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Cited by 50Monoclonal and Polyclonal Antibodies ResearchToxin Mechanisms and ImmunotoxinsSynthesis and pharmacology of benzodiazepine derivatives

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Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy

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Wang, Yanming, Fan, Shiyong, Xiao, Dian, Xie, Fei, Li, Wei, Zhong, Wu, Zhou, Xinbo·2019·Cancers
DOI 10.3390/cancers11070957PMC PMC6678733
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Abstract

Antibody-drug conjugate (ADC) is a novel efficient drug delivery system that has been successfully used in clinical practice, and it has become a research hotspot in the anti-tumor drug field. Acid-cleavable linkers were first used in clinical ADCs, but their structural variety (e.g., hydrazone and carbonate) is still limited, and their stability is usually insufficient. Designing novel acid-cleavable linkers for the conjugation of the popular cytotoxin monomethyl auristatin E (MMAE) has always been a significant topic. In this paper, we generate a novel, silyl ether-based acid-cleavable antibody-MMAE conjugate, which skillfully achieves efficient combination of amino-conjugated MMAE with the acid-triggered silyl ether group by introducing p-hydroxybenzyl alcohol (PHB). The stability, acid-dependence cleavage, effective mechanism, efficacy and safety of the resulting ADC were systematically studied; the results show that it exhibits a significant improvement in stability, while maintaining appropriate efficacy and controlled therapeutic toxicity. This strategy is expected to expand a new type of acid-cleavable linkers for the development of ADCs with highly potent payloads.

