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Novel Human Monoclonal Antibody Cures Leukemia in Mouse Model

By BiotechDaily International staff writers
Posted on 01 Apr 2013
A novel monoclonal antibody that binds to the intracellular WT1 protein, which is expressed in many types of cancer but only rarely in normal cells, was used to cure leukemia in a mouse model that mimicked the human disease.

The Wilms' tumor 1 gene (WT1) has been identified as a tumor suppressor gene involved in the etiology of Wilms' tumor. Approximately 10% of all Wilms' tumors carry mutations in the WT1 gene. Alterations in this gene have also been observed in other tumor types, such as leukemia, mesothelioma, and desmoplastic small round cell tumor. Dependent on the tumor type, WT1 proteins might function either as tumor suppressor proteins or as survival factors. Mouse models have proven the critical importance of WT1 expression for the development of several organs, including the kidneys, the gonads, and the spleen. The WT1 proteins seem to perform two main functions; they regulate the transcription of a variety of target genes and may be involved in post-transcriptional processing of RNA.

Investigators at Memorial Sloan-Kettering Cancer Center (New York, NY, USA) and the biotech company Eureka Therapeutics (Emeryville, CA, USA) used phage display technology to develop a fully human “T cell receptor-like” monoclonal antibody (mAb), ESK1, specific for the WT1 RMF peptide/HLA-A0201 complex.

They reported in the March 13, 2013, online edition of the journal Science Translational Medicine that ESK1 bound to several leukemia and solid tumor cell lines and primary leukemia cells, in a WT1- and HLA-A0201-restricted manner. ESK1 mediated antibody-dependent human effector cell cytotoxicity in vitro. Low doses of naked ESK1 antibody cleared established, disseminated, human acute lymphocytic leukemia and Philadelphia chromosome-positive leukemia in nonobese diabetic/severe combined immunodeficient mouse models. At therapeutic doses, no toxicity was seen in HLA-A0201 transgenic mice.

“This is a new approach for attacking WT1, an important cancer target, with an antibody therapy. This is something that was previously not possible,” said senior author Dr. David A. Scheinberg, professor of molecular pharmacology at the Memorial Sloan-Kettering Cancer Center. “There has not been a way to make small molecule drugs that can inhibit WT1 function. Our research shows that you can use a monoclonal antibody to recognize a cancer-associated protein inside a cell, and it will destroy the cell.”

“ESK1 represents a paradigm change for the field of human monoclonal antibody therapeutics,” said Dr. Cheng Liu, president and CEO of Eureka Therapeutics. “This research suggests that human antibody therapy is no longer limited to targeting proteins present outside cancer cells, but can now target proteins within the cancer cell itself.”

Related Links:
Memorial Sloan-Kettering Cancer Center
Eureka Therapeutics


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