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 Table of Contents  
MAJOR REVIEW
Year : 2018  |  Volume : 30  |  Issue : 2  |  Page : 76-86

Biological response modifiers in Ophthalmology: New horizons, new challenges and new hopes


Assistant Professor of Ophthalmology, Department of Surgery, College of Medicine, King Faisal University, Al Ahsa, Saudi Arabia

Date of Web Publication28-Aug-2018

Correspondence Address:
Kaberi Biswas Feroze
Faculty of Ophthalmology, College of Medicine, King Faisal University, Al-Ahsa
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_46_18

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  Abstract 

“Biologic response modifier”(BRM) treatment refers to the treatment of human diseases with a diverse group of agents which are generated from living cells, and which act on the immune system, altering the body's immune response. The principal mechanism of action of these agents includes immunomodulation, interference with cellular proliferation, and direct toxic action on cells. They are designed targeted to specific genes or protein receptors, thus making their mechanisms highly attractive as they act on individual entities in the inflammatory pathway. In ophthalmology, biological response modifiers are being studied for use in the treatment of conditions such as noninfectious uveitis, scleritis, Sjogren syndrome, ocular cicatricial pemphigoid, macular edema, idiopathic inflammatory pseudotumors, Behcet's disease, ocular surface disorders, neovascular disorders, and intraocular lymphoma to name a few. BRMs represent a novel and highly exciting mode of therapeutic intervention in some ocular conditions, especially those resistant to conventional treatment. Although newer molecules are being discovered, a lot of research is still needed to evaluate the long-term efficacy and the safety profile of these agents.

Keywords: Biologic response modifiers, immunoglobulins, tumor necrosis factor inhibitors, interleukin antagonists, vascular endothelial growth factor inhibitors


How to cite this article:
Feroze KB. Biological response modifiers in Ophthalmology: New horizons, new challenges and new hopes. Kerala J Ophthalmol 2018;30:76-86

How to cite this URL:
Feroze KB. Biological response modifiers in Ophthalmology: New horizons, new challenges and new hopes. Kerala J Ophthalmol [serial online] 2018 [cited 2018 Oct 24];30:76-86. Available from: http://www.kjophthal.com/text.asp?2018/30/2/76/239979


  Introduction Top


“Biologic response modifier” (BRM) or simply, biological therapy refers to the treatment of human diseases with a diverse group of agents which are generated from living cells, and which act on the immune system, altering the body's immune response.[1],[2],[3],[4] The history of the development of BRMs dates back to the late 19th century, when William B Coley, who is also considered the father of BRMs, first noticed an improvement in cancer patients following postoperative infections. This led him to conclude that fever upregulates the subject's immunity, causing the host immune system to attack the tumor cells.[5] Cytokines such as interferons (IFNs), tumor necrosis factor (TNF), and interleukins (ILs) were used for cancer treatment in the 1970s and colony-stimulating factor use was started in 1980s.[5] In ophthalmology, BRMs were used for the first time in the 1990s to treat ocular inflammation.[6] BRMs are utilized in the management of cancers and numerous immune-related disorders such as rheumatoid diseases, systemic and inflammatory, and vasoproliferative eye diseases.[2]

BRMs are drugs which are produced by living systems. They include erythropoietin, IFNs, ILs, colony-stimulating factors, granulocyte, and macrophage colony-stimulating factors, stem-cell growth factors, monoclonal antibodies, TNF inhibitors, and vaccines.[5],[7] They act mainly on the immune system, causing either immunosuppression or immunostimulation.[8] Methods of production of the agents include extraction from biological tissues, recombinant DNA techniques, hybridoma techniques, etc.[9] The cost of production of BRMs is much more compared to the conventional chemical drugs, and they require special handling due to their unstable nature.

