Zalutumumab
Encyclopedia
Zalutumumab is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor
(EGFr). It is a product developed by Genmab
in Utrecht
, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma
of the head and neck (SCCHN), a type of cancer
. The current treatment for SCCHN includes tyrosine kinase inhibitors and human monoclonal antibodies. In addition, murine mAbs were tested successfully in mice, but caused an immune response in humans and were thus determined as ineffective in therapeutics.
. Its structure includes an extracellular binding domain
, a transmembrane lipophilic
segment, and an intracellular tyrosine kinase domain.
or TGF alpha
, dimerization occurs, leading to autophosphorylation
on the intracellular tyrosine residues. Following phosphorylation, the Grb2
-SOS signaling complex is stimulated. This causes the activation of the G protein RAS through the exchange of guanosine diphosphate
(GDP) for guanosine triphosphate
(GTP). The exchange of GDP for GTP induces a conformational change of RAS to allow it to bind to Raf-1. Raf-1 is then activated through another multistep mechanism in which dephosphorylation of inhibitory sites by protein phosphatase 2A (PP2A), as well as the phosphorylation of activating sites by p21 activated kinase (PAK) occurs. After this, Raf-1 activates MAPK/ERK kinase (MEK), which then goes on to activate extracellular-signal-regulated kinase (ERK). ERK is then able to enter the cell nucleus and control gene expression by phosphorylating various transcription factors, such as Elk-1. It is from there that the specific gene transcription occurs to initiate the cell cycle
. Through this mechanisam, apoptosis
is inhibited, angiogenesis
, migration
, adhesion
, and invasion occur. Each of these is a functional element to the progression and development of cancer, which is defined as an abnormal growth of cells with a tendency to proliferate in an uncontrolled way and, in some cases, to metastasize.
. In doing this it is also acting as a competitive antagonist
for the EGF ligand
. In the inactive conformation, the distance between the intracellular tyrosine kinase residues is larger, which inhibits dimerization. Phosphorylation is consequently inhibited, so that no signal is released. Without a signal, cell cycle characteristics to enhance tumor growth are inhibited and the cancer progression is suppressed.
This is not the only way in which zalutumumab works. It also is responsible for some antitumor affects through antibody-dependent cellular cytotoxicity
(ADCC). The Fab, or fragment antigen binding
region of the antibody, binds to the antigen on the EGFr expressing tumor cells. Through an immunological response, the body’s natural killer (NK) cells
, which are a type of lymphocyte
, recognize and bind to the Fc
portion on the antibody through an Fc receptor, CD16
. The NK cell is then activated through the cross linking of the Fc receptors which sends a signal to induce apoptosis and cell death. The target tumor cell is then destroyed.
by the U.S. Food and Drug Administration for patients suffering from SCCHN who have failed standard therapies and have no other options. The drug has undergone pre-clinical and Phase I and II studies and is also in Phases I and II for SCCHN front-line with chemo-radiation and SCCHN with radiation. Additionally, a Phase II is under way for SCCHN and Phase III studies are also being performed for SCCHN and SCCHN front-line with radio therapy. A phase III study reported a non significant improvement in overall survival, and a significant improvement in Progression-free survival
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFr). It is a product developed by Genmab
Genmab
Genmab A/S is a Danish biotechnology company, founded in February 1999 and based in Copenhagen. Internationally, it operates through the subsidiaries Genmab BV in Utrecht, The Netherlands, and Genmab, Inc in Princeton, New Jersey, USA. The Company is publicly traded on the NASDAQ OMX Copenhagen A/S...
in Utrecht
Utrecht (city)
Utrecht city and municipality is the capital and most populous city of the Dutch province of Utrecht. It is located in the eastern corner of the Randstad conurbation, and is the fourth largest city of the Netherlands with a population of 312,634 on 1 Jan 2011.Utrecht's ancient city centre features...
, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
of the head and neck (SCCHN), a type of 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...
. The current treatment for SCCHN includes tyrosine kinase inhibitors and human monoclonal antibodies. In addition, murine mAbs were tested successfully in mice, but caused an immune response in humans and were thus determined as ineffective in therapeutics.
