Internalizing moieties for treatment of cancer

1. A method of treating a tumor in a subject in need thereof, comprising administering an antibody or antigen-binding fragment to the subject, wherein the antibody or antigen-binding fragment comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain; wherein the VH domain comprises:

a VH CDR1 having the amino acid sequence of SEQ ID NO: 1;

a VH CDR2 having the amino acid sequence of SEQ ID NO: 2; and

a VH CDR3 having the amino acid sequence of SEQ ID NO: 3,

which CDRs are according to the IMGT system; or

wherein the VH domain comprises:

a VH CDR1 having the amino acid sequence of SEQ ID NO: 32;

a VH CDR2 having the amino acid sequence of SEQ ID NO: 49; and

a VH CDR3 having the amino acid sequence of SEQ ID NO: 34,

which CDRs are according to the Kabat system;

and the VL domain comprises:

a VL CDR1 having the amino acid sequence of SEQ ID NO: 35 or 50;

a VL CDR2 having the amino acid sequence of SEQ ID NO: 51; and

a VL CDR3 having the amino acid sequence of SEQ ID NO: 37,

which CDRs are according to the Kabat system,

wherein the antibody binds DNA with a K D of less than 100 nM and promotes transit across cellular membranes via an equilibrative nucleoside transporter 2 (ENT2) transporter.

2. The method of treating a tumor of claim 1 , wherein the method includes reducing tumor growth, proliferation or survival.

3. The method of claim 2 , wherein a reduction in tumor growth, proliferation or survival is determined by assessing mitotic markers in a tumor sample.

4. The method of claim 2 , wherein a reduction in tumor growth, proliferation or survival is determined by assessing Ki-67 staining in a tumor sample.

5. The method of treating a tumor of claim 1 , wherein the method includes promoting collapse of capillary blood vessels in a tumor.

6. The method of claim 5 , wherein a collapse of capillary blood vessels in a tumor is determined by observing CD-31 staining patterns in a tumor sample.

7. The method of claim 1 , wherein the tumor is in a subject, and the subject is a human.

8. The method of claim 1 , wherein the tumor is a colorectal cancer, an ovarian cancer, a pancreatic cancer, a hereditary non-polyposis colon cancer (HNPCC), or an adenocarcinoma.

9. The method of claim 1 , wherein the tumor is platin-resistant, or

wherein the tumor is resistant to treatment with DNA repair inhibitors.

10. The method of claim 1 , wherein the tumor is associated with microsatellite instability.

11. The method of claim 1 , wherein the tumor has deficient DNA mismatch repair, or

wherein the tumor has a mutation in any of the hMSH2, hMSH6 or hMLH1 genes, or

wherein the tumor is BRCA2 deficient, or

wherein the tumor is BRCA2 proficient.

12. The method of claim 1 , wherein the method comprises administering the antibody or antigen-binding fragment more than once according to a dose and dosing schedule.

13. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is administered to the subject as a monotherapy.

14. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is administered to the subject in combination with an additional therapeutic treatment.

15. The method of claim 1 , wherein the antibody or antigen-binding fragment is administered to the subject intravenously, intramuscularly, or subcutaneously.

16. The method of claim 1 , wherein the antibody or antigen-binding fragment is a full length antibody or comprises a portion of an Fc domain, and which antibody or antigen-binding fragment is effective at a lower dose than a murine 3E10 full length antibody.

17. The method of claim 1 , wherein the antibody or antigen-binding fragment is a Fab or Fab′, and which antibody or antigen-binding fragment is effective at a lower dose than a murine 3E10 Fv or scFv.

18. The method of claim 1 , wherein the antibody or antigen-binding fragment is a F(ab′)2 fragment, and which antibody or antigen-binding fragment is effective at a lower dose than a murine a F(ab′)2 fragment.

19. The method of claim 1 , wherein the internalizing moiety is a full length antibody comprising a heavy chain constant domain and a light chain constant domain.

20. The method of claim 1 , wherein the VH domain comprises:

the amino acid sequence of SEQ ID NO: 38,

the amino acid sequence of SEQ ID NO: 39, or

the amino acid sequence of SEQ ID NO: 10; and

wherein the VL domain comprises:

the amino acid sequence of SEQ ID NO: 40, or

the amino acid sequence of SEQ ID NO: 8.

21. A method of inhibiting proliferation of a cancerous cell or tumor cell, comprising contacting the tumor cell with an antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain; wherein the VH domain comprises:

a VH CDR1 having the amino acid sequence of SEQ ID NO: 1;

a VH CDR2 having the amino acid sequence of SEQ ID NO: 2; and

a VH CDR3 having the amino acid sequence of SEQ ID NO: 3,

which CDRs are according to the IMGT system; or

wherein the VH domain comprises:

a VH CDR1 having the amino acid sequence of SEQ ID NO: 32;

a VH CDR2 having the amino acid sequence of SEQ ID NO: 49; and

a VH CDR3 having the amino acid sequence of SEQ ID NO: 34,

which CDRs are according to the Kabat system;

and the VL domain comprises:

a VL CDR1 having the amino acid sequence of SEQ ID NO: 35 or 50;

a VL CDR2 having the amino acid sequence of SEQ ID NO: 51; and

a VL CDR3 having the amino acid sequence of SEQ ID NO: 37,

which CDRs are according to the Kabat system,

wherein the antibody binds DNA with a K D of less than 100 nM and promotes transit across cellular membranes via an equilibrative nucleoside transporter 2 (ENT2) transporter.

22. A method of decreasing Ki-67 or CD31 expression in a tumor, comprising contacting the tumor cell with an antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain; wherein the VH domain comprises:

a VH CDR1 having the amino acid sequence of SEQ ID NO: 1;

a VH CDR2 having the amino acid sequence of SEQ ID NO: 2; and

a VH CDR3 having the amino acid sequence of SEQ ID NO: 3,

which CDRs are according to the IMGT system; or

wherein the VH domain comprises:

a VH CDR1 having the amino acid sequence of SEQ ID NO: 32;

a VH CDR2 having the amino acid sequence of SEQ ID NO: 49; and

a VH CDR3 having the amino acid sequence of SEQ ID NO: 34,

which CDRs are according to the Kabat system;

and the VL domain comprises:

a VL CDR1 having the amino acid sequence of SEQ ID NO 35 or 50;

a VL CDR2 having the amino acid sequence of SEQ ID NO 51; and

a VL CDR3 having the amino acid sequence of SEQ ID NO: 37,

which CDRs are according to the Kabat system,

wherein the antibody binds DNA with a K D of less than 100 nM and promotes transit across cellular membranes via an equilibrative nucleoside transporter 2 (ENT2) transporter.