Integrin Alpha10 Antibody
AssigneeTarginta AB
InventorsEvy Lundgren Åkerlund, Katarzyna Chmielarska Masoumi, Xiaoli Huang
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Abstract
The present invention relates to a novel integrin alphalO antibody, as well as uses thereof in medicine. 25 humanized antibodies (abs) derived from the known mouse mAb365 (the hybridoma deposited under the accession number DSM ACC2583) are disclosed. The ones which bind specifically the integrin alpha 10 beta 1 were selected. Out of the 25 humanized variants 5 were selected as lead candidates (designated TAR-Ab8, TAR-Ab9, TAR-Abl3, TAR-Abl4 and TAR-Ab23) since these 5 entire antibodies were shown to have improved thermal stability as compared to the chimeric antibody designated TAR-Ab0. There is further functional characterization only of TAR-Ab23 which has higher binding affinity than mAb365.
Claims91
An antibody or antigen-binding fragment thereof with binding specificity for integrin alpha10, wherein the antibody or antigen-binding fragment comprises:
- a light chain variable region comprising
- a) a CDR-L1 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 1;
- b) a CDR-L2 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:
- 2, and SEQ ID NO:
- 4;
- and
- c) a CDR-L3 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 5;
- and/or
- a heavy chain variable region comprising
- d) a CDR-H1 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:
- 7, SEQ ID NO:
- 6 and SEQ ID NO:
- 8;
- e) a CDR-H2 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 9;
- and
- f) a CDR-H3 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 10.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims wherein the integrin alpha10beta1 is human integrin alpha10beta1.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the integrin alpha10 polypeptide is a part of an integrin alpha10 beta1 heterodimer.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims wherein the integrin alpha10beta1 is expressed on the surface of a cell.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims wherein the antibody or antigen-binding fragment thereof binds to the extracellular I-domain of integrin alpha10beta1.
The antibody or antigen-binding fragment according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of
- a) the amino acid sequence of SEQ ID NO:
- 13,
- or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:
- 13, for example at least 90%, 95%, 98% or 99% sequence identity;
- or
- b) an amino acid sequence selected from the group consisting of SEQ ID NO:
- 11, SEQ ID NO:12;
- SEQ ID NO:
- 13;
- SEQ ID NO:
- 14 and SEQ ID NO:15, or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:
- 11, SEQ ID NO:12;
- SEQ ID NO:
- 13;
- SEQ ID NO:
- 14 and SEQ ID NO:15, for example at least 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NO:
- 11, SEQ ID NO:12;
- SEQ ID NO:
- 14 and SEQ ID NO:15.
The antibody or antigen-binding fragment according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:
- 13, or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:
- 13, for example at least 90%, 95%, 98% or 99% sequence identity.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of
- a) the amino acid sequence of SEQ ID NO:
- 19;
- or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:
- 19 for example at least 90%, 95%, 98% or 99% sequence identity;
- or
- b) an amino acid sequence selected from the group consisting of SEQ ID NO:
- 16, SEQ ID NO:
- 17, SEQ ID NO:
- 18, and SEQ ID NO:
- 20;
- or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:
- 16, SEQ ID NO:
- 17, SEQ ID NO:
- 18, and SEQ ID NO:
- 20, for example at least 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NO:
- 16, SEQ ID NO:
- 17, SEQ ID NO:
- 18, and SEQ ID NO:
- 20.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:
- 19;
- or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:
- 19 for example at least 90%, 95%, 98% or 99% sequence identity.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising
- a) a CDR-L1 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 1;
- b) a CDR-L2 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:
- 2, and
- c) a CDR-L3 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 5;
- and
- a heavy chain variable region comprising
- a) a CDR-H1 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:
- 7,
- b) a CDR-H2 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 9;
- and
- c) a CDR-H3 comprising or consisting of an amino acid sequence of SEQ ID NO:
- 10;
- or an amino acid sequence having at least 70% sequence identity to SEQ ID NO:
- 1, SEQ ID NO:
- 2, SEQ ID NO:
- 5, SEQ ID NO:
- 7, or SEQ ID NO:
- 9, SEQ ID NO:
- 10, for example at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region which comprises or consists of SEQ ID NO:
- 13 and a heavy chain variable region which comprises or consists of SEQ ID NO:
- 19.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is capable of inhibiting cell adhesion, cell proliferation, cell growth, cell migration, cell survival, or any combination thereof.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is capable of inhibiting metastasis.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein any one of the amino acids of the framework region of the light chain variable region has been altered for another amino acid, with the proviso that no more than 5 amino acids have been so altered, such as 4 amino acids, no more than 3 amino acids, such as 2 amino acids or no more than 1 amino acid.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein any one of the amino acids of the framework region of the heavy chain variable region has been altered for another amino acid, with the proviso that no more than 5 amino acids have been so altered, such as 4 amino acids, no more than 3 amino acids, such as 2 amino acids or no more than 1 amino acid.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein any one of the amino acids of the framework region of the light chain variable region and/or the heavy chain variable region has been altered for another amino acid, with the proviso that no more than 5 amino acids have been so altered, such as 4 amino acids, no more than 3 amino acids, such as 2 amino acids or no more than 1 amino acid.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a light chain constant region, or part thereof.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region, or part thereof.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein any one of the amino acids of the light chain constant region and/or the heavy chain constant region has been altered for another amino acid, with the proviso that no more than 5 amino acids have been so altered, such as 4 amino acids, no more than 3 amino acids, such as 2 amino acids or no more than 1 amino acid.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises an Fc region.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims comprising or consisting of an intact antibody.
