Zalutumumab (proposed trade name HuMax-EGFR) is a fully human IgG1
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 ...
(mAb) directed towards the
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor rece ...
(EGFR). It is a product developed by
Genmab
Genmab A/S is a Danish biotechnology company, founded in February 1999 by Florian Schönharting, at the time managing director of BankInvest Biomedical venture fund. The company is based in Copenhagen, Denmark - internationally, it operates thr ...
in
Utrecht
Utrecht ( , , ) is the fourth-largest city and a municipality of the Netherlands, capital and most populous city of the province of Utrecht. It is located in the eastern corner of the Randstad conurbation, in the very centre of mainland Net ...
, the Netherlands. Specifically, zalutumumab is designed for the treatment of
squamous cell carcinoma of the head and neck (
SCCHN), a type of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.
Mechanism of action
Zalutumumab works through inhibition of the EGFR signal. The EGFR is a
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) 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 kin ...
. Its structure includes an extracellular
binding domain
In molecular biology, binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. A protein domain is a part of a protein sequence and a tertiary structure that can change or evolve, function, and liv ...
, a transmembrane
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
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 factor or
TGF alpha
Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors ...
,
dimerization occurs, leading to auto
phosphorylation on the intracellular tyrosine residues. Following phosphorylation, the
Grb2-SOS signaling complex is stimulated. This causes the activation of the G protein
RAS
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
through the exchange of
guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine.
GDP is the product ...
(GDP) for
guanosine triphosphate
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only d ...
(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 Protein phosphatase 2A may refer to:
* Protein phosphatase 2
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, ...
(PP2A), as well as the phosphorylation of activating sites by
p21 activated kinase
p21 activated kinases (PAKs) are members of a family of enzymes. They serve as targets for the small GTP binding proteins CDC42 and Rac and have been implicated in a wide range of biological activities.
Members include:
* PAK1, regulating cell ...
(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
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
. Through this mechanism,
apoptosis is inhibited,
angiogenesis,
migration
Migration, migratory, or migrate may refer to: Human migration
* Human migration, physical movement by humans from one region to another
** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
,
adhesion
Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another).
The forces that cause adhesion and cohesion can b ...
, 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
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
.
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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 agonist. In doing this it is also acting as a
competitive antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of r ...
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
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose ...
(ADCC). The Fab, or
fragment antigen binding
The fragment antigen-binding region (Fab region) 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. The variable domain contains the paratope (the ant ...
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
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
, recognize and bind to the
Fc portion on the antibody through an Fc receptor,
CD16
CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRI ...
. 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
2009: Zalutumumab treatment was approved for
Fast Track status
Fast track is a designation by the United States Food and Drug Administration (FDA) of an investigational drug for expedited review to facilitate development of drugs that treat a serious or life-threatening condition and fill an unmet medical ne ...
by the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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.
2010:A phase III study (of zalutumumab as an addition to 'best supportive care' in patients after failed standard platinum-based
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. Chemothe ...
) reported a
non-significant improvement in
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 ...
, and a
significant 61% improvement in
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 ...
2014:A study of zalutumumab as addition to chemoradiation for SCCHN showed no benefit,
and 94% developed a skin rash (11% severe enough to discontinue).
2015:Genmab not proceeding with zalutumumab.
References
{{Growth factor receptor modulators
Monoclonal antibodies for tumors
Abandoned drugs