Selective Targeting of Immune Checkpoints HLA-G and CD47 Using Novel Dual Signaling Protein DSP216 Promotes Innate...

Area of Science:

• Immunology
• Oncology
• Computational Chemistry

Background:

• Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, has revolutionized cancer treatment.
• However, resistance to current ICIs necessitates the development of next-generation therapeutics.
• Many patients and tumor types exhibit limited response to existing immunotherapies.

Purpose of the Study:

• To introduce and evaluate Dual Signaling Protein 216 (DSP216), a novel ligand-based immunotherapeutic.
• DSP216 is designed as a dual inhibitor of the immune checkpoints CD47 and HLA-G.
• To assess DSP216's specificity, binding characteristics, and functional efficacy in preclinical models.

Main Methods:

• Computational chemistry was employed to optimize DSP216's affinity for HLA-G.
• DSP216 binding was tested against cancer cells, peripheral blood mononuclear cells (PBMCs), and red blood cells (RBCs).
• Functional assays included macrophage polarization, phagocytosis, and natural killer (NK) cell cytotoxicity.

Main Results:

• DSP216 demonstrated selective binding to cells co-expressing CD47 and HLA-G.
• The active form of DSP216 (DSP216a) triggered CD16-signaling, unlike the inactive form (DSP216i).
• Combination therapy with checkpoint blockade and antibody-dependent cell-mediated cytotoxicity (ADCC) by DSP216a enhanced NK cell activity.

Conclusions:

• DSP216 represents a promising new immunotherapeutic strategy targeting dual immune checkpoints.
• Its design aims to improve efficacy and reduce side effects by targeting specific cancer cell populations.
• Further preclinical evaluation is warranted based on these encouraging findings.