Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity

Ronit Mazor; Masanori Onda; Dong Park; Selamawit Addissie; Laiman Xiang; Jingli Zhang; Raffit Hassan; Ira Pastan

doi:10.18632/oncotarget.9171

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Priority Research Papers:

Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity

Ronit Mazor, Masanori Onda, Dong Park, Selamawit Addissie, Laiman Xiang, Jingli Zhang, Raffit Hassan and Ira Pastan _

Oncotarget. 2016; 7:29916-29926. https://doi.org/10.18632/oncotarget.9171

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Abstract

Ronit Mazor1, Masanori Onda1, Dong Park1,3, Selamawit Addissie1, Laiman Xiang1,*, Jingli Zhang2, Raffit Hassan2 and Ira Pastan1

1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

2 Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

3 New Business Development Department, Medytox Inc., Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea

* Retired

Correspondence to:

Ira Pastan, email:

Keywords: epitope, immunogenicity, rational design, mesothelioma, pancreatic cancer

Received: March 22, 2016 Accepted: April 22, 2016 Published: May 04, 2016

Abstract

Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a portion of a protein toxin. Their clinical success is limited by their immunogenicity. Our goal is to produce a new RIT that targets mesothelin and is non-immunogenic by combining mutations that decrease B- and T-cell epitopes. Starting with an immunotoxin that has B-cell epitopes suppressed, we added mutations step-wise that suppress T-cell epitopes. The final protein (LMB-T14) has greatly reduced antigenicity as assessed by binding to human anti-sera and a greatly decreased ability to activate helper T-cells evaluated in a T-cell activation assay. It is very cytotoxic to mesothelioma cells from patients, and to cancer cell lines. LMB-T14 produces complete remissions of a mesothelin expressing cancer (A431/H9) xenograft. The approach used here can be used to de-immunize other therapeutic foreign proteins.

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PII: 9171

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Priority Research Papers:

Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity

Abstract