The majority of BRMs are antibodies or antagonists of cytokines or cell-surface receptors [Table 1]. They are designed targeted to specific genes or protein receptors, thus making their mechanisms highly attractive as they act on individual entities in the inflammatory pathway.[10] The principal mechanism of action of these agents includes immunomodulation (immunosuppression and immune enhancement),[7] interference with cellular proliferation,[2] and direct toxic action on cells. In ophthalmology, biological response modifiers are being studied for use in the treatment of noninfectious uveitis, scleritis, Sjogren syndrome, Ocular cicatricial pemphigoid, macular edema, idiopathic inflammatory pseudotumors, Behcet's disease (BD), ocular surface disorders, neovascular disorders, intraocular lymphoma to name a few.[4] A broad classification of biological response modifiers [Table 1] with special reference to those agents used in ophthalmology includes the following:
Table 1: Description of biologic response modifiers

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  1. TNF inhibitors-infliximab, adalimumab, etanercept, golimumab, certolizumab
  2. IL antagonist-anakinra, tocilizumab, canakinumab, gevokizumab, daclizumab
  3. IFs-IFN alpha2a, IFNalpha 2b, IFN beta 1
  4. Immunoglobulins
  5. Lymphocyte inhibitors-rituximab, abatacept, basiliximab
  6. Vascular endothelial growth factor (VEGF) inhibitor-bevacizumab, ranibizumab
  7. Anti IG E antibody-omalizumab
  8. Others-nerve growth factor, epidermal growth factor, transforming growth factor-beta (TGF-beta), lymphocyte function-associated antigen 1, beta-2 macroglobulin, substance P.



  Tumor Necrosis Factor Inhibitors Top


TNF is mainly produced by macrophages, but can also be formed by lymphocytes, endothelial cells, mast cells, fibroblasts, adipose cells, etc.[11] TNF was first identified when the serum of mice pretreated with BCG and exposed to endotoxins caused tumor necrosis in animals having preexisting tumors.[12] It is the first cytokine to be released into the blood following any injury or stress.[13] Two types of TNF exist-TNFα and TNFβ. TNFα is the most important member of this class and is sometimes referred to as simply, TNF.[11] TNF β is a cytokine inhibited by IL 10. TNF promotes the inflammatory response either by direct cytotoxicity or indirectly by controlling the release of proinflammatory cytokine mediators, arachidonic acid mediators, reactive oxygen species, metalloproteinases, chemokines, adhesion molecules, etc.[6] This molecule is thought to play an important role in the mediation of chronic inflammatory conditions and immune-mediated disorders, thus making it an important weapon in the anti-inflammatory armamentarium.

The biological effects of TNF are mediated by acting through two receptors-TNFR1 (p55/CD120a), which is expressed on all nucleated cells and TNFR2 (p75/CD120b), which can be induced on lymphocytes, endothelial cells, and neurons.[13],[14] Activation of TNFR1 receptors induces proinflammatory responses, whereas TNFR2 activation appears to be important in repair and homeostasis.

There are five commonly used TNF inhibitors. Of these, adalimumab, infliximab, and golimumab are monoclonal antibodies, etanercept is a soluble receptor and certolizumab is the fab fragment of monoclonal antibody coupled with polyethylene glycol.[6]

Infliximab

It is a chimeric IgG anti-human monoclonal antibody, which binds to both membrane-bound and circulating TNF.[3] It is approved for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS), ulcerative colitis, Crohn's disease, psoriatic arthritis, and plaque psoriasis. It has been described as very effective in the treatment of BD related uveitis and retinal vasculitis.[3] The usual dose is 3–5 mg/kg body weight, which may be increased to 10 mg/kg, repeated after 2 and 6 weeks and every 8 weeks.[14] It is also used to treat juvenile idiopathic arthritis (JIA) and its associated uveitis.[14] It has also been reported to be effective in the treatment of different uveitis entities such as HLA-B27 associated anterior uveitis, uveitis associated with sarcoidosis, inflammatory bowel disease, Vogt-Koyanagi-Harada (VKH), psoriasis, Takayasu disease, chronic and relapsing uveitis,[3] birdshot chorioretinopathy (BSCR), recalcitrant uveitis cystoid macular edema (CME), pars planitis, multifocal choroiditis, diffuse subretinal fibrosis, sympathetic ophthalmia, idiopathic uveitis [3] and in the treatment of resistant scleritis,[15] and resistant peripheral ulcerative keratitis (PUK). In the latter, it is thought to act mainly by inhibiting matrix metalloproteinases, which promote stromal lysis.[16] Topically administered infliximab (10 mg/ml) was found to be as effective and less toxic than mitomycin C in modulating postglaucoma filtration surgery wound healing [17] and as a topical antiangiogenic agent in corneal neovascularization.[18] Some case series report off-label use of infliximab in the treatment of resistant extraocular inflammations such as orbital inflammation in thyroid eye disease and Wegener's granulomatosis, optic neuritis, myositis, and Sjogren syndrome.[19] Studies have shown encouraging results in patients with refractory diabetic macular edema, neovascular.[20],[21] Side effects of infliximab include hypersensitivity reactions, heart failure, lupus-like reactions, pulmonary embolism, coronary thrombosis, optic neuritis, etc.[6] Chronic treatment may cause a reduction in efficacy as well.

