Penetration of a Topically Administered Anti–Tumor Necrosis Factor Alpha Antibody Fragment into the Anterior Chamber of the Human Eye

Thiel, Michael; Wild, Andreas B.; Schmid, Martin; Job, Oliver; Bochmann, Frank; Loukopoulos, Vlasios; Alcantara, Wolfan; Schmidt, Annette; Lichtlen, Peter; Escher, Dominik

doi:10.1016/j.ophtha.2012.12.015

Cited by 26 publications

(15 citation statements)

References 21 publications

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“…Consequently, the ability of topically applied antibody to penetrate the surface of the eye has been extensively studied in recent years. Low-MW antibody fragments in the form of eye drops have been shown to give good ocular penetration with the potential to reach therapeutic levels within the anterior and even posterior chambers (Figure 2) in human and animal models (Berdugo et al, 2012;Brereton et al, 2005;Ferrari et al, 2013;Furrer et al, 2009;Lichtlen et al, 2010;Ottiger et al, 2009;Stevenson et al, 2012;Thiel et al, 2002;Thiel et al, 2013;Williams et al, 2013). Preliminary clinical studies with topical VEGF inhibitor monoclonal antibodies indicated that the low-MW (48 kDa) Fab (Ranibizumab) is modestly superior to the larger MW (149 kDa) IgG (Bevacizumab) at inhibiting corneal neovascularization via this route (Stevenson et al, 2012).…”

Section: Ocular Usementioning

confidence: 99%

Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications

Jones

Martino

2015

Critical Reviews in Biotechnology

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Therapeutic antibodies provide important tools in the "medicine chest" of today's clinician for the treatment of a range of disorders. Typically monoclonal or polyclonal antibodies are administered in large doses, either directly or indirectly into the circulation, via a systemic route which is well suited for disseminated ailments. Diseases confined within a specific localized tissue, however, may be treated more effectively and at reduced cost by a delivery system which targets directly the affected area. To explore the advantages of the local administration of antibodies, we reviewed current alternative, non-systemic delivery approaches which are in clinical use, being trialed or developed. These less conventional approaches comprise: (a) local injections, (b) topical and (c) peroral administration routes. Local delivery includes intra-ocular injections into the vitreal humor (i.e. Ranibizumab for age-related macular degeneration), subconjunctival injections (e.g. Bevacizumab for corneal neovascularization), intra-articular joint injections (i.e. anti-TNF alpha antibody for persistent inflammatory monoarthritis) and intratumoral or peritumoral injections (e.g. Ipilimumab for cancer). A range of other strategies, such as the local use of antibacterial antibodies, are also presented. Local injections of antibodies utilize doses which range from 1/10th to 1/100th of the required systemic dose therefore reducing both side-effects and treatment costs. In addition, any therapeutic antibody escaping from the local site of disease into the systemic circulation is immediately diluted within the large blood volume, further lowering the potential for unwanted effects. Needle-free topical application routes become an option when the condition is restricted locally to an external surface. The topical route may potentially be utilized in the form of eye drops for infections or corneal neovascularization or be applied to diseased skin for psoriasis, dermatitis, pyoderma gangrenosum, antibiotic resistant bacterial infections or ulcerated wounds. Diseases confined to the gastrointestinal tract can be targeted directly by applying antibody via the injection-free peroral route. The gastrointestinal tract is unusual in that its natural immuno-tolerant nature ensures the long-term safety of repeatedly ingesting heterologous antiserum or antibody materials. Without the stringent regulatory, purity and clean room requirements of manufacturing parenteral (injectable) antibodies, production costs are minimal, with the potential for more direct low-cost targeting of gastrointestinal diseases, especially with those caused by problematic antibiotic resistant or toxigenic bacteria (e.g. Clostridium difficile, Helicobacter pylori), viruses (e.g. rotavirus, norovirus) or inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease). Use of the oral route has previously been hindered by excessive antibody digestion within the gastrointestinal tract; however, this limitation may be overcome by intelligently applying one or more strate...

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Section: Ocular Usementioning

confidence: 99%

Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications

Jones

Martino

2015

Critical Reviews in Biotechnology

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“…com ) which involves the generation of stable humanized single-chain Fv fragments from rabbit monoclonal antibodies (Borras et al 2010 ). A few scFv candidates, directed against TNFα (ESBA105) and VEGF were developed up to clinical phase II for topical application on the eye (Strohl and Strohl 2012 ;Thiel et al 2013 ). Further development was pursued in the form of the PENTRA ® body technology (Delenex, http://www.delenex.com ) for local application in dermatology, where the anti-TNFα scFv (DLX105) appeared to induce a clinical response in psoriasis patients after intradermal administration (Tsianakas et al 2014 ).…”

Section: Functional Ig Fragments: From Fab To Domain Antibodymentioning

confidence: 99%

Biobetters

2015

AAPS Advances in the Pharmaceutical Sciences Series

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“…Monoclonal antibody therapy is also evolving. For example, technology now exists to deliver isolated antibody light chains that might have a wide biodistribution in the eye after topical application 130. It is also possible to develop monoclonal antibodies that recognize two or more targets and thus might be more efficacious than an inhibitor of a single target.…”

Section: Future Targets Limitations and Unknownsmentioning

confidence: 99%

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

Pasadhika¹,

Rosenbaum²

2014

BTT

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Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis.

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Penetration of a Topically Administered Anti–Tumor Necrosis Factor Alpha Antibody Fragment into the Anterior Chamber of the Human Eye

Cited by 26 publications

References 21 publications

Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications

Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications

Biobetters

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

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