Biologics

Biologic therapy and kidney diseases

Marwa Fathy Oraby

Definition

• Biologics are substances whose active component is derived from a biological source by being produced in microorganisms and cells (humans and animals) using biotechnology

Classification• hormones (e.g. insulin, growth hormone somatotropin)

• growth factors (e.g. erythropoietin)

• cytokines(e.g. interferons (IFNs), interleukin (IL)-2, granulocyte macrophage colony stimulating factor (GM-CSF)

• vaccines

• Enzymes

• antibodies (e.g. monoclonal antibodies (mAbs) against tumor necrosis factor (TNF)a, IL-2 receptor ,lymphocyte function-associated antigen 1, epidermal growth factor receptor)

• fusion proteins (soluble receptors and cellular ligands)

• hybrid proteins (e.g. diphtheria toxin: IL-2)

Classification Based on their pharmacological action and therapeutic application

regulating activity (e.g. recombinant proteins, cytokines)

specific targeting capability (e.g.mAbs)

vaccines

diagnostics

Biological therapies used to block innate immunity and systemic inflammatory response in glomerular diseases

Biological therapies used to block adaptative immunity in glomerular diseases

Monoclonal anti bodies

Cytokines and anti cytokines

Interleukin-2 (IL-2)• a nonspecific T-cell growth

factor, can result in the expansion of all T-cell subsets, including T-cytotoxic, helper, and regulatory cells.

• After initial recognition of the antigen, the T-cell function is modified by complex interactions between co-stimulatory or co-inhibitory proteins and their ligands expressed on the APCs (or in some cases tumor cells) and on the T cells; these interactions constitute the secondary regulatory signal that fine-tunes the immune response.

• metastatic RCC high-dose IL-2 FDA approved in 1992

IL2-RABasiliximab, (chimeric MAb) Simulect

Daclizumab (humanized MAb) Zenapex

Bind the CD25 antigen (interleukin-2 [IL2] receptor a-chain) at the surface of activated T-lymphocytes and thereby competitively inhibit IL2-mediated lymphocyte activation, a crucial phase in cellular immune response of allograft rejection.

Anti CD3 mAb• OKT3 is a mouse derived monoclonal antibody (mab) directed against the human

CD3 antigen, which is expressed on T cell membrane surfaces as part of the heteromeric T cell receptor (TCR) complex

• the therapeutic mechanism of OKT3 is considered to be due to reduced cell-mediated immunity by in vivo removal of T cells expressing CD3 or ATG antigens.

• binding of OKT3 to CD3 triggers T cell activation with subsequent massive cytokine release substantially contributing to treatment-related morbidity upon first application of therapeutic dosages of OKT3.

• In addition, because antibodies against murine proteins [human anti-mouse antibodies (HAMA)] frequently arise in humans treated with OKT3, efficacy of repeated administrations might decline.

• prophylactic administration of OKT3 in induction therapy is most effective in high risk renal graft recipients who are sensitized , have two human leukocyte antigen (HLA)-DR mismatches, or experience prolonged cold ischemia time .

• In particular, the sequential induction therapy with single OKT3 followed by cyclosporine resulted in superior 3-year graft survival than treatment with simultaneous administration of both components or cyclosporine alone

• primary treatment of acute rejection but also in cases of rejection resistant to conventional therapies

Indications to use biologics in renal transplantation

Timing biologic use in renal transplantation

Anti-C5 monoclonal antibody• Eculizumab (Soliris) :recombinant fully humanized IgG2/IgG4 monoclonal

antibody directed at human complement component C5 approved both by the European Medicines Agency (EMA) and by the US Food and Drug Administration (FDA) in September of 2011

• aHUS: Prevention of C5 activation has been shown to ameliorate spontaneous and experimental glomerulonephritis in CFH deficient mice

• approved only for treatment of atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria

• aHUS both before end-stage renal disease (ESRD) and after kidney transplantation. (case reports)

• It is conceivable that in lupus nephritis, eculizumab could prevent direct complement-mediated injury to intrinsic glomerular cells and attenuate kidney inflammation by reducing renal leukocyte recruitment. it was shown to be safe and well-tolerated in a phase 1 trial in SLE.

