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| Monoclonal antibody | |
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| Type | ? |
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| Other names | GSK3196165; MOR103 |
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Otilimab (development codesMOR103 andGSK3196165) is a fully humanantibody which has been developed by thebiotechnology companyMorphoSys.[1] 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 thegranulocyte-macrophage colony stimulating factor (GM-CSF), a monomericglycoprotein functioning as a cytokine promoting both proliferation and activation ofmacrophages andneutrophils.
Otilimab, as itsmonoclonal antibody, 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 ofinflammation (through cytokines e.g. TNF-α, IL-1, IL-6),chemotaxis (via chemokines e.g. IL-8), tissue degradation (caused by e.g.MMPs,H2O2) orT andB cell response (following up-regulatedMHC II level).
Beyond its role in natural immune pathways, GM-CSF has been shown to be involved inautoimmune diseases such asmultiple sclerosis (MS) andrheumatoid arthritis (RA) in which cases GM-CSF levels are elevated and mediate an increased production of pro-inflammatory elements (cytokines,chemokines,proteases). The factor is also known to be involved inosteoarthritis of the hand. Research has thus been working on it as a molecular target for the treatment of such disorders, notably throughimmunotherapy such asmonoclonal antibody therapy which is known to be efficient against autoimmune diseases.
There already exist treatments of rheumatoid arthritis through monoclonal antibodies (i.e.infliximab,adalimumab). These drugs are not targeting GM-CSF but TNF-α which is another cytokine involved in the disease. However, the major involvement ofTNF-α 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 ashepatitis B andtuberculosis. The number of reported cases of severe side effects, including fatal ones, has led theFDA 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.
In multiple sclerosis (MS), GM-CSF is produced byT helper cells (Th1 andTh17). It is able to cross theblood-brain barrier (BBB) and bind to CD52 on macrophages surface. Along with other pro-inflammatory events, this will participate in thecentral nervous system (CNS) inflammation process typically occurring in MS.
There are numerous existing monoclonal antibodies used in the treatment of multiple sclerosis:natalizumab (targets α4-integrin),daclizumab andalemtuzumab (both binding to CD25, the α-subunit ofIL-2 receptor on the surface of maturelymphocytes),ocrelizumab (against CD20 marker on B-cells).[2] However, the frequent adverse effects notified, including secondary autoimmune phenomena,[3] 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 undergoingclinical trials to determine whether it could be used as treatment and has so far shown to be generally well tolerated by bothrelapsing-remitting multiple sclerosis (RRMS) andsecondary progressive multiple sclerosis (SPMS) patients. Indeed, most TEAEs (treatment-emergent adverse events) which were observed were mild to moderate. There isn't evidence ofimmunogenecity either: no anti-otilimab antibodies were detected in patients following treatment. These results provide Class I evidence in regards to acceptabletolerance in MS patients and reveal that otilimab remains a fitted candidate for the treatment of multiple sclerosis[4]
