Immunotherapy targeting a leader sequence cathepsin G-derived peptide

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Myeloid azurophil granules contain intracellular leukemia antigens, including Cathepsin G (CG).
• Cathepsin G exhibits higher expression in acute myeloid leukemia (AML) blasts compared to normal myeloid progenitors.
• The HLA-A*0201 (HLA-A2) molecule preferentially presents leader sequence (LS)-derived peptides, such as CG1 (FLLPTGAEA).

Purpose of the Study:

• To engineer and evaluate a novel bispecific antibody (CG1/A2xCD3) targeting the CG1/HLA-A2 complex for AML immunotherapy.
• To assess the preclinical efficacy and safety of CG1/A2xCD3 in targeting acute myeloid leukemia.

Main Methods:

• Engineering of a T cell-engager bispecific antibody (CG1/A2xCD3) targeting the CG1/HLA-A2 complex.
• Evaluation of binding affinity to CG1/HLA-A2 monomers, CD3-Fc fusion protein, and AML/T cells.
• Assessment of in vitro and in vivo killing of HLA-A2+ primary AML and cell lines.
• Monitoring of T cell activation, cytokine secretion, and activity against normal bone marrow.

Main Results:

• CG1/A2xCD3 demonstrated high binding affinity to target complexes and cells.
• The antibody induced potent killing of primary AML and cell lines both in vitro and in vivo.
• Tumor- and antibody-dependent T cell activation and cytokine secretion were observed.
• CG1/A2xCD3 showed no activity against normal bone marrow cells.

Conclusions:

• Targeting leader sequence-derived peptides, like CG1, represents a viable strategy for AML immunotherapy.
• The novel bispecific antibody CG1/A2xCD3 exhibits promising preclinical efficacy and safety.
• These findings support the continued clinical development of CG1/A2xCD3 for the treatment of acute myeloid leukemia.