Methods and compositions for liver cancer therapy

Patent metadata

Field	Value
Publication number	US-10533050-B2
Application number	US-201113189403-A
Country	US
Kind code	B2
Filing date	Jul 22, 2011
Priority date	Jul 26, 2010
Publication date	Jan 14, 2020
Grant date	Jan 14, 2020

Abstract

The present disclosure provides methods of treating liver cancer and preventing liver cancer recurrence with anti-progastrin antibodies, methods of monitoring treatment efficacy of anti-progastrin therapy for liver cancer, and compositions useful therefore.

First claim

What is claimed is:

1. A method of reducing recurrence of liver cancer in a subject, comprising:
administering to a human patient who has been treated for liver cancer an amount of a C-terminal anti-hPG monoclonal antibody sufficient to provide a therapeutic benefit,
wherein the C-terminal anti-hPG monoclonal antibody binds to human progastrin peptide (hPG) having an amino acid sequence of SEQ ID NO:20 but does not detectably bind to amidated gastrin 17 consisting of SEQ ID NO:104, glycine-extended gastrin 17 consisting of SEQ ID NO:105, or C-terminal flanking peptide (CTFP) consisting of SEQ ID NO:106, wherein binding specificity is determined by an ELISA assay, and
wherein the C-terminal anti-hPG monoclonal antibody comprises six CDRs, wherein the six CDRs are the CDRs of MAb5, MAb6, MAb7, MAb8, MAb11, MAb12, or MAb13.

2. The method of claim 1 , wherein said anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V H CDR 1.8 (SEQ ID NO:37), CDR2 comprises the amino acid sequence of V H CDR 2.8 (SEQ ID NO:41), and CDR3 comprises the amino acid sequence of V H CDR 3.8 (SEQ ID NO:45), and a light chain variable region in which CDR1 comprises the amino acid sequence of V L CDR 1.8 (SEQ ID NO:49), CDR2 comprises the amino acid sequence of V L CDR 2.8 (SEQ ID NO:52), and CDR3 comprises the amino acid sequence of V L CDR 3.8 (SEQ ID NO:55).

3. The method of claim 1 , wherein said anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V H CDR 1.13 (SEQ ID NO:38), CDR2 comprises the amino acid sequence of V H CDR 2.13 (SEQ ID NO:42), and CDR3 comprises the amino acid sequence of V H CDR 3.13 (SEQ ID NO:46), and a light chain variable region in which CDR1 comprises the amino acid sequence of V L CDR 1.13 (SEQ ID NO:50), CDR2 comprises the amino acid sequence of V L CDR 2.13 (SEQ ID NO:53), and CDR3 comprises the amino acid sequence of V L CDR 3.13 (SEQ ID NO:56).

4. The method of claim 1 , wherein said anti-hPG monoclonal antibody comprises heavy chain variable region comprising mV H .8 (SEQ ID NO:59) and a light chain variable region comprising mV L .8 (SEQ ID NO: 63).

5. The method of claim 1 , wherein said anti-hPG monoclonal antibody comprises heavy chain variable region comprising mV H .13 (SEQ ID NO:60) and a light chain variable region comprising mV L .13 (SEQ ID NO:64).

6. The method of claim 1 , in which the C-terminal anti-hPG monoclonal antibody competes for binding with a reference antibody, wherein said C-terminal anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V H CDR 1.8 (SEQ ID NO:37), CDR2 comprises the amino acid sequence of V H CDR 2.8 (SEQ ID NO:41), and CDR3 comprises the amino acid sequence of V H CDR 3.8 (SEQ ID NO:45), and a light chain variable region in which CDR1 comprises the amino acid sequence of V L CDR 1.8 (SEQ ID NO:49), CDR2 comprises the amino acid sequence of V L CDR 2.8 (SEQ ID NO:52), and CDR3 comprises the amino acid sequence of V L CDR 3.8 (SEQ ID NO:55).

7. The method of claim 1 , in which the C-terminal anti-hPG monoclonal antibody competes for binding with a reference antibody, wherein said C-terminal anti-hPG monoclonal antibody comprises a heavy chain variable region in which CDR1 comprises the amino acid sequence of V H CDR 1.13 (SEQ ID NO:38), CDR2 comprises the amino acid sequence of V H CDR2.13 (SEQ ID NO:42), and CDR3 comprises the amino acid sequence of V H CDR 3.13 (SEQ ID NO:46), and a light chain variable region in which CDR1 comprises the amino acid sequence of V L CDR 1.13 (SEQ ID NO:50), CDR2 comprises the amino acid sequence of V L CDR 2.13 (SEQ ID NO:53), and CDR3 comprises the amino acid sequence of V L CDR 3.13 (SEQ ID NO:56).

8. The method of claim 1 , wherein the human patient has liver cancer stem cells, wherein the C-terminal anti-hPG monoclonal antibody inhibits growth of said liver cancer stem cells, and wherein said liver cancer stem cells express progastrin.

9. A method of inhibiting proliferation of a liver cancer stem cell, comprising:
exposing the cell to an amount of a C-terminal anti-hPG monoclonal antibody sufficient to inhibit its proliferation,
wherein the C-terminal anti-hPG monoclonal antibody binds to human progastrin peptide (hPG) having an amino acid sequence of SEQ ID NO:20 but does not detectably bind to amidated gastrin 17 consisting of SEQ ID NO:104, glycine-extended gastrin 17 consisting of SEQ ID NO:105, or C-terminal flanking peptide (CTFP) consisting of SEQ ID NO:106, wherein binding specificity is determined by an ELISA assay, and
wherein the C-terminal anti-hPG monoclonal antibody comprises six CDRs, wherein the six CDRs are the CDRs of MAb5, MAb6, MAb7, MAb8, MAb11, MAb12, or MAb13.

10. The method of claim 9 , wherein the method is carried out in vitro.

11. The method of claim 9 , wherein the method is carried out in vivo.

Assignees

• Houhou Leila
• Dume Anne Sophie
• Joubert Dominique
• Hollande Frederic
• Inst Nat Sante Rech Med
• Centre Nat Rech Scient
• Les Laboratories Servier

Inventors

• Houhou Leïla
• Dumé Anne-Sophie
• Joubert Dominique
• Hollande Frédéric

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• G01N2333/595

  Gastrins; Cholecystokinins [CCK] · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title