Design, Synthesis, and Evaluation of Camptothecin-Based Antibody–Drug Conjugates with High Hydrophilicity and Structural Stability

In this study, we constructed a linear antibody–drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine p...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Vol. 30; no. 7; p. 1398
Main Authors: Xiong, Tingyu, Jin, Jiyu, Liu, Dongliang, Jin, Chen
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 21.03.2025
Subjects:
Analog to digital converters
Animals
Antibodies
antibody–drug conjugates
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biopharmaceutics
Breast cancer
Camptothecin
Camptothecin - analogs & derivatives
Camptothecin - chemistry
Camptothecin - pharmacology
Cathepsins
Cell Line, Tumor
Chromatography
Cytotoxicity
Drug Design
Drug Stability
Enzymes
Ethylenediaminetetraacetic acid
Humans
Hydrophobic and Hydrophilic Interactions
Immunoconjugates - chemistry
Immunoconjugates - pharmacology
Mice
Phosphates
Polyethylene glycol
Polyols
polysarcosine
topoisomerase I inhibitor
Viral antibodies
Xenograft Model Antitumor Assays
Japan
China
polyethylene glycol
polysarcosine
topoisomerase I inhibitor
antibody–drug conjugates
ISSN:1420-3049, 1420-3049
Online Access:Get full text
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Summary:In this study, we constructed a linear antibody–drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine pairs with different water-soluble substituents to further modify the linker and synthesized side-chain ADCs 7300-LP3004 and 7300-LP2004, modified by polysarcosine and polyethylene glycol, respectively. In vitro experiments showed that, after incubation at 55 °C in phosphate-buffered saline for 48 h, 7300-LP3004 aggregation was 45.24%, which was significantly lower than that of 7300-LP1003 (77.14%). Cell cytotoxicity assays demonstrated that the side-chain ADCs, 7300-LP3004 and 7300-LP2004, exhibited significantly higher activity (IC50 values of 39.74 nM and 32.17 nM, respectively) compared to the linear ADC and 7300-Deruxtecan (IC50 of 186.5 nM and 124.5 nM, respectively). In the subcutaneous model of SHP-77 NOD scid gamma mice, when the ADC dose was 5 mg/kg, 7300-LP3004 showed the highest tumor inhibition rate with a tumor growth inhibition (TGI) of 106.09%, which was superior to that of the positive control 7300-Deruxtecan, which had a TGI of 103.95%. In conclusion, 7300-LP3004 demonstrated strong antitumor activity and high physicochemical stability, highlighting the need for further research and development of ADC drugs.
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ISSN:1420-3049
1420-3049
DOI:10.3390/molecules30071398