Caspase-cleavable peptide-doxorubicin conjugate in combination with CD47-antagonizing nanocage therapeutics for immune-mediated elimination of colorectal cancer

  • Biomaterials. 2021 Oct:277:121105. doi: 10.1016/j.biomaterials.2021.121105.
Na Kyeong Lee  1 ,  Jeong Uk Choi  2 ,  Ha Rin Kim  1 ,  Seung Woo Chung  3 ,  Yoon Gun Ko  4 ,  Young Seok Cho  1 ,  Seong Jin Park  1 ,  Eun Jung Lee  5 ,  Sang Yoon Kim  6 ,  In-San Kim  7 ,  Youngro Byun  8
Affiliations
  • 1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2. College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • 3. Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
  • 4. Pharosgen, Inc., 2-404 Jangji-dong 892, Songpa-Gu, Seoul, 05852, Republic of Korea.
  • 5. Department of Chemical Engineering, School of Applied Chemical Engineering, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • 6. Department of Otolaryngology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 7. Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea. Electronic address: [email protected].
  • 8. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: [email protected].
PMID: 34478928 DOI: 10.1016/j.biomaterials.2021.121105
Abstract

Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal Cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8+ T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.2% (p < 0.001) tumor growth inhibition in an established CRC model. T cell-mediated elimination of tumors was also confirmed by the tumor-specific activation of T cells detected by IFNγ and tumor-free mice were observed (95%) that bared a memory response when re-challenged. The strategically developed MPD-1 is an ideal Adjuvant to immunotherapy and the combination with FS nanocage triggers potent immunity against MSS CRC. In summary, we present an approach to initiate and stimulate immune-mediated eradication of Cancer cells using synergistic immunogenic agents targeting the MSS CRC.

Keywords
CD47 antagonist; Caspase-cleavable peptide-doxorubicin conjugate; Immunotherapy combination; MSS colorectal Cancer; Nanocage therapeutics.
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