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A Peptide-Based Checkpoint Immunomodulator Alleviates Immune Dysfunction in Murine Polymicrobial Sepsis.

Timothy W Phares1, Vinayaka Kotraiah1, Chun-Shiang Chung2

  • 1Explorations in Global Health (ExGloH), Leidos Inc, Frederick, Maryland.

Shock (Augusta, Ga.)
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A novel peptide therapeutic, LD01, effectively treats sepsis by enhancing immune responses and improving survival. This approach offers a promising alternative to antibody therapies, reducing adverse events in sepsis treatment.

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Area of Science:

  • Immunology
  • Pharmacology
  • Infectious Diseases

Background:

  • Sepsis-induced immunosuppression is linked to increased programmed cell-death protein 1 (PD-1) expression, correlating with poor patient outcomes.
  • Blocking PD-1 with antibodies improves survival in sepsis models but can cause immune-related adverse events (irAEs).
  • Peptide-based therapeutics offer a rapid pharmacokinetic profile, potentially reducing irAEs.

Purpose of the Study:

  • To evaluate the efficacy of the peptide-based PD-1 antagonist, LD01, in improving survival, bacterial clearance, and host immunity in a murine polymicrobial sepsis model.
  • To assess LD01's impact on immune cell function and inflammatory markers.

Main Methods:

  • Utilized the cecal-ligation and puncture (CLP) method to induce polymicrobial sepsis in mice.
  • Administered LD01 treatment to assess its effects on survival, bacterial burden, and immune responses.
  • Measured macrophage phagocytic activity, T-cell interferon-γ production, myeloperoxidase levels, and esterase-positive cells.

Main Results:

  • LD01 treatment significantly enhanced survival rates and reduced bacterial burden in CLP-induced sepsis.
  • Improved survival was correlated with enhanced macrophage phagocytic activity and increased T-cell interferon-γ production.
  • LD01 treatment led to significant reductions in myeloperoxidase levels and esterase-positive cells.

Conclusions:

  • LD01 effectively modulates host immunity, demonstrating therapeutic potential for sepsis.
  • This peptide-based approach shows promise in alleviating immunosuppression associated with sepsis and other infectious diseases.
  • LD01 represents a viable therapeutic candidate with a potentially improved safety profile compared to antibody-based therapies.