Adalumimab

It is a fully human monoclonal ant TNF α antibody, which is injected subcutaneously in doses of about 40 mg/2 weeks in adults and approximately 24 mg/m 2 in children.[13],[14] Adalimumab is considered a promising treatment option in the management of AS, BD associated uveitis, refractory uveitis, pediatric uveitis, uveitis associated with sarcoidosis, VKH, BSCR to name a few.[3],[22] Randomized controlled trials have demonstrated that Adalimumab is an effective, steroid-sparing agent in patients having noninfectious intermediate uveitis, posterior uveitis and panuveitis, and reduced the severity of uveitic flares.[23] It can also be an effective agent in treating severe, resistant nodular scleritis [15],[21] The immune-related adverse effects are similar but milder compared to infliximab, however reduction of efficacy can occur with prolonged use.[3]

Etanercept

It is a dimeric fusion protein of the TNFR2 receptor and an IgG1Fc, which binds free TNF α and β.[13] It is widely used for the treatment of AS and may be effective in its accompanying uveitis.[14] It is generally believed to be less effective than infliximab and Adalimumab in the treatment of ocular inflammatory conditions.[3]

Golimumab

It is a fully human anti-TNF α monoclonal antibody, which was used for the treatment of noninfectious uveitis in 2011.[24] Studies have reported encouraging results in recalcitrant JIA and BD associated uveitis, spondyloarthropathies, and occlusive retinal vasculitis.

Certolizumab

It is a PEGylated Fab anti-TNF α agent. The absence of the Fc fragment renders it less immunogenic, and pegylation increases the duration of action. It has been found to be effective in a case of RA associated scleritis [15],[25] and in refractory uveitis.[26]


  Interleukin Antagonists Top


The word IL is derived from its two components “inter” meaning between and “leukin” referring to leukocytes.[11] They are the cytokines produced by lymphocytes. There are many ILs which are numbered based on the order of their discovery. Different classes of ILs act in various ways like promoting activation of T helper cells which in turn induce killer T cell multiplication and also activation of other cells such as B cells and NK cells. IL antagonists thus help to block the immune response and are used in a variety of ocular inflammations.

Anakinra

It is a recombinant version of the human IL 1 receptor antagonist, approved for treatment of RA and found to be effective in multisystem inflammatory conditions.[27] It is administered daily by subcutaneous injections. It is being considered for the treatment of BD associated uveitis.[3] Topical use has also been shown to be effective in the treatment of dry eye disease, cornea graft rejection, allergic conjunctivitis, and chemical burns associated inflammation in animal experiments.[27],[28] A study has also reported the improvement of ocular inflammation in a patient having neonatal-onset multisystem inflammatory disease (NOMID).[29]

Tocilizumab

It is an anti-IL-6 receptor monoclonal antibody approved for the treatment of RA and multisystem and systemic JIA. Studies have demonstrated its efficacy in resistant JIA, BD, BSCR associated uveitis, in uveitis-associated macular edema, retinal vasoproliferative tumors and also in combination with steroids in resistant RA associated anterior necrotising scleritis.[3],[28],[30],[31],[32] Animal studies have demonstrated the effectiveness of subconjunctival tocilizumab in the management of corneal neovascularization [33],[34]

Canakinumab

It is a monoclonal antibody that selectively inhibits IL 1 β binding to the IL receptors.[35] Case studies have found it to be effective in resistant BD associated uveitis,[36],[37] NOMID associated uveitis and stromal keratitis,[38],[39] in resistant pediatric uveitis without any major adverse effects.[40],[41] A prospective study on patients with proliferative diabetic retinopathy administered canakinumab showed an improvement in macular edema.[42] Unlike Anakinra, it does not need daily injections and may be administered fortnightly to 8 weekly depending on the indication.

