Page 1239 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 89 Biological Modifiers of Inflammatory Diseases 1201

clinical development. Sarilumab (human anti–IL-6R) has been
Interleukin-6 Inhibitors shown in phase III trials to have demonstrated efficacy in the
IL-6 mediates the activation of macrophages and osteoclasts, treatment of RA. Vobarilizumab is a nanobody construct consisting
terminal proliferation and differentiation of B cells, differentiation of an IL-6R–specific non-Fc IgG heavy chain covalently linked
of T-helper 17 (Th17) cells, and production of liver acute-phase to serum albumin that blocks binding of IL-6 to both membrane-
33
proteins. However, IL-6 also governs homeostatic processes, bound and soluble IL-6R, currently being evaluated for treatment
including granulopoiesis, enteric epithelial proliferation, and of SLE. Sirukumab and Olokizumab are humanized anti–IL-6
antiinflammatory responses involved in resolution of inflam- constructs that have also been shown in phase II trials to have
mation, including production of the soluble TNFR p55 and the efficacy in RA. Clazakizumab (humanized anti–IL-6) has shown
IL-1Ra. 34 promising results for the treatment of RA as well as musculoskeletal
The biology of IL-6 signaling is complex in that signaling symptoms in patients with psoriatic arthritis. By virtue of
may occur directly through the cell membrane–bound IL-6 engineered aglycosylation, clazakizumab has a longer half-life
receptor (IL-6R)/gp130 protein complex (classic signaling) or than other mAb reagents targeting IL-6 or IL-6R, thereby requiring
through binding of IL-6 to soluble IL-6R (sIL-6R) with the less frequent dosing; however, with higher dose ranges, the
resulting heterodimer and then ligating a variety of other gp130- frequency of serious adverse events and infections appears to
containing membrane receptors (trans-signaling) that mediate be increased.
signaling from cytokines other than IL-6. IL-6R is expressed Of potentially greater interest is the development of soluble
primarily on leukocytes, hepatocytes, and megakaryocytes, whereas gp130 covalently linked to immunoglobulin Fc (sgp130:Fc),
gp130-containing receptor complexes are expressed in almost a construct with specificity for the IL-6/sIL-6R heterodimer
all organs, including the heart, kidneys, spleen, liver, lungs, that mediates IL-6 trans-signaling. Selective inhibition of the
placenta, and brain. In murine models of inflammation employing trans-signaling pathway linked to inflammatory responses
sgp130:Fc constructs that selectively bind and neutralize IL-6/ may be superior to complete IL-6 blockade because important
sIL-6R, trans-signaling appears to mediate many of the observed physiological functions of IL-6 mediated through membrane-
inflammatory consequences of the upregulation of IL-6, whereas bound IL-6R are left intact. These differences have been
classic signaling through membrane IL-6R mediates homeostatic emphasized in a murine model of peritonitis, where selective
processes, such as granulopoiesis, thrombopoiesis, and epithelial inhibition of IL-6 trans-signaling by sgp130:Fc as opposed to
35
cell proliferation. With greater understanding of the different complete blockade of IL-6 signaling by anti–IL-6 mAb was
IL-6 signaling pathways in humans, implementation of therapeutic shown to significantly improve survival and completely prevent
40
strategies targeting IL-6 will require consideration of the impact intestinal epithelial cell apoptosis. Observations in murine
of blocking classic membrane-bound IL-6R signaling and IL-6/ models of tuberculosis have further confirmed the absence of
sIL-6R trans-signaling. any impaired response to disease resolution in the setting of
Tocilizumab is a humanized mAb with specificity for the human either sgp130:Fc transfection or administration of sgp130:Fc
IL-6 receptor. Tocilizumab blocks the binding of IL-6 to IL-6R, constructs. 41
inhibiting both classic signaling by IL-6 through membrane IL-6R
and formation of IL-6/sIL-6R heterodimer ligands that engender Interleukin-12/-23 Inhibitors
36
trans-signaling. Treatment with tocilizumab improves tender IL-12 and IL-23 are heterodimeric molecules that share a common
and swollen joint counts and slows the development of joint p40 subunit but have different immunological effects on T-cell
37
erosions in patients with RA. Treatment with tocilizumab is lineage development. IL-12 comprises p35/p40 subunits and
also reported to be of benefit in patients with soJIA, AoSD, and promotes the development and maturation of Th1 lineage T
Castleman disease. 38,39 cells, a significant source of IFN-γ. IL-23 comprises p19/p40
Presumably related to the role of IL-6 in promoting granu- subunits and promotes the maturation and survival of Th17
lopoiesis, neutropenia may be observed in some patients following lineage T cells. Initial strategies targeting the shared p40 subunit
treatment with tocilizumab, but this is uncommon. Thrombo- of IL-12/IL-23 in murine models of autoimmune inflammation
cytopenia and elevated serum aminotransferase levels have also yielded promising results and prompted human trials in psoriasis,
been observed on rare occasions. A predictable mild increase in RA, and IBD. Subsequent comparative IL12/IL-23 p40, IL-12
serum lipid levels is observed following the initiation of treatment p35, and IL-23 p19 knock-out studies in the murine models
with tocilizumab; the clinical significance of this remains inde- suggest that the observed ameliorative effects of anti-p40 on
terminate, but monitoring of lipid levels is recommended. inflammation in the models studied were by virtue of IL-23
42
Reactivation of tuberculosis and invasive fungal infections can inhibition. As a consequence, selectively targeting IL-23 and
occur, and rare instances of gastric and intestinal rupture have IL-17 (the primary effector cytokine of Th17 cells) has evolved
been reported in patients treated with tocilizumab. These observed as a strategy to treat autoimmune inflammation.
effects on hematopoiesis and loss of intestinal integrity reflect Ustekinumab is a humanized IgG1κ mAb with specificity for
the potential downsides of complete blockade of IL-6–mediated the p40 subunit component of IL-12 and IL-23. Approved for
functions that is inherent in the use of mAb reagents that block the treatment of psoriasis and psoriatic arthritis, ustekinumab
the interaction of IL-6 with the IL-6R and emphasize the potential significantly improves skin lesions as measured by the psoriasis
advantages of more selective IL-6 pathway inhibition (see below, area and severity index (PASI), and has been shown to decrease
sgp130:Fc). both peripheral and axial joint/enthesis manifestations in psoriatic
43
arthritis. Although not yet approved for patients with IBD,
On the Horizon: Other Anti–IL-6R and Anti–IL-6 mAbs and significant improvements in Crohn disease activity have been
Sgp130:Fc Reagents reported in patients treated with ustekinumab, most notably
Several other recombinant mAb-based reagents that inhibit both among patients who failed to respond adequately to anti–TNF-α
classic and trans-signaling mediated by IL-6 are in advanced therapies. 44