Immunotoxins with decreased immunogenicity and improved activity

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Recombinant immunotoxins often trigger neutralizing antibodies against the bacterial toxin component.
• Moxetumomab pasudotox (anti-CD22 Fv fused to Pseudomonas exotoxin PE38) is a therapeutic candidate with potential immunogenicity issues.

Purpose of the Study:

• To reduce the immunogenicity of moxetumomab pasudotox while maintaining or improving its anti-cancer activity.
• To identify and modify B-cell epitopes on the PE38 toxin component.

Main Methods:

• Characterized PE38 B-cell epitopes using 60 monoclonal antibodies and alanine mutagenesis.
• Engineered an epitope-mutant (HA22-8X) and a truncated toxin variant (HA22-LR) of moxetumomab pasudotox.
• Assessed cytotoxicity, immunogenicity in mice, and anti-tumor efficacy in murine xenografts.

Main Results:

• Identified seven major PE38 epitope groups with 13 subgroups.
• HA22-8X showed greatly reduced immunogenicity in mice.
• HA22-LR retained CD22+ cell line cytotoxicity, exhibited enhanced potency against primary chronic lymphocytic leukemia cells, demonstrated reduced mouse toxicity, and improved anti-tumor activity.

Conclusions:

• Modifying B-cell epitopes and truncating toxin sections are effective strategies to optimize recombinant immunotoxin immunogenicity and efficacy.
• Engineered immunotoxins like HA22-LR show promise for improved therapeutic applications in cancer treatment.