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

antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

which has been developed by the

biotechnology Biotechnology is a multidisciplinary field that involves the integration of natural sciences and Engineering Science, engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists ...

company

MorphoSys MorphoSys AG is a German biopharmaceutical company founded in 1992. The company is headquartered near Munich, Germany, and has a wholly owned subsidiaryMorphoSys US Inc. in Boston, Massachusetts, in the US. The company has various antibody, prote ...

. 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 Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

functioning as a cytokine promoting both proliferation and activation of

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s and

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

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 antibodie ...

, 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 ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

(through cytokines e.g. TNF-α, IL-1, IL-6),

chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...

(via chemokines e.g. IL-8), tissue degradation (caused by e.g. MMPs, H₂O₂) or T and

B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

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, macrophages, some endothelial cells, thymic epithelial cells, and B cell ...

level).

Medical uses

Beyond its role in natural immune pathways, GM-CSF has been shown to be involved in

autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

s such as

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

(MS) and

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

(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 produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

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 addit ...

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

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

osteoarthritis Osteoarthritis is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone. A form of arthritis, it is believed to be the fourth leading cause of disability in the world, affect ...

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 antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffectiv ...

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 ...

adalimumab Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn' ...

). 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), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

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), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...

. 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 considere ...

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 actually inhibit Treg differentiation. Howe ...

). 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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(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 intrav ...

(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 and multiple sclerosis. In chronic lymphocytic leukemia, it has been used as both a first line and second lin ...

(both binding to CD25, the α-subunit of

IL-2 receptor The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2. Composition IL-2 binds to the IL-2 receptor, which has ...

on the surface of mature

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...

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

(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 subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

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 Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to transmit signals, resultin ...

(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