
Granted
Jul 7, 2026
Kind
B2
Art Unit
1646
USPC
424/133.1
Abstract

Provided herein are antigen-binding protein constructs capable of specifically binding FOLR1 or an epitope of FOLR1 presented on the surface of a target mammalian cell, wherein said antigen binding is pH-dependent. Provided are also uses of said antigen-binding protein constructs.

Claims (63)

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 FOLR1 or an epitope of FOLR1 presented on the surface of a target cancer cell,

wherein the first antigen-binding domain comprises:

(a) a heavy chain variable domain comprising any one of SEQ ID NOs: 14, 17, 19, 21-24, 26, 30, 31, 33-36, 43-46, 48, 49, 51, 53, and 85-103 and a light chain variable domain comprising SEQ ID NO: 2; or

(b) a heavy chain variable domain comprising SEQ ID NO: 1 and a light chain variable domain comprising any one of SEQ ID NOs: 58, 60-62, 64-66, 70, 74, 76-81, and 83; 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 (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0.

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

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

4 . The pharmaceutical composition of claim 3 , wherein the antigen-binding domain is a scFv.

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

6 . The pharmaceutical composition of claim 5 , wherein the ABPC is an antibody.

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

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

9 . A method of treating a cancer having a population of cancer cells that have FOLR1 or an epitope of FOLR1 presented on their surface, the method comprising:

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

10 . A method of reducing the volume of a tumor in a subject, wherein the tumor has a population of cancer cells that have FOLR1 or an epitope of FOLR1 presented on their surface, the method comprising:

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

11 . A method of inducing cell death in a cancer cell in a subject, wherein the cancer cell has FOLR1 or an epitope of FOLR1 presented on its surface, wherein the method comprises:

administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a subject previously identified as having a cancer having the cancer cell.

12 . 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 has a population of cancer cells that have FOLR1 or an epitope of FOLR1 presented on their surface the method comprising:

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

13 . 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 FOLR1 or an epitope of FOLR1 presented on the surface of a target cancer cell; and

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

wherein the first antigen-binding domain comprises:

(a) a heavy chain variable domain comprising any one of SEQ ID NOs: NO: 14, 17, 19, 21-24, 26, 30, 31, 33-36, 43-46, 48, 49, 51, 53, and 85-103 and a light chain variable domain comprising SEQ ID NO: 2; or

(b) a heavy chain variable domain comprising SEQ ID NO: 1 and a light chain variable domain comprising any one of SEQ ID NOs: 58, 60-62, 64-66, 70, 74, 76-81, and 83; 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 (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD 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 cancer cell as compared to a composition comprising the same amount of a control ABPC;

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

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

14 . The pharmaceutical composition of claim 13 , wherein the ABPC comprises two or more polypeptides.

15 . The pharmaceutical composition of claim 14 , wherein the ABPC is an antibody.

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

a first antigen-binding domain that is capable of specifically binding FOLR1 or an epitope of FOLR1 presented on the surface of a target cancer cell,

wherein the first antigen-binding domain comprises:

(a) a heavy chain variable domain comprising any one of SEQ ID NOs: NO: 14, 17, 19, 21-24, 26, 30, 31, 33-36, 43-46, 48, 49, 51, 53, and 85-103 and a light chain variable domain comprising SEQ ID NO: 2; or

(b) a heavy chain variable domain comprising SEQ ID NO: 1 and a light chain variable domain comprising any one of SEQ ID NOs: 58, 60-62, 64-66, 70, 74, 76-81, and 83; 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 (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0.

17 . The ABPC of claim 16 , wherein the ABPC comprises two or more polypeptides.

18 . The ABPC of claim 16 , wherein the ABPC is an antibody.

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

a first antigen-binding domain that is capable of specifically binding FOLR1 or an epitope of FOLR1 presented on the surface of a target cancer cell; and

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

wherein the first antigen-binding domain comprises:

(a) a heavy chain variable domain comprising any one of SEQ ID NOs: NO: 14, 17, 19, 21-24, 26, 30, 31, 33-36, 43-46, 48, 49, 51, 53, and 85-103 and a light chain variable domain comprising SEQ ID NO: 2; or

(b) a heavy chain variable domain comprising SEQ ID NO: 1 and a light chain variable domain comprising any one of SEQ ID NOs: 58, 60-62, 64-66, 70, 74, 76-81, and 83; 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 (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD 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 cancer cell as compared to a composition comprising the same amount of a control ABPC;

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

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

20 . The ABPC of claim 19 , wherein the ABPC comprises two or more polypeptides.

21 . The ABPC of claim 20 , wherein the ABPC is an antibody.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 21, 2021
From: NICHOLS, ALEXANDER J.; FISKE, BRIAN P.; GERA, NIMISH
To: MYTHIC THERAPEUTICS, INC.
Reel/Frame 058442/0179 →
Continuity (3)
Provisional Application 62897965 · Sep 9, 2019
Provisional Application 62858310 · Jun 6, 2019
Related Publication 20220298260A1 · Sep 22, 2022
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