Pretargeting : A concept refraining traditional flaws in tumor targeting

Abhinav Bhise,유정수 대한방사성의약품학회 2020 Journal of radiopharmaceuticals and molecular prob Vol.6 No.1

Pretargeting is a two-component strategy often used for tumor targeting to enhance the tumor-to-background ratio in cancer diagnosis as well as therapy. In the multistep strategy, the highly specific unlabeled monoclonal antibodies (mAbs) with the reactive site is allowed to get localized at tumor site first, and then small and fastclearing radiolabeled chelator with counter reactive site is administered which covalently attaches to mAbs via inverse electron demand Diels-Alder reaction (IEDDA). The catalyst-free IEDDA cycloaddition reaction between 1,2,4,5-tetrazines and strained alkene dienophiles aid with properties like selective bioconjugation, swift and high yielding bioorthogonal reactions are emergent in the development of radiopharmaceutical. Due to its fast pharmacokinetics, the in vivo formed radioimmunoconjugates can be imaged at earlier time points by short-lived radionuclides like 18F and 68Ga; it can also reduce radiation damage to the normal cells. Ultimately, this review elucidates the updated status of pretargeting based on antibodies and IEDDA for tumor diagnosis (PET and SPECT) and therapy.

Pretargeting : A concept refraining traditional flaws in tumor targeting

Bhise, Abhinav,Yoo, Jeongsoo Korean Society of Radiopharmaceuticals and Molecul 2020 Journal of radiopharmaceuticals and molecular prob Vol.6 No.1

Pretargeting is a two-component strategy often used for tumor targeting to enhance the tumor-to-background ratio in cancer diagnosis as well as therapy. In the multistep strategy, the highly specific unlabeled monoclonal antibodies (mAbs) with the reactive site is allowed to get localized at tumor site first, and then small and fastclearing radiolabeled chelator with counter reactive site is administered which covalently attaches to mAbs via inverse electron demand Diels-Alder reaction (IEDDA). The catalyst-free IEDDA cycloaddition reaction between 1,2,4,5-tetrazines and strained alkene dienophiles aid with properties like selective bioconjugation, swift and high yielding bioorthogonal reactions are emergent in the development of radiopharmaceutical. Due to its fast pharmacokinetics, the in vivo formed radioimmunoconjugates can be imaged at earlier time points by short-lived radionuclides like ¹⁸F and ⁶⁸Ga; it can also reduce radiation damage to the normal cells. Ultimately, this review elucidates the updated status of pretargeting based on antibodies and IEDDA for tumor diagnosis (PET and SPECT) and therapy.

Antibody radiolabeling with diagnostic Cu-64 and therapeutic Lu-177 radiometal

Abhinav Bhise,유정수 대한방사성의약품학회 2022 Journal of radiopharmaceuticals and molecular prob Vol.8 No.1

With the development of monoclonal antibodies, therapeutic or diagnostic radioisotope has been successfully delivered at tumor sites with high selectivity for antigens. Different approaches have been applied to improve the tumor-to-normal ratio by considering the in vivo stability of radioimmunoconjugates as a prerequisite. Various stable and inert antibody radiolabeling techniques for radioimmunoconjugate preparation have been extensively evaluated to enhance in vivo stability. Antibody radiolabeling techniques should be rapid and easy; they should not disrupt the immunoreactivity and in vivo behavior of antibodies, which are coupled with a bifunctional chelator (BFC) to stably coordinate with a radiometal. For the design of BFCs, radiometal coordination properties must be considered. However, various diagnostic radionuclides, such as 89Zr, 64Cu, 68Ga, 111In, and 99mTc, or therapeutic radionuclides, such as 177Lu, 67Cu, 90Y, and 225Ac, have been increasingly used for antibody radiolabeling. In addition to useful radionuclides, 64Cu and 177Lu with the most accessible or the highest production rates in many countries should be considered. In this review, we mainly discussed antibody radiolabeling techniques and conditions that involve 64Cu and 177Lu radiometals.

Synthesis of a PEGylated tracer for radioiodination and evaluation of potential in tumor targeting

Abhinav Bhise,Sushil K. Dwivedi,이기웅,임정은,수브라므니 라즈쿠말,이웅희,조성환,유정수 대한방사성의약품학회 2021 Journal of radiopharmaceuticals and molecular prob Vol.7 No.2

Radiopharmaceuticals are important for tumor diagnosis and therapy. To deliver a radio-tracer at the desired target excluding non-targeted tissues is difficult. The development of a targeted tracer that has a good clearance profile while maintaining high biostability and biocompatibility is key to optimizing its biodistribution and transport across biological barriers. Improving the hydrophilicity of radiotracers by PEGylation can reduce serum binding, allowing the tracer to circulate without retention and reducing its affinity for non-targeted tissues. In this study, we synthesized a new benzamido tracer (SnBz-PEG36) with the introduction of a low molecular weight polyethylene glycol unit (PEG36, ~2100 Da). The tumor-targeting efficiency and biodistribution of [131I]-Bz-PEG36 or radiotracer-loaded liposomes were evaluated after their administration to normal mice or mouse tumor models including CT26 (xenograft) and 4T1 (xenograft and orthotopic). Most of the radiotracer was cleared out rapidly (1-24 h post-administration) through the kidney and there was little tumor uptake.