Mechanism of action
Zalutumumab works through inhibition of the EGFr signal. The EGFr is a receptor tyrosine kinaseReceptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
. Its structure includes an extracellular binding domain
Binding domain
A binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. Upon binding, proteins may undergo a conformational change. Binding domains are essential for the function of many proteins....
, a transmembrane lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
segment, and an intracellular tyrosine kinase domain.
Mechanism of EGFr
EGFr is over-expressed by many tumor cells. Upon binding by a ligand, such as the epidermal growth factorEpidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
or TGF alpha
TGF alpha
Transforming growth factor alpha is upregulated in some human cancers. It is produced in macrophages, brain cells, and keratinocytes, and induces epithelial development. It is closely related to EGF, and can also bind to the EGF receptor with similar effects...
, dimerization occurs, leading to autophosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
on the intracellular tyrosine residues. Following phosphorylation, the Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
-SOS signaling complex is stimulated. This causes the activation of the G protein RAS through the exchange of guanosine diphosphate
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
(GDP) for guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(GTP). The exchange of GDP for GTP induces a conformational change of RAS to allow it to bind to Raf-1. Raf-1 is then activated through another multistep mechanism in which dephosphorylation of inhibitory sites by protein phosphatase 2A (PP2A), as well as the phosphorylation of activating sites by p21 activated kinase (PAK) occurs. After this, Raf-1 activates MAPK/ERK kinase (MEK), which then goes on to activate extracellular-signal-regulated kinase (ERK). ERK is then able to enter the cell nucleus and control gene expression by phosphorylating various transcription factors, such as Elk-1. It is from there that the specific gene transcription occurs to initiate the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Through this mechanisam, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
is inhibited, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, and invasion occur. Each of these is a functional element to the progression and development of cancer, which is defined as an abnormal growth of cells with a tendency to proliferate in an uncontrolled way and, in some cases, to metastasize.
Mechanism of zalutumumab
In order to combat SCCHN, zalutumumab was designed to inhibit the EGFr signaling. Specifically, it binds to the EGFr Domain III on the cell surface. This locks the receptor in an inactive conformation, making the drug an inverse agonistInverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
. In doing this it is also acting as a competitive antagonist
Competitive antagonist
A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...
for the EGF ligand
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
. In the inactive conformation, the distance between the intracellular tyrosine kinase residues is larger, which inhibits dimerization. Phosphorylation is consequently inhibited, so that no signal is released. Without a signal, cell cycle characteristics to enhance tumor growth are inhibited and the cancer progression is suppressed.
This is not the only way in which zalutumumab works. It also is responsible for some antitumor affects through antibody-dependent cellular cytotoxicity
Antibody-dependent cellular cytotoxicity
Antibody-Dependent Cell-Mediated Cytotoxicity is a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune...
(ADCC). The Fab, or fragment antigen binding
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...
region of the antibody, binds to the antigen on the EGFr expressing tumor cells. Through an immunological response, the body’s natural killer (NK) cells
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
, which are a type of lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
, recognize and bind to the Fc
Fragment crystallizable region
The fragment crystallizable region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system...
portion on the antibody through an Fc receptor, CD16
CD16
CD16 is a low affinity Fc receptor.It is a cluster of differentiation found on the surface of natural killer cells, neutrophil polymorphonuclear leukocytes, monocytes and macrophages...
. The NK cell is then activated through the cross linking of the Fc receptors which sends a signal to induce apoptosis and cell death. The target tumor cell is then destroyed.
Developmental status
Zalutumumab treatment was approved for Fast Track statusFDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
by the U.S. Food and Drug Administration for patients suffering from SCCHN who have failed standard therapies and have no other options. The drug has undergone pre-clinical and Phase I and II studies and is also in Phases I and II for SCCHN front-line with chemo-radiation and SCCHN with radiation. Additionally, a Phase II is under way for SCCHN and Phase III studies are also being performed for SCCHN and SCCHN front-line with radio therapy. A phase III study reported a non significant improvement in overall survival, and a significant improvement in Progression-free survival