Imaging methods using 18F-radiolabeled biologics
The invention relates to water soluble 18 F-prosthetic groups and the synthesis and use of 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 monitoring the progress of an anti-tumor therapy against target-expressing tumors in a subject, the method 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 steps (a) and (b) are conducted at least 1, 2, 3, 4 or 5 time points, one of which is prior to the initiation of the anti-tumor therapy, and at least one of which during the immunotherapy treatment, or wherein all time points are during the anti-tumor therapy, wherein the imaging agent comprises a protein linked to a radioactive PET tracer by a bifunctional conjugating moiety (BFC) comprising a reactive group that forms a covalent bond with an amine, carboxyl, carbonyl or thiol functional group on the protein, and
wherein the dimension and location of the diseased cells or tissue at each time point is indicative of the progress of the target-expressing tumor.
2. The method of claim 1 , wherein the protein is an antibody, an antigen binding fragment of an antibody, or a fibronectin Type III (Fn3 domain).
3. The method of claim 1 , wherein the radioactive PET tracer is 18 F.
4. The method of claim 1 , wherein the BFC is a cyclooctyne comprising a reactive group that forms a covalent bond with an amine, carboxyl, carbonyl or thiol functional group on the protein.
5. The method of claim 4 , wherein the cyclooctyne is selected from the group consisting of dibenzocyclooctyne (DIBO), biarylazacyclooctynone (BARAC), dimethoxyaza-cyclooctyne (DIMAC) and dibenzocyclooctyne (DBCO).
6. The method of claim 1 , wherein the BFC further comprises a polyethylene glycol (PEG) y spacer arm, wherein y is an integer from 1 to 8.
7. The method of claim 1 , wherein the BFC is DBCO-PEG4-NHS-Ester, DBCO-Sulfo-NHS-Ester, DBCO-PEG4-15 Acid, DBCO-PEG4-Amine or DBCO-PEG4-Maleimide.
8. The method of claim 7 , wherein the cysteine residue is at the C-terminus of the protein.
9. The method of claim 1 , wherein the BFC is covalently linked to a thiol group on a cysteine residue of the protein.
10. The method of claim 1 , wherein the Fn3 domain is a human tenth fibronectin type III domain ( 10 Fn3).
11. The method of claim 1 , wherein the anti-tumor therapy is an immunotherapy agent.
12. The method of claim 11 , wherein the immunotherapy agent is a PD-1 antagonist.
13. The method of claim 12 , wherein the PD-1 antagonist is an anti-PD-1 antibody.
14. The method of claim 13 , wherein the anti-PD-1 antibody is nivolumab or pembrolizumab or atezolizumab.
15. The method of claim 3 , wherein the 18 F-radiolabeled prosthetic group comprises the structure
or a pharmaceutically acceptable salt thereof.
16. The method of claim 3 , wherein the 18 F-radiolabeled prosthetic group comprises the structure
or a pharmaceutically acceptable salt thereof.
17. The method of claim 3 , wherein the 18 F-radiolabeled prosthetic group comprises the structure
or a pharmaceutically acceptable salt thereof.
18. The method of claim 3 , 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.
19. The method of claim 18 , wherein the cysteine residue is at the C-terminus of the protein.
20. The method of claim 18 , wherein the protein comprises a human 10 Fn3 domain.