Internal note – SCANCELL HOLDINGS PLC: Multiple Arrows in its Quiver

ABSTRACT
Scancell is an early-stage bio-technology company that is well positioned with 4 distinct technology platforms, in the high-growth immuno-oncology space. If all 4 platforms were successful, the company could generate around $12bn in peak aggregate revenues by the early to mid-2030.

CONTENTS

• Investment summary
• Company Background and Business Overview
• Overall Cancer Market
• Development Pipeline
• Scancell’s Addressable Market Opportunity
• Patents Granted / Pending – buttress competitive positioning
• Competitive Landscape
• Board of Directors and Senior Management Team
• Financial Statements
• Appendix 1: Understanding the science behind Scancell’s platforms
• Disclaimers and Important Notes

INVESTMENT SUMMARY

Introduction: Scancell is an early-stage bio-technology company that is well positioned in the highly appealing immuno-oncology space. It has years of solid research in 2 main areas: a) cancer vaccines – produced across the Moditope® and ImmunoBody® platforms, and b) antibody products – produced across the GlyMab^TM and AvidiMab® platforms.

A significant addressable market: Scancell’s platforms are targeting over 10 types of solid tumours. If all 4 platforms were successful across the many multiple indications, this company could generate $12bn in peak annual revenues by the early to mid-2030s. Even applying a 10% rate of success, this could be a company which could generate over $1bn in annual revenues by the next decade.  We believe the market will begin to discount these prospects much sooner, as there are several value creation inflection points through 2023 (detailed in the following point).

De-risked business model, with multiple shots on goal: Scancell’s business model has great appeal both from a science and a business perspective for the following reasons: 1) With 4 distinct platforms, catering to a plethora of indications in the solid cancer space, the company is de-risked from a business perspective unlike peers that might be narrowly focused on only 1 or 2 therapeutic indications. As an example, the Modi-1 vaccine is focused on 4 types of solid tumours (triple negative breast cancer, ovarian, renal and head and neck cancers). The risk of failure (a way of life in the biotech industry) is thus substantially mitigated, with Scancell’s business model. 2) The availability of real options – with multiple platforms and multiple indications, Scancell’s management has real choices about which products or indications it wants to pursue further, and which assets it wants to sell or licence out or develop in partnership. This enables the company to raise cash (critical for development of future assets) as also avoid dilution at low valuation levels.

Positive Catalysts: There are several value creation inflection points coming along in 2023: 1) Modi-1, is progressing through a phase I/II trial targeting 4 tumour types with results through 2023. If the data is positive for even 1 of the 4 indications (triple negative breast, ovarian, renal and head & neck cancer), it could result in a substantial uptick in share price performance given the probability of success (PoS) assigned will rise from 15% to around 25%; 2) SCIB1 is in a phase II study on malignant melanomas, and 3) The Glymab antibodies are generating interesting preclinical data – another deal similar to the one with Genmab, but with probably superior economics, would be a fillip to the share price as the PoS will (at the bare minimum) double to 10%.   

Valuation: We view the current share price as derisory; reflective of poor market sentiment for biotech stocks and the early-stage nature of the business, with management too focused on the science, rather than medium- and long-term commercial aspects. If Modi 1 were successful across all 4 tumour indications, it could deliver c.$2.8bn in aggregate profits (present – value adjusted, but not probability adjusted) based on our (Vulpes) estimates. Even adjusted with a 10% PoS (probability of success) that would imply a market value of c.$280m – a c.62% uptick vis-à-vis the current market cap of around $173m. And this is from a single asset. Modi-2, which addresses other solid tumours like colorectal cancer, non-small cell lung cancer, and prostate cancer, among others, could (if successful across all indications) deliver c.$2.3bn in profits (our estimates; present – value adjusted, but not probability adjusted). Even adjusted with a 7% PoS that would imply a market value of c.$160m – which again equates to almost the entire current market capitalisation of the company.

Source: Vulpes

Immuno-therapy holds great appeal with solid growth prospects: The cancer immuno-therapy market was globally estimated at US$85.6bn in 2021 (Source: marketresearchcommunity.com) and forecast to grow at c.13.7% CAGR to $272bn by 2030. It’s a high growth area, with no ‘standard’ treatment for cancer, and with new emerging technologies constantly creating new profit pools for successful companies. The 2 major risk factors are constantly evolving technologies and competitors – but the rapid pace of change also creates opportunities for small players like Scancell with differentiated technologies. Another significant advantage of being in the immune-therapy space is the relative latitude of the authorities (especially in the United States) with respect to pricing. Based on our discussions with a clutch of industry experts, there is general acceptance of the fact that immuno-therapy is at the cutting edge of medical advancement, and is priced to reflect this reality. Pricing of therapies can range from $50k / patient-treatment-duration to almost US$200k and more.

