Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester-containing ADC linkers

Jackson, Courtney P.; Fang, Siteng; Benjamin, Samantha R.; Alayi, Tchilabalo Dilezitoko; Hathout, Yetrib; Gillen, Sarah M.; Handel, Jillian P.; Brems, Brittany M.; Howe, Justin M.; Tumey, L. Nathan

doi:10.1016/j.bmcl.2022.128953

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…This work builds on our recently published work describing the stability of an ester-linked dexamethasone ADC. 15 In our previous publication, we demonstrated that a CD11a-targeting ADC linked to dexamethasone via an ester linkage was not readily cleaved by lysosomal enzymes, but was able to modestly suppress LPS-induced TNFα production. Herein, we expand on this work by exploring various monocyte-targeting antibodies and by redesigning the linker to more efficiently release dexamethasone upon lysosomal uptake.…”

Section: Introductionmentioning

confidence: 86%

“…4, Rxn 1) are not readily cleaved by lysosomal enzymes and thus are generally unsuitable for delivery of dexamethasone. 15 Instead, we designed a small set of amine-containing self-immolative spacers that are sterically constrained in order to promote rapid lactam formation upon cleavage of a peptidic bond. In this manner, we would be able to rely on traditional proteases such as cathepsin B or legumain that are known to be highly active in lysosomes.…”

Section: Linker Designmentioning

confidence: 99%

“…13 Given our team's long-standing interest in ADC linker technology and immune-modulating ADCs, we recently undertook a project to design ADCs to deliver dexamethasone to broad sets of lymphocytes and myeloid cells. [14][15][16] For the purposes of optimizing the design of the ADC, we began with a focus on monocytes. Monocytes are a key component of the innate immune system and play an important role in a variety of immunological disorders.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes

Howe,

Fang,

Watts

et al. 2023

RSC Med. Chem.

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Section: Introductionmentioning

confidence: 86%

Section: Linker Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes

Howe,

Fang,

Watts

et al. 2023

RSC Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Peptide linkers rely on proteases for cleavage, with the FDA-approved Hodgkin's lymphoma drug brentuximab vedotin using an CD30 antibody with a peptide cleavable linker and MMAE [39]. Furthermore, various enzyme-based linkers, such as β-glucuronidase and β-galactosidase linkers, have been developed [40][41][42][43] (Figure 4). These are degraded by enzymes present in lysosomes, rendering them more stable in the bloodstream compared to chemically cleavable linkers.…”

Section: Linkermentioning

confidence: 99%

Trends in the Development of Antibody-Drug Conjugates for Cancer Therapy

Song,

Jeong,

et al. 2023

Antibodies

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In cancer treatment, the first-generation, cytotoxic drugs, though effective against cancer cells, also harmed healthy ones. The second-generation targeted cancer cells precisely to inhibit their growth. Enter the third-generation, consisting of immuno-oncology drugs, designed to combat drug resistance and bolster the immune system’s defenses. These advanced therapies operate by obstructing the uncontrolled growth and spread of cancer cells through the body, ultimately eliminating them effectively. Within the arsenal of cancer treatment, monoclonal antibodies offer several advantages, including inducing cancer cell apoptosis, precise targeting, prolonged presence in the body, and minimal side effects. A recent development in cancer therapy is Antibody-Drug Conjugates (ADCs), initially developed in the mid-20th century. The second generation of ADCs addressed this issue through innovative antibody modification techniques, such as DAR regulation, amino acid substitutions, incorporation of non-natural amino acids, and enzymatic drug attachment. Currently, a third generation of ADCs is in development. This study presents an overview of 12 available ADCs, reviews 71 recent research papers, and analyzes 128 clinical trial reports. The overarching objective is to gain insights into the prevailing trends in ADC research and development, with a particular focus on emerging frontiers like potential targets, linkers, and drug payloads within the realm of cancer treatment.

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Hochgradig cytotoxische Cryptophycine mit modifiziertem Fragment D zur Konjugation

Dessin,

Schachtsiek,

Voss

et al. 2024

Angewandte Chemie

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Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2‐hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X‐ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug‐resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur‐containing derivatives. X‐ray crystallographic analysis of a tubulin‐bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D.

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Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester-containing ADC linkers

Cited by 5 publications

References 33 publications

ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes

ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes

Trends in the Development of Antibody-Drug Conjugates for Cancer Therapy

Hochgradig cytotoxische Cryptophycine mit modifiziertem Fragment D zur Konjugation

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