Gevokizumab

It is a partially humanized recombinant monoclonal antibody that binds IL 1 β with a long circulating half-life permitting once monthly administration. Clinical trials in BD have shown encouraging results, and it is also being evaluated for the management of resistant scleritis.[3],[43]

Daclizumab

It is a humanized monoclonal antibody which blocks the IL 2 receptor. Studies have demonstrated promising outcomes in patients with JIA associated and other chronic uveitis entities, but researches consider it less carcinogenic than other immunosuppressants, dermatological complications including malignancies were observed.[44],[45],[46] It may also be effective in patients unresponsive to anti-VEGF agents and in reducing the need for anti-VEGF injections in neovascular age-related macular degeneration (AMD).[47],[48] It has been withdrawn from the market by its manufacturer.


  Interferons Top


IFNs are a group of proteins called cytokines, which are produced by lymphocytes, fibroblasts etc., as part of the immune response against viruses and some other triggers.[11] The IFNs are classified as IFN 1 (IFN α and β) and IFN 2 (IFN α). IFN α is produced by virus-infected leukocytes, IFN β by virus-infected fibroblasts and epithelial cells and IFN α by activated T-cells. IFNs have immunomodulatory and antiproliferative actions, thus they are used in chronic inflammations, autoimmune conditions, and in malignancies.[5] Adverse effects of IFNs include injection site reactions, flu-like reactions, and bone marrow suppression.[3]

IFN α was the biologic agent used in the management of BD before the advent of TNF inhibitors. IFN α 2a therapy has been found to be an effective management tool in resistant BD [3],[49],[50],[51] and the recommended dosage is initial injections of 3 × 106-9 × 106 IU/day which may be subsequently tapered to 3 × 106 IU 2–3 times/week with cessation of steroid and immunosuppressive therapy.[49] It have also been studied for treatment of infection associated CME, resistant uveitic CME, resistant chronic pseudophakic CME, with encouraging results [52],[53],[54],[55] and also for noninfective poster and panuveitis and also in refractory uveitis.[56],[57]

Studies have demonstrated that IFN α 2b is effective in treating uveitic CME,[58] capillary hemangioma in children,[59],[60] conjunctival, and corneal intraepithelial neoplasia (topically solely or in combination with retinoic acid),[61],[62],[63],[64],[65] refractory vernal keratoconjunctivitis,[66] and subconjunctival injections as a treatment of scarring in filtering bleb.[67]

IFN β has been studied for the management of optic neuritis in MS and on experimentally induced choroidal neovascularization with good results.[68],[69] and both IFN β and α have been found to have good anti adenoviral action in in vitro studies.


  Immunoglobulins Top


Intravenous immunoglobulins (IVIG) are preparations of pooled immunoglobulins obtained from healthy human subjects.[4] It is thought to contain 95% IgG, 2.5% IgA and small quantities of IgM.[70] The mechanism of action of IVIG are manifold, including interference with complement and cytokine system activation, blocking of IgG receptors, modulation of differentiation and effector functions of T–cells, B-cells and dendritic cells, neutralization of circulating antibodies, etc. The usual dose is 0.8–2 g/kg over 1–5 days and repeated 4–6 times every 4 weeks as required. IVIG is reported to be safe with few side effects such as headaches nausea, anaphylactic reactions in patients with IgA deficiency, and rarely thromboembolic events, renal failure etc. IVIG has been studied for the treatment of resistant optic neuritis,[70],[71] BSCR,[72] resistant ocular cicatricial pemphigoid,[73] acute retinal necrosis (in combination with antivirals),[74] keratolimbal allograft rejection,[75] and thyroid eye disease [76],[77]


  Lymphocyte Inhibitors Top


Rituximab

It is a mouse-human chimeric monoclonal antibody directed against the CD 20 transmembrane protein on B-lymphocytes. It is administered by intravenous infusion, the dose varying according to the indication.[3] Rituximab represents a promising option in the management of thyroid eye disease, especially steroid-resistant cases and studies show good treatment response in some and ambiguous treatment response in some.[77],[78],[79],[80] Studies demonstrate that it is effective in cases of recalcitrant scleritis,[15],[81],[82],[83] in ocular cicatricial pemphigoid either as monotherapy or in combination with conventional immunosuppressants [84],[85] and in refractory uveitis.[86],[87] Rituximab has been found to be an excellent treatment option in ocular adnexal MALT tumors, intralesionally in conjunctival lymphomas and primary iris lymphoma, eliminating the disabling adverse effects of radiotherapy.[88],[89],[90],[91],[92] It is also being studied in the management of dry eye in Sjogren syndrome and in refractory PUK [93],[94],[95],[96] Adverse effects of rituximab include infusion reactions, especially when administered along with Infliximab, and infections such as pneumonia and septicemia.[4]

