Polyethylene glycol-based linkers as hydrophilicity reservoir for antibody-drug conjugates

Tedeschini, Tommaso; Campara, Benedetta; Grigoletto, Antonella; Bellini, Marino; Salvalaio, Marika; Matsuno, Yoshihiro; Suzuki, Akira; Yoshioka, Hiroki; Pasut, Gianfranco

doi:10.1016/j.jconrel.2021.07.041

Cited by 25 publications

(20 citation statements)

References 47 publications

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“…Overall ADC incorporating the pendant PEG linker may exhibit the better hydrophilic properties than that of straight PEG linker. (Lyon et al., 2015 ; Tedeschini et al., 2021 ; Xiao et al., 2021 ) Compound 4 reacted with activated Fmoc-Lys (PEG 8 )-OH to provide compound 9. Fmoc deprotection followed by maleimide incorporation yielded the desired compound 11 containing the pendant PEG moiety.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates

Liu¹,

Xie²,

Xiao³

et al. 2021

Drug Delivery

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Camptothecins, traditional chemotherapy drugs, have been clinically used in antibody-drug conjugates (ADCs), which refreshes the recognition that ADCs preferably incorporate highly potent payloads. However, SN-38, active metabolite of irinotecan from camptothecins, tended to be incorporated into ADCs with an unstable acid sensitive bond, not with the widely used Cathepsin B (CTSB) sensitive bond, which may pose the risk of off-target. Herein, we reported a novel strategy to construct highly releasable and structurally stable SN-38-conjugates, in which CTSB linkers directly connected to the 10-OH group through ether bond, not to the common 20-OH group of lactones of SN-38. In this paper, rapid release of SN-38 was skillfully demonstrated by utilizing the fluorescence properties of SN-38. The SN-38-ether-ADC displayed highly stable serum stability with the half-life over 10 days. Moreover, the drug-antibody-ratio (DAR) of ADC could be elevated to 7.1 through the introduction of polyethylene glycol (PEG) moieties without aggregation. The optimized ADC exhibited potent in vitro activities up to 5.5 nM, comparable to SN-38. Moreover, this ADC group significantly delayed tumor growth in vivo . In conclusion, the novel strategy has the potential to promote the development of SN38-ADCs and enrich the conjugation approaches for hydroxyl-bearing payloads.

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates

Liu¹,

Xie²,

Xiao³

et al. 2021

Drug Delivery

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“…In cases of SG and LT, polyethylene glycol (PEG) groups were inserted to increase solubility and reduce aggregation of hydrophobic cytotoxic drugs in blood plasma. 36 BV, EV and PV ( Fig. 3 ) and LT ( Fig.…”

Section: Introductionmentioning

confidence: 95%

Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody–drug conjugates

et al. 2021

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“…The absorbance of 4C9-DM1 was higher than that of 4C9 at 252 nm (Figure 3B). The drug-antibody ratio (DAR) was determined as described previously [36] and the DAR was approximately 2.16. SDS-PAGE analysis exhibited that the conjugation of SMCC-DM1 to the 4C9 antibody resulted in a slight size shift (Supplementary Figure S2).…”

Section: Generation and Characterization Of Adc (4c9-dm1)mentioning

confidence: 99%

“…The average drug-antibody ratio (DAR) of 4C9-DM1 was determined by comparing the absorbance of the naked antibody and ADC at 252 nm. In addition, the molar concentration of the linked DM1 was assessed by UV spectroscopy by measuring the different absorbance maxima of 4C9 and SMCC-DM1 at 280 and 252 nm, respectively, as reported previously [36]:…”

Section: Generation Of Adcmentioning

confidence: 99%

Antibody-Drug Conjugate Targeting c-Kit for the Treatment of Small Cell Lung Cancer

Kim

Park

et al. 2022

IJMS

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Lung cancer is the leading cause of cancer-related deaths. Small cell lung cancer (SCLC) accounts for 15–25% of all lung cancers. It exhibits a rapid doubling time and a high degree of invasiveness. Additionally, overexpression of c-Kit occurs in 70% of SCLC patients. In this study, we evaluated an antibody-drug conjugate (ADC) that targets c-Kit, which is a potential therapeutic agent for SCLC. First, we generated and characterized 4C9, a fully human antibody that targets c-Kit and specifically binds to SCLC cells expressing c-Kit with a binding affinity of KD = 5.5 × 10−9 M. Then, we developed an ADC using DM1, a microtubule inhibitor, as a payload. 4C9-DM1 efficiently induced apoptosis in SCLC with an IC50 ranging from 158 pM to 4 nM. An in vivo assay using a xenograft mouse model revealed a tumor growth inhibition (TGI) rate of 45% (3 mg/kg) and 59% (5 mg/kg) for 4C9-DM1 alone. Combination treatment with 4C9-DM1 plus carboplatin/etoposide or lurbinectedin resulted in a TGI rate greater than 90% compared with the vehicle control. Taken together, these results indicate that 4C9-DM1 is a potential therapeutic agent for SCLC treatment.

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Polyethylene glycol-based linkers as hydrophilicity reservoir for antibody-drug conjugates

Cited by 25 publications

References 47 publications

Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates

Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates

Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody–drug conjugates

Antibody-Drug Conjugate Targeting c-Kit for the Treatment of Small Cell Lung Cancer

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