• Effective in other glomerular diseases involving alternative pathway activation, such as membranoproliferative glomerulonephritis and C3 glomerulopathy orendothelial dysfunction, such a catastrophic antiphospholipid syndrome or antibody mediated acute rejection in kidney transplantation

anti-VEGF

• Bevacizumab:(Avastin) IV anti-VEGF monoclonal antibody used in combination with s.c. injected INF-α.

This combination was approved by the FDA in August 2009 for the first-line treatment of patients with advanced RCC or mRCC

Anti-IL-6 mAb

• IL-6 is a multifunctional cytokine produced by leukocytes and intrinsic kidney cells that affects inflammation, increases mesangial cell proliferation, and also contributes to autoimmunity by stimulating terminal B-cell differentiation, autoantibody secretion, and T cell differentiation.

• IL-6 works in synergy with IL-1 and TNF-α to promote inflammation, but also can be anti-inflammatory by termination of IL-1– and TNF-α mediated inflammatory cascades

• In murine and human SLE, IL-6 levels are increased in serum, urine, and glomeruli and correlate with disease activity

• Neutralizing IL-6 or blocking the IL-6 receptor mitigates diseasein murine models of lupus nephritis

• Toculizumab: is a humanized monoclonal antibody that blocks IL-6 from binding to its receptor.

• Sirukumab: humanized monoclonal antibody against IL-6• treatment of lupus nephritis clinical trials phase 1&2

interferon-α (INF-α)

• IFN-α drives the maturation of conventional dendritic cells into potent antigen-presenting cells, induces B-cell differentiation to plasma cells , and contributes to the development of CD4 helper T (TH) cells and CD8 central memory T cells.

• IFN-α is effective in the treatment of hepatitis C-induced cryoglobulinemic vasculitis & non viral essential cryoglobulinemic vasculitis

• metastatic RCC

HCV infection in renal transplant recipient

IFN-α Ab Kidney-specific autoimmunity may be facilitated by intrarenal

interferon α (IFN-α)expression.

IFN-α drives the maturation of conventional dendritic cells into potent antigen-presenting cells,induces B-cell differentiation to plasma cells , and contributes to the development of CD4 helper T (TH) cells and CD8 central memory T cells.

IFN-α– inducible genes are upregulated in peripheral-blood leukocytes of many patients with SLE, referred to as the IFN-α signature.

The major source of IFN-α is the plasmacytoid dendritic cell (pDC).

IFN-α is induced after engagement of pDC endosomal Toll-like receptors 7 and 9 (TLR7 and TLR9) by nucleic acids. In lupus nephritis, pDCs leave the circulation and accumulate in the kidneys, where they conceivably can interact with renal immune complexes and increase IFN-α levels within the kidneys

IFN-α Ab• Rontalizumab Humanized antibodies to IFN-α• Sifalimumab Humanized antibodies to IFN-α• Given the critical role of IFN-α in autoimmunity, neutralizing its activity appear to be a

good strategy in preventing further disease flares after kidney inflammation has been controlled.

• In 49 patients with SLE, 22% were found to have naturally occurring anti–IFN-α antibodies and a lower IFN-α gene signature than patients without such antibodies. These antibody positive patients also tended to have a lower SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score, fewer positive lupus serologic test results, and higher complement levels than patients with the high IFN-α signature. However, ~35% of this cohort were low IFN-α signature but did not have anti–IFN-α autoantibodies, suggesting that not all patients will benefit from exogenous anti–IFN-α therapy. On the positive side, IFN-α gene signature may be a good biomarker for deciding which patients will benefit most from anti–IFN-α therapy.

