# US 12,180,269 B2 · GRP78-binding antibodies and uses thereof in detecting or neutralizing GRP78

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- Number: US 12,180,269 B2
- Document ID: US12180269B2
- Status: Granted
- Kind: B2
- Application number: 17/837,943
- Filed: 2022-06-10
- Published: 2023-01-26
- Granted: 2024-12-31
- Earliest claimed: 2016-09-21
- Assignees: Rutgers, The State University of New Jersey
- Applicants: Rutgers, The State University of New Jersey
- Inventors: Renata Pasqualini; Wadih Arap; Fernanda Iamassaki Staquicini; Fortunato Ferrara; Sara D'Angelo; Andrew R. M. Bradbury
- Web page: https://patentgrep.com/patent/US12180269B2

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61K 38/07: Tetrapeptides
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/68033: {the drug being a maytansine}
- A61K 47/6843: {the antibody targeting a material from animals or humans}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61P 35/00: Antineoplastic agents
- C07K 16/18: against material from animals or humans
- C07K 16/30: from tumour cells
- G01N 33/575: for cancer
- A61K 2039/505: {comprising antibodies}
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/35: Valency
- C07K 2317/55: Fab or Fab'
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/77: Internalization into the cell
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Isolated or recombinant EphA5 or GRP78 targeting antibodies are provided. In some cases, antibodies of the embodiments can be used for the detection, diagnosis and/or therapeutic treatment of human diseases, such as cancer. A method of rapidly identifying antibodies or antibody fragments for the treatment of cancer using a combination of in vitro and in vivo methodologies is also provided.

## Claims

### Claim 1

An isolated monoclonal antibody, wherein the antibody specifically binds to GRP78 (78 kDa glucose-regulated protein) and comprises:
a heavy chain variable region (VH) comprising a VH CDR1 having the amino acid sequence set forth in SEQ ID NO: 55, a VH CDR2 having the amino acid sequence set forth in SEQ ID NO: 56, and a VH CDR3 having the amino acid sequence set forth in SEQ ID NO: 57;
and
a light chain variable region (VL) comprising a VL CDR1 having the amino acid sequence set forth in SEQ ID NO: 58, a VL CDR2 having the amino acid sequence set forth in SEQ ID NO: 59, and a VL CDR3 having the amino acid sequence set forth in SEQ ID NO: 60.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence that is at least 90% identical to SEQ ID NO: 53 and a VL having an amino acid sequence that is at least 90% identical to SEQ ID NO: 54.

### Claim 3 (depends on 1)

The antibody of claim 1, wherein the antibody comprises a VH having an amino acid sequence that is at least 95% identical to SEQ ID NO: 53 and a VL having an amino acid sequence that is at least 95% identical to SEQ ID NO: 54.

### Claim 4 (depends on 1)

The antibody of claim 1, wherein the antibody comprises the VH having the amino acid sequence set forth in SEQ ID NO: 53 and the VL having the amino acid sequence set forth in SEQ ID NO: 54.

### Claim 5 (depends on 1)

The antibody of claim 1, wherein the antibody is a recombinant antibody.

### Claim 6 (depends on 1)

The antibody of claim 1, wherein the antibody is an IgG, IgM, IgA, or an antigen binding fragment thereof.

### Claim 7 (depends on 1)

The antibody of claim 1, wherein the antibody is a Fab′, a F(ab′)2, a F(ab′)3, a monovalent scFv, or a bivalent scFv.

### Claim 8 (depends on 1)

The antibody of claim 1, wherein the antibody is a full length antibody.

### Claim 9 (depends on 1)

The antibody of claim 1, wherein the antibody is a human, humanized antibody, or de-immunized antibody.

### Claim 10 (depends on 1)

An immunoconjugate comprising the antibody of claim 1 conjugated to at least one effector moiety selected from an imaging agent, a chemotherapeutic agent, a toxin, and a radionuclide.

### Claim 11 (depends on 10)

The immunoconjugate of claim 10, wherein there is one effector moiety, and wherein the one effector moiety is a toxin.

### Claim 12 (depends on 11)

The immunoconjugate of claim 11, wherein the toxin is auristatin.

### Claim 13 (depends on 12)

The immunoconjugate of claim 12, wherein the toxin is monomethyl auristatin E (MMAE).

### Claim 14 (depends on 1)

A composition comprising the antibody of claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 15 (depends on 10)

A composition comprising the immunoconjugate of claim 10 and at least one pharmaceutically acceptable carrier.

### Claim 16 (depends on 12)

A composition comprising the immunoconjugate of claim 12 and at least one pharmaceutically acceptable carrier.

### Claim 17 (depends on 13)

A composition comprising the immunoconjugate of claim 13 and at least one pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A method of treating or ameliorating a cancer in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 1.

### Claim 19 (depends on 10)

A method of treating or ameliorating a cancer in a subject, the method comprising administering to the subject an effective amount of the immunoconjugate of claim 10.

### Claim 20 (depends on 1)

A method of detecting a cancer in a subject, the method comprising testing for the presence of elevated GRP78 in a sample from the subject relative to a control, wherein the testing comprises contacting the sample with an antibody of claim 1.

### Claim 21 (depends on 1)

A method of detecting GRP78, neutralizing GRP78, or counteracting the effects of GRP78, the method comprising contacting the GRP78 with the antibody of claim 1.

### Claim 22 (depends on 21)

The method of claim 21, wherein the GRP78 is in a cultured cell.

### Claim 23 (depends on 21)

The method of claim 21, wherein the GRP78 is on a surface of a cell.

### Claim 24 (depends on 21)

The method of claim 21, wherein the GRP78 is in a subject.

### Claim 25 (depends on 24)

The method of claim 24, wherein the GRP78 is in or on a surface of a cancer cell in the subject.

### Claim 26 (depends on 25)

The method of claim 25, wherein the subject is a human.