Recent progress in selective bioconjugation

수브라므니 라즈쿠말,Abhinav Bhise,BOBBA KONDAPA NAIDU,유정수 대한방사성의약품학회 2020 Journal of radiopharmaceuticals and molecular prob Vol.6 No.2

Selective installation of proteins using chemical reagents is important for the development of potential biomaterials for the treatment of human diseases. However, modification in a chemo- and regioselective manner under physiological conditions is a great challenge due to the presence of multiple reactive centers in the protein. Currently, the majority of conjugations are limited to lysine (Lys)- and cysteine (Cys)-selective reagents. Thus, they have been extensively studied. Apart from Lys and Cys, widespread site selectivity has been recently achieved through most of the 20 naturally occurring amino acid-bearing reactive functional groups. Consequently, this review focused on several recent achievements in site-selective modification of the rarest amino acid backbones (e.g., methionine, serine, glutamic acid, and tyrosine).

Radioiodination strategies for carborane compounds

Rajkumar Subramani,Abhinav Bhise,유정수 대한방사성의약품학회 2022 Journal of radiopharmaceuticals and molecular prob Vol.8 No.1

The development of methods for the inert and stable radiohalogenation of targeted radiopharmaceuticals is a prerequisite for real-time diagnosis and therapy using radiohalogenated radiopharmaceuticals. Radiohalogenated carboranes demonstrate superior stability in vivo and versatile applications compared with directly labeled tyrosine analogues or synthetically modified organic compounds. Herein, we focus on the most common approaches for the radioiodination (123I, 124I, 125I, and 131I) of carborane derivatives.

Recent progress of enzyme cleavable linker in antibody–drug conjugates: sulfatase and phosphatase

Sushil K. Dwivedi,Abhinav Bhise,Rajkumar Subramani,유정수 대한방사성의약품학회 2021 Journal of radiopharmaceuticals and molecular prob Vol.7 No.1

Recently, antibody–drug conjugates (ADCs) are used to deliver efficient cytotoxic payloads selectively in cancer cells. In the designing of an ADC, the antibody is connected to a toxic payload via a covalent linker, which helps to solubilizes the typical hydrophobic payload as well as stabilizes the linkage over circulation. The development of the linkers for the antibody drug conjugate is still in demand. Initially, the acid, disulfide, and cathepsin-sensitive ADCs attracted considerable attention for the delivery of a potent cytotoxic payload but suffer from instability in human and mouse plasma with a short half-life. In addition, It also suffer from a solubility issue that induces aggregation, which is the major problem in their development. ADCs associated with sulfatase and phosphatase cleavable linker are highly soluble due to the anionic nature of sulfate and phosphate groups. The ADCs also showed high stability in human and mouse plasma. Therefore, to overcome these limitations, sulfatase and phosphatase cleavable linkers were developed. This review focuses on the recently reported advantages of sulfatase and phosphatase cleavable linkers for ADCs.

Role of polyethylene glycol (PEG) linkers: trends in antibody conjugation and their pharmacokinetics

BOBBA KONDAPA NAIDU,Abhinav Bhise,수브라므니 라즈쿠말,이웅희,유정수 대한방사성의약품학회 2020 Journal of radiopharmaceuticals and molecular prob Vol.6 No.2

Polyethylene glycol (PEG) has been the most commonly used polymer for the past few decades in the field of biomedical applications due to its gold standard stealth effect. PEGylation of antibody–drug conjugates, liposomes, peptides, nanoparticles, and proteins is done to improve their pharmaceutical efficacy and pharmacokinetic properties. PEGylation of antibodies with various PEG linkers improves targeting ability by increasing the blood circulation time and thus enhances the biodistribution profiles. It also assists in minimizing the immediate capture by the reticuloendothelial system. In this review, we summarize the effect of PEG linkers in an antibody conjugation and their pharmacokinetics in the field of biomedical imaging.

Selective tyrosine conjugation with a newly synthesized PCB -TE2A-luminol bifunctional chelator

수브라므니 라즈쿠말,박현,Abhinav Bhise,조성환,김정영,이교철,유정수 대한방사성의약품학회 2021 Journal of radiopharmaceuticals and molecular prob Vol.7 No.2

Selective amino acid conjugation of bulky antibodies is a valuable asset for real-time diagnosis and therapy. However, selective conjugation incorporating a chelate-bearing radioactive atom into an antibody without affecting its immunoreactivity is a challenging task. A bifunctional chelator (BFC), a selective amino acid-targeting probe, and a linker have been developed to overcome this problem. Here, we report the synthesis of a novel propylene cross-bridged chelator (PCB)‒1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane (TE2A)‒luminol BFC via a click reaction and radiolabel it with a 64Cu ion for tyrosine-selective conjugation of trastuzumab. In the initial optimization study, we tried different oxidative addition conditions such as electro-oxidation, hemin, horseradish peroxidase, iodogen tube, chloramine-T, and iodo beads. In this study, up to 82% of 64Cu-PCB-TE2A-luminol was conjugated with the antibody in an iodo bead-catalyzed oxidative addition reaction with an isolated yield of 24.4%.