• rontalizumab and sifalimumab inhibited the gene signature in a dose-dependent fashion, although inhibition was short lived and did not completely reverse the expression of IFN-α–activated genes

• sifalimumab caused an average IFN- α signature inhibition of 39%.• rontalizumab did not decrease protein levels of IFN-α–activated genes or the patients’

autoantibody levels, Despite decreasing the gene signature, • Unexpectedly, a preliminary report of a phase 2 study of rontalizumab in SLE showed more

benefit in patients who were low IFN-α signature, suggesting that higher antibody doses may be required to attenuate IFN-α activity in patients with a high gene signature

IFN-α receptor blocker

• Medi-546 is a humanized anti–IFN-α receptor monoclonal antibody that currently is under investigation

• This may be more effective than directly blocking IFN-α because there are several type 1 IFN isotypes that all work through the same receptor.

TGFβ mAb• Fresolimumab: a humanized IgG4 monoclonal antibody that

neutralizes all 3 isoforms of TGFβ. • It currently is undergoing a trial in primary focal segmental

glomerulosclerosis• fresolimumab is being used in patients with lupus nephritis who

have ongoing proteinuria and declining kidney function in the absence of (biopsy-proven) continued kidney inflammation. An argument could be made that patients who have >25% interstitial inflammation, and thereby a poor Prognosis, should be treated with an anti fibrotic at diagnosis

• However, the consequences of blocking TGFβ during active inflammation are unpredictable and may be detrimental in lupus nephritis because TGFβ has important anti-inflammatory and immune tolerance effects.Thus the timing of when to add fresolimumab in lupus nephritis will need to be critically evaluated

Anti-IL5 antibody

• Mepolizumab : humanised anti-interleukin-5 (IL5) monoclonal antibody was used in an open-label pilot study in patients with CSS (churg strauss syndrome)

• The primary objective was to assess whether mepolizumabsafely decreased CSS disease activity and permitted steroid tapering. In addition to assessment of treatment-related adverse effects, the primary outcome was the lowest prednisone dose achieved at the end of the treatment phase.

• It was safe and well tolerated, offering clinical benefit by enabling steroid tapering . However, on cessation of mepolizumab, CSS manifestations recurred, necessitating further courses of glucocorticoids

Anti TNFα

• Infliximab chimeric monoclonal antibodyimprove severe lupus nephritis,but holds the risk of

enhancing autoimmunity and promoting severe infectious complications• Etanercept a a soluble TNF- α inhibitor

controlled randomized trial evaluating in granulomatous forms of ANCA vasculitis showed no beneficial effects on the rate of disease relapse• Adalimumab (Humira) humanised anti-TNF- α monoclonal

antibody . phase 1 trial of, a monoclonal antibody to TNF-α, given to FSGS patients was published in 2010 showing a significant improvement in proteinuria for 4 out of the 10 patients included.

Etanercept did not reduce the rate or the severity of relapses and was associated with a higher rate of solid tumors and is therefore not recommended. Although not tested, the use of other anti–tumor necrosis factor agents is not recommend also

Anti-TWEAK• TWEAK ( tumor necrosis factor–like weak inducer of apoptosis) and its

receptor fibroblast growth factor inducible 14 (FN14) are expressed at low levels in healthy adult kidneys.

Under stress, including the immunologic injury of lupus nephritis,renalTWEAK and FN14 are upregulated, and binding of TWEAK to FN14 activates NF-κB in renal tubular cells• Through NF-κB, TWEAK induces renal tubular cell expression of several

cytokines and chemokines, including MCP-1, IL-6, IP-10 (IFN-γ–induced protein 10), MIP-1α (macrophage inflammatory protein 1), ICAM-1(intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and RANTES (regulated on activation normal T cell expressed)

• Sustained NF-κB activation by TWEAK promotes renal tubular epithelial cell proliferation, inflammation, and apoptosis.

