Anti-CD22 immunotoxin
Encyclopedia
Anti-CD22 immunotoxin
is a monoclonal antibody (to CD22
) linked to a toxic substance. They are being studied in the treatment of some types of B-cell cancer
.
They bind to CD22
, a receptor protein
on the surface of normal B cells and B-cell tumors, and, upon internalization, kill the cells.
CAT-3888 and CAT-8015
CAT-3888, formerly called BL22 or GCR-3888, is an anti-CD22 immunotoxin
and completed a Phase I clinical (human) trial and was in a Phase II clinical trial for the treatment of hairy cell leukemia
at the NIH in the U.S. It may be useful against any B cell leukemia
or lymphoma
.
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..
When it was BL22, 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..
In 2001 results were reported of remissions in a phase I trial for leukemia
.
CAT-3888 is very similar to the newer HA22, which 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.
CAT-8015 (formerly GCR-8015 and HA22) is an anti-CD22 immunotoxin comprising a modified Pseudomonas exotoxin
and an anti-CD22
antibody fragment.
CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888.
In November 2005 Cambridge Antibody Technology
acquired these two oncology product candidates, named at that time GCR-3888 and GCR-8015, from Genencor, a subsidiary of Danisco
. CAT's language such as "CAT will support the NCI's ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.
CAT was then purchased in 2007 by British pharmaceutical company AstraZeneca
.
Also in 2007 AstraZeneca acquired MedImmune
for about $15.2 billion. AstraZeneca consolidated its biologics portfolio in MedImmune and Cambridge Antibody Technology which was rebranded to create a dedicated biologics division known as 'MedImmune'.
AstraZeneca discontinued development of CAT-3888 in 2008, and research is being carried on directly by the National Cancer Institute. Whilst CAT-8015 is being developed by MedImmune.
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
. Cambridge Antibody Technology
acquired CAT-5001 from Enzon Pharmaceuticals in May 2006.
Immunotoxin
An immunotoxin is a human-made protein that consists of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell...
is a monoclonal antibody (to CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
) linked to a toxic substance. They are being studied in the treatment of some types of B-cell cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
They bind to CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
, a receptor protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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, formerly called BL22 or GCR-3888, is an anti-CD22 immunotoxin
Immunotoxin
An immunotoxin is a human-made protein that consists of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell...
and completed a Phase I clinical (human) trial and was in a Phase II clinical trial for the treatment of hairy cell leukemia
Hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia...
at the NIH in the U.S. It may be useful against any B cell leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
or lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
.
Technically, CAT-3888 is an anti-CD22 immunotoxin fusion protein between a murine anti-CD22 disulfide-linked Fv (dsFv) antibody fragment
Fragment antigen binding
The fragment antigen-binding is a region on an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope — the antigen-binding site — at the amino terminal end of the monomer...
and an edited copy of bacterial Pseudomonas exotoxin PE38. The toxin is activated intracellularly, by the low pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
into which the entire protein was internalized via the CD22 receptor. The toxin kills the targeted cell through ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
inactivation..
When it was BL22, CAT-3888 was initially designed and produced at the U.S. National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
, one of the agencies which make up the NIH. Early development of BL22 was funded by California biotech Genencor..
In 2001 results were reported of remissions in a phase I trial for leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
.
CAT-3888 is very similar to the newer HA22, which 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.
CAT-8015 (formerly GCR-8015 and HA22) is an anti-CD22 immunotoxin comprising a modified Pseudomonas exotoxin
Pseudomonas exotoxin
The Pseudomonas exotoxin is an exotoxin produced by Pseudomonas aeruginosa.It inhibits elongation factor-2. It does so by ADP-ribosylation of EF2. This then causes the elongation of polypeptides to cease.It has been investigated as a treatment for hepatitis B....
and an anti-CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
antibody fragment.
CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888.
In November 2005 Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
acquired these two oncology product candidates, named at that time GCR-3888 and GCR-8015, from Genencor, a subsidiary of Danisco
Danisco
Danisco A/S is a Danish bio-based company with activities in food production, enzymes and other bioproducts as well as a wide variety of pharmaceutical grade excipients. It was formed in 1989 from the largest Danish industrial merger ever of the two old C.F...
. CAT's language such as "CAT will support the NCI's ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.
CAT was then purchased in 2007 by British pharmaceutical company AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
.
Also in 2007 AstraZeneca acquired MedImmune
MedImmune
MedImmune, LLC, headquartered in Gaithersburg, Maryland, became a wholly owned subsidiary of AstraZeneca in 2007. Since being acquired, MedImmune has remained a Maryland-based biotechnology development enterprise...
for about $15.2 billion. AstraZeneca consolidated its biologics portfolio in MedImmune and Cambridge Antibody Technology which was rebranded to create a dedicated biologics division known as 'MedImmune'.
AstraZeneca discontinued development of CAT-3888 in 2008, and research is being carried on directly by the National Cancer Institute. Whilst CAT-8015 is being developed by MedImmune.
CAT-5001
CAT-5001 (formerly SS1P) - is a Pseudomonas exotoxin
Pseudomonas exotoxin
The Pseudomonas exotoxin is an exotoxin produced by Pseudomonas aeruginosa.It inhibits elongation factor-2. It does so by ADP-ribosylation of EF2. This then causes the elongation of polypeptides to cease.It has been investigated as a treatment for hepatitis B....
immunotoxin
Immunotoxin
An immunotoxin is a human-made protein that consists of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell...
that targets mesothelin
Mesothelin
Mesothelin also known as MSLN is a protein that in humans is encoded by the MSLN gene.- Function :Mesothelin is a 40kDa protein present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The protein was first...
, which is a cell surface glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
present on normal mesothelial cells that is overexpressed in numerous cancers including pleural and peritoneal mesothelioma
Peritoneal mesothelioma
Peritoneal mesothelioma is the name given to the cancer that attacks the lining of the abdomen. This type of cancer affects the lining that protects the contents of the abdomen and which also provides a lubricating fluid to enable the organs to move and work properly.The peritoneum is made of two...
, ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
and pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
. Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
acquired CAT-5001 from Enzon Pharmaceuticals in May 2006.
External links
- Anti-CD22 immunotoxin entry in the public domain NCI Dictionary of Cancer Terms