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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Leshem, Yasmin; O'Brien, James; Liu, Xiufen et al. (2017) Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anticancer Immunity. Cancer Immunol Res 5:685-694
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
Müller, Fabian; Stookey, Stephanie; Cunningham, Tyler et al. (2017) Paclitaxel synergizes with exposure time adjusted CD22-targeting immunotoxins against B-cell malignancies. Oncotarget 8:30644-30655
Mazor, Ronit; Kaplan, Gilad; Park, Dong et al. (2017) Rational design of low immunogenic anti CD25 recombinant immunotoxin for T cell malignancies by elimination of T cell epitopes in PE38. Cell Immunol 313:59-66
Liu, Xiufen; Müller, Fabian; Wayne, Alan S et al. (2016) Protein Kinase Inhibitor H89 Enhances the Activity of Pseudomonas Exotoxin A-Based Immunotoxins. Mol Cancer Ther 15:1053-62
Hassan, Raffit; Alewine, Christine; Pastan, Ira (2016) New Life for Immunotoxin Cancer Therapy. Clin Cancer Res 22:1055-8
Mazor, Ronit; Onda, Masanori; Park, Dong et al. (2016) Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity. Oncotarget 7:29916-26
Ali-Rahmani, Fatima; FitzGerald, David J; Martin, Scott et al. (2016) Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1. Cancer Res 76:1560-8
Guha, Rajarshi; Mathews Griner, Lesley A; Keller, Jonathan M et al. (2016) Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens. J Biomol Screen :
Awuah, Prince; Bera, Tapan K; Folivi, Messan et al. (2016) Reduced Shedding of Surface Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins. Mol Cancer Ther 15:1648-55

Showing the most recent 10 out of 116 publications