I’ve read an abstract recently on “Monoclonal antibody treatments for rheumatoid arthritis” by L. Bossaller and A. Rothe (Link: http://www.ncbi.nlm.nih.gov/pubmed/23789825).
As we already have quite a number of agents and more will be added, let’s have a look at targets already being uses successfully and possible targets.
TNF-alpha: TNF stands for tumor necrosis factor. We already have five TNF-alpha-Inhibitors.
IL-6: IL stands for interleukin. Interleukins for a large group of cytokines, which have the task to communicate between white blood cells (leukocytes), hence the word interleukins. IL-6 is a multitask cytokine, which induces acute phase proteins, plays a role in B cell differentiation and hepatocytes as well as others. We already use one IL-6 inhibitor – tocilizumab. Another IL-6 inhibitor is near to be launched: Sarilimumab (Link: http://rheumatologe.blogspot.de/2013/07/sarilumab-at-eular-2013-meeting.html). An we have an anti-IL-6 receptor nanobody® (ALX-0061), which would be different to the the MABs, but also interfering with the IL-6 signal.
IL-1: we already have anakinra, an interleukin-1 receptor antagonist, which isn’t as successful as TNF alpha inhibitors, when it comes to rheumatoid arthritis. Anakinsa is successful in some familial periodic fever syndromes. Maybe to treat RA it’s the wrong approach.
IL-17: some IL-17 inhibitors are studied in rheumatoid arthritis: secukinumab, ixekizumab and brodalumab (Link: http://rheumatologe.blogspot.de/2013/06/targeting-interleukin-17-in-patients.html). I’m not too optimistic we’ll hear much more about IL-17 inhibition as a treatment of rheumatoid arthritis.
VEGF: Vascular endothelial growth factor is a signal protein that stimulates vasculo-/angiogenesis. TNF alpha stimulates the release of VEGF in rheumatoid arthritis, so that more capillaries are formed and permeability of vessels is increased, which would result in more swelling. “VEGF – appears to be a promising avenue for the future treatment of RA.” Were the concluding remarks of Ewa M Paleolog in 2002 (Link: http://www.biomedcentral.com/content/pdf/ar575.pdf). As we haven’t heard more by now, it doesn’t seem to be the broad road to a successful therapy.
RANKL: it’s the receptor activator of nuclear factor kappa-B ligand, which is important for otheoclast formation and differentiation. Osteoclasts break down bone tissue. As this is what happens in erosions, RANKL is interesting in the treatment of rheumatoid arthritis. We already have denosumab, a RANKL inhibitor (MAB), which has been developed against osteoporosis, and is effective against erosions, but it isn’t effective against articular signs and symptoms of rheumatoid arthritis (Link: http://www.hopkinsarthritis.org/arthritis-news/denosumab-suppresses-erosions-but-has-no-effect-on-articular-signs-and-symptoms-in-rheumatoid-arthritis/).
B-cell function (CD20 [rituximab], CD38 [only of use in leukaemia?], B-cell activating factor [doubtful in RA], transmembrane activator and calcium-modulating and cyclophilin interactor) T-cell function (CD3 [CIA study in 2010], CD4 [no big breakthrough during the past 3 years], CD28 [?]) will be added later.
CD
20: We have rituximab. Other MABs are being studied: ocaratuzumab, which failed to
show new data at the EULAR 2013 (Link
to more information: http://rheumatologe.blogspot.de/2012/12/ocaratuzumab-at-acr-2012-in-washington.html),
or ocrelizumab, which also failed to show new data at the EULAR 2013 (Link:
http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html).
But there’s also ofatumumab, on which there had been news prior to the EULAR
meeting (Link: http://rheumatologe.blogspot.de/2013/06/ofatumumab-just-before-eular-2013.html).
All in all there is activity to get a new anti-CD 20 MAB, but it isn’t a new
principle. So it’s only someone else reaching for the pie.
CD
38: There’s bortezomib being tested in multiple
myeloma. A. Chillemi and colleagues don’t mention rheumatoid arthritis in a
recent overview article (Link: http://molmed.org/files/1047).
BAFF: Tabalumab is an anti-BAFF Monoclonal Antibody, which
has been disappointing at the EULAR 2013 (Link: http://rheumatologe.blogspot.de/2013/06/tabalumab-at-eular-2013-meeting.html),
but there are two articles on tabalumab in the fresh from the press issue of the Annals of the
Rheumatic Diseases (September 2013), so that I might have to revise my former
statement on tabalumab. I’ll deal with this new information in a blog post of
its’ own.
TACI:
TACI is short for transmembrane activator and calcium modulator and cyclophilin
ligand interactor, which also interacts with BAFF. There’s atacicept, but it
isn’t working in RA (Link: http://rheumatologe.blogspot.de/2012/06/atacicept.html).
CD 3:
There has been a CIA study in 2010, but I haven’t found anything
new since then.
CD
4: The lack 0f CD 4 cell depletion in rituximab
patients is associated with no response (Link: http://www.ncbi.nlm.nih.gov/pubmed/23918413).
There had been a study in mice, which Rawarrior commented on 3 years ago (Link:
http://rawarrior.com/will-cd4-lead-to-a-rheumatoid-arthritis-cure/).
Since then nothing new.
CD
28: Do you remember TGN1412? Here’s the Wikipedia
link: http://en.wikipedia.org/wiki/TGN1412.
Maybe we do better not trying the luck of people again.
To treat rheumatoid arthritis, we might get
another IL-6 inhibitor (sarilimumab), another anti-CD 20 agent, and maybe
tabalumab will prove to be effective (I’m still sceptical, but I’ll tell you
more about the recent studies on tabalumab in another blog post).
