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

Lead Research Organisation: University College London
Department Name: Institute of Ophthalmology


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.

Technical Summary

This is a proposal to conduct a Phase I/IIa clinical trial (LABINA) of Magacizumab, a humanised monoclonal antibody against LRG1, in patients with neovascular age-related macular degeneration (AMD). The methodology follows a conventional series of preclinical steps including the development of a master cell line and preparation of clinical grade antibody, then safety and toxicology testing in pigs and human Lrg1 knock-in mice specifically generated for this purpose as part of our current DPFS project. We will then secure ethical and regulatory approval before progressing to Phase I of the clinical trial. This will take the form of a dose-escalation study in patients who respond poorly to standard of care (SOC), and will be followed by Phase IIa in which Magacizumab is tested in combination with SOC in naive or newly diagnosed patients. The primary endpoint of the LABINA trial will be safety but in Phase IIa we will also look for indications of biological activity using techniques such as optical coherence tomography, fluorescein angiography and visual acuity testing. A successful outcome to this project will mark a major step towards improving therapeutic outcomes for patients with neovascular AMD, among whom there are many who either do not respond to SOC or become refractory. In addition, we will generate new intellectual property that will add to the patents we already hold around LRG1. This will place us in a strong position for onward exploitation of the research through licensing or creation of a spinout.

Planned Impact

The primary beneficiaries of this research will be patients with age-related macular degeneration (AMD) and the clinicians who provide their health care. There are currently more than 3,000,000 individuals in North America and Europe affected by the neovascular form of AMD, and around 10 to 15% of those patients either fail to respond or respond poorly to treatment with VEGF blockers such as Lucentis and Eylea. The loss of central vision in AMD leads to affected individuals being unable to read, drive or distinguish faces. This is a chronic disabling condition that is on the increase due to people living longer. For patients with AMD, better therapeutic outcomes means less demand on support services and care providers, greater independence, and a significant improvement in quality of life.

The eventual development of Magacizumab as a front line therapeutic would also benefit the National Health Service and NICE by providing i), a therapeutic approach that when used in combination is more effective than VEGF blockade alone, ii), a potential monotherapy alternative to VEGF blockade and thus a more competitive market, and iii), a therapy likely to have applications in other vascular pathologies.

Full commercialisation of the antibody would enhance the economic competitiveness of the UK by bringing benefits to several parties, including UCL (who hold all the intellectual property around LRG1), and any pharma or biotech partners, or third party investors who choose to license the technology or support a spin-out company. The wet AMD market is currently worth around $8bn per annum (Syed et al., 2012), and is dominated by the two VEGF blockers Lucentis and Eylea. We would expect Magacizumab to capture a share of this market, either as monotherapy in the 10-15% of patients who fail to respond to VEGF blockers, or as combination therapy with Lucentis or Eylea if this brings improved outcomes for patients.

The timescale for these benefits to be realized is reflected in the milestones that form this proposal. Thus, we expect this study to conclude in late 2020, by which time we would expect to have a licensing deal, a joint partnership or established a spinout to advance to later phase trials. The full health benefits of our work will only be realized after a successful Phase III trial, most likely around 2023. However, economic benefits may emerge at an earlier date, for example through a licensing deal with a pharma partner. Indeed we started discussions with a number of companies two years ago, and several are maintaining an on-going dialogue with us as the project advances.


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Title Transgenic mouse 
Description A human LRG1 knock-in mouse 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Too soon 
Title Development of a therapeutic antibody targeting LRG1 
Description We are developing a therapeutic antibody against the pathogenic molecule LRG1 fro the treatment of vascular dysfunction in disease. We have secured MRC DPFS and DCS funding to develop the therapy, manufacture the drug and complete all pre-clinical requirements before taking this into phase I clinical trials in 2019. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact None 
Title MagaFab 
Description MagaFab is the Fab fragment of the antibody Magacizumab. We have developed this in the lab and shown that it retains the properties of the full-length parent IgG. We have also shown that it targets vascular lesions in the eye and that it inhibits angiogenesis in the mouse metatarsal model. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact None yet. 
Company Name LRG1 LTD 
Description The company has been set up to advance the development of the LRG1 blocking antibody Magacizumab, and also its Fab fragment (that we term MagaFab) specifically for use in ocular indications. The first objectives of the company are to establish that MagaFab is tolerated in the eye and is therefore suitable for onward development towards early stage clinical trials. The company operates under the name PanAngium Therapeutics, and as of early 2021 has a CEO who is leading the search for investment. 
Year Established 2019 
Impact The company was formed at the start of 2019, so no notable impacts just yet.
Description Clinical Trial Facebook Page 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact We set up a Facebook page for the forthcoming clinical trial to alert AMD patients about the work. There are already several such pages for patient groups, and it is clear that members of those groups are interested in what we are doing. By setting this up well in advance of Phase I we also hope that increasing awareness may help to enhance patient recruitment.
Year(s) Of Engagement Activity 2016
URL https://www.facebook.com/UCL.LABINA/