Fatty Acid Derivatization and Cyclization of the Immunomodulatory Peptide RP-182 Targeting CD206high Macrophages Improve Antitumor Activity

Tumor-associated macrophages (TAMs), specifically those expressing high levels of the mannose receptor CD206, are critical drivers of tumor progression and immune evasion. While the linear peptide RP-182 has shown potential in reprogramming these cells, its therapeutic utility is severely limited by poor metabolic stability and a very short plasma half-life. This study sought to develop more stable and potent analogs of RP-182 to improve its clinical potential for cancer immunotherapy.

The researchers synthesized a library of RP-182 analogs featuring various chemical modifications, including cyclic structures and fatty acid-conjugated tails (lipidation). They evaluated these candidates for metabolic stability using liver microsomes, binding affinity to CD206 via microscale thermophoresis (MST), and biological activity in CD206high M2-polarized macrophages. Finally, they assessed the antitumor performance of the lead candidate, 1a, in syngeneic B16 melanoma and autochthonous KPC pancreatic cancer mouse models.

The fatty acid-derivatized analog 1a significantly outperformed the parent peptide RP-182. Lipidation not only increased the peptide’s stability against enzymatic degradation but also strengthened its interaction with the CD206 receptor's hydrophobic binding motif. Mechanistically, 1a triggered a more potent reprogramming of CD206high macrophages, characterized by increased cancer cell phagocytosis and enhanced expression of proinflammatory M1-like markers. In tumor-bearing mice, 1a treatment effectively shifted the tumor immune microenvironment, resulting in superior tumor growth control and increased infiltration of effector T cells compared with RP-182.

This work provides a successful blueprint for medicinal chemistry optimization of therapeutic peptides targeting the innate immune system. By enhancing the stability and target affinity of a CD206-activating agent, the researchers successfully converted a non-viable research tool into a promising candidate for further preclinical development in solid tumors where immunosuppressive macrophages impede treatment success.