Anti-CD22 immunotoxin

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An anti-CD22 immunotoxin is a monoclonal antibody (targeting CD22) linked to a cytotoxic agent. They are being studied in the treatment of some types of B-cell cancer.

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They bind to CD22, a receptor protein on the surface of normal B cells and B-cell tumors, and, upon internalization, kill the cells.

Therapeutic immunotoxins that use Pseudomonas exotoxin

As of August 2009, several anti-CD22 immunotoxins are undergoing clinical trials.

CAT-3888 and CAT-8015

CAT-3888 (or BL22) is an anti-CD22 immunotoxin and completed a Phase I clinical (human) trial for the treatment of hairy cell leukemia [1] at the NIH in the U.S.

Technically, CAT-3888 is an anti-CD22 immunotoxin fusion protein between a murine anti-CD22 disulfide-linked Fv (dsFv) antibody fragment and an edited copy of bacterial Pseudomonas exotoxin PE38. The toxin is activated intracellularly, by the low pH of the lysosome into which the entire protein was internalized via the CD22 receptor. The toxin kills the targeted cell through ribosome inactivation. [2]

CAT-3888 was initially designed and produced at the U.S. National Cancer Institute, one of the agencies which make up the NIH. Early development of BL22 was funded by California biotech Genencor. [3]

In 2001 results were reported of remissions in a phase I trial for leukemia. [4]

CAT-3888 was succeeded by moxetumomab pasudotox (CAT-8015, HA22), an anti-CD22 immunotoxin comprising a modified Pseudomonas exotoxin and an anti-CD22 antibody fragment. [5]

Like CAT-3888, CAT-8015 changes three amino acids in the antibody fragment to increase the binding affinity for the target molecule. Both of these proteins are designed to bind to the same part of the CD22 receptor on the surface of B cells.[ citation needed ]

Research is being carried on directly by Dr. Robert J. Kreitman at the National Cancer Institute. [6] The patent holder is MedImmune, a subsidiary of AstraZeneca. [7] MedImmune discontinued development of CAT-3888 in 2008 and continues to develop CAT-8015. [8]

Early Phase I results find that CAT-8015 exhibits a greater affinity for CD22 than CAT-3888. [9] It may be useful against any B cell leukemia or lymphoma, and indeed is currently in a Phase I clinical trial, also at NIH, in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). [10] [11] [12]

Cambridge Antibody Technology acquired CAT-3888 and CAT-8015 in 2005 from Genencor, a subsidiary of Danisco [3] (where they were known as GCR-3888 and GCR-8015). [13] CAT was then purchased in 2007 by British pharmaceutical company AstraZeneca for $15.2 billion. [14] [15] AstraZeneca consolidated its biologics portfolio in MedImmune and Cambridge Antibody Technology which was rebranded to create a dedicated biologics division known as 'MedImmune'. [16]

CAT-5001

CAT-5001 (formerly SS1P) is a Pseudomonas exotoxin immunotoxin that targets mesothelin, which is a cell surface glycoprotein present on normal mesothelial cells that is overexpressed in numerous cancers including pleural and peritoneal mesothelioma, ovarian cancer and pancreatic cancer. [5] Cambridge Antibody Technology acquired CAT-5001 from Enzon Pharmaceuticals in May 2006. [17]

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<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

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<span class="mw-page-title-main">Hairy cell leukemia</span> Hematological malignancy

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<span class="mw-page-title-main">CD22</span> Lectin molecule

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References

  1. ↑ m. d, Robert Kreitman (7 October 2015). "Retreatment Protocol for BL22 Immunotherapy in Relapsed or Refractory Hairy Cell Leukemia".
  2. ↑ "Cambridge Antibody Technology Group PLC (CATG) Acquires Oncology Product Candidates From Genencor International, Inc. (GCOR)". 1 Nov 2005. Archived from the original on 1 August 2009. Retrieved 20 May 2010.
  3. 1 2 "Cambridge Antibody Technology Acquires Oncology Product Candidates from Genencor". 1 Nov 2005.
  4. ↑ "Scientists Report Complete Remissions in Early Leukemia Trial".
  5. 1 2 http://www.cambridgeantibody.com/__data/assets/pdf_file/10857/CAT-3888,_CAT-8015_and_CAT-5001_Nov06.pdf Archived 2007-02-27 at the Wayback Machine CAT URL Redirects to Medimmune home page
  6. ↑ "Clinical Trials at NIH: Health Care Professionals: Investigator Profiles: Robert J. Kreitman, M.D." Archived from the original on 2011-10-15. Retrieved 2011-12-16.
  7. ↑ "MedImmune". Archived from the original on 2011-07-14. Retrieved 2010-11-25.
  8. ↑ "CAT-3888 MedImmune discontinued, USA (hairy cell leukemia)." 28 January 2008. R & D Focus Drug News. IMSworld Publications Ltd.
  9. ↑ "Phase I trial of recombinant immunotoxin CAT-8015 (HA22) in multiply relapsed hairy cell leukemia. -- Kreitman et al. 28 (15): 6523 -- ASCO Meeting Abstracts". Archived from the original on 2012-07-10. Retrieved 2011-12-16.
  10. ↑ "Chronic Lymphocytic Leukemia (CLL) Clinical Trial: A Phase 1-2 Study of CAT-8015 in Adult…". Archived from the original on 2012-07-11. Retrieved 2011-12-16.
  11. ↑ "CCR Clinical Trials at NIH: Patients and General Public: Clinical Trials Search at NIH". Archived from the original on 2011-12-11. Retrieved 2011-12-16.
  12. ↑ "CCR Clinical Trials at NIH: Patients and General Public: Clinical Trials Search at NIH". Archived from the original on 2011-12-11. Retrieved 2011-12-16.
  13. ↑ "America's Local Small Business Directory - Manta". Archived from the original on 2021-10-31. Retrieved 2010-05-20.
  14. ↑ "Media Centre - AstraZeneca".
  15. ↑ AstraZeneca Successfully Completes Acquisition of MedImmune Archived January 13, 2010, at the Wayback Machine
  16. ↑ AstraZeneca Presents its Global Biologics Organisation, MedImmune, at 2007 Analyst and Investor R&D Day
  17. ↑ "Mesothelioma Treatment product candidate SS1P renamed CAT-5001".

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