Engineered Glatiramoid Peptides Emulate Glatiramer Acetate Activity in Solid Tumors

Abstract Glatiramer acetate (GA) is a heterogeneous mixture of peptides that we have previously explored as an intratumoral immunomodulator. However, its chemical complexity complicates the mechanistic interpretation and rational design. In this study, we evaluated a set of sequence-defined “glatiramoid” peptides engineered to preserve the amino acid composition while varying the primary sequence. Biophysical characterization by circular dichroism, fluorescence spectroscopy, and transmission electron microscopy revealed sequence-dependent differences in supramolecular organization without pronounced changes in the secondary structure. Treatment of murine bone marrow-derived dendritic cells with these peptides produced distinct innate cytokine and chemokine secretion profiles, suggesting that sequence order influences immune signaling outcomes in vitro. In the CT26 mouse model of colon carcinoma, intratumoral administration of selected glatiramoid peptides in combination with anti-PD-1 therapy produced tumor growth responses that were not statistically distinguishable from those of commercial GA formulations. Systemic cytokine levels measured at study termination were generally lower for the sequence-defined peptide relative to GA. Together, these findings indicate that sequence-defined glatiramoid peptides reproduce selected GA-like biophysical and immunomodulatory properties. Further studies are required to establish their mechanisms of action, intratumoral behavior, and therapeutic contribution to checkpoint blockade.