Antibody labelling with functionalised cyclam macrocycles

Morphy, J. Richard; Parker, David; Alexander, Rikki; Bains, Amarjit; Carne, Alex F.; Eaton, Michael A. W.; Harrison, A.; Millican, Andrew T.; Phipps, Alison; Rhind, Stephen K.; Titmas, Richard C.; Weatherby, David

doi:10.1039/c39880000156

Cited by 56 publications

(28 citation statements)

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“…In addition, the availability of 62 Zn- 62 Cu generators and 64 Cu with high specific activity makes it more feasible to develop target-specific radiopharmaceuticals with copper radionuclide. Copper radionuclide production, coordination chemistry, radiochemistry, and nuclear medicine applications have been reviewed exhaustively [6,7,13,72,[224][225][226][227][228].…”

Section: Why Copper Radionuclides?mentioning

confidence: 99%

“…Because of the d 9 configuration, Cu(II) complexes are often kinetically labile with respect to ligand dissociation. Therefore, the design of BFCs (Figure 11) for copper radionuclides has been focused on macrocyclic chelators that are able to form Cu(II) complexes with both high thermodynamic stability and kinetic inertness [224][225][226][227][228]. BFCs for radiolabeling of biomolecules with copper radionuclide have been reviewed recently [225].…”

Section: Copper Chemistrymentioning

confidence: 99%

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Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

Liu

2008

Advanced Drug Delivery Reviews

372

339

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Receptor-based radiopharmaceuticals are of great current interest in molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a "carrier" for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals.

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Section: Why Copper Radionuclides?mentioning

confidence: 99%

Section: Copper Chemistrymentioning

confidence: 99%

Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

Liu

2008

Advanced Drug Delivery Reviews

372

339

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“…Numerous chelators have been reported for complexing copper [5][6][7][8][9][10][11][12][13][14][15][16] and several of these have been functionalized to allow attachment to antibodies [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and are now commercially available. The choice of antibody/BFC combination will affect efficacy as an imaging or therapy agent.…”

Section: Introductionmentioning

confidence: 99%

Comparison of ⁶⁴Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability

et al. 2012

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High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with 64 Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p- , three DTPA derivatives (p-SCN-Bn-DTPA, p-SCN-CHX-A"-DTPA and ITC-2B3M-DTPA) and a macrobicyclic hexamine ("sarcophagine") chelator (sar-CO 2 H) = (1-NH 2 -8-NHCO(CH 2 ) 3 CO 2 H)sar where sar = sarcophagine = 3, 6,10,13,16,19-hexaazabicyclo[6.6.6]icosane). Radiolabeling efficiency under various conditions, in vitro stability in serum at 37°C and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO 2 H were conjugated to rituximab by thiourea bond formation with an average of 4.9 +/− 0.9 chelators per antibody molecule. Sar-CO 2 H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody molecule. Efficiencies of 64 Cu radiolabeling were dependent on the concentration of immunoconjugate. Notably, the 64 Cu-NOTA-rituximab conjugate demonstrated highest radiochemical yield (95%) under very dilute conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, containing 1/10 th the number of chelators per antibody compared to other conjugates retained high labeling efficiency (98 %) at an antibody concentration of 250 nM. In contrast to the radioimmunoconjugates containing DTPA derivatives, which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6 % dissociation of 64 Cu over 48 h. In vivo biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. Whilst all the macrocyclic bifunctional chelators are suitable for molecular imaging using 64 Cu-labeled antibody conjugates, NOTA and sar-CO 2 H show significant advantages over the others in that they can be radiolabeled rapidly at room temperature, under dilute conditions resulting in high specific activity. Europe PMC Funders Group

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“…Such macrocycles have been made by a variety of methods, including high-dilution techniques [2] and routes based on template effects [3]. The groups of Kimura [4] and Morphy [5] reported that, consistent with earlier findings of Tabushi et al [6], neither high-dilution nor templates are required for the condensation of diesters with a,w-diamines to form macrocyclic diamides. Later, we found that this reaction can even be carried out at room temperature [7] and that various diesters, as long as they possess a heteroatom in a-position to the CO group, are efficient substrates [8 ± 11].…”

mentioning

confidence: 60%

Factors Influencing the Course of the Macrocyclization of α,ω‐Diamines with Esters of α,ω‐Dicarboxylic Acids

Gryko

Sierzputowska-Gracz

et al. 2004

Helvetica Chimica Acta

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The efficient synthesis of eight new macrocyclic amides (lactams) via reaction of diesters with diamines under normal dilution conditions is described. The role of intermolecular H-bond formation and steric hindrance is discussed based on 1 H-and 15 N-NMR studies of appropriate model compounds. Principles for the optimal choice of esters that can be efficiently transformed into diamides have been developed.Introduction. ± The architecture of naturally occurring macrocycles has long provided the stimulus for the development of new methods for the synthesis of cyclic polyaza and polyoxa compounds [1]. The synthesis of macrocycles possessing both Nand O-atoms to produce receptors with distinct properties has been pursued by many research groups due to the potential application of these compounds in medicine, catalysis, and sensor technology, etc. [9], were successfully used, whereas esters of simple aliphatic diacids (e.g., adipinate) were found to be unreactive unless high pressure was applied [7b]. Recently, we have optimized the reaction conditions for macrocyclizations [11], using MeONa as a catalyst, which speeds up the reaction, improves the yields, and broadens the scope of the reaction by including less-reactive esters like dimethyl phthalate. Our results showed that there is no template effect operating in these reactions. Others have also made use of these (or similar) conditions for the synthesis of a wide scope of macrocyclic amides [12] [13].Our interest in the reaction of diesters and diamines has been motivated not only by its broad scope, but also by the amazing observation that standard dilution of reagents is enough to obtain high yields of macrocyclization. For this reason and keeping with our long-standing interest in diazacoronands, we undertook detailed studies to gain

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Antibody labelling with functionalised cyclam macrocycles

Abstract: Functionalised 'cyclam' macrocyclic ligands have been selectively attached t o thiol residues on a monoclonal antibody and form kinetically inert complexes with Cup+ and TcV.

Cited by 56 publications

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Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

Comparison of ⁶⁴Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability

Factors Influencing the Course of the Macrocyclization of α,ω‐Diamines with Esters of α,ω‐Dicarboxylic Acids

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Antibody labelling with functionalised cyclam macrocycles

Abstract: Functionalised 'cyclam' macrocyclic ligands have been selectively attached t o thiol residues on a monoclonal antibody and form kinetically inert complexes with Cup+ and TcV.

Cited by 56 publications

References 0 publications

Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

Comparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability

Factors Influencing the Course of the Macrocyclization of α,ω‐Diamines with Esters of α,ω‐Dicarboxylic Acids

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Comparison of ⁶⁴Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability