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An Improved Anti-Mesothelin Immunotoxin for Treatment of Mesothelioma, Lung Cancer Ovarian Cancer and Pancreatic Cancer

Posted Jul 04 2011 8:00pm

Description of Invention:
Mesothelin is a cell surface glycoprotein that is highly expressed in many cancers (e.g., malignant mesothelioma, lung cancer, ovarian cancer, and pancreatic cancer). Because of its differential expression, mesothelin is an excellent target for the selective killing of cancer cells. For instance, anti-mesothelin monoclonal antibodies can carry cellular toxins specifically to mesothelin-expressing cancer cells, resulting in their selective killing while healthy, essential cells remain unharmed.

A high affinity anti-mesothelin antibody (SS1) was previously combined with a functional fragment of Pseudomonas Exotoxin A (PE), producing the immunotoxin SS1P. SS1P selectively killed mesothelin-expressing cancer cells, suggesting it could be an excellent therapeutic agent. Unfortunately, PE-based immunotoxins can lose therapeutic efficacy following multiple administrations, due to the formation of neutralizing antibodies against the PE portion of the molecule. As a result, less immunogenic variants of PE have been created in order to develop immunotoxins that do not induce the formation of neutralizing antibodies.

Improved PE variants have been created which lack lysosomal protease sites, a dominant T-cell epitope (PE-LR), and several major B-cell epitopes (PE-LR/8M). Although these new PE variants demonstrate efficient cell killing activity when used in combination with certain antibodies, their activity when using SS1 as the targeting agent (SS1-LR and SS1-LR/8M) was less impressive. Fortunately, the inventors surprisingly discovered that the addition of a small linker peptide within these immunotoxins was able to restore their cell killing activity to the level of SS1P.

These new SS1-targeted immunotoxins (e.g., SS1-LR/GGS and SS1-LR/GGS/8M) have the cell-killing activity of SS1P, but are less likely to generate neutralizing antibodies. As a result, these immunotoxins are considered to be very promising prospects for treating patients suffering from mesothelin-expressing cancers.

  • Treatment of mesothelin expressing cancers, including mesothelioma, pancreatic cancer, ovarian cancer and lung adenocarcinoma
  • Treatment in combination with standard chemotherapy
  • Diagnostic agent for the detection of mesothelin-expressing cancers

  • Immunotoxins are highly selective for cancer cells, reducing side-effects due to the non-specific killing of essential, healthy cells
  • Less immunogenic PE variants increase the efficacy of the immunotoxin by reducing the formation and action of neutralizing antibodies
  • PE variants include the removal of both B-cell and T-cell epitopes
  • Use of a small linker peptide offers an unexpected advantage of strong cell-killing activity with reduced immunogenicity

Development Status:
Preclinical stage of development for anti-mesothelin immunotoxins; immunotoxins directed to other targets have some clinical data to demonstrate proof-of-concept

Ira H Pastan (NCI)

Patent Status:
HHS, Reference No. E-117-2011/0
US, Application No. 61/483,531 filed 06 May 2011
US, Application No. 61/495,085 filed 09 Jun 2011

For More Information:
  • US Patent 7,081,518 (HHS technology E-139-1999/0-US-07)
  • US Patent Publication US 20090142341 A1 (HHS technology E-262-2005/0-US-06)
  • US Patent Publication US 20100215656 A1 (HHS technology E-292-2007/0-US-06)
  • PCT Publication WO 2011/032022 (HHS technology E-269-2009/0-PCT-02)

Licensing Status:
Available for licensing

For Licensing Information Please Contact:
David Lambertson Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4632
Fax: 301-402-0220

Ref No: 2279

Updated: 07/2011

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