Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• The erbB2 proto-oncogene is overexpressed in several aggressive human cancers, making it a promising therapeutic target.
• Immunotoxins, combining antibody-mediated targeting with cytotoxic payloads, offer a strategy for selective cancer cell killing.

Purpose of the Study:

• To develop and evaluate novel immunotoxins targeting the human erbB2 gene product (HER2) for cancer treatment.
• To assess the efficacy of different immunotoxin constructs, including chemically conjugated and recombinant forms, against erbB2-expressing cancer cells.

Main Methods:

• Five murine monoclonal antibodies against human erbB2 were conjugated with LysPE40, a Pseudomonas exotoxin (PE) fragment.
• A recombinant immunotoxin, e23(Fv)PE40, was engineered and expressed in Escherichia coli.
• A modified version, e23(Fv)PE38KDEL, featuring an improved PE38KDEL payload, was constructed and tested in vivo.

Main Results:

• All five immunotoxin conjugates exhibited specific cytotoxicity against erbB2-overexpressing cancer cell lines.
• The e23-LysPE40 conjugate showed the highest activity among the chemically conjugated forms.
• The recombinant e23(Fv)PE38KDEL selectively killed erbB2-expressing cells and inhibited N87 gastric cancer tumor growth in immunodeficient mice.

Conclusions:

• Engineered immunotoxins targeting erbB2 are effective against cancer cells overexpressing this protein.
• The recombinant immunotoxin e23(Fv)PE38KDEL represents a promising therapeutic candidate for erbB2-positive cancers, demonstrating significant preclinical efficacy.