Monitoring In Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging

Cahuzac, Héloïse; Sallustrau, Antoine; Malgorn, Carole; Beau, Fabrice; Barbe, Peggy; Babin, Victor; DuBois, Steven G.; Palazzolo, Alberto; Thaï, Robert; Correia, Isabelle; Lee, Ki Baek; Garcia‐Argote, Sébastien; Lequin, Olivier; Keck, Mathilde; Nozach, Hervé; Feuillastre, Sophie; Ge, Xin; Pieters, Grégory; Devel, Laurent

doi:10.1021/acs.jmedchem.2c00401

Cited by 9 publications

(6 citation statements)

References 53 publications

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“…monitor the in vivo fate of an ADC (Figure 5) which was dual-labeled with 3 H and 14 C (Cahuzac et al, 2022).These studies confirmed the feasibility of dual radiolabeling for pharmacokinetic study of ADCs. Moreover, liquid scintillation counter (LSC) is a radioactivity meter that uses a liquid scintillator to accept radiation and convert it into fluorescent photons.…”

Section: Cahuzac Et Al Used Dual Radiolabeling and Ex Vivo Digital Im...supporting

confidence: 56%

Bioanalytical Assays for Pharmacokinetic and Biodistribution Study of Antibody-Drug Conjugates

Yin

Zhang

et al. 2023

Drug Metab Dispos

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Antibody-drug conjugates (ADCs) are produced by the chemical linkage of cytotoxic agents and monoclonal antibodies. The complexity and heterogeneity of ADCs and the low concentration of cytotoxic agent released in vivo poses big challenges to their bioanalysis. Understanding the pharmacokinetic behavior, exposure-safety and exposure-efficacy relationships of ADCs is needed for their successful development.Accurate analytical methods are required to evaluate intact ADCs, total antibody, released small molecule cytotoxins and related metabolites. The selection of appropriate bioanalysis methods for comprehensive analysis of ADCs is mainly dependent on the properties of cytotoxic agents, the chemical linker, and the attachment sites. The quality of the information about whole pharmacokinetic profile of ADCs have been improved due to the development and improvement of analytical strategies for detection of ADCs just like ligand-binding assays and mass spectrometry related techniques. In this article, we will focus on the bioanalytical assays that have been used in pharmacokinetic study of ADCs and discuss their advantages, current limitations and potential challenges. SIGNIFICANCE STATEMENTThis article describes bioanalysis methods which have been used in pharmacokinetic study of ADCs and discusses the advantages, disadvantages and potential challenges of these assays. This review is useful and helpful and will provide insights and reference for bioanalysis and development of ADCs.

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Section: Cahuzac Et Al Used Dual Radiolabeling and Ex Vivo Digital Im...supporting

confidence: 56%

Bioanalytical Assays for Pharmacokinetic and Biodistribution Study of Antibody-Drug Conjugates

Yin

Zhang

et al. 2023

Drug Metab Dispos

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“…Conversion of the Bud-RG intermediates to full linkers was achieved convergently by the direct reaction of these HCl salts with p -nitrocarbonates represented by 20 in the presence of N , N -diisopropylethylamine (DIPEA) (Scheme ). , We chose to terminate our linkers in a standard maleimide–caproamide (MC) conjugation group for screening purposes. This conjugation motif is prevalent in the ADC field, featuring prominently across FDA-approved ADC therapies, thereby providing a useful benchmark.…”

Section: Resultsmentioning

confidence: 99%

Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody–Drug Conjugates

Marvin,

Hobson,

McPherson

et al. 2023

Bioconjugate Chem.

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Antibody–drug conjugates consist of potent small-molecule payloads linked to a targeting antibody. Payloads must possess a viable functional group by which a linker for conjugation can be attached. Linker-attachment options remain limited for the connection to payloads via hydroxyl groups. A releasing group based on 2-aminopyridine was developed to enable stable attachment of para-aminobenzyl carbamate (PABC) linkers to the C21-hydroxyl group of budesonide, a glucocorticoid receptor agonist. Payload release involves a cascade of two self-immolative events that are initiated by the protease-mediated cleavage of the dipeptide–PABC bond. Budesonide release rates were determined for a series of payload–linker intermediates in buffered solution at pH 7.4 and 5.4, leading to the identification of 2-aminopyridine as the preferred releasing group. Addition of a poly(ethylene glycol) group improved linker hydrophilicity, thereby providing CD19-budesonide ADCs with suitable properties. ADC23 demonstrated targeted delivery of budesonide to CD19-expressing cells and inhibited B-cell activation in mice.

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“…Standard methods for evaluating the pharmacokinetic and tissue distribution profiles of a drug candidate involve tissue harvesting, homogenization, and quantification using liquid chromatography/tandem mass spectrometry (LC-MS/MS). While those methods will still be necessary for full characterization of a lead compound, direct radiolabeling provides a unique way to visually assess and quantify the whole-body distribution of multiple drug candidates early in their development and has mainly been used in preclinical evaluation of antibody-drug conjugates (ADCs) and nanoparticles. − Here, we used the MMC scaffold to directly label MMC(TMZ)-TOC and (i) determined the amount of conjugate that reached the tumor and (ii) quantified biodistribution in nontumor tissues in vivo using noninvasive nuclear imaging (PET/CT scan) and ex vivo γ counting. We observed a favorable biodistribution profile for the PDC that was similar to that of 68 Ga-DOTA-TOC: high tumor uptake, rapid kidney clearance, and low accumulation in normal tissues (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Somatostatin Receptor Subtype-2 Targeting System for Specific Delivery of Temozolomide

AghaAmiri,

Ghosh,

Hernandez Vargas

et al. 2024

J. Med. Chem.

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Temozolomide (TMZ) is a DNA alkylating agent that produces objective responses in patients with neuroendocrine tumors (NETs) when the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) is inactivated. At high doses, TMZ therapy exhausts MGMT activity but also produces doselimiting toxicities. To reduce off-target effects, we converted the clinically approved radiotracer 68 Ga-DOTA-TOC into a peptidedrug conjugate (PDC) for targeted delivery of TMZ to somatostatin receptor subtype-2 (SSTR2)-positive tumor cells.We used an integrated radiolabeling strategy for direct quantitative assessment of receptor binding, pharmacokinetics, and tissue biodistribution. In vitro studies revealed selective binding to SSTR2-positive cells with high affinity (5.98 ± 0.96 nmol/L), internalization, receptor-dependent DNA damage, cytotoxicity, and MGMT depletion. Imaging and biodistribution analysis showed preferential accumulation of the PDC in receptor-positive tumors and high renal clearance. This study identified a trackable SSTR2targeting system for TMZ delivery and utilizes a modular design that could be broadly applied in PDC development.

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Monitoring In Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging

Cited by 9 publications

References 53 publications

Bioanalytical Assays for Pharmacokinetic and Biodistribution Study of Antibody-Drug Conjugates

Bioanalytical Assays for Pharmacokinetic and Biodistribution Study of Antibody-Drug Conjugates

Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody–Drug Conjugates

Somatostatin Receptor Subtype-2 Targeting System for Specific Delivery of Temozolomide

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