• Neutralization of TWEAK in lupus nephritis thus would be expected to decrease kidney inflammation and injury, an outcome that has been demonstrated in several animal models of kidney disease

• BIIB023 : a monoclonal antibody against Anti-TWEAK currently is being evaluated in a phase 3 lupus nephritis trial

B cell directed therapies

Depleting B-cells anti-CD20 mAb anti-CD52 Anti CD74

Blocking B-cell Activation proteasome inhibitors anti-B-cell-activating factor (BAFF), also known as B-

lymphocyte stimulator (BLyS) Anti CD22 spleen tyrosine kinase (Syk) inhibitors

anti-CD20 mAb• B cell-specific antigen CD20, a cell surface protein believed to function

in B cell cycle initiation and differentiation . CD20 protein is expressed on immature and mature B lymphocytes (pre-B to memory B cells), but not in early B cells precursors or plasma cells

• Rituximab: chimeric anti-CD20 monoclonal antibody (mAb) (LUNAR Trial ) . (Lupus Nephritis Assessment with Rituximab) and EXPLORER (Exploratory Phase II/III SLE Evaluation of Rituximab), the 2 large, prospective, placebo-controlled trials, failed to find a benefit of rituximab in renal or non renal lupus when added to standard-of-care treatment.In LUNAR, rituximab plus corticosteroids and MMF did not increase complete renal responses at 1 year compared to placebo plus corticosteroids and MMF.

Rituximab exerts additional effects on the immune system that account for its effect on disease activity in SLE. Rituximab therapy is associated with a diminution of expression of CD40L (CD154) and other activation markers of T lymphocytes.• Ocrelizumab Fully humanized anti-CD20 monoclonal antibody (mAb)

(BELONG Trial) (BEGIN) terminated due to serious infections .

• Rituximab recently has been compared to cyclophosphamide in ANCA-associated vasculitis. Although short-term remissions were similar with both therapies, patients in the rituximab arms were not given maintenance immunosuppression and did as well as the cyclophosphamide group, which received maintenance azathioprine. This finding supports the idea that attenuation of autoimmune mechanisms by B-cell depletion may be very effective at preventing reactivation of kidney diseases that typically relapse.

• The most frequent indications for rituximab in nephrology are ANCA vasculitis Membranoproliferative glomerulonephritis due to hepatitis C virus- and non

hepatitis C virus-related cryoglobulinemia Membranous nephropathy Refractory Lupus nephritis Antiglomerular basement membrane disease Fibrillary glomerulonephritis Also in diseases with no recognized nephrotoxic autoantibody, such as

idiopathic nephrotic syndrome Steroid-resistant minimal change disease and Focal segmental glomerulosclerosis (FSGS), and especially In frequently-relapsing idiopathic nephrotic syndrome IgA nephropathy Monoclonal gammopathy of renal significance

anti-CD52

• Alemtuzumab (Campath-1)

• depleting monoclonal antibodies targetingmultiple cell populations B-cells, activated T cells and monocytes

• refractory renal transplant rejection

• inducing remission of refractory and relapsing ANCA vasculitis

Anti CD74

• Milatuzumab, a depleting antibody which binds to CD74,a marker expressed by cells of both T- and B-lymphocyte lineages

• tested in B-cell hemopathies as well as in lupus nephritis

proteasome inhibitors• Bortezomib (Velcade)

• carfilzomib

• delanzomib

proteasome inhibitors used for the treatment of multiple myeloma

• found to be effective in 2 murine models of SLE and lupus nephritis and can both prevent lupus nephritis and ameliorate established lupus nephritis

• because the transcription factor NF-κB needs a functional proteasome for activation, these drugs block the induction of several NF-κB–dependent proinflammatory cytokines and also appear to increase Tregs in models of lupus

• proteasome inhibitors may have a dual effect in the induction phase of lupus nephritis treatment, acting both as an anti-inflammatory agent and to clear out autoantibodies for rituximab

• A study of bortezomib in an experimental model of anti neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis showed that bortezomibworked well only if started early in the disease course

Anti CD22• CD22 is a 135-kDa B cell-specific transmembrane

sialoglycoprotein that is expressed at the cell surface on mature IgM+ IgD+ B cells, but absent on plasma cells and memory B cells.