Abatacept

It is a selective T-cell costimulation modulator, which binds to the CD80 and CD86 T cell receptors, and acts by inhibiting the costimulatory signals necessary for full T-cell activation.[97],[98] It has been tried in refractory JIA associated uveitis with encouraging results.[99],[100]

Basiliximab

It is a chimeric monoclonal antibody binding to and blocking the CD20 receptor on the activated T-lymphocytes, being studied for the management of chronic uveitis.[3]


  Anti Ige Antibody Top


Omalizumab

It is a monoclonal, chimeric anti-IgE antibody which binds to the Cέ domain of the circulating IgE antibody, inactivating it and causing its removal from the bloodstream, reducing the circulating IgE levels and reducing IgE-mediated reactions. It is administered by subcutaneous injections every 2–4 weeks. Studies have demonstrated marked efficacy in severe refractory cases of vernal keratoconjunctivitis, but more research is required to determine the clinical regimen.[101]

Vascular endothelial growth factor inhibitors

This group represent one of the most promising biological approaches to ocular diseases.[3] VEGF plays an important role in inflammation, causes vasodilatation and increases vascular permeability.[102],[103] It is the principal mediator of ocular angiogenesis and plays an important role in development of pathological neovascularization. It was first reported that anti VEGF agents inhibit the growth of tumor cells in nude mice.[104] Subsequently, the VEGF inhibitor, bevacizumab was discovered, which reduced tumor perfusion, volume and microvascular density in patients with colorectal cancers.[105]

Bevacizumab

It is a full length, recombinant humanized anti VEGF monoclonal antibody. It has been approved by the FDA for treatment of colorectal cancers and is used off label intravitreally for the treatment of wet AMD, diabetic macular edema, and macular edema following central retinal vein occlusion (CRVO).[103]

Ranibizumab

It is a humanized recombinant anti VEGF monoclonal antibody fragment, which has been approved by the FDA for the treatment of wet AMD, diabetic macular edema and macular edema following CRVO.[103]

Pegaptanib

Pegaptanib is a 28 molecule RNA aptamer which specifically binds to the VEGF-A 165 isomer,[102] which is the one mainly implicated in ocular pathologies. It has been FDA approved for the treatment of wet AMD.[103]

Aflibercept

Aflibercept is a recombinant fusion protein and is FDA approved for the treatment of wet AMD, diabetic macular edema and macular edema following CRVO. Some studies show its equal efficacy to ranibizumab in wet AMD,[106] however a large NIH study showed better results in aflibercept treated group in a population of diabetic macular edema patients compared to ranibizumab.[107] Adverse effects of the VEGF inhibitors include traumatic complications of the intravitreal injections, endophthalmitis (which was found to be slightly higher for bevacizumab).


  Others Top


Ustekinumab

It is fully humanized monoclonal antibody acting against the shared p40 subunit of IL12 and IL-23, thus obstructing their actions. It has been studied for the management of BD,[108] and refractory giant cell arteritis with good outcome.[109]


  Newer Biologic Response Modifiers Top


Mongersen

It is an oral SMAD 7 antisense oligonucleotide. This acts as an inhibitor of SMAD 7, which normally inhibits TGF-β. TGF-β acts to inhibit cytokine production, thus, Mongersen restores TGF–β function, helping in anti-inflammatory activity.[110]

Tofacitinib

It is a small oral molecule which inhibits the Janus kinase family, thus inhibiting multiple cytokines and T and B cell functions.[110]

Ozanimod

It inhibits the sphingosine 1 phosphate receptor and prevents the exodus of lymphocytes from the lymph nodes.[110]

Natalizumab

It reduces inflammatory cell migration by binding to α 4 integrin.[111]

BRMs are thus an exciting prospect in the treatment of chronic inflammatory and autoimmune conditions. Although some of these agents are extremely effective and demonstrate good outcomes, especially in refractory conditions, others have not been found to be so encouraging in therapeutic responses and some agents have even been withdrawn. However, they still represent a novel mode of intervention, especially in ocular conditions not responding to conventional treatments. Discovery of newer modalities of intervention in the inflammatory pathways may lead to unraveling of newer BRM molecules. Although newer molecules are being discovered, a lot of research is still going on to evaluate the long-term efficacy and the safety profile of these agents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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