Targeting the Phosphatidylserine-Immune Checkpoint with a Small-Molecule Maytansinoid Conjugate

Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, ph...

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Published inJournal of medicinal chemistry Vol. 65; no. 19; pp. 12802 - 12824
Main Authors Lo, Chen-Fu, Chiu, Tai-Yu, Liu, Yu-Tzu, Pan, Pei-Yun, Liu, Kuan-Liang, Hsu, Chia-Yu, Fang, Ming-Yu, Huang, Yu-Chen, Yeh, Teng-Kuang, Hsu, Tsu-An, Chen, Chiung-Tong, Huang, Li-Rung, Tsou, Lun Kelvin
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.10.2022
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CELLS
LEAFLET
DRUG CONJUGATE
IMMUNOTHERAPY
STRATEGY
ANTIBODY
EXPRESSION
DELIVERY
ANTIGEN
PROBES
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Summary:Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, pharmacokinetics profiling, in vivo anti-pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer efficacies with quantitative mRNA analysis of treated-tumor tissues, we demonstrated that conjugate 40a not only induced lasting regression of tumor growth, but it also rejuvenated the once immunosuppressive tumor microenvironment to an “inflamed hot tumor” with significant elevation of gene expressions that were not accessible in the vehicle-treated tumor. In turn, the immune checkpoint-targeting small molecule drug conjugate from this work represents a new pharmacodelivery strategy that can be expanded with combination therapy with existing immune-oncology treatment options.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c00631