• Blocking CD22 with epratuzumab depletes naïve and transitional B cells via antibody-dependent cellular cytotoxicity, which lowers peripheral B cell counts by 40%. This effect can improve moderate-to-severe non renal flares in SLE patients, but efficacy data on lupus nephritis are not yet available

• Epratuzumab humanized monoclonal antibody targeting CD22 receptors on B lymphocytes

• Administration of this molecule induces mild B-cell depletion, but marked B cell anergy, via a mechanism called trogocytosis. Although not yet tested in lupus nephritis, preliminary studies have shown interesting results in moderate-to severe forms of SLE

anti-BLyS• BLyS (B lymphocyte stimulator) is a B cell survival factor

• Belimumab a monoclonal antibody that neutralizes BAFF(has recently been approved by the FDA for therapy of lupus nephritis)

It would not be unreasonable to use circulating BAFF as a biomarker and initiate belimumab therapy when BAFF levels start to increase over baseline. Belimumab therapy would be continued until peripheral B cells have been reconstituted, and then possibly withdrawn.

A recent post hoc analysis of phase 3 belimumab trials in non renal SLE examined renal outcomes and showed that belimumab treated patients tended to have fewer renal flares, providing some support for the use of B cell directed therapies in the maintenance phase of lupus nephritis .

Belimumab is now being evaluated for the treatment of idiopathic membranous nephropathy and in ANCA vasculitis

• Tabalumab monoclonal antibody that antagonises BLyS in both membrane and soluble forms (unlike Belimumab,which is thought to target soluble BLyS only)

• blisibimod human peptibody immunoglobulin synthetically produced to selectively target BLyS, and has recently been evaluated in a Phase II Clinical trial (PEARL-SC)

• Tabalumab & blisibimod, are also being tested in SLE and IgA nephropathy

• Atacicept : Soluble recombinant fusion protein containing both human IgG and the extracellular section of the B cell surface receptor TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), inhibiting BLyS and APRIL(A proliferation inducing ligand) receptor (BMS and ACCESS Trials) terminated due so severe hypogammaglobulinaemia and severe infection

spleen tyrosine kinase (Syk) inhibitor

• This tyrosine kinase is recruited and activated after B-cell receptor signaling and is crucial for several downstream events amplifying the B-cell response.

• Fostamatinib is a selective inhibitor of Syk. Importantly, Syk is also involved in the activation of mesangial cells after IgA1 binding, leading to production of proinflammatorycytokines in the glomerulus and cell proliferation.

• preclinical data have shown that this compound could arrest the pathophysiological process of IgA nephropathy.

• A phase 2 clinical trial is about to start in this disease

• How the immune system is reconstituted in LN patients after biologic therapy is uncertain which may be of critical importance for relapses and late outcome. For instance, it is known that serum BLyS levels increase after RTX treatment , which might negatively impact the autoimmune repertoire, potentially facilitating renal relapses.

• The soon to be started CALIBRATE trial (Combination of Antibodies in Lupus Nephritis: Belimumab and Rituximab Assessment of Tolerance and Efficacy) is therefore aimed at testing whether a low-BLyS environment would favourrecovery of a non autoreactive B cell compartment following RTX therapy.Last, but not least, relapses of LN are likely driven by long-lived plasma cells which are not targeted by current immunosuppressive and biologic agents.

• Proteasome inhibitors have been shown to be efficacious in preclinical models , but this approach raises toxicity issues, as autoimmune long-lived plasma cells are unlikely to be specifically targeted by agents like bortezomib.

• RITUXILUP, CALIBRATE, RING.

these trials were endorsed by the recently launched Lupus Nephritis Trials Network, whose aim is to improve outcomes for LN patients through the conduct of clinical trials designed to prevent chronic kidney disease and through the development of clinical trial methodologies that improve and simplify the assessment of therapeutic agents (http://lupusnephritis.org).

APC and T cell interaction

anti-CD40L mAb

• CD40 and CD40L promote costimulation of T cells , but three trials with anti-CD40L failed to demonstrate efficacy

• Phase 2 in lupus nephritis stopped early; thromboembolic events

CTLA-4/Ig Abatacept: CTLA-4/Ig fusion protein binding to

CD80/86 and inhibiting interactions with CD28 (ACCESS [Abatacept and Cyclophosphamide

Combination Therapy for Lupus Nephritis]abatacept in combination with low-dose

cyclophosphamide was able to induce complete lupus nephritis remission in mice with established nephritis. Unfortunately, abatacept did not improve complete renal response rates in either clinical trial. abatacept-treated complete responders in the

ACCESS trial were not started on maintenance immunosuppression after 6 months of induction therapy. During the following 6 months, 50% of these patients maintained their complete responses with no further immunosuppression.

