A Phase I/IIa Clinical Trial of a Humanised Monoclonal Antibody Against LRG1

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The aim of this proposal is to conduct a Phase I/IIa clinical trial of a new drug targeting a secreted protein named leucine-rich alpha-2 glycoprotein 1 (LRG1). Our group discovered LRG1 a few years ago in a search for new therapeutic targets in retinal vascular disease. We showed that LRG1 stimulates abnormal blood vessel growth in the eye, and demonstrated using a variety of experimental strategies that pathological angiogenesis (new blood vessel growth) can be prevented by inhibiting LRG1. This led us to speculate that we could target LRG1 in retinal vascular disease by using a function-blocking monoclonal antibody directed against this protein.With support from a MRC DPFS award we recently completed the development of Magacizumab, a fully humanized de-immunised function-blocking monoclonal antibody against LRG1. The humanisation of the antibody prevents its rejection by the patients' immune system. This antibody has high affinity and specificity for LRG1, and in a mouse model of "wet" age-related macular degeneration (AMD) we established that the antibody is as effective as the current standard of care (SOC), Eylea, in preventing lesion formation. Moreover, unlike current SOC our therapy targets a different angiogenic pathway and as such may provide greater benefit when administered either alone or in combination. Based on these proof of concept observations we designed the LABINA trial, a first in man examination of the humanized LRG1 antibody, in patients with the 'wet' form of AMD.The LABINA trial comprises two parts. In Phase I we will perform a dose-escalation study in which individual patients are given increasing doses of Magacizumab in order to establish safety of the therapy and the maximum tolerated dose. In Phase IIa we will administer Magacizumab in combination with SOC, with a control group of patients receiving SOC alone plus sham injection. Although the primary endpoint of the trial is safety and tolerability, we have designed the study so as to maximize the chances of seeing clinical benefit.A successful outcome to the LABINA trial will pave the way for larger scale trials and onward commercialization. We have a strong position with regard to intellectual property, and given the substantial economic potential of antibody therapies plus the scope for application in other clinical indications, such as cancer, we are confident of finding either a pharmaceutical partner or investors to support a spin-out company.