Development of a new immunotoxin with low immunogenicity for Mesothelin expressing cancers by diminishing B and T cell epitopes

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NCI	IMMUNO-11

Authors

• R. Mazor
• D. Park
• R. Beers
• I. Pastan

Abstract

Recombinant immunotoxins (RIT) are chimeric proteins that combine the “magic bullet” specificity of an antibody with the high potency of a toxin. SS1P is a RIT that consists of PE38, a fragment of Pseudomonas exotoxin A, fused to an anti-mesothelin antibody fragment. Patients that received SS1P developed an immunogenicity response that neutralized the RIT and prevented further treatments. To diminished the immune response against PE38, we made a new immunotoxin (LMB14) that incorporates mutations that silence T cell epitopes, mutations that silence B cell epitopes (and reduces the binding of the RIT to patient sera), and a large deletion that eliminates 3 more T cell epitopes. LMB14 is highly cytotoxic to mesothelioma and pancreatic cancer cell lines with IC50s lower than the original SS1P. It was also very active in killing mesothelioma cells obtained directly from patients. LMB14 was evaluated in mice bearing mesothelin-expressing tumors and produced complete tumor regressions in 10/12 mice without significant toxic side effects. LMB14 should be more effective in cancer treatment, because more treatment cycles can be given. Furthermore, the approach described can be applied to de-immunize other therapeutically useful foreign proteins.

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