Bortezomib reduces preexisting antibodies to recombinant immunotoxins in mice

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NCI	IMMUNO-10

* FARE Award Winner

Authors

• M.L. Manning
• E. Mason-Osann
• M. Onda
• I. Pastan

Abstract

Recombinant immunotoxins (RITs) are chimeric proteins designed to kill cancer cells composed of an Fv fused to a portion of Pseudomonas exotoxin A. RIT therapy is limited by neutralizing antibodies (NAbs); most patients with normal immune systems make NAbs after one RIT cycle, preventing repeated dosing. Furthermore, some patients have preexisting antibodies from environmental exposure to Pseudomonas exotoxin, which elicits the NAb response. Bortezomib is an FDA-approved proteasome inhibitor that selectively kills plasma cells, which are necessary for a NAb response. We hypothesized bortezomib may abrogate NAb levels. We immunized mice with RIT then treated them with bortezomib, which lowered RIT antibody levels by 59% compared to an 18% decrease in control mice. We hypothesized memory cells, not susceptible to bortezomib, were the source of remaining antibody. To further diminish NAbs we combined bortezomib with a pentostatin and cyclophosphamide (P/C) immunosuppression regimen that kills B and T cells. Combination treatment lowered antibody levels by 87% while levels increased 21% in control mice. We also observed significantly fewer plasma cells in combination-treated mice. In summary bortezomib reduces antibody levels in mice with preexisting antibodies to RIT. Addition of the immunosuppressive P/C regimen nearly abrogates antibody levels.

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