Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-
CD20
B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity.
In humans CD20 is encoded by the ''MS4A1'' gene.
This gene e ...
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
, originated by GlycArt Biotechnology AG and developed by
Roche
F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX S ...
as a cancer treatment.
It can be used as a first-line treatment for
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
in combination with
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
or with
venetoclax
Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).
The most common side effects are l ...
, as a first-line treatment for
follicular lymphoma
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normal ...
in combination with chemotherapy, and as treatment for relapsed or refractory
follicular lymphoma
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normal ...
in combination with
bendamustine
Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.
Common s ...
chemotherapy.
Medical uses
Obinutuzumab is used in combination with
chlorambucil as a first-line treatment for
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
.
[ Its ]progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...
is significantly better than rituximab in the same combination (26.7 months vs. 15.2 months, p < 0.001) but its overall survival
Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...
is not significantly better (death rate 8% vs. 12%, p = .08).[
It is also used in combination with ]bendamustine
Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.
Common s ...
followed by obinutuzumab monotherapy for the treatment of people with follicular lymphoma
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normal ...
as a second line treatment to a regimen containing rituximab.
It was not tested in pregnant women.
Side effects
Obinutuzumab has two black box warnings: hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
reactivation and progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (''-pathy'') or inflammation of the white matter (''leuko-'') of the brain (''-encephalo-'') at multiple locations (''mu ...
.
In the pivotal clinical trial of obinutuzumab in combination with chlorambucil, clinical trial subjects experienced infusion reactions (69%; 21% grade 3/4), neutropenia (40%; 34% grade 3/4), thrombocytopenia (15%; 11% grade 3/4), anemia (12%), and pyrexia and cough (10% each). More than 20% of subjects had abnormal lab tests including low calcium and sodium, high potassium, increases in serum creatinine and liver function tests, and low albumin levels.[
There is a risk of ]thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
and hemorrhage with obinutuzumab; consideration should be given to withholding medications that may increase the risk of bleeding.[
]
Chemistry
Obinutuzumab is a fully humanized monoclonal antibody that binds to an epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
on CD20 that partially overlaps with the epitope recognized by rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric p ...
.
GlycArt's technology platform allowed control of protein glycosylation
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...
; the cells in which obinutuzumab is produced were engineered to overexpress two glycosylation enzymes, MGAT3
Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the ''MGAT3'' gene.
There are believed to be over 100 different glycosyltransferases involved in the synthesis of protein-bound and li ...
and Golgi mannosidase Mannosidase is an enzyme which hydrolyses mannose.
There are two types:
* alpha-Mannosidase
* beta-Mannosidase
A deficiency is associated with mannosidosis Mannosidosis is a deficiency in mannosidase, an enzyme.
There are two types:
* Alpha-manno ...
2, which reduce the amount of fucose attached to the antibody, which in turn increases the antibody's ability to activate natural killer cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
.
Details of the antibody's structure are disclosed in the 2008 WHO INN naming proposal.
History
Obinutuzumab was created by scientists at GlycArt Biotechnology, which had been founded in 2000 as a spin-out company of the Swiss Federal Institute of Technology in Zurich
(colloquially)
, former_name = eidgenössische polytechnische Schule
, image = ETHZ.JPG
, image_size =
, established =
, type = Public
, budget = CHF 1.896 billion (2021)
, rector = Günther Dissertori
, president = Joël Mesot
, a ...
to develop afucosylated monoclonal antibodies Afucosylated monoclonal antibodies are monoclonal antibodies engineered so that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units. When antibodies are afucosylated, antibody-dependent cellular cytotoxicity (ADC ...
; GA101 was one of its lead products when it was acquired by Roche in 2005.
Roche developed the drug in the US through its US subsidiary, Genentech, and in Japan through its Japanese subsidiary, Chugai. Genentech partnered with Biogen Idec
Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide.
History
...
to explore the use of the drug for primary biliary cirrhosis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build ...
but as of 2014 it appeared the development in that indication had halted.[
On November 13, 2013, the US ]Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved obinutuzumab in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
, and was the first drug with breakthrough therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
designation to gain approval.
In October 2014, NICE
Nice ( , ; Niçard: , classical norm, or , nonstandard, ; it, Nizza ; lij, Nissa; grc, Νίκαια; la, Nicaea) is the prefecture of the Alpes-Maritimes department in France. The Nice agglomeration extends far beyond the administrative c ...
announced that NHS England
NHS England, officially the NHS Commissioning Board, is an executive non-departmental public body of the Department of Health and Social Care. It oversees the budget, planning, delivery and day-to-day operation of the commissioning side of the ...
would not fund use of the drug, due to data uncertainties in Roche's application. In June 2015, NICE announced that it would fund restricted use of the drug.
In their final recommendation of obinutuzumab, in the January 2015 Pan-Canadian Oncology Drug Review (pERC) for treatment of chronic lymphocytic leukemia, published by the Canadian Agency for Drugs and Technologies in Health
The Canadian Agency for Drugs and Technologies in Health, or CADTH, is a Canadian national organisation that provides research and analysis to healthcare decision-makers.
The organisation was established in 1989 by the country's federal governme ...
, the list price of obinutuzumab provided by the manufacturer Hoffmann-La Roche
F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...
was $CDN 5,275.54 per 1,000 mg vial. At the recommended dose obinutuzumab costs $15,826.50" for the first 28-day cycle and "$5275.50 per 28 day cycle for subsequent cycles."
In February 2016, obinutuzumab was approved by the FDA under the Priority Review
Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
program for use in combination with bendamustine
Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.
Common s ...
followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normal ...
as a secondline treatment to a regimen containing rituximab.[FDA, Feb 26, 201]
Press Release: Obinutuzumab
/ref>
In January 2019, the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved ibrutinib
Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...
in combination with obinutuzumab for people with chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
/small lymphocytic lymphoma
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
who have not received prior treatment.
Research
As of 2014 clinical trials had been conducted exploring the use of obinutuzumab as a second line monotherapy in relapsed/refractory chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
, as a monotherapy for relapsed/refractory non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
in people who had high expression of CD20; and in combination with CHOP chemotherapy as a first line treatment for people with advanced CD20-positive diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibody, antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual Incidence (epidemiology), in ...
.[ It was called GA101 during research.
]
References
External links
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{{Portal bar , Medicine
Hoffmann-La Roche brands
Genentech brands
Breakthrough therapy
Monoclonal antibodies for tumors