Immunogenicity of Immunotoxins Containing Pseudomonas Exotoxin A: Causes, Consequences, and Mitigation.

Frontiers in Immunology
Ronit Mazor, Ira Pastan

Abstract

Immunotoxins are cytolytic fusion proteins developed for cancer therapy, composed of an antibody fragment that binds to a cancer cell and a protein toxin fragment that kills the cell. Pseudomonas exotoxin A (PE) is a potent toxin that is used for the killing moiety in many immunotoxins. Moxetumomab Pasudotox (Lumoxiti) contains an anti-CD22 Fv and a 38 kDa portion of PE. Lumoxiti was discovered in the Laboratory of Molecular Biology at the U.S. National Cancer Institute and co-developed with Medimmune/AstraZeneca to treat hairy cell leukemia. In 2018 Lumoxiti was approved by the US Food and Drug Administration for the treatment of drug-resistant Hairy Cell Leukemia. Due to the bacterial origin of the killing moiety, immunotoxins containing PE are highly immunogenic in patients with normal immune systems, but less immunogenic in patients with hematologic malignancies, whose immune systems are often compromised. LMB-100 is a de-immunized variant of the toxin with a humanized antibody that targets mesothelin and a PE toxin that was rationally designed for diminished reactivity with antibodies and B cell receptors. It is now being evaluated in clinical trials for the treatment of mesothelioma and pancreatic cancer and is showing so...Continue Reading

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Citations

Feb 23, 2021·Journal of Drug Targeting·Mohammad Reza KhirehgeshBahman Akbari
May 3, 2021·Current Opinion in Chemical Biology·Nikki DellasGjalt W Huisman
May 6, 2021·Oncogene·Rebecca S Goydel, Christoph Rader
Jun 3, 2021·International Journal of Molecular Sciences·Olga ShilovaSergey Deyev
Jul 17, 2021·Seminars in Cancer Biology·Prabodh Chander SharmaRamesh K Goyal
Aug 28, 2021·Biomedicines·Philipp Wolf

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
ELISA
phage display

Clinical Trials Mentioned

NCT02449239
NCT00001805
NCT03258593
NCT01829711
NCT00924170
NCT02219893
NCT00006981
NCT02798536

Software Mentioned

Rosetta
Propred
IEDB Consensus

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