Otilimab (development codes MOR103 and GSK3196165) is a fully human

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

which has been developed by the

biotechnology Biotechnology is the integration of natural sciences and engineering sciences in order to achieve the application of organisms, cells, parts thereof and molecular analogues for products and services. The term ''biotechnology'' was first used ...

company

MorphoSys MorphoSys AG is a biopharmaceutical company founded in 1992. The company is headquartered near Munich, Germany and has a wholly owned subsidiaryMorphoSys US Inc. in Boston MA in the US. The company has various antibody, protein and peptide technol ...

. It can also be referred to as HuCAL antibody, HuCAL standing for Human Combinatorial Antibody Library and being a technology used to generate monoclonal antibodies. Otilimab is directed against the granulocyte-macrophage colony stimulating factor (GM-CSF), a monomeric glycoprotein functioning as a cytokine promoting both proliferation and activation of macrophages and

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

Mode of action

Otilimab, as its

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 ...

, specifically binds to GM-CSF which is consequently neutralised and incapable of binding its targeted inflammatory cells as it should in order to allow their proliferation and activation. There is no following induction of

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

(through cytokines e.g. TNF-α, IL-1, IL-6), chemotaxis (via chemokines e.g. IL-8), tissue degradation (caused by e.g.

MMPs Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...

, H₂O₂) or T and B cell response (following up-regulated

MHC II MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...

level).

Medical uses

Beyond its role in natural immune pathways, GM-CSF has been shown to be involved in autoimmune diseases such as multiple sclerosis (MS) and

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

(RA) in which cases GM-CSF levels are elevated and mediate an increased production of pro-inflammatory elements (

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s). The factor is also known to be involved in

osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...

of the hand. Research has thus been working on it as a molecular target for the treatment of such disorders, notably through

immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

such as

monoclonal antibody therapy Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those ...

which is known to be efficient against autoimmune diseases.

Rheumatoid arthritis

There already exist treatments of rheumatoid arthritis through monoclonal antibodies (i.e.

infliximab Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...

adalimumab Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurati ...

). These drugs are not targeting GM-CSF but TNF-α which is another cytokine involved in the disease. However, the major involvement of

TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

in immunity makes its suppression delicate: it diminishes the immune defenses of treated patients against potential new infections and may allow the reactivation of latent ones such as

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. ...

and

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, i ...

. The number of reported cases of severe side effects, including fatal ones, has led the

FDA 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 ...

to instruct tight monitoring of patients before and during a treatment by TNF-inhibiting drugs. Nevertheless, another way to circumvent such outcomes may be to target an alternate cytokine.

Multiple sclerosis

In multiple sclerosis (MS), GM-CSF is produced by

T helper cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...

s ( Th1 and

Th17 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...

). It is able to cross the blood-brain barrier (BBB) and bind to CD52 on macrophages surface. Along with other pro-inflammatory events, this will participate in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

(CNS) inflammation process typically occurring in MS. There are numerous existing monoclonal antibodies used in the treatment of multiple sclerosis:

natalizumab Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenou ...

(targets α4-integrin),

daclizumab Daclizumab (trade name Zinbryta) is a therapeutic humanized monoclonal antibody which was used for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor ...

and

alemtuzumab Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia (CLL) and multiple sclerosis. In CLL, it has been used as both a first line and second line treatment. In MS it ...

(both binding to CD25, the α-subunit of IL-2 receptor on the surface of mature lymphocytes),

ocrelizumab Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis (MS). It is a humanized anti- CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and hence is an immunosuppressive drug. ...

(against CD20 marker on B-cells). However, the frequent adverse effects notified, including secondary autoimmune phenomena, suggest that the uncovering of a new molecular target for monoclonal antibody therapy would be welcomed in the research for an improved treatment against MS. Otilimab is currently undergoing

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s to determine whether it could be used as treatment and has so far shown to be generally well tolerated by both relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients. Indeed, most TEAEs (treatment-emergent adverse events) which were observed were mild to moderate. There isn't evidence of immunogenecity either: no anti-otilimab antibodies were detected in patients following treatment. These results provide Class I evidence in regards to acceptable tolerance in MS patients and reveal that otilimab remains a fitted candidate for the treatment of multiple sclerosis{{cite journal , vauthors = Constantinescu CS, Asher A, Fryze W, Kozubski W, Wagner F, Aram J, Tanasescu R, Korolkiewicz RP, Dirnberger-Hertweck M, Steidl S, Libretto SE, Sprenger T, Radue EW , display-authors = 6 , title = Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis , journal = Neurology , volume = 2 , issue = 4 , pages = e117 , date = August 2015 , pmid = 26185773 , pmc = 4442097 , doi = 10.1212/NXI.0000000000000117

References

Monoclonal antibodies Arthritis