Page 1242 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1204 ParT TEN Prevention and Therapy of Immunological Diseases

The major concern with regard to the use of natalizumab is increase in the number of circulating memory B cells is observed
the occurrence of reactivation of John Cunningham (JC) polyoma immediately after administration of belimumab, with numbers
virus in patients who are carriers, resulting in progressive multifo- gradually returning to the pretreatment baseline level over the
cal leukoencephalopathy (PML). This complication has a very course of several months of treatment. Total numbers of circulat-
low rate of occurrence, but it is quite debilitating and often fatal, ing B cells are decreased by 20–25% following 1-year treatment
resulting in dampened enthusiasm for the use of natalizumab. periods, with no observed decreases in CD4 and CD8 T lym-
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However, the risk of PML can be mitigated by limiting the phocytes. Levels of autoantibodies, including anti-dsDNA,
duration of natalizumab treatment to 1 year in known carriers anti-Smith, anti-SSA, and anti-cardiolipin, are decreased by
of JC virus (as defined by seroconversion) and not administering 40–50% percent after the first year of treatment and continue
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natalizumab concurrent with other immunosuppressive therapy. to decrease over time with long-term treatment. In contrast,
Vedolizumab is a humanized mAb that specifically binds to total antibody levels decrease, on average, by only 15%, with no
α 4 β 7 integrin, blocking its interaction with MAdCAM-1 on significant decreases in measured preexisting antibody titers to
intestinal endothelial cells. Since vedolizumab does not bind to influenza, tetanus toxoid, or pneumococcal serotypes; furthermore,
or block the interaction of the α 4 β 1 integrin to its addressin treatment with belimumab does not appear to have any significant
ligand in the CNS, the risk of developing PML during treatment effects on the primary immune responses to pneumococcal
is substantially lower than that associated with the use of bacterial antigens. 64,65 In two major randomized trials, the fre-
natalizumab. In clinical trials, vedolizumab has been shown to quency of infections was not shown to be increased in the
significantly improve disease activity and reduce flare-ups in belimumab treatment arms.
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patients with Crohn disease or UC. This strategy may prove Receptors for BLyS (BAFF-R) and BCMA have also recently
to be particularly useful in subsets of patients with IBD as well been identified on murine T-follicular helper (Tfh) cells, with
as clinical features of SLE; in these patients, use of anti–TNF-α ligation of BAFF-R promoting activation of Tfh and ligation of
agents may carry an increased risk of SLE exacerbation. BCMA appearing to play a role in downregulation of Tfh
responses. The significance of these findings in human SLE and
Inhibitors of B-Cell Activation what impact treatment with belimumab has on Tfh responses
Identified targets for regulation of B-cell activation include growth remain to be determined. 66
and survival factors, such as B-lymphocyte stimulator (BLyS;
BAFF) and its respective receptors (BAFF-R, transmembrane On the Horizon: Other Inhibitors of B-Cell Activation
activator and CAML interactor [TACI], and B-cell maturation Atacicept is a recombinant human fusion protein containing the
antigen [BCMA]); costimulatory receptors and their ligands, extracellular, ligand-binding portion of the receptor TACI and a
such as CD40/CD40-ligand; and cell surface receptors, such as modified Fc portion of human IgG. Atacicept binds both BLyS
CD22 or FcγRIIb, which engender inhibitory signaling when (BAFF) and a proliferation-inducing ligand (APRIL), thereby
ligated. Given the prominent role of multiple autoantibodies functioning as an antagonist to the ability of these two ligands
and generalized B-cell activation in SLE, most of the clinical to stimulate B lymphocytes. Amelioration of disease manifesta-
trials, to date, employing strategies targeting B-cell activation tions in murine SLE models employing TACI-Ig transfections
have been in patients with this disorder. provided a mechanistic rationale for pursuing human SLE studies
Belimumab is a recombinant human genome–derived IgG1 using TACI-Ig as a therapeutic intervention; such studies are still
mAb with specificity for soluble (non–membrane-bound) BLyS ongoing. However, the therapeutic window with this approach
(BAFF). Through ligation of the BAFF-R and TACI receptors may be relatively narrow, as membrane-bound TACI is the major
on B lymphocytes, BLyS promotes the maturation of B cells receptor mediating Ig class switching during B-cell maturation,
into antibody-secreting plasmablasts. On the basis of the and excess of the soluble receptor administered over time may
hypothesis that autoreactive B lymphocytes may have greater result in significant humoral immune deficiency as a result of
dependency on BLyS to survive and proliferate, a number of decreases in IgG-secreting B cells and plasma cells. 67
preclinical studies were undertaken to target BLyS using gene Blisibimod is a recombinant fusion polypeptide heterodimer
knock-out strategies or soluble receptor (TACI) transfections in consisting of a BlyS (BAFF)–binding domain covalently linked
murine models of SLE. Following encouraging results in these to the N-terminus of the Fc region of human IgG1. The tetravalent
models, human studies using belimumab were undertaken, and peptibody construct binds to both soluble and cell membrane–
improvement in SLE disease activity was demonstrated by using bound BlyS, with reported higher binding affinities compared
validated disease activity measures (SLE Disease Activity Index with conventional mAbs, inhibiting the interaction of BlyS with
[SLEDAI] and British Isles Lupus Assessment Group [BILAG]) BAFF-R and TACI. Blisibimod and has been shown to have
as well as additional secondary endpoints related to disease biological effects in early-phase human trials, but the clinical
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flare-ups and sparing of corticosteroid use. Consistent with significance of the membrane-binding attribute of blisibimod
its mechanism of action of targeting a growth and survival has not been determined. 68
factor, noted clinical improvements do not become manifest Anti-CD40-ligand mAb reagents interfere with the interaction
until after 6 months of treatment with belimumab. The majority of T-cell CD40L with B-cell CD40, thereby blocking costimulatory
of observed clinical improvements have been observed in the signals required for cognate T-cell help that promotes antigen-
musculoskeletal, mucocutaneous, and serological domains of specific B-cell proliferative responses. Following favorable results
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disease activity. The potential effects on more severe neurological with targeting of CD40L in murine SLE models, human trials
or renal domains of disease activity have not been assessed in with anti-CD40L were undertaken but halted in the context
controlled trials. of observed thrombotic complications. Subsequent studies
Significant decreases in the measured numbers of circulating demonstrated upregulation of CD40L on platelets, with platelet
activated B cells and plasmacytoid B lymphocytes are observed aggregation occurring in the context of complement fixation
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following 6 months’ treatment with belimumab. Transient to platelet membrane–bound anti-CD40L. Newer anti-CD40L