Imaging methods using 18F-radiolabeled biologics
The invention relates to water soluble 18 F-prosthetic groups and the synthesis and use 18 F-labeled biological molecules containing the 18 F-prosthetic groups for imaging various processes within the body, for detecting the location of molecules associated with disease pathology, and for monitoring disease progression are disclosed.
1. A method of visualizing a target molecule in a subject, comprising
a. administering to the subject an imaging agent that binds specifically to the target molecule at a dose of about 3-10 mCi (100-333 MBq); and
b. conducting a PET scan of the subject about 30-120 minutes after step (a), wherein the imaging agent comprises
(i) an 18 F-radiolabeled prosthetic group comprising the structure
or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 8 the 18 F-radiolabel is attached ortho to the N atom of the pyridine; and
(ii) a protein linked to the 18 F-radiolabeled prosthetic group by a bifunctional conjugating (BFC) moiety, wherein the protein is an antibody, an antigen binding fragment of an antibody, or a fibronectin type III (Fn3) domain.
2. The method of claim 1 , wherein the subject has at least one tumor.
3. The method of claim 2 , comprising determining the level of the target molecule in the at least one tumor of the subject.
4. The method of claim 3 , wherein the level of target molecule in the at least one tumor is indicative of whether a subject is likely to respond to a treatment with an immuno-oncology agent.
5. The method of claim 4 , wherein the target molecule is human PD-L1, and the immune-oncology agent is a PD-1 or PD-L1 antagonist.
6. The method of claim 5 , wherein the PD-1 antagonist is an anti-PD-1 antibody.
7. The method of claim 1 , wherein the 18 F-radiolabeled prosthetic group comprises the structure
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the 18 F-radiolabeled prosthetic group comprises the structure
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the 18 F-radiolabeled prosthetic group comprises the structure
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the 18 F-radiolabeled prosthetic group is linked to a fibronectin type III (Fn3) domain.
11. The method of claim 10 , wherein 18 F-radiolabeled prosthetic group comprises the following structure,
12. The method of claim 10 , wherein 18 F-radiolabeled prosthetic group comprises the following structure,
13. The method of claim 10 , wherein the 18 F-radiolabeled prosthetic group has the structure
14. The method of claim 10 , wherein the imaging agent has the following structure,
wherein the maleimide group of the BFC is covalently linked to the thiol group on a cysteine residue of the protein.
15. The method of claim 14 , wherein the cysteine residue is at the C-terminus of the protein.
16. The method of claim 1 , wherein the target molecule is associated with a disease.
17. The method of claim 1 , wherein the Fn3 domain is a human 10 Fn3 domain.
18. The method of claim 1 , wherein the BFC comprises a cyclooctyne selected from the group consisting of a dibenzocyclooctyne, a biarylazacyclooctynone and a dimethoxyazacyclooctyne.
19. The method of claim 18 , wherein the BFC is DBCO-PEG4-NHS-Ester, DBCO-Sulfo-NHS-Ester, DBCO-PEG4-Acid, DBCO-PEG4-Amine or DBCO-PEG4-Maleimide.
20. A method of visualizing a target molecule in a subject, comprising
a. administering to the subject an imaging agent that binds specifically to the target molecule at a dose of about 3-10 mCi (100-333 MBq); and
b. conducting a PET scan of the subject about 30-120 minutes after step (a), wherein the imaging agent comprises
(i) an 18 F-radiolabeled prosthetic group having the structure
wherein “OPEG” is [O(CH 2 ) 2 ] x , and x is an integer from 1 to 8, or a pharmaceutically acceptable salt thereof, and
(ii) a protein linked to the 18 F-radiolabeled prosthetic group by a bifunctional conjugating (BFC) moiety, wherein the protein is an antibody, an antigen binding fragment of an antibody, or a fibronectin type III (Fn3) domain.
21. The method of claim 20 , wherein the 18 F-radiolabeled prosthetic group is linked to a fibronectin type III (Fn3).