Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment

Moataz Reda, Worapol Ngamcherdtrakul, Molly A. Nelson, Natnaree Siriwon, Ruijie Wang, Husam Y. Zaidan, Daniel S. Bejan, Sherif Reda, Ngoc Ha Hoang, Noah A. Crumrine, Justin P. C. Rehwaldt, Akash Bindal, Gordon B. Mills, Joe W. Gray and Wassana Yantasee ()
Additional contact information
Moataz Reda: PDX Pharmaceuticals, Inc.
Worapol Ngamcherdtrakul: PDX Pharmaceuticals, Inc.
Molly A. Nelson: PDX Pharmaceuticals, Inc.
Natnaree Siriwon: Oregon Health and Science University
Ruijie Wang: PDX Pharmaceuticals, Inc.
Husam Y. Zaidan: PDX Pharmaceuticals, Inc.
Daniel S. Bejan: PDX Pharmaceuticals, Inc.
Sherif Reda: PDX Pharmaceuticals, Inc.
Ngoc Ha Hoang: Oregon Health and Science University
Noah A. Crumrine: PDX Pharmaceuticals, Inc.
Justin P. C. Rehwaldt: PDX Pharmaceuticals, Inc.
Akash Bindal: Oregon Health and Science University
Gordon B. Mills: Oregon Health and Science University
Joe W. Gray: Oregon Health and Science University
Wassana Yantasee: PDX Pharmaceuticals, Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we report on a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor. ARAC is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a feedforward manner. ARAC reduces effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model (LLC-JSP) and the effect is mainly mediated by CD8+ T cells. ARAC also shows efficacy in another lung tumor model (KLN-205), which does not respond to CTLA-4 and PD-1 inhibitor combination. This study highlights a rational combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once.

Date: 2022
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DOI: 10.1038/s41467-022-31926-9

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