Binding proteins 1
The present disclosure relates to cell penetrating anti-DNA binding proteins. Compositions comprising these binding proteins may be may be useful for delivering agents to cells and treating diseases such as cancer.
1. A cell penetrating anti-DNA binding protein having an antigen binding domain, wherein the antigen binding domain binds to DNA and comprises:
a heavy chain variable region (V H ) having a complementarity determining region (CDR) 1 as shown in SEQ ID NO: 1, a CDR2 as shown in SEQ ID NO: 3 and a CDR3 as shown in SEQ ID NO: 4; and
a light chain variable region (V L ) having a CDR1 as shown in SEQ ID NO: 6, a CDR2 as shown in SEQ ID NO: 7 and a CDR3 as shown in SEQ ID NO: 8.
2. The binding protein of claim 1 comprising:
(i) a V H comprising a sequence at least 95% identical to the sequence as shown in any one of SEQ ID NOs: 21 to 23;
(ii) a V L comprising a sequence at least 95% identical to the sequence as shown in any one of SEQ ID NOs: 27 to 29; or
(iii) a V H comprising a sequence at least 95% identical to the sequence as shown in any one of SEQ ID NOs: 21 to 23 and a V L comprising a sequence at least 95% identical to the sequence as shown in any one of SEQ ID NOs: 27 to 29.
3. The binding protein according to claim 1 , wherein the V H and a V L are separated by a linker which comprises the sequence shown in SEQ ID NO: 30.
4. The binding protein of claim 1 , wherein, the V H and V L are in a single polypeptide chain.
5. The binding protein of claim 4 , which is:
(i) a single chain Fv fragment (scFv);
(ii) a dimeric scFv (di-scFv);
(iii) a trimeric scFv (tri-scFv); or
(iv) any one of (i), (ii) or (iii) linked to a constant region of an antibody, Fc or a heavy chain constant domain C H 2 and/or C H 3 .
6. The binding protein of claim 4 , which is a scFv.
7. The binding protein of claim 4 , which is a di-scFv.
8. The binding protein according to claim 1 , wherein, the V H and V L are in a separate polypeptide chain.
9. The binding protein of claim 8 , which is:
(i) a diabody;
(ii) a triabody;
(iii) a tetrabody;
(iv) a Fab;
(v) a F(ab') 2 ;
(vi) a Fv; or
(vii) one of (i) to (vi) linked to a constant region of an antibody, Fc or a heavy chain constant domain C H 2 and/or C H 3 ; or,
(viii) an antibody.
10. The binding protein according to claim 1 , which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 41-47.
11. The binding protein of claim 1 , which is conjugated to another compound.
12. The binding protein of claim 1 , wherein the VH comprises a sequence at least 99% identical to the sequence as shown in SEQ ID NO: 21 and the VL comprises a sequence at least 99% identical to the sequence as shown in SEQ ID NO: 27.
13. The binding protein of claim 1 , wherein the VH comprises the sequence shown in SEQ ID NO: 21 and the VL comprises the sequence shown in SEQ ID NO: 27.
14. A nucleic acid encoding a binding protein defined by claim 1 .
15. An expression construct or recombinant cell comprising a nucleic acid defined by claim 14 .
16. A method of treating cancer in a subject, the method comprising administering to the subject and effective amount of a binding protein defined claim 1 .
17. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a binding protein or Fv fragment defined by claim 1 and a PARP inhibitor.
18. The method of claim 17 , wherein the PARP inhibitor is olaparib.
19. The method of claim 17 , wherein the cancer is substantially HDR deficient, substantially BRCA2 deficient, substantially PTEN deficient or resistant to PARP inhibition.
20. The method of claim 17 , wherein the cancer is colon cancer, brain cancer, prostate, ovarian, breast, endometrial, melanoma, or pancreatic cancer, a triple negative breast cancer or glioblastoma.