A Novel Family of Acid-Cleavable Linker Based on Cyclic Acetal Motifs for the Production of Antibody-Drug Conjugates with High Potency and Selectivity

Rady, Tony; Turelli, Lorenzo; Nothisen, Marc; Tobaldi, Elisabetta; Erb, Stéphane; Thoreau, Fabien; Hernandez‐Alba, Oscar; Cianférani, Sarah; Daubeuf, François; Wagner, Alain; Chaubet, Guilhem

doi:10.1021/acs.bioconjchem.2c00314

Cited by 5 publications

(3 citation statements)

References 27 publications

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“…However, these linkers show high stability under acidic conditions (even at pH < 1), limiting their use as pH-sensitive linkers [ 225 , 252 ]. Recently, a novel class of cyclic methoxybenzaldehyde acetals demonstrates high stability in neutral pH/plasma and cleavage at acidic pH [ 253 ]. When installed as a pH-sensitive linker connecting the MMAF drug to the antibody trastuzumab, significant potency in vitro and in vivo was observed, indicating that cyclic methoxybenzaldehyde acetals are excellent candidates to be used as pH-sensitive linkers for drug release applications where endocytosis is expected.…”

Section: Cleavable and Non-cleavable Linkers In Oligonucleotide Conju...mentioning

confidence: 99%

Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

Mangla,

Vicentini,

Biscans

2023

Cells

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The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.

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Section: Cleavable and Non-cleavable Linkers In Oligonucleotide Conju...mentioning

confidence: 99%

Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

Mangla,

Vicentini,

Biscans

2023

Cells

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“…Thio/acetals are popular functional groups in fluorescent probes. Thioacetals have been used for mercury sensing, − quenching, − and the detection of reactive oxygen species, − while acetals have been used to sense pH changes, − detect metal ions, − visualize and modulate enzyme activity, − and for photochromic switching − and super-resolution microscopy . Usually, the conversion of aldehydes into thio/acetals is designed to turn off fluorescence, or vice versa , for different reasons.…”

Section: Introductionmentioning

confidence: 99%

Fluorogenic In Situ Thioacetalization: Expanding the Chemical Space of Fluorescent Probes, Including Unorthodox, Bifurcated, and Mechanosensitive Chalcogen Bonds

Chen,

Gomila,

García-Arcos

et al. 2023

JACS Au

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Progress with fluorescent flippers, small-molecule probes to image membrane tension in living systems, has been limited by the effort needed to synthesize the twisted push−pull mechanophore. Here, we move to a higher oxidation level to introduce a new design paradigm that allows the screening of flipper probes rapidly, at best in situ. Late-stage clicking of thioacetals and acetals allows simultaneous attachment of targeting units and interfacers and exploration of the critical chalcogen-bonding donor at the same time. Initial studies focus on plasma membrane targeting and develop the chemical space of acetals and thioacetals, from acyclic amino acids to cyclic 1,3-heterocycles covering dioxanes as well as dithiolanes, dithianes, and dithiepanes, derived also from classics in biology like cysteine, lipoic acid, asparagusic acid, DTT, and epidithiodiketopiperazines. From the functional point of view, the sensitivity of membrane tension imaging in living cells could be doubled, with lifetime differences in FLIM images increasing from 0.55 to 1.11 ns. From a theoretical point of view, the complexity of mechanically coupled chalcogen bonding is explored, revealing, among others, intriguing bifurcated chalcogen bonds.

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“…Since the approval of the first antibody-drug conjugate (ADC), Mylotarg (gemtuzumab ozogamicin), for the treatment of acute myeloid leukemia (AML) 1 , ADCs have emerged as a very promising class of 2 therapeutics for targeted cancer therapy, with 13 ADCs approved by the food and drug administration (FDA), and more than 100 in clinical stages in 2022 [2][3][4] . ADCs are constructed by conjugating highly potent drugs via a linker to a receptor-targeting monoclonal antibody (mAb) delivering the payload directly to tumor cells to reduce systemic toxicity and increase the selectivity of the treatment [5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

SEC-MS in Denaturing Conditions (dSEC-MS) for In-Depth Analysis of Rebridged Monoclonal Antibody-Based Formats

Benazza

Koutsopetras

Vaur

et al. 2023

Preprint

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Disulfide rebridging methods are emerging recently as new ways to specifically modify antibody-based entities and produce future conjugates. Briefly, the solvent-accessible disulfide bonds of antibodies or antigen-binding fragments (Fab) thereof are reduced under controlled conditions and further covalently attached with a rebridging agent allowing the incorporation of one payload per disulfide bond. There are many examples of successful rebridging cases providing homogeneous conjugates due to the use of symmetrical reagents, such as dibromomaleimides. However, partial rebridging due to the use of unsymmetrical ones, containing functional groups with different reactivity, usually leads to the development of heterogeneous species that cannot be identified by a simple SDS-PAGE gel due to its lack of sensitivity, resolution and low mass accuracy. LC-MS approaches have already been demonstrated as highly promising alternatives for the characterization of newly developed ADCs and mAb-based formats. We report here the in-depth characterization of covalently rebridged antibodies and Fab fragments in-development, using size-exclusion chromatography hyphenated to mass spectrometry in denaturing conditions (Denaturing SEC-MS, dSEC-MS). DSEC-MS was used to monitor closely the rebridging reaction of a conjugated Trastuzumab, in addition to conjugated Fab fragments, which allowed an unambiguous identification of the covalently rebridged products along with the unbound species. This all-in-one approach allowed a straightforward analysis of the studied samples with precise mass measurement; critical quality attributes assessment along with rebridging efficiency determination.

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A Novel Family of Acid-Cleavable Linker Based on Cyclic Acetal Motifs for the Production of Antibody-Drug Conjugates with High Potency and Selectivity

Cited by 5 publications

References 27 publications

Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

Fluorogenic In Situ Thioacetalization: Expanding the Chemical Space of Fluorescent Probes, Including Unorthodox, Bifurcated, and Mechanosensitive Chalcogen Bonds

SEC-MS in Denaturing Conditions (dSEC-MS) for In-Depth Analysis of Rebridged Monoclonal Antibody-Based Formats

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