ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development

Walles, Markus; Connor, Anu; Hainzl, Dominik

doi:10.2174/1568026618666180118153502

Cited by 32 publications

(26 citation statements)

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“…In the cytotoxicity test, although the IC 50 value of ionized Cys-15 can be reduced by two orders of magnitude compared to MMAE, we deduced that it is mainly caused by its poorer membrane permeability (MlogP values of Cys-15 and MMAE are −2.093 and 1.191). Generally, the conventional cytotoxicity test cannot effectively reflect its true efficacy in ADC applications [11], which lead to some challenges in designing and screening the ionized cytotoxins of ADCs [35]. Herein, we applied a rapid screening method at the tubulin molecular level and confirmed that the efficacy of Cys-linker-MMAE conjugates did not significantly decrease compared to MMAE.…”

Section: Discussionmentioning

confidence: 69%

“…We designed and synthesized a series of linker-MMAE constructs (11)(12)(13)(14)(15) based on different non-cleavable linkers. After these linker-MMAE constructs were modified on the Cys site of the antibodies, the resulting ADCs can be metabolized into stable Cys-linker-MMAE conjugates in the target cells to exert pharmacodynamic effects.…”

Section: Design and Synthesis Of The Cys-linker-mmae-based Adc Payloadsmentioning

confidence: 99%

“…Although the current MMAE-based ADCs with cleavable linkers have achieved great success in clinical applications, there are still limitations in the design concept and the antitumor activity should always be balanced by safety considerations [5,11]. These ADCs work by releasing MMAE in its unmodified form under the catalysis of enzymes (cathepsin B, etc.)…”

Section: Introductionmentioning

confidence: 99%

“…Herein, we propose the hypothesis of using non-cleavable L-Cysteine (Cys)-linker-MMAE as the potent payload directly. The ionized effector molecules skillfully use receptor-mediated endocytosis of the antibody to enter tumor cells and produce cumulative effects [11], meanwhile, their ionic characteristics effectively reduce toxicity by an accelerated in vivo clearance process and reduce penetration into normal cells ( Figure 1B) [22]. Although this design strategy has been applied to other cytotoxins, such as DM1 which was used in the marketed Kadcyla ® [23], MMAE has rarely been modified in ADCs thus far, and the conclusions of the only relevant research were negative [24].…”

Section: Introductionmentioning

confidence: 99%

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Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.

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Section: Discussionmentioning

confidence: 69%

Section: Design and Synthesis Of The Cys-linker-mmae-based Adc Payloadsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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show abstract

“…By definition, NC linkers are more stable, but the rate of cargo release cannot be controlled. This strategy relies on the total degradation of the Ab after ADC is internalized and the exposure to lysosomal enzymes . On the other hand, cleavable linkers offer controllable drug release mechanisms, but they display lower systemic stability.…”

Section: Antibody–drug Conjugatesmentioning

confidence: 99%

Protease‐activated prodrugs: strategies, challenges, and future directions

Poręba

2020

The FEBS Journal

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Proteases play critical roles in virtually all biological processes, including proliferation, cell death and survival, protein turnover, and migration. However, when dysregulated, these enzymes contribute to the progression of multiple diseases, with cancer, neurodegenerative disorders, inflammation, and blood disorders being the most prominent examples. For a long time, disease-associated proteases have been used for the activation of various prodrugs due to their well-characterized catalytic activity and ability to selectively cleave only those substrates that strictly correspond with their active site architecture. To date, versatile peptide sequences that are cleaved by proteases in a site-specific manner have been utilized as bioactive linkers for the targeted delivery of multiple types of cargo, including fluorescent dyes, photosensitizers, cytotoxic drugs, antibiotics, and pro-antibodies. This platform is highly adaptive, as multiple protease-labile conjugates have already been developed, some of which are currently in clinical use for cancer treatment. In this review, recent advancements in the development of novel protease-cleavable linkers for selective drug delivery are described. Moreover, the current limitations regarding the selectivity of linkers are Abbreviations AAC, antibody-antibiotic conjugate; Ab, antibody; ACC, 7-amino-4-carbamoylmethylcoumarin; ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; ADC, antibody-drug conjugate; aPSs, activatable photosensitizers; BHQ-3, black hole quencher 3; Boc, tert-butyloxycarbonyl group; BT20, a type of mammary gland carcinoma; Cas9, CRISPR-associated protein 9;

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Antibody–Pattern Recognition Receptor Agonist Conjugates: A Promising Therapeutic Strategy for Cancer

Li²,

2022

Advanced Biology

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To date, 12 ADCs (gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, moxetumomab pasudotox, polatuzumab vedotin, trastuzumab deruxtecan, enfortumab vedotin, sacituzumab govitecan, belantamab mafodotin, loncastuximab tesirine-lpyl, and tisotumab vedotin-tftv) have been approved by the FDA to treat various solid tumors and hematological malignancies. [3] An ADC is typically composed of a monoclonal antibody (mAb; recognizes a specific target) linked to a potent cytotoxic molecule (payload drug). In addition, a linker is required to connect these two components and maintain ADC stability. [4] Two types of linkers, namely cleavable [5] and noncleavable linkers, [6] have been developed, and these have met different requirements of preclinical and clinical studies. Cleavable linkers are designed to remain stable in the bloodstream and selectively release the payload drug in the target cell, whereas noncleavable linkers mainly rely on lysosomal degradation to release the payload drug after ADC internalization. [7] All components of an ADC can be distinctively designed to maximize its binding affinity and therapeutic effect (Figure 1).The ADC as a complex fully exerts biological effect of the two components and selectively delivers the payload drug to target tissues through the mAb. The ADC initially binds to cell surface antigens and enters tumor cells through clathrin-mediated endocytosis. [8] It is then transported to the early endosome, and it subsequently enters the lysosome where it is degraded by proteolytic enzymes to release the payload drug into the cytoplasm. [9] Ultimately, cytotoxic drugs induce tumor cell death or apoptosis via different mechanisms, such as by damaging DNA or inhibiting microtubule synthesis. [10] This process results in minimal systemic toxic effects, but it improves the treatment window of cytotoxic drugs, and the therapeutic efficacy is enhanced accordingly. [11] Development History of Antibody-Drug ConjugatesThe history of ADC drug development occurred in three stages and provided three generations of ADCs. For first-generation ADCs, cytotoxic drugs were mainly conjugated with mouse mAbs via non-cleavable linkers. This increased the possibility of inducing antidrug antibody effects. In addition, off-target Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to cytotoxic payload drugs, each of which can be diversely designed in accordance with pharmacological and clinical requirements. The use of ADCs is effective for the treatment of different diseases, including cancers, and is gaining widespread attention. To date, 12 ADCs have been approved by the U.S. Food and Drug Administration for treating cancer and improving the quality of life of patients. To expand the application of ADCs and improve their treatment efficiency, various formats have recently been manufactured, including pattern recognition receptor (PRR) agonist-based ADCs. The antibody has a unique structure that enables the specific delivery of PRR agonists ...

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ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development

Cited by 32 publications

References 0 publications

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Protease‐activated prodrugs: strategies, challenges, and future directions

Antibody–Pattern Recognition Receptor Agonist Conjugates: A Promising Therapeutic Strategy for Cancer

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