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Single Domain Human Monoclonal Antibodies To Mesothelin for Treatment of Cancer

Posted Jan 23 2013 7:00pm

Description of Invention:
Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer and pancreatic cancer. This selective expression makes mesothelin an excellent candidate for targeted therapeutics such as monoclonal antibodies (mAbs) and corresponding chimeric molecules. Unfortunately, current anti-mesothelin mAb candidates have drawbacks, such as competition with a serum protein (MUC16/CA125) for binding to mesothelin, the formation of neutralizing antibodies because they are non-human antibodies, and the inability to trigger complement-dependent cytotoxicity (CDC).

In order to address this concern, NIH inventors generated two single domain human mAbs: SD1 and SD2. SD1 recognizes a unique epitope in region III of mesothelin which is not out-competed for binding by MUC16/CA125. SD1 was also capable of triggering CDC, as well as antibody-dependent cellular cytotoxicity (ADCC). Due to its human origin, SD1 is also less likely to elicit the formation of neutralizing antibodies when administered to patients. Each of these characteristics suggests SD1 may be an effective therapeutic agent. Indeed, SD1 was able to inhibit tumor growth in mouse xenograft models, and corresponding immunotoxins were able to inhibit tumor cell growth in vitro, supporting the use of SD1 as a therapeutic mAb.

Applications:
  • Therapeutic use, such as treatment of mesothelin-expressing cancers as a stand-alone mAbs or as a mAb-drug conjugate (e.g., an immunotoxin).
  • Diagnosis of mesothelin-expressing cancers.
  • Antibody-related research use, including immunoprecipitation, western blot analysis, immunohistochemistry, ELISA, etc.


Advantages:
  • Binding of a new epitope on mesothelin may improve therapeutic applications due to non-competition from serum proteins.
  • Human origin may significantly limit the formation of neutralizing antibodies, thereby increasing therapeutic potential of the mAb.
  • Ability to trigger both CDC and ADCC may elicit a more complete therapeutic response.


Development Status:
  • Early-stage
  • In vitro data available
  • In vivo data available (animal)


Inventors:
Ira H Pastan (NCI)
Mitchell Ho (NCI)
Dimiter S Dimitrov (NCI)
Zhewei Tang (NCI)
Mingqian Feng (NCI)
Wei Gao (NCI)


Patent Status:
HHS, Reference No. E-236-2012/0
US, Application No. 61/706,396 filed 27 Sep 2012


Related Technologies:
US, Patent No. 6,809,184, Issued 26 Oct 2004, Reference No. E-021-1998/0
US, Patent No. 7,081,518, Issued 25 Jul 2006, Reference No. E-139-1999/0
US, Application No. 13/259,138 filed 23 Mar 2010, Reference No. E-091-2009/0
US, Application No. 60/160,071 filed 27 May 1999, Reference No. E-139-1999/0
US, Application No. 61/162,778 filed 24 Mar 2009, Reference No. E-091-2009/0


Relevant Publication:
  1. Ho M. [ PMID 21942912 ]


Collaborative Research Opportunity:
The NCI Laboratory of Molecular Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize single-domain human antibodies (SD1 and SD2) to mesothelin for cancer therapy or diagnostics. For collaboration opportunities, please contact John Hewes, Ph.D. at hewesj@mail.nih.gov .


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


Ref No: 2519

Updated: 01/2013

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