Methods and compositions for liver cancer therapy
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.
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.