Immunogenicity In the past year we have succeeded in identifying all the major B cell epitopes recognized by the mouse immune system and have made a new immunotoxin HA22-LR-8M that is fully active and does not induce antibodies when injected i.v. into mice. We are now trying to identify the human specific B cell epitopes. We have also initiated a program to identify and remove human specific T cell epitopes. We have used information gained in the HA22 studies to improve the immunotoxin SS1P directed at mesotheliomas. We have made a new immunotoxin SS1-LR-GGS-8M that has very low immunogenicity yet retains high cytotoxic activity. We have studied the mechanism of mesothelin shedding and identified the major enzyme involved in the shedding process. Inhibition of this enzyme could increase the activity of immunotoxins. In collaboration with D. FitzGerald we have begun to study how protein synthesis arrest leads to apoptosis and identified BAK and Mcl-1 as critical players in this process. In collaboration with Alan Wayne POB, we have analyzed the response of cells directly isolated from patients with ALL to HA22 killing and set up an assay that may help predict if patients will respond to treatment. We have also isolated HA22 resistant cell lines and are using these to understand the basis of clinical drug resistance.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Kaplan, Gilad; Mazor, Ronit; Lee, Fred et al. (2018) Improving the In Vivo Efficacy of an Anti-Tac (CD25) Immunotoxin by Pseudomonas Exotoxin A Domain II Engineering. Mol Cancer Ther 17:1486-1493
Bera, T K; Abe, Y; Ise, T et al. (2018) Recombinant immunotoxins targeting B-cell maturation antigen are cytotoxic to myeloma cell lines and myeloma cells from patients. Leukemia 32:569-572
Wei, Junxia; Bera, Tapan K; Liu, Xiu Fen et al. (2018) Recombinant immunotoxins with albumin-binding domains have long half-lives and high antitumor activity. Proc Natl Acad Sci U S A 115:E3501-E3508
Mazor, Ronit; King, Emily M; Pastan, Ira (2018) Strategies to Reduce the Immunogenicity of Recombinant Immunotoxins. Am J Pathol 188:1736-1743
Müller, Fabian; Cunningham, Tyler; Beers, Richard et al. (2018) Domain II of Pseudomonas Exotoxin Is Critical for Efficacy of Bolus Doses in a Xenograft Model of Acute Lymphoblastic Leukemia. Toxins (Basel) 10:
Mazor, Ronit; King, Emily M; Onda, Masanori et al. (2018) Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity. Proc Natl Acad Sci U S A 115:E733-E742
King, Emily M; Mazor, Ronit; Çuburu, Nicolas et al. (2018) Low-Dose Methotrexate Prevents Primary and Secondary Humoral Immune Responses and Induces Immune Tolerance to a Recombinant Immunotoxin. J Immunol 200:2038-2045
Müller, Fabian; Cunningham, Tyler; Stookey, Stephanie et al. (2018) 5-Azacytidine prevents relapse and produces long-term complete remissions in leukemia xenografts treated with Moxetumomab pasudotox. Proc Natl Acad Sci U S A 115:E1867-E1875
Liu, Xiu-Fen; Zhou, Qi; Hassan, Raffit et al. (2017) Panbinostat decreases cFLIP and enhances killing of cancer cells by immunotoxin LMB-100 by stimulating the extrinsic apoptotic pathway. Oncotarget 8:87307-87316
Mazor, Ronit; Addissie, Selamawit; Jang, Youjin et al. (2017) Role of HLA-DP in the Presentation of Epitopes from the Truncated Bacterial PE38 Immunotoxin. AAPS J 19:117-129

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