University of Liverpool

<p><strong>Overview</strong></p>
<p>For advancement of learning and ennoblement of life - This has been our mission since the University was founded in 1881. To this day, these values focus our efforts as we strive to achieve our ambitions and tackle the grand challenges of the age.</p>
<p><strong>Research</strong></p>
<p>Research is the key to solving our world’s greatest challenges. It can make a positive difference – to individuals, industries, economies and entire countries. It can change the world.</p>
<p>We are committed to driving research excellence and innovation on a global scale. With 81% of our research ranked ‘world-leading’ and ‘internationally excellent’ in the latest Research Excellence Framework (REF), we are addressing some of the world’s toughest challenges.</p>
<p>We have gained recognition for international research excellence in personalised health, advanced materials, and infectious disease. Our strength lies in bringing together academics from across all our faculties to produce research that is globally relevant, as evident in our digital research, an emerging area of strength.</p>
<p><strong>Industry Partnerships</strong></p>
<p>The University of Liverpool is in a strong position to develop innovative solutions and approaches to tackle many of today’s complex social, economic and environmental challenges, for business, industry and even world economies.</p>
<p>Exchanging knowledge and expertise are an integral part of the University and accelerate the utilisation of our research achievements, which are at the forefront of scientific development worldwide.</p>
<p>Importantly, our research is enhanced through partnerships we have with a wide-range of private, public, and third-sector organisations. These partnerships are a key way of translating our groundbreaking research to real situations, while helping organisations to accelerate innovation and economic growth.</p>
<p>By facilitating access to our expertise, facilities and networks, we offer the means to transform ideas into creative solutions, improved performance, new technologies, strategies, applications, products or skills.</p>


<h1 id="background">Background</h1>
<p>TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death (apoptosis). TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumour cells, by binding to certain death receptors (DR4- TRAIL-RI and DR5- TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases.</p>
<p>TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, these have not shown significant survival benefit. In clinical trials only a small proportion of cancer patients have responded to various drugs that target TRAIL death receptors. Many cancer cell lines develop resistance to TRAIL and this limits the efficacy of TRAIL-based therapies.</p>
<p>The present invention addresses this issue.</p>
<h1 id="technology-overview">Technology Overview</h1>
<p>University of Liverpool researchers are developing a novel gene therapy, which kills cancer cells selectively and with high potency . The invention consists of a novel genetic construct encoding a CD40LTRAIL fusion protein.</p>
<p>The TRAIL death receptor pathway is a well validated target for cancer therapeutics, with multiple agonistic antibodies entering clinical trials in the last 10 years. However many of these mAbs failed in the clinic due to poor efficacy. This novel fusion protein overcomes these issues by generating a more potent apoptotic signal.</p>
<p>The improvements employ the use of membrane-anchoring moieties to amplify the effectiveness of this modality of TRAIL-based therapeutic inventions. Significantly improved cancer cell-killing activity has been observed compared to the natural derivatives or soluble equivalents.</p>
<p>Features:</p>
<ul>
<li>CD40LTRAIL fusion protein induces cell death in DR4- and DR5- positive carcinomas (<img src="https://s3-eu-west-1.amazonaws.com/assets.in-part.com/figures/cnmf7uaUQgGfVQdQi9gL_Screen%20Shot%202019-11-26%20at%2016.30.53.png" alt="Figure 1" />)</li>
<li>CD40LTRAIL fusion protein induces more potent growth inhibitory effects compared to wild type TRAIL or treatment with soluble TRAIL ligand in a range of cancer cell lines (pancreatic, cervical and bladder).</li>
<li>CD40LTRAIL fusion protein induces caspase 3/7 activation suggesting specific activation of the death receptor pathway.</li>
</ul>
<h3 id="-stage-of-development-"><strong>Stage of Development</strong></h3>
<p>Early stage project:</p>
<ul>
<li>Preliminary <em>in vitro</em> results suggest great potential for this approach in overcoming efficacy issues with TRAIL mAbs</li>
<li>Ongoing studies to trial different delivery vehicles for gene construct</li>
</ul>
<h1 id="benefits">Benefits</h1>
<ul>
<li>TRAIL is a member of TNF superfamily that upon binding to its receptors induces cell death with high specificity for carcinoma cells</li>
<li>Novel construct tethers the death receptor ligand TRAIL to the cell membrane</li>
<li>Membrane anchorage increases the cytotoxicity of TRAIL in a range of TRAIL receptor-positive carcinomas</li>
</ul>
<h1 id="applications">Applications</h1>
<p>Significant market opportunity:</p>
<ul>
<li>Widespread TRAIL expression in cancer tissue suggests this therapy has the potential to treat various forms of cancer.</li>
<li>Potential to combine with other chemotherapies and targeted therapies in difficult-to-treat cancers.</li>
</ul>
<h1 id="opportunity">Opportunity</h1>
<p>Seeking partners to advance project through preclinical and clinical development. The technology is most applicable to those companies developing viral delivery vector based oncology products.</p>
