Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
Radiolabeled anti-PD-L1 antibodies and their use in immuno-PET imaging are provided herein. Included are methods of detecting the presence of PD-L1 proteins in a patient or sample.
1. A radiolabeled antibody conjugate comprising an antibody or antigen binding fragment thereof that binds monomeric human program death ligand 1 (PD-L1), a chelating moiety, and a positron emitter, wherein:
(i) the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 84 with no more than one amino acid substitution; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 86 with no more than one amino acid substitution; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 88 with no more than one amino acid substitution; a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 92 with no more than one amino acid substitution; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 94 with no more than one amino acid substitution; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 96 with no more than one amino acid substitution;
(ii) the chelating moiety comprises desferrioxamine; and
(iii) the positron emitter is 89 Zr.
2. The conjugate of claim 1 , wherein said antibody or antigen-binding fragment thereof is covalently bonded to one or more moieties of Formula (A):
-L-M z (A)
wherein L is the chelating moiety; M is the positron emitter; and z, independently at each occurrence, is 0 or 1 wherein at least one of z is 1; and wherein -L-M is
wherein Zr is the positron emitter 89 Zr.
3. The conjugate of claim 2 , wherein the antibody or antigen-binding fragment thereof is covalently bonded to one, two, or three moieties of Formula (A).
4. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 82.
5. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 82.
6. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 82 with no more than 5 amino acid substitutions.
7. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 82 with no more than one amino acid substitution.
8. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 90.
9. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 90.
10. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence of SEQ ID NO: 90 with no more than 5 amino acid substitutions.
11. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence of SEQ ID NO: 90 with no more than one amino acid substitution.
12. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 82 with no more than one amino acid substitution and an LCVR having an amino acid sequence of SEQ ID NO: 90 with no more than one amino acid substitution.
13. The conjugate of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises the HCDR1 comprises the amino acid sequence of SEQ ID NO: 84; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 86; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 88; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 94; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 96.
14. A method of imaging a tissue that expresses PD-L1 comprising:
administering to the tissue a radiolabeled antibody conjugate comprising:
an antibody or antigen binding fragment thereof that binds monomeric human (PD-L1),
a chelating moiety, and
a positron emitter; and
visualizing PD-L1 expression in the tissue by positron emission tomography (PET) imaging, wherein visualized radiolabeled antibody conjugate in the tissue indicates the presence of PD-L1; and
wherein:
(i) the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 84 with no more than one amino acid substitution; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 86 with no more than one amino acid substitution; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 88 with no more than one amino acid substitution; a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 92 with no more than one amino acid substitution; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 94 with no more than one amino acid substitution; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 96 with no more than one amino acid substitution;
(ii) the chelating moiety comprises desferrioxamine; and
(iii) the positron emitter is 89 Zr.
15. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof is covalently bonded to one or more moieties of Formula (A):
-L-M z (A)
wherein L is the chelating moiety; M is the positron emitter; and z, independently at each occurrence, is 0 or 1 wherein at least one of z is 1; and wherein -L-M is
wherein Zr is the positron emitter 89 Zr.
16. The method of claim 15 , wherein the antibody or antigen-binding fragment thereof is covalently bonded to one, two, or three moieties of Formula (A).
17. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 82.
18. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 82.
19. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 82 with no more than 5 amino acid substitutions.
20. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 82 with no more than one amino acid substitution.
21. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region (LCVR) having an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 90.
22. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 90.
23. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence of SEQ ID NO: 90 with no more than 5 amino acid substitutions.
24. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR having an amino acid sequence of SEQ ID NO: 90 with no more than one amino acid substitution.
25. The method of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 82 with no more than one amino acid substitution and an LCVR having an amino acid sequence of SEQ ID NO: 90 with no more than one amino acid substitution.
26. The method of claim 14 , wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 84; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 86; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 88; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 94; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 96.