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Jacques Gaudreault, Tea Gunde, Heather S. Floyd, Joel Ellis, Julia Tietz, Daniela Binggeli, Barbara Keller, Anne Schmidt, Dominik Escher; Preclinical Pharmacology and Safety of ESBA1008, a Single-chain Antibody Fragment, Investigated as Potential Treatment for Age Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3025. doi: https://doi.org/.
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ESBA1008 is a humanized monoclonal single-chain FV (scFv) antibody fragment targeting VEGFA and is currently investigated in patients with Age Related Macular Degeneration. The smaller size of scFv (26kDa), compared to full length IgG (150 kDa) or Fab fragments (50kDa), might allow better ocular tissue penetration and is well suited for ophthalmology. Prior to initiation of clinical trials, ESBA1008 pharmacology and toxicology were characterized in in vitro and in vivo studies.
ESBA1008 in vitro pharmacology was characterized by BiaCore, ELISA and inhibition of human umbilical endothelial cells (HUVEC) proliferation. ESBA1008 potential toxicities were determined in cynomolgus monkeys (N=30) who received a total of 3 IVT injections of ESBA1008 or vehicle (50 uL) every 3 weeks, in doses ranging from 0 to 6000 ug/eye.
In vitro ESBA1008 binds to all isoforms of VEGFA, including VEGF165, with a KD of 28.4 pM. ESBA1008 neutralized binding of VEGF165 to VEGFR2 with an IC50 of 0.86 nM and inhibited VEGF induced HUVEC proliferation with an IC50 of 0.19 nM. In cynomolgus monkeys, ESBA1008 was well tolerated with no ocular or systemic toxicity and with minimal ocular inflammation which was comparable in the vehicle and active-treated groups. Mean serum cmax was 0.0405 and 0.286 ug/mL for the 500 ug and the 6000 ug group.
ESBA1008 is a potent inhibitor of VEGF and can be administered safely in animals at doses as high as 6000 ug/eye, and results in more than 4-fold lower systemic exposure compared to other antiVEGF agents, as shown in primate toxicology studies. Since high doses were well tolerated in animals and ESBA1008 shows high affinity for VEGF, ESBA1008 has the potential in humans to be administered at intervals greater than monthly, hence reducing the treatment burden in patients. In addition, based on the predicted low systemic exposure in patients, the risk of systemic adverse events might be lower with ESBA1008.
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