Epitope specific antibodies that bind cell surface GRP78 and their use for cancer detection

Patent metadata

Field	Value
Publication number	US-11845792-B2
Application number	US-202017077514-A
Country	US
Kind code	B2
Filing date	Oct 22, 2020
Priority date	Mar 14, 2013
Publication date	Dec 19, 2023
Grant date	Dec 19, 2023

Abstract

This application provides, inter alia, antibodies or antigen-binding fragments thereof, targeting cell surface GRP78 expressed on tumor cells, tumor endothelial cells, and tumor initiating cancer cells. These anti-GRP78 antibodies, or antigen-binding fragments thereof, have a high affinity for GRP78 and are less immunogenic compared to their unmodified parent antibodies in a given species, e.g., a human, and function to inhibit GRP78. Importantly, these isolated novel antibodies and antigen-binding fragments thereof, attenuate PI3K signaling and promote apoptosis in tumor cells, while leaving normal cells unaffected. The antibodies and antigen-binding fragments are useful for UPR-targeted cancer therapeutic treatments.

First claim

What is claimed is:

1. An isolated antibody or antigen-binding fragment thereof that binds to human cell surface glucose regulated protein 78 (GRP78)(SEQ ID NO: 1), wherein said antibody or antigen-binding fragment binds to an epitope depicted in SEQ ID NO: 31 comprises a heavy chain variable region and a light chain variable region having at least 90% sequence identity to a sequence selected from the group consisting of the following pairs of sequences: SEQ ID NO: 13 and SEQ ID NO: 23; SEQ ID NO: 15 and SEQ ID NO: 27; SEQ ID NO: 17 and SEQ ID NO: 25; SEQ ID NO: 19 and SEQ ID NO: 25; SEQ ID NO: 19 and SEQ ID NO: 29; or SEQ ID NO: 21 and SEQ ID NO: 23; and
wherein the antibody or antigen-binding fragment comprises a heavy chain complementarity determining region (HCDR) 1 comprising SEQ ID NO: 3, a HCDR2 comprising SEQ ID NO: 4, a HCDR3 comprising SEQ ID NO: 5, a light chain complementarity determining region (LCDR) 1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7, and a LCDR3 comprising SEQ ID NO: 8.

2. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or antigen-binding fragment thereof is less immunogenic in a human subject than the monoclonal antibody which comprises heavy chain variable region having at least 90% sequence identity to a sequence comprising SEQ ID NO: 9 and a light chain variable region consisting of SEQ ID NO: 11 and comprising a heavy chain complementarity determining region (HCDR) 1 comprising SEQ ID NO: 3, a HCDR2 comprising SEQ ID NO: 4, a HCDR3 comprising SEQ ID NO: 5, a light chain complementarity determining region (LCDR) 1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7, and a LCDR3 comprising SEQ ID NO: 8;
wherein said antibody or antigen-binding fragment thereof binds said cell surface GRP78 with a similar or greater binding affinity than the monoclonal antibody which comprises a heavy chain variable region consisting of SEQ ID NO: 9 and a light chain variable region consisting of SEQ ID NO: 11; and/or
wherein said antibody or antigen-binding fragment thereof binds to said cell surface GRP78 with a dissociation constant (K D ) of at least about 1×10− 3 M, at least about 1×10− 4 M, at least about 1×10− 5 M, at least about 1×10− 6 M, at least about 1×10− 7 M, at least about 1×10− 8 M, at least about 1×10− 9 M, at least about 1×10− 10 M, at least about 1×10− 11 M, or at least about 1×10− 12 M.

3. An isolated antibody or antigen-binding fragment thereof according to claim 1 ,
wherein said antibody or antigen-binding fragment thereof is a polyclonal antibody, a monoclonal antibody or antigen-binding fragment thereof, a recombinant antibody, a diabody, a chimerized or chimeric antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a fully human antibody or antigen-binding fragment thereof, a CDR-grafted antibody or antigen-binding fragment thereof, a single chain antibody, an Fv, an Fd, an Fab, an Fab′, or an F(ab′) 2 , or synthetic or semi-synthetic antibodies.

4. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to claim 1 in pharmaceutically acceptable carriers or excipients.

5. An isolated antibody or antigen-binding fragment thereof according to claim 1 , wherein said antibody or antigen-binding fragment is labeled, wherein said label is a fluorescent label, a radioactive label, or a label having a distinctive nuclear magnetic resonance signature.

6. An isolated immunoconjugate comprising an antibody or antigen-binding fragment according to claim 1 linked to an effector molecule.

7. An immunoconjugate of claim 6 , wherein the effector molecule is an immunotoxin, cytokine, chemokine, therapeutic agent, or a chemotherapeutic agent.

Assignees

• Univ Southern California

Inventors

• Gill Parkash
• Liu Ren
• Lee Amy

Classifications

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K16/28 Primary

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title