IL-23 a promising target or have we been there and done that?

Shajarian M, Alsahebfosoul F, Etemadifar M, Sedaghat N, Shahbazi M, Firouzabadi FP, Dezashibi HM.IL-23 Plasma level measurement in relapsing remitting multiple sclerosis (RRMS) patients compared to healthy subjects. Immunol Invest. 2014 Aug 1:1-9. [Epub ahead of print]

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease with unknown etiology and variable clinical evolution. Interleukin-23 (IL-23), a member of the IL-12 cytokine family is a heterodimeric cytokine composed of the IL-12p40 subunit, and with a novel p19 subunit, its ability to enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses.
Objective: The objective of the project is to measure IL-23 level in plasma of multiple sclerosis (MS) patients in comparison with healthy control subjects. Methods: In a case-control study, plasma was collected from healthy subjects as control group (n = 40) and patients with relapsing remitting multiple sclerosis (RRMS) (n = 40). The plasma level of IL-23 was assessed by ELISA method.
Results: Plasma level of IL-23 in MS patients was significantly increased compared to control subjects (p Value < 0.001).
Conclusions: Our findings revealed the increased IL-23 level in patients’ group. In conclusion, the inhibition of IL-23 might be a novel and promising therapeutic strategy, especially in the therapy of autoimmune inflammatory diseases. IL-23 plays a pivotal role in development of MS and might be a specific marker and therapeutic target for MS

Promising but what actually happens in MS when IL-23 is blockedSegal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH; Ustekinumab MS Investigators.
Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796-804. doi: 10.1016/S1474-4422(08)70173-X

BACKGROUND: Repeated subcutaneous injections of a monoclonal antibody against the p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat patients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug’s safety, efficacy, and pharmacokinetics.
METHODS: In this phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18-65 years, were eligible to be assigned equally (by a central randomisation procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that received placebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. This trial is registered with, number NCT00207727.
FINDINGS: From August, 2004, to December, 2006, 249 patients underwent randomisation (49 for placebo; 50 for each ustekinumab group). Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded.
INTERPRETATION: Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis.

OK….So nothing happened….So what happened in relapsing EAE

Heremans H, Dillen C, Groenen M, Matthys P, Billiau A. Role of endogenous interleukin-12 (IL-12) in induced and spontaneous relapses of experimental autoimmune encephalomyelitis in mice. Eur Cytokine Netw. 1999 Jun;10(2):171-80

Actively induced, chronic relapsing experimental autoimmune encephalomyelitis (CREAE) was studied in SJL/J and in Biozzi ABH mice. In Biozzi ABH mice, relapses occurred spontaneously with high frequency. In SJL/J mice, spontaneous relapses occurred infrequently; however they could be induced reproducibly by reimmunization. In both models, moderately increased levels of serum IL-12(p40) were consistently found shortly before primary attacks, but irregularly at later times. Injections of anti-IL-12 antibody inhibited disease development in both SJL/J and in Biozzi ABH mice. The time window during which treatment needed to be initiated in order to be effective, ranged from before induction until shortly before the symptoms of primary attacks emerged. Such treatment inhibited not only the first attack but also the spontaneous or induced relapses. Most significantly, anti-IL-12 antibody given during remission of primary disease inhibited actively re-induced relapses in SJL/J, but not spontaneous relapses in Biozzi ABH mice. These results indicate that endogenous IL-12 favours EAE development by crucially affecting the active induction process, but that a second burst of IL-12 production may not be necessary for triggering spontaneous relapses.

Nothing happened in relapsing EAE either, it was great at stopping EAE developing, but as we don’t treat people before they have MS, this information is much less relevant. An example where the animal model is blamed for poor translation, but maybe pharma and Neuros need to accept their part by not reading the literature. 

However, until you do the experiment in humans you can’t be sure what will happen. It may not work in animals, but work in MS.

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