Page 1240 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1202 ParT TEN Prevention and Therapy of Immunological Diseases

In the reported clinical trials for psoriasis, there were no In clinical trials of secukinumab in patients with psoriasis,
increased occurrences of serious infections or other serious adverse rates of infection are increased over that observed in patients
events in the ustekinumab-treatment arms relative to the placebo- randomized to placebo, but not in excess of the infection rates
treatment arms. Higher than expected rates of infection or noted with anti-TNF therapy. Increased rates of serious infection
malignancy have also not been observed in other controlled have not been observed in relatively short-term RA clinical trials
studies of ustekinumab in spondylitis or IBD. Nonetheless, with secukinumab. However, given the pivotal role of Th17 in
vigilance for mycobacterial, fungal, and Salmonella infections is host responses to chronic and acute infections by bacteria, para-
recommended, given the role of IL-12 and IL-23 in host defense sites, and fungi, it is possible that alterations in the containment
against these pathogens. of microbial pathogens in the enteric mucosa may account for
the failure of targeting IL-17 in IBD.
On the Horizon: IL-23 Specific Inhibitors
Tildrakizumab and Guselkumab are fully human IL-23 p19–specific Ixekizumab
mAbs currently being evaluated in clinical trials for treatment Ixekizumab is a humanized IgG4 mAb targeting IL-17A that has
of psoriasis. been shown to be effective and approved for the treatment of
plaque psoriasis. Similar to what has been observed in clinical
Interleukin-17 Inhibitors trials with secukinumab, rates of infection are slightly increased
IL-17 is a cytokine elaborated primarily by the Th17 lineage of in patients treated with ixekizumab versus placebo, but in short-
+
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effector T cells, which differentiate from Foxp3 CD4 thymocytes term studies conducted so far, the rate of serious infections has
under the influence of IL-6 and transforming growth factor-β not been observed to be increased relative to that observed in
(TGF-β) and proliferate/survive under the influence of IL-23. patients randomized to placebo or a comparative arm of patients
Th17 cells are prevalent in the inflammatory lesions of a variety randomized to anti-TNF treatment with etanercept. 50
of inflammatory disorders, including RA, IBD, psoriasis, and
spondyloarthropathies. IL-17 is produced by a variety of innate On the Horizon: Il17 Receptor Antagonists
immune cells, including neutrophils, mast cells, keratinocytes, Brodalumab is an anti–IL-17Ra monoclonal antibody. Data from
macrophages, NK cells, NKT cells, and innate lymphoid cells two identically designed phase III randomized trials support the
(ILCs; LLC/LTi), triggering the induction and release of IL-6, efficacy of brodalumab for treatment of moderate to severe plaque
TNF-α, CCL2, CCL3, MMPs from macrophages, inducing psoriasis. Efficacy with regard to clearing skin lesions was noted
activation of osteoclasts at sites of bone resorption, and promoting to be significantly greater than that observed in a comparator
the proliferation, maturation, and chemotaxis of neutrophils. 45,46 group receiving ustekinumab, but Candida infections and
As such, IL-17 is important both in the initial innate host defense neutropenia were more frequent in the brodalumab groups than
to infection and also inflammation driven by acquired immune in the ustekinumab and placebo groups. 51
responses. Given the multitude of effects mediated by IL-17 in
perpetuating inflammation in a number of autoimmune disorders,
mAb reagent–based strategies have been developed targeting Other Immunomodulatory Cytokines and
IL-17 and its receptor (Table 89.2). Cytokine Inhibitors
On the Horizon: Inhibitors of the Type 1 Interferon Pathway
With increasing recognition of the role of type 1 IFNs in the
immunopathogenesis of SLE, strategies to target IFN-α for
KEY CONCEPTS treatment of SLE have emerged. Initial trials with mAb reagents,
Approaches to IL-17 Inhibition such as rontalizumab or sifalimumab with specificity to one or
more of the known IFN-α subtypes (14 known presently), have
• Selective inhibition of pathways promoting differentiation and activation yielded modest results, emphasizing the complexity of the IFN
products of T-helper 17 (Th17) cells is of significant benefit in the
treatment of psoriasis and the seronegative spondyloarthropathies. system in SLE. This strategy is further complicated by the recogni-
• Selective inhibition of interleukin (IL)-17A appears to be of marginal tion that autoantibodies to IFN-α are often prevalent in SLE
benefit in the treatment of inflammatory bowel disease (IBD), whereas sera. The alternative approach of targeting the type 1 IFN receptor
inhibition of both IL-12 and IL-23 by targeting their shared p40 subunit (IFN-1R) in a recent phase II trial with anifrolumab has yielded
appears to be of benefit in both psoriasis and IBD. more encouraging results. Targeting the IFN-1R may also prove
52
efficacious in other autoimmune disorders, such as SLE and
Sjögren syndrome, which are associated with an enhanced type
1 IFN signature. Other approaches targeting the production of
Secukinumab type 1 IFNs currently under investigation include the use of
Secukinumab is a fully human IgG1 mAb that selectively binds mAb reagents to deplete plasmacytoid dendritic cells (pDCs),
to and neutralizes IL-17A. In clinical trials, secukinumab has perceived to be the major source of IFN-1 in SLE.
been shown to significantly decrease the activity of skin lesions In the relatively short-term clinical trials conducted thus far
in patients with psoriasis, decrease tender and swollen joints in with antibodies targeting IFN-α or IFN-1R, increased susceptibil-
patients with psoriatic arthritis, and decrease axial pain and ity to viral pathogens has not been observed. Whether depleting
limitation in patients with ankylosing spondylitis. 47,48 Clinical pDCs, blocking one or more TLRs linked to upregulation of
responses to secukinumab in patients with RA have been less type 1 IFNs, blocking IFN-1R, or using mAb reagents capable
robust. Despite the apparent role of Th17 cells in patients with of neutralizing multiple IFN subtypes critically important in
IBD, no significant improvement and was observed in patients SLE and related autoimmune disorders will prove efficacious
with Crohn disease, and in some of these patients, the disease but not at the expense of susceptibility to viral disease remains
worsened during treatment with secukinumab. 49 to be determined in phase III trials.