pH-dependent antigen-binding constructs specific to FOLR 1
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.
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.