Abstract

We have developed an immunotoxin SS1P that targets ovarian cancers, mesotheliomas and pancreatic cancers that is currently in clinical trials. We are carrying out laboratory experiments to produce improved forms of SS1P that are less immunogenic so that several treatment cycles can be given. We have also investigated how to improve the activity of SS1P against solid tumors and found that if chemotherapy is give before SS1P there is profound synergy. We are investigating the mechanism of this synergy.

We have studied mesothelin expression in lung cancer and demonstrated lung cancer cells are good targets for SS1P therapy.

We have developed a new method of displaying Fvs on the surface of human cells and used this method to isolate new high affinity antibodies that react with CD22 and mesothelin.

We prepared a new immunotoxin targeting a stem cell antigen on leukemias and showed it rapidly killed leukemia cells expressing CD123.

Hematopoietic Tumors- Immunotoxin BL22 has shown excellent clinical activity in patients with Hairy Cell Leukemia. To increase the usefulness of BL22 in other leukemias and lymphomas we have mutated the protein to increase its affinity for CD22 and also mutated the toxin to increase its ability to reach the cytosol and kill target cells. An improved form of BL22 called HA22 has been licensed to Cambridge Antibody Technology who will sponsor trials in various B cell leukemias and lymphomas. Other high affinity forms of BL22 are now being prepared.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008753-25
Application #
7592584
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2007
Total Cost
$1,528,851
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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
Shancer, Zoe; Williams, Matthew; Igelman, Austin et al. (2018) Preclinical development of anti-BCMA immunotoxins targeting multiple myeloma. Antib Ther 1:19-25
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
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
Bera, Tapan K; Onda, Masanori; Kreitman, Robert J et al. (2014) An improved recombinant Fab-immunotoxin targeting CD22 expressing malignancies. Leuk Res 38:1224-9
Sathyanarayana, Bangalore K; Hahn, Yoonsoo; Patankar, Manish S et al. (2009) Mesothelin, Stereocilin, and Otoancorin are predicted to have superhelical structures with ARM-type repeats. BMC Struct Biol 9:1
Ochiai, Hidenobu; Archer, Gary E; Herndon 2nd, James E et al. (2008) EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells. Cancer Immunol Immunother 57:115-21
Du, Xing; Beers, Richard; Fitzgerald, David J et al. (2008) Differential cellular internalization of anti-CD19 and -CD22 immunotoxins results in different cytotoxic activity. Cancer Res 68:6300-5
Du, Xing; Nagata, Satoshi; Ise, Tomoko et al. (2008) FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins. Blood 111:338-43
Epel, Malka; Carmi, Irit; Soueid-Baumgarten, Sharon et al. (2008) Targeting TARP, a novel breast and prostate tumor-associated antigen, with T cell receptor-like human recombinant antibodies. Eur J Immunol 38:1706-20

Showing the most recent 10 out of 52 publications