Although abatacept proved to be highly efficacious for autoimmune T cell-mediated autoimmune disorders, such as rheumatoid arthritis and psoriasis, it was found to be an inadequate maintenance immunosuppressive agent in nonhuman primate models of transplantation.

CTLA-4/Ig Belatacept humanized antibody

that inhibits T cell costimulationselective T cell costimulation blocker

In case of lupus nephritis Maintenance in renal

transplantation Reassuringly, data from a Phase II

belatacept renal transplant study showed that costimulation blockade did not interfere with Treg homeostasis BENEFIT-EXT (Belatacept Evaluation

of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) three year, Phase III clinical trial study in renal transplant recipients receiving an extended criteria donor kidney allograft.

It was originally anticipated that costimulation blockade would be successful in achieving immunologic allograft tolerance, but based upon current data this does not appear to be the case. Thus, the new paradigm revolves around the use of belatacept(among other molecules) for avoidance of calcineurin inhibitor nephrotoxicity and minimization of long-term cardiovascular and metabolic side effects.

On a positive note, animal and human studies have demonstrated that the use of belatacept can lead to better renal function,along with a lower incidence of diabetes and cardiovascular risk factors. Although acute rejection seems to be more frequent with belatacept, so far there are no data to suggest that long-term renal allograft survival is shortened. Of course, the observed benefits in renal function as measured by calculated glomerular filtration rate will need to be confirmed using hard end points, including patient and allograft survival

Clinical trials of belatacept in renal transplantation

Antigen-presenting cell modulator

• Laquinimod

small-molecule derivative of quinolone 3-carboxamide

downregulation of proinflammatory cytokines;

upregulation of IL-10.

modulate the inflammatory environment by polarizing T cells toward Tregs and away from TH1 and TH17 phenotypes

• phase 2 trial in lupus nephritis.

Immune checkpoint blockade

Anti-CTLA-4 mAB

• Ipilimumab (Yervoy) : fully humanized monoclonal antibody against CTLA-4

• Tremelimumab fully human IgG2 monoclonal antibody

• metastatic RCC a phase- II trial conducted primarily at the National Cancer Institute (NCI)

anti-programmed death 1 antibody• PD-1 ,An immune checkpoint

molecule that is expressed on activated T cells and is involved in regulating the balance between immune activation and tolerance. It shares homology with CTLA-4 but with distinct immune-inhibitory signals.

• member of the B7-CD28 family,is a cell-surface co-inhibitory receptor that plays a critical role in the negative regulation of T-cell activation

• PD-1, Expressed on T Cells, Interacts With Molecules in the B7 Family of Molecules to Down-Regulate the Peripheral T-Cell Response; B7 Family Molecules Are Also Found on Tumor Cells, Protecting Them Against Tumor Cell–Specific T-Cell Activity

• MDX-1106 (nivolumab)fully human monoclonal antibody

• MDX1105-01

• Clinical trials in RCC

Vaccines

• Cancer vaccines are used in approaches that seek to raise a specific T-cell or B-cell response against cancer . When a vaccine is injected into the skin, components of the vaccine known as pathogen-associated molecular patterns activate resting dendritic cells (DC) and programme them to migrate to a local lymph node. Thus, a vaccine generally includes components intended to activate DCs and the precise agents used vary widely between different vaccines.

Mechanism of action of cancer vaccines

Cancer vaccines work by providing a target antigen or antigens to a specialized cell known as the dendritic cell (DC). These cells reside at the site of antigen injection (usually intradermal), where they take up and process antigen.

Immunostimulatory molecules in the vaccine preparation (adjuvants) activate DCs, which respond by upregulating the molecules they need to interact with (T cells), and migrating toa lymph node.

Once in a lymph node, activated DCs present antigen to T cells; if the T cell recognizes its cognate antigen in the proper context, it is then activated.

