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Single-chain antibody fragments in ophthalmology

Session Details

Session Title: AMD I

Session Date/Time: Thursday 17/09/2015 | 08:30-10:30

Paper Time: 08:30

Venue: Athena

First Author: : D.Escher SWITZERLAND

Co Author(s): :    A. Schmidt   P. Steiner   P. Maurer   G. Weissgerber     

Abstract Details

PURPOSE:A single-chain antibody fragment (scFv) represents the smallest functional unit of an antibody that still retains full binding capacity to its target. It comprises only the variable domains of the monoclonal antibody responsible for binding to the target. This translates into a small protein size of 26kDa compared to 52kDa for a Fab fragment like ranibizumab or to 150kDa for an antibody like bevacizumab. However, the majority of scFvs exhibit poor biophysical properties and cannot be developed for therapeutic purposes. We will present results showing the development of the first scFv in ophthalmology into phase III for neovascular AMD.


Despite its advantages of a small protein drug, so far no scFv has been approved for commercial use in human diseases.


We have designed and developed a novel technology that allowed selecting fully human, highly stable and soluble scFv frameworks. These frameworks are then used to graft the antigen-specific complementarity determining regions (CDRs) which allow binding to the respective targets with very high specificity and very high affinity. Based on that technology, a number of scFvs were developed which are at different stages of development for ophthalmic uses. The most advanced is RTH258 (ESBA1008), which neutralizes all isoforms of VEGF-A.


We have applied a novel technology platform that delivers highly stable and soluble scFvs. RTH258 is the most advanced scFv stemming from that technology and entered phase III in neovascular AMD in December 2014. RTH258 binds to VEGF with very high affinity and potently inhibits the activation of the VEGF receptors. Due to its favorable biophysical properties, RTH258 can be concentrated to 120 mg/ml, which allows for delivery of 6 mg of RTH258 in a 50 μL volume for intravitreal injections. This corresponds to a 24-fold molar excess over the clinical dose of 0.5 mg of ranibizumab that could potentially translate into improved efficacy for some patients and a longer duration of action, thus a decreased treatment burden. Due to its small protein size, RTH258 also has an excellent tissue penetration in the eye reaching high concentrations in the retina and RPE/choroid. Systemic clearance is very fast, again due to the small protein size, minimizing the risk of systemic adverse events. RTH258 was shown to be safe and well tolerated in phase II studies.


With the advancement of this novel scFv platform technology, it has become possible to deliver high molar amounts of new drugs to the patients. This is expected to translate into better efficacy, longer duration and thus a reduced treatment burden for the patients. Fast systemic clearance of the scFv will translate into low systemic burden and may lower the risk of systemic adverse events. RTH258 is the most advanced scFv in clinical development and could be the first of several scFvs in ophthalmology.

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