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Figure 1 Structures of the chemically labile antibody-drug conjugates (ADCs) with acid-cleavable linkers, and the drug release mechanism of ADCs with monomethyl auristatin E (MMAE) as the payload. (A) The doxorubicin-based ADC with the pH-sensitive hydrazone linker; (B) the calicheamicin-based ADC with the pH-sensitive hydrazone linker; (C) the SN-38-based ADC with the pH-sensitive carbonate linker; (D) the designed MMAE-based ADC with the pH-sensitive silyl ether linker, and its drug release mechanism.
Figure 1 Structures of the chemically labile antibody-drug conjugates (ADCs) with acid-cleavable linkers, and the drug release mechanism of ADCs with monomethyl auristatin E (MMAE) as the payload. (A) The doxorubicin-based ADC with the pH-sensitive hydrazone linker; (B) the calicheamicin-based ADC with the pH-sensitive hydrazone linker; (C) the SN-38-based ADC with the pH-sensitive carbonate linker; (D) the designed MMAE-based ADC with the pH-sensitive silyl ether linker, and its drug release mechanism.CC BY · PubMed Central
Figure 2 General synthetic route for the linker-MMAE conjugate (compound 6). Reagents and conditions: (a) NMM, EA, 0 °C, 2 h, 99%; (b) 2-(2-aminoethoxy)ethan-1-ol, NaHCO3, H2O, 0 °C ~ room temperature (rt), 1 h, 57%; (c) dichlorodiisopropylsilane, 4-hydroxybenzaldehyde, TEA, DCM, 0 °C ~ rt, 2 h, 76%; (d) NaBH4, THF, −5 °C–0 °C, 3 h, 23%; (e) Bis(4-Nitrophenyl) Carbonate, DIPEA, DMF, rt, 5 h, 72%; (f) MMAE, HOBt, DIPEA, DMF, rt, overnight, 62%.
Figure 2 General synthetic route for the linker-MMAE conjugate (compound 6). Reagents and conditions: (a) NMM, EA, 0 °C, 2 h, 99%; (b) 2-(2-aminoethoxy)ethan-1-ol, NaHCO3, H2O, 0 °C ~ room temperature (rt), 1 h, 57%; (c) dichlorodiisopropylsilane, 4-hydroxybenzaldehyde, TEA, DCM, 0 °C ~ rt, 2 h, 76%; (d) NaBH4, THF, −5 °C–0 °C, 3 h, 23%; (e) Bis(4-Nitrophenyl) Carbonate, DIPEA, DMF, rt, 5 h, 72%; (f) MMAE, HOBt, DIPEA, DMF, rt, overnight, 62%.CC BY · PubMed Central
Figure 3 Stability assays of silyl ether-based ADC (mil40-6) and its payload conjugate (NAC-6) in human plasma. ADC and NAC-6 were incubated at 37 °C for 7 days. Error bars represent standard deviation from three independent experiments (triplicates). Results are shown as the mean ± SD. NAC: N-acetyl-L-cysteine.
Figure 3 Stability assays of silyl ether-based ADC (mil40-6) and its payload conjugate (NAC-6) in human plasma. ADC and NAC-6 were incubated at 37 °C for 7 days. Error bars represent standard deviation from three independent experiments (triplicates). Results are shown as the mean ± SD. NAC: N-acetyl-L-cysteine.CC BY · PubMed Central
Figure 4 pH-dependent drug release of acid-sensitive ADC (mil40-6). Typical time course of MMAE cleaved from ADC in PBS that pH 7.4, pH 5.5, and pH 4.5. Error bars represent standard deviation from three independent experiments (triplicates). Data are shown as mean ± SD. DAR: drug/antibody ratio.
Figure 4 pH-dependent drug release of acid-sensitive ADC (mil40-6). Typical time course of MMAE cleaved from ADC in PBS that pH 7.4, pH 5.5, and pH 4.5. Error bars represent standard deviation from three independent experiments (triplicates). Data are shown as mean ± SD. DAR: drug/antibody ratio.CC BY · PubMed Central
Figure 5 Receptor-mediated internalization of ADC mil40-6 by HER2+ breast cancer cell line BT-474. Red fluorescence-labeled mil40-6 (1 μg/mL) was incubated with GFP-labeled BT-474 cells at 37 °C for 16 h while mil40-6 was endocytosed into the cell and located in lysosomes. The cell nuclei were stained with DAPI (blue), the lysosomes were labeled with a lysosomes-GFP (green), and the antobody were labeled with pHrodo Red (red). GFP: green fluorescent protein; DAPI: 4′,6-diamidino-2-phenylindole. Scale bar = 50 μm.
Figure 5 Receptor-mediated internalization of ADC mil40-6 by HER2+ breast cancer cell line BT-474. Red fluorescence-labeled mil40-6 (1 μg/mL) was incubated with GFP-labeled BT-474 cells at 37 °C for 16 h while mil40-6 was endocytosed into the cell and located in lysosomes. The cell nuclei were stained with DAPI (blue), the lysosomes were labeled with a lysosomes-GFP (green), and the antobody were labeled with pHrodo Red (red). GFP: green fluorescent protein; DAPI: 4′,6-diamidino-2-phenylindole. Scale bar = 50 μm.CC BY · PubMed Central
Figure 6 The inhibition tests of microtubule polymerization. The cytotoxin MMAE and the Cys-linker-MMAE (Cys-6) were tested in a microtubule polymerization assay. Free MMAE was included as a positive control. Paclitaxel and CaCl2 were included as a promoter and inhibitor, respectively, of microtubule polymerization. The buffer control indicates the polymerization rate of untreated microtubules.
Figure 6 The inhibition tests of microtubule polymerization. The cytotoxin MMAE and the Cys-linker-MMAE (Cys-6) were tested in a microtubule polymerization assay. Free MMAE was included as a positive control. Paclitaxel and CaCl2 were included as a promoter and inhibitor, respectively, of microtubule polymerization. The buffer control indicates the polymerization rate of untreated microtubules.CC BY · PubMed Central
Figure 7 The effects of the ADC (mil40-6) on cell cycle arrest. The BT-474 cells cycle arrest results analyzed by flow cytometry (FCM). ADC was tested in three doses of 10 ng/mL, 50 ng/mL, and 100 ng/mL. The concentration of the ADC is calculated as the concentration of the antibody.
Figure 7 The effects of the ADC (mil40-6) on cell cycle arrest. The BT-474 cells cycle arrest results analyzed by flow cytometry (FCM). ADC was tested in three doses of 10 ng/mL, 50 ng/mL, and 100 ng/mL. The concentration of the ADC is calculated as the concentration of the antibody.CC BY · PubMed Central
Figure 8 Xenograft studies of the ADC (mil40-6). Nude mice were implanted subcutaneously with NCI-N87 cells. When the tumors reached ~ 120 mm3, the animals were given vehicle, mil40, and ADC on: Days 0, 7, 14, and 21. Results are shown as mean ± SD, n = 6/group. (A) The tumor volume of the test animals during the treatment and observation period; (B) changes in body weight of the mice during the observation period. To compare the difference in activity between antibody and ADC, unpaired two-tailed t tests for multiple comparisons were used, and statistical analyses were performed using Prism5 for Windows.
Figure 8 Xenograft studies of the ADC (mil40-6). Nude mice were implanted subcutaneously with NCI-N87 cells. When the tumors reached ~ 120 mm3, the animals were given vehicle, mil40, and ADC on: Days 0, 7, 14, and 21. Results are shown as mean ± SD, n = 6/group. (A) The tumor volume of the test animals during the treatment and observation period; (B) changes in body weight of the mice during the observation period. To compare the difference in activity between antibody and ADC, unpaired two-tailed t tests for multiple comparisons were used, and statistical analyses were performed using Prism5 for Windows.CC BY · PubMed Central
Figure 9 Hematological analysis of acid-sensitive ADC (mil40-6). WBC: white blood cells; RBC: red blood cells; HGB: hemoglobin; PLT: platelets; Neuts: neutrophils; Lymph: lymphocytes; Mono: monocyte; Eos: eosinophils; LUC: large unstained cell. Results are shown as mean ± SD, n = 6/group.
Figure 9 Hematological analysis of acid-sensitive ADC (mil40-6). WBC: white blood cells; RBC: red blood cells; HGB: hemoglobin; PLT: platelets; Neuts: neutrophils; Lymph: lymphocytes; Mono: monocyte; Eos: eosinophils; LUC: large unstained cell. Results are shown as mean ± SD, n = 6/group.CC BY · PubMed Central

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Metadata

Authors
Wang, Y., Fan, S., Xiao, D., Xie, F., Li, W., Zhong, W., & Zhou, X.
Affiliations
National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Corresponding author
  • Zhong, Wu
  • Zhou, Xinbo
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2019-07-08
Volume
11
Issue
7
Pages
957
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers11070957
PMC
PMC6678733
OpenAlex
W2955413137
Cited by
50
References
0
Citations by year
2026: 9 · 2025: 10 · 2024: 8 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 1
FWCI
2.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Science and Technology Major Project for Major New Drugs Innovation and Development (2018ZX09711003-009)
  • Chinese National Natural Science Foundation (81872736)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and pharmacology of benzodiazepine derivatives
Keywords
antibody-drug conjugates, silyl ethers, monomethyl auristatin E, p-hydroxybenzyl alcohol, linker stability, cytotoxic payloads, targeted cancer therapy

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