Upon activation, CD4+ T cells produce cytokines that help CD8 T cells to fully mature. Upon full maturation, CD8+ T cells in turn proliferate and then leave the lymph node to traffic widely throughout the body. When an activated T cell senses a cell bearing its target antigen (tumourantigen) in the periphery, it can then lyse that cell, potentially mediating an antitumourresponse.

Vaccines for RCC

Pathomechanisms in SLE and lupus nephritis

Systemic lupus erythematosus pathogenesis. The B cell has three key roles:B–T cell antigen presentation,

cytokine release and autoantibody formation,which together contribute to the clinical manifestations of lupus through direct inflammation, tissue damage and immune complex deposition

Impending targets for novel B cell biologics in lupus. Targeting B cells to prevent antigen presentation (T cell interaction), cytokine release and autoantibody formation is an appealing therapeutic strategy in order to specifically ameliorate the clinical manifestations of lupus. The green biologics are beyond the scope of this review whereas the efficacy of those in blue is discussed.

Pathomechanisms and treatment targets in lupus nephritis.

Pathomechanisms and treatment targets in lupus nephritis.

Pathomechanisms and treatment targets in lupus nephritis.

This algorithm represents a hypothetical approach to using B-cell–directed therapies in a lupus nephritis trial. The algorithm matches therapies to the pathogenic stage of the clinical disease and uses novel biomarkers of B-cell activity to guide initiation and termination of specific drugs. The timeline provided is a (non–evidence-based) guide to the desired or ideal clinical milestones after initiation of treatment.

References

• Lupus Nephritis: The Evolving Role of Novel Therapeutics Am J Kidney Dis. 2014 April ; 63(4): 677–690.

• New Biologics for Glomerular Disease on the Horizon Nephron Clin Pract Published online: November 7, 2014

• Biologic Therapy in Lupus Nephritis Nephron Clin Pract Published online: November 11, 2014

• In-/off-label use of biologic therapy in systemic lupus erythematosus BMC Medicine 2014,

• Biologic Therapy in Lupus Nephritis Nephron Clin Pract Published online: November 11, 2014

• The efficacy of novel B cell biologics as the future of SLE treatment: A review , Autoimmun Rev (2014)

• Breathing new life into immunotherapy: review of melanoma,lung and kidney cancer Nat Rev ClinOncol. 2014 January ; 11(1): 24–37.

• Lupus Nephritis: From Pathogenesis to Targets for Biologic Treatment Nephron Clin Pract Published online: November 8, 2014

• When biologics should be used in systemic lupus erythematosus? Presse Med (2014

• Biologics in renal transplantation Pediatr Nephrol online 2014

• Treatment of Systemic Lupus Erythematosus2013 Update Bulletin of the Hospital for Joint Diseases 2013;71(3):208-13

• Complement disorders and hemolytic uremic syndrome Curr Opin Pediatr. 2013 April ; 25(2): 209–215

• Emerging immunotherapies for renal cell carcinoma Annals of Oncology 23 Supplement 8): viii35–viii40, 2012.

• Immunogenicity to Biologics: Mechanisms, Prediction and Reduction Arch. Immunol. Ther. Exp. (2012) 60:331–344 .

• The role of biologics in treatment of ANCA-associated vasculitis Mod Rheumatol (2012) 22:319–326

• Profile of belatacept and its potential role in prevention of graft rejection following renal transplantation Drug Design, Development and Therapy 2010:4 375–382

• High-Dose Interleukin-2: Is It Still Indicated for Melanoma and RCC in an Era of Targeted Therapies? Review Article | July 15, 2013 | Oncology Journal

• Atypical Hemolytic Uremic Syndrome:Update on the Complement System and What Is New Nephron Clin Pract 2010;114:c219–c235

• Biologics in the prevention and treatment of graft rejection Springer Semin Immun (2006) 27:457–476

• Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated? Hematology 2012

• Update on the treatment of lupus nephritis Kidney International (2006) 70, 1403–1412.• Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to

conventional therapy: a pilot study Arthritis Research & Therapy 2006Vol 8 No 3