Cyclam te1pa for<sup>64</sup>Cu PET imaging. Bioconjugation to antibody, radiolabeling and preclinical application in xenografted colorectal cancer

Frindel, Mathieu; Saëc, Patricia Le; Beyler, Maryline; Navarro, Amparo Sánchez; Saï-Maurel, Catherine; Alliot, Cyrille; Chérel, Michel; Gestin, Jean‐François; Faivre-Chauvet, Alain; Tripier, Raphaël

doi:10.1039/c6ra26003a

Cited by 17 publications

(41 citation statements)

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“…When considering a 60% radiochemical yield of 64 Cu-PCB-TE2A-tetrazine ( 7 ), the overall radiochemical yields of 64 Cu-PCB-TE2A-trastuzumab ( 9 ) and 64 Cu-PCB-TE2A-PEG 4 -trastuzumab ( 11 ) from Cu-64 ions were 37 and 44%, respectively. The calculated specific activities of the radioimmunoconjugates were 2.6 ± 0.2 MBq/μg ( 9 ) and 2.8 ± 0.4 MBq/μg ( 11 ), which were superior to the previously reported typical values of 64 Cu-labeled immunoconjugates. , …”

Section: Resultsmentioning

confidence: 50%

“…The calculated specific activities of the radioimmunoconjugates were 2.6 ± 0.2 MBq/μg (9) and 2.8 ± 0.4 MBq/μg (11), which were superior to the previously reported typical values of 64 Cu-labeled immunoconjugates. 18,50 We also prepared 64 Cu-NOTA-Bn-NCS-trastuzumab (12) (Figure S30) to directly compare the in vivo stabilities of the antibodies radiolabeled by using the different bifunctional chelators. NOTA is a non-cross-bridged macrocyclic chelator known to form stable copper complexes, and it is widely used as a bifunctional chelator for 64 Cu radiolabeling.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Successful Application of CuAAC Click Reaction in Constructing ⁶⁴Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Lee

Sarkar

Pal

et al. 2021

ACS Appl. Bio Mater.

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Immuno-positron emission tomography (immuno-PET) is a rapidly growing imaging technique in which antibodies are radiolabeled to monitor their in vivo behavior in real time. However, effecting the controlled conjugation of a chelate-bearing radioactive atom to a bulky antibody without affecting its immunoreactivity at a specific site is always challenging. The in vivo stability of the radiolabeled chelate is also a key issue for successful tumor imaging. To address these points, a facile ultrastable radiolabeling platform is developed by using the propylene cross-bridged chelator (PCB-TE2A-alkyne), which can be instantly functionalized with various groups via the click reaction, thus enabling specific conjugation with antibodies as per choice. The PCB-TE2A-tetrazine derivative is selected to demonstrate the proposed strategy. The antibody trastuzumab is functionalized with the trans-cyclooctene (TCO) moiety in the presence or absence of the PEG linker. The complementary 64 Cu-PCB-TE2A-tetrazine is synthesized via the click reaction and radiolabeled with 64 Cu ions, which then reacts with the aforementioned TCO-modified antibody via a rapid biorthogonal ligation. The 64 Cu-PCB-TE2Atrastuzumab conjugate is shown to exhibit excellent in vivo stability and to maintain a higher binding affinity toward HER2-positive cells. The tumor targeting feasibility of the radiolabeled antibody is evaluated in tumor models. Both 64 Cu-PCB-TE2A-trastuzumab conjugates show high tumor uptakes in biodistribution studies and enable unambiguous tumor visualization with minimum background noise in PET imaging. Interestingly, the 64 Cu-PCB-TE2A-PEG 4 -trastuzumab containing an additional PEG linker displays a much faster body clearance compared to its counterpart with less PEG linker, thus affording vivid tumor imaging with an unprecedentedly high tumor-to-background ratio.

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Section: Resultsmentioning

confidence: 50%

Section: ■ Results and Discussionmentioning

confidence: 99%

Successful Application of CuAAC Click Reaction in Constructing ⁶⁴Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Lee

Sarkar

Pal

et al. 2021

ACS Appl. Bio Mater.

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“…For example, CB-TE2P shows good labeling with 64 Cu, even at room temperature, − although CB-TE2A requires prolonged heating at high temperature. Recently, cyclams with picolinate pendant arm(s) (e.g., TE1PA, Chart ) have been suggested as ligands for efficient radiocopper incorporation. − Among ligand skeletons, cyclam-based ligands are known to have the best thermodynamic selectivity for Cu(II). We have previously shown that Cu(II) selectivity is preserved in phosphonic acid cyclam derivatives and is associated with the good kinetic inertness of Cu(II) complexes of these ligands. − On the basis of our experience with cyclam phosphonic acid derivatives and on studies on simple geminal bis(phosphinates), , we have recently designed cyclam-based ligands with one geminal bis(phosphinate) ( te1bpin ) or geminal phosphino-phosphonate ( te1pp ) pendant arm (Chart ) for fast complexation of Cu(II) ions .…”

