Fatty Acid Derivatization and Cyclization of the Immunomodulatory Peptide RP-182 Targeting CD206high Macrophages Improve Antitumor Activity
As tumor-associated macrophages (TAM) exercise a plethora of protumor and immune evasive functions, novel strategies targeting TAMs to inhibit tumor progression have emerged within the current arena of cancer immunotherapy. Activation of the mannose receptor 1 (CD206) is a recent approach that recognizes immunosuppressive CD206high M2-like TAMs as a drug target. Ligation of CD206 both induces reprogramming of CD206high TAMs toward a proinflammatory phenotype and selectively triggers apoptosis in these cells. CD206-activating therapeutics are currently limited to the linear, 10mer peptide RP-182, 1, which is not a drug candidate. In this study, we sought to identify a better suitable candidate for future clinical development by synthesizing and evaluating a series of RP-182 analogs. Surprisingly, fatty acid derivative 1a [RP-182-PEG3-K(palmitic acid)] not only showed improved stability but also increased affinity to the CD206 receptor through enhanced interaction with a hydrophobic binding motif of CD206. Peptide 1a showed superior in vitro activity in cell-based assays of macrophage activation which was restricted to CD206high M2-polarized macrophages. Improvement in responses was disproportionally skewed toward improved induction of phagocytosis including cancer cell phagocytosis. Peptide 1a reprogrammed the immune landscape in genetically engineered murine KPC pancreatic tumors toward increased innate immune surveillance and improved tumor control and effectively suppressed tumor growth of murine B16 melanoma allografts.
Authors
- Tino W. Sanchez (ORCID: https://orcid.org/0000-0002-2901-2211)
- Udo Rudloff (ORCID: https://orcid.org/0000-0003-2137-9040)
- Bolormaa Baljinnyam (ORCID: https://orcid.org/0000-0001-9548-4965)
- Dandan Li (ORCID: https://orcid.org/0000-0001-9139-3118)
- Dingyin Tao (ORCID: https://orcid.org/0000-0001-6531-2740)
- Anju Kumari (ORCID: https://orcid.org/0000-0001-5130-4774)
- Christopher A. LeClair (ORCID: https://orcid.org/0000-0002-2746-5938)
- Yuhong Fang (ORCID: https://orcid.org/0000-0001-6742-5677)
- Anton Simeonov (ORCID: https://orcid.org/0000-0002-4523-9977)
- Saifun Nahar (ORCID: https://orcid.org/0000-0003-4696-617X)
- Juan Marugán (ORCID: https://orcid.org/0000-0002-3951-7061)
- Emily Major (ORCID: https://orcid.org/0009-0000-6105-6575)
- Mark J. Henderson (ORCID: https://orcid.org/0000-0001-8590-7338)
- Raul Calvo (ORCID: https://orcid.org/0000-0001-5967-1296)
- Sitanshu S. Singh (ORCID: https://orcid.org/0000-0003-3141-0224)
- Rushikesh Sable (ORCID: https://orcid.org/0000-0002-6128-2190)
- Rintaro Kato (ORCID: https://orcid.org/0009-0003-7868-633X)
- Xin Hu (ORCID: https://orcid.org/0000-0003-1164-5130)
- Xin Xu (ORCID: https://orcid.org/0000-0003-1163-9304)
- Jian Zhou
- Sarah Gray Castle
- Liang Liu
Institutions
- MetLife (United States) (US)
- National Institutes of Health (US)
- University of Louisville (US)
- National Cancer Institute (US)
- National Center for Advancing Translational Sciences (US)
- Center for Cancer Research (US)
- National Institutes of Health Clinical Center (US)
- Teikoku Pharma (United States) (US)
Publication Details
- Journal
- Molecular Cancer Therapeutics
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1158/1535-7163.mct-23-0790
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.24
Funders
- National Institutes of Health
- National Cancer Institute
- National Center for Advancing Translational Sciences