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 ...

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, ...

.What is Cancer
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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