Section: Introductionmentioning

confidence: 99%

Improved Conjugation, 64-Cu Radiolabeling, in Vivo Stability, and Imaging Using Nonprotected Bifunctional Macrocyclic Ligands: Bis(Phosphinate) Cyclam (BPC) Chelators

et al. 2018

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Bifunctional derivatives of bis(phosphinate)-bearing cyclam (BPC) chelators bearing a carboxylate, amine, isothiocyanate, azide, or cyclooctyne in the BP side chain were synthesized. Conjugations required no protection of phosphinate or ring secondary amine groups. The ring amines were not reactive (proton protected) at pH < ∼8. For isothiocyanate coupling, oligopeptide N-terminal α-amines were more suitable than alkyl amines, e.g., Lys ω-amine (p K ∼7.5-8.5 and ∼10-11, respectively) due to lower basicity. The Cu-64 labeling was efficient at room temperature (specific activity ∼100 GBq/μmol; 25 °C, pH 6.2, ∼100 ligand equiv, 10 min). A representative Cu-64-BPC was tested in vivo showing fast clearance and no nonspecific radioactivity deposition. The monoclonal anti-PSCA antibody 7F5 conjugates with thiocyanate BPC derivative or NODAGA were radiolabeled and studied in PC3-PSCA tumor bearing mice by PET. The radiolabeled BPC conjugate was accumulated in the prostate tumor with a low off-target uptake, unlike Cu-64-labeled NODAGA-antibody conjugate. The BPC chelators have a great potential for theranostic applications of the Cu-64/Cu-67 matched pair.

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“…The C -functionalization strategy was developed to provide a second functionality to the macrocycle, different from the one introduced with N -chelating units . We and others have largely contributed to this chemistry using these derivatives for several applications, especially for the conjugation of the macrocycles to an external support or a targeting moiety. − The structural modifications introduced through C -functionalization of the cyclam framework affect the biological properties of the complexes by modifying the lipophilic character of the ligands as well as by directing the complex to the desired target in vivo.…”

Section: Introductionmentioning

confidence: 99%

Complexation of C-Functionalized Cyclams with Copper(II) and Zinc(II): Similarities and Changes When Compared to Parent Cyclam Analogues

et al. 2021

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Herein, we report a comprehensive coordination study of the previously reported ligands cyclam, CB-cyclam TMC, DMC, CB-DMC, and of their C-functional analogues, cyclam-E, CB-cyclam-E, TMC-E, DMC-E and CB-DMC-E. This group of ligands includes cyclam, cross-bridged cyclams, their di-or tetramethylated derivatives and the analogues bearing an additional hydroxyethyl group on one β-N position of the ring. These Cu(II) and Zn(II) complexes of these macrocycles have been highlighted previously for the biological interest, but the details of their structures in the solid state and in solution remained largely unexplored. In particular, we analyzed the impact that adding non-coordinating Nmethyl and C-hydroxyethyl functionalities has in the structures of the complexes. All the Cu(II) and Zn(II) complexes were synthetized and investigated using single crystal X-ray diffraction and NMR, electronic absorption and EPR spectroscopies, along with DFT studies. Dissociation kinetics experiments in acidic conditions and an electrochemical study were also performed. A special attention was paid to analyze the different configurations present in solution and in the solid state, as well as the impact of the Cappended hydroxyethyl group on the coordination behavior. Various ratios of the trans-I, trans-III, and cis-V configurations have been observed depending on the degree of N-methylation and the presence of the ethylene cross-bridge.

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Cyclam te1pa for⁶⁴Cu PET imaging. Bioconjugation to antibody, radiolabeling and preclinical application in xenografted colorectal cancer

Abstract: te1pa conjugated to an F6 antibody was confirmed to be an interesting alternative to dota for64Cuin vivoPET imaging.

Cited by 17 publications

References 64 publications

Successful Application of CuAAC Click Reaction in Constructing ⁶⁴Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Successful Application of CuAAC Click Reaction in Constructing ⁶⁴Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Improved Conjugation, 64-Cu Radiolabeling, in Vivo Stability, and Imaging Using Nonprotected Bifunctional Macrocyclic Ligands: Bis(Phosphinate) Cyclam (BPC) Chelators

Complexation of C-Functionalized Cyclams with Copper(II) and Zinc(II): Similarities and Changes When Compared to Parent Cyclam Analogues

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Cyclam te1pa for64Cu PET imaging. Bioconjugation to antibody, radiolabeling and preclinical application in xenografted colorectal cancer

Abstract: te1pa conjugated to an F6 antibody was confirmed to be an interesting alternative to dota for64Cuin vivoPET imaging.

Cited by 17 publications

References 64 publications

Successful Application of CuAAC Click Reaction in Constructing 64Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Successful Application of CuAAC Click Reaction in Constructing 64Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Improved Conjugation, 64-Cu Radiolabeling, in Vivo Stability, and Imaging Using Nonprotected Bifunctional Macrocyclic Ligands: Bis(Phosphinate) Cyclam (BPC) Chelators

Complexation of C-Functionalized Cyclams with Copper(II) and Zinc(II): Similarities and Changes When Compared to Parent Cyclam Analogues

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Cyclam te1pa for⁶⁴Cu PET imaging. Bioconjugation to antibody, radiolabeling and preclinical application in xenografted colorectal cancer

Successful Application of CuAAC Click Reaction in Constructing ⁶⁴Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

Successful Application of CuAAC Click Reaction in Constructing ⁶⁴Cu-Labeled Antibody Conjugates for Immuno-PET Imaging