The antibody or antigen-binding fragment thereof according to any one of the preceding claims comprising or consisting of an antigen-binding fragment selected from the group consisting of Fv fragments (e.g. single chain Fv and disulphide-bonded Fv), Fab-like fragments (e.g. Fab fragments, Fab′ fragments and F(ab)2 fragments) and domain antibodies (e.g. single VH variable domains or VL variable domains).
The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is capable of inhibiting signalling of integrin alpha10beta1.
The antibody or antigen-binding fragment thereof with binding specificity for integrin alpha10beta1 is capable of inhibiting cell adhesion, cell proliferation, cell growth, cell migration, cell survival, or any combination thereof, of cells expressing integrin alpha10beta1.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is conjugated to an additional moiety.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the additional moiety comprises a detectable moiety, such as a detectable moiety selected from the group consisting of a fluorophore, an enzyme and a radioactive tracer or radioisotope.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the additional moiety comprises a cytotoxic moiety.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the cytotoxic moiety is selected from a group consisting of a toxin, a chemotherapeutic agent and a radioactive agent, or combinations thereof.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the cytotoxic moiety is a toxin.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims wherein said toxin is selected from the group selected from microtubule toxins, DNA toxins and transcription toxins.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims wherein said microtubule toxins are selected from the group consisting of Auristatin-based toxins, Maytansinoid-based toxins, Tubulysins-based toxins and Eribulin.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims wherein said transcription toxin is an RNA polymerase II inhibiting agent.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims wherein said transcription toxin is selected from the group consisting of Doxorubicin, Doxorubicin derivatives and Amanitin.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims wherein said Doxorubicin derivative is 3′-deamino-3″-4′-anhydro-[2″(S)-methoxy-3″(R)-hydroxy-4″-morpholinyl]doxorubicin.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the transcription toxin is selected from the group consisting of shiga and shiga-like toxins;
- type I ribosome inactivating proteins, type II ribosome inactivating proteins and saporin, or combinations thereof.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the type I ribosome inactivating protein is trichosanthin and/or luffin.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the type II ribosome inactivating protein is ricin, agglutinin and/or abrin.
The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the transcription toxin is selected from the group consisting of shiga and shiga-like toxins;
- type I ribosome inactivating proteins, type II ribosome inactivating proteins and saporin, or combinations thereof.
The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein the cells are malignant cells and/or tumor-associated cells.
The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein the malignant cells or tumor-associated cells are cancer associated fibroblast (CAFs), stromal cells, stem cells and/or stem-like cells and/or cells of the tumor microenvironment such as tumor-associated macrophages (TAMs), immune cells, endothelial cells.
The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein the treatment is initiated upon detection of an integrin alpha10 polypeptide in a cancer cell in a tumor of a subject.
The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein the antibody or antigen-binding fragment is administered to an individual in need thereof in combination with radiation therapy and/or surgical removal of cancer.
The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein the antibody or antigen-binding fragment is administered to an individual in need thereof prior to radiation therapy and/or surgical removal of cancer.
The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein the antibody or antigen-binding fragment is administered to an individual in need thereof after radiation therapy and/or surgical removal of cancer.
A polynucleotide encoding an antibody or antigen-binding fragment thereof according to any one of the preceding claims or a component polypeptide chain thereof.
Dependencies are inferred from the claim text.