Photochemical Conjugation and One-Pot Radiolabelling of Antibodies for Immuno-PET

Monoclonal antibodies (mAbs), immunoglobulin fragments, and other proteins are important scaffolds in the development of radiopharmaceuticals for diagnostic immuno‐positron emission tomography (immuno‐PET) and targeted radioimmunotherapy (RIT). Conventional methods for radiolabelling proteins with metal ions such as 68Ga, 64Cu, 89Zr, and 90Y require multi‐step procedures involving pre‐purification, functionalisation with a chelate, and subsequent radiolabelling. Standard coupling chemistries are time‐consuming, difficult to automate, and involve synthesis, isolation, and storage of an intermediate, new molecular entity (the conjugated mAb) whose biochemical properties can differ from those of the parent protein. To circumvent these issues, we developed a photoradiochemical approach that uses fast, chemoselective, light‐induced protein modification under mild conditions with novel metal‐ion‐binding chelates derivatised with aryl azide (ArN3) groups. Experiments show that one‐pot photochemical conjugation and radiolabelling of formulated mAbs can be achieved in <20 min

Light-induced synthesis of protein conjugates and its application in photoradiosynthesis of 89Zr-radiolabeled monoclonal antibodies

Efficient methods to functionalize proteins are essential for the development of many diagnostic and therapeutic compounds, such as fluorescent probes for immunohistochemistry, zirconium-89 radiolabeled mAbs (89Zr-mAbs) for positron emission tomography and antibody-drug conjugates (ADCs). This protocol describes a step-by-step procedure for the light-induced functionalization of proteins with compounds bearing the photochemically active aryl azide group. As an illustration of the potential utility of our approach, this protocol focuses on the synthesis of 89Zr-mAbs using photoactivatable derivatives of the metal ion binding chelate desferrioxamine B (DFO). The light-induced synthesis of 89Zr-mAbs is a unique, one-pot process involving simultaneous radiolabeling and protein conjugation. The photoradiochemical synthesis of purified 89Zr-mAbs, starting from unmodified proteins, [89Zr][Zr(C2O4)4]4– (89Zr-oxalate), and a photoactivatable DFO derivative, can be performed in <90 min. The method can be easily adapted to prepare other radiolabeled proteins, ADCs or fluorescently tagged proteins by using drug molecules or fluorophores functionalized with photoactive moieties

In vitro metabolic profile and in vivo antischistosomal activity studies of (η(6)-Praziquantel)Cr(CO)3 derivatives

In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05)

Design, synthesis and biological evaluation of organometallic antibacterial agents

In dieser Arbeit werden zwei verschiedene Strategien für die Entwicklung antibakterieller organometallischer Wirkstoffe beschrieben. Einerseits wurde die komplexe, tetrazyklische Struktureinheit des natürlich vorkommenden Antibiotikums Platensimycin durch verschiedene stabile (a)chirale organometallische Komplexe mit ähnlichem sterischen Anspruch ersetzt. Die antibakterielle Aktivität der organometallischen Derivate wurde auf verschiedenen Gram-positiven und Gram-negativen Bakterienstämmen getestet. Studien zum Wirkmechanismus des aktivsten organometallischen Platensimycinderivats zeigten starke Unterschiede zu Platensimycin selbst. Andererseits wurden kleine PNA-Monomer-Derivate mit mehreren organometallischen Resten synthetisiert, wobei einige davon starke antibakterielle Wirkung in mikromolaren Konzentrationen zeigten.In this work, two different approaches towards the development of novel organometallic antibacterial agents are described. In the first strategy, bioorganometallics were designed by replacing the complex tetracyclic cage of the naturally occurring antibiotic platensimycin by various stable achiral and chiral organometallic cores with similar steric demand. The antibacterial activities were evaluated against various Gram-positive and Gram-negative bacterial strains. Mechanism of action study of the most active organometallic analogue of platensimycin revealed that the compound has completely different mode of action compared to the same of the parent compound. As a second approach, multi-organometallic containing small PNA monomer derivatives were synthesized and screened for their antibacterial activities. Some of them were discovered to be potent antibacterial agent at low micromolar concentrations

Organometallic compounds, an opportunity for chemical biology

Organometallic compounds are renowned for their remarkable applications in the field of catalysis, but much less is known about their potential in chemical biology. Indeed, such compounds have long been considered to be either unstable under physiological conditions or cytotoxic. As a consequence, little attention has been paid to their possible utilisation for biological purposes. Because of their outstanding physicochemical properties, which include chemical stability, structural diversity and unique photo- and electrochemical properties, however, organometallic compounds have the ability to play a leading role in the field of chemical biology. Indeed, remarkable examples of the use of such compounds—notably as enzyme inhibitors and as luminescent agents—have recently been reported. Here we summarise recent advances in the use of organometallic compounds for chemical biology purposes, an area that we define as “organometallic chemical biology”. We also demonstrate that these recent discoveries are only a beginning and that many other organometallic complexes are likely to be found useful in this field of research in the near future

How Risky Are the Options? A Comparison with the Underlying Stock Using MaxVaR as a Risk Measure

This paper investigates the risk exposure for options and proposes MaxVaR as an alternative risk measure which captures the risk better than Value-at-Risk especially. While VaR is a measure of end-of-horizon risk, MaxVaR captures the interim risk exposure of a position or a portfolio. MaxVaR is a more stringent risk measure as it assesses the risk during the risk horizon. For a 30-day maturity option, we find that MaxVaR can be 40% higher than VaR at a 5% significance level. It highlights the importance of MaxVaR as a risk measure and shows that the risk is vastly underestimated when VaR is used as the measure for risk. The sensitivity of MaxVaR with respect to option characteristics like moneyness, time to maturity and risk horizons at different significance levels are observed. Further, interestingly enough we find that the MaxVar to VaR ratio is higher for stocks than the options and we can surmise that stock returns are more volatile than options. For robustness, the study is carried out under different distributional assumptions on residuals and for different stock index options

An aphasic child with behavioral abnormality: Landau–Kleffner syndrome

Acquired epileptic aphasia, otherwise known as Landau–Kleffner syndrome, is a childhood epilepsy syndrome, characterized by acquired aphasia, seizures, behavioral abnormalities, and abnormal electroencephalography (EEG), in various combinations. Sometimes, some intracranial pathologies, such as brain tumor, head injury, demyelination, and neurocysticercosis, have been found in association. Here, we report a case of a 5-year-old male child presenting with gradual loss of speech, behavioral abnormalities, such as hyperactivity, inattentiveness, and abnormal EEG findings, but without the classical seizures seen with this syndrome

Photoactive chelates for radiolabelling proteins

Photochemical reactions are an attractive foundation for the synthesis of radiolabelled antibodies, immunoglobulin fragments and other proteins/peptides. The synthesis, 68Ga-radiochemistry and photochemical reactivity of three macrocyclic chelates functionalised with an arylazide group is described. Experiments with trastuzumab confirmed that photoradiochemistry facilitates fast, one-pot synthesis of radiolabelled proteins