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, 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.