Relative ease of patient recruitment in trials: A big stumbling block for companies in phase 1-3 trials is the difficulty of recruiting patients – both from a time and cost perspective. Scancell’s treatments are targeting relatively hard – to- treat cancers like ovarian, head and neck, triple negative breast cancer and so on. Its relative ease in recruiting patients for its Modi-1 phase I/IItrial (and the speed with which the data will be released) is a big advantage for Scancell, given the potential for positive value inflection from favourable outcomes in trial data.

Risk factors: There are generic risks which all bio-tech companies are susceptible to:

1. Adverse results from trials,
2. Competitive intensity from other players targeting the same indications with competing therapies, and
3. The funding environment which is dependent on external macro-economic factors.

The idiosyncratic risk that we see in Scancell, which need to be managed are:

• The current management’s focus is too involved with the science. In our view, we see a situation evolving wherein the multiple early- stage assets (whilst excellent from a de-risking perspective) could create a ‘problem of plenty’. The company’s management team needs to be strengthened with members from a commercial background, who can provide sufficient analytics and decision support so that management can sequence the assets better. A better sequencing of assets would result in lower equity dilution as funds are utilised to take 1 or 2 assets to later stages – which can then be partnered out or sold at higher valuations
• The second company specific risk in our view is that of key person risk – Scancell is still an early clinical stage company, and there is key person risk with Professor Lindy Durrant chairing the dual roles of Chief Executive Officer and Chief Science Officer. The company’s patents and intellectual property is built upon and around her work. If she were to become unavailable, due to unforeseen circumstances, it could impact the company’s prospects and might make it difficult to secure future funding.

SHAREHOLDING PATTERN

Source: Bloomberg, as at Feb 2023

COMPANY BACKGROUND AND BUSINESS OVERVIEW

Scancell is an Oxford based clinical – stage biotechnology company. The company has its roots as a spin out from the University of Nottingham in 1996. Professor Lindy Durrant, the current CEO and CSO, co-founded Scancell. Whilst the company initially focused on blood markers to detect Down’s syndrome, it gradually pivoted to immunotherapies to treat various types of cancers.

With cancer, there is no one “standard” treatment, as the appropriate treatment for a particular patient depends on many factors, including the type and stage of cancer, the patient’s overall health and medical history, and the patient’s personal preferences. Treatment options for cancer, were until recently limited to surgery, chemotherapy, radiation therapy, and/or targeted therapy, and often a combination of these approaches. Over the last few decades, the use of monoclonal antibodies (which is a form of immunotherapy) such as the blockbuster, immune checkpoint inhibitors have shown real success in patients, though even these don’t induce an anti-tumour response in all patients. Future therapies will be combinational therapies, combining the checkpoint inhibitors with technologies such as those being developed by Scancell.

What is immunotherapy? Essentially it is a type of treatment that helps to stimulate the immune system to fight cancer or other diseases more effectively. It is an increasingly popular treatment option that has shown promising results in many cases. There are several different types of immunotherapy, each with its own pros and cons.

One of the most common types of immunotherapy is monoclonal antibody therapy, which involves the use of artificial antibodies to target specific proteins or cells in the body. This type of therapy can be very effective in treating some types of cancer, but it can also have significant side effects, such as allergic reactions and infusion reactions. 

Another type of immunotherapy is cancer vaccines, which are designed to stimulate the immune system to attack cancer cells. These vaccines are still being developed and tested, and they have shown some promising results in clinical trials. However, they are not yet widely available, and more research is needed to determine their long-term effectiveness. 

Other types of immunotherapy include adoptive cell transfer, which involves the transfer of immune cells from the patient to the laboratory, where they are modified to recognise and attack cancer cells, and checkpoint inhibitors, these drugs block proteins that cancer cells use to evade the immune system. By blocking these proteins, checkpoint inhibitors can help to improve the ability of the immune system to recognise and attack cancer cells.

Classification of immuno-oncology agents used in cancer treatment. (Source; doi:10.1136/ jitc-2021-003231)

Overall, immunotherapy has the potential to be an effective treatment option for many types of cancer and other diseases, but it is still a relatively new field, and more research is needed to fully understand its risks and benefits.

Cancer Immunology

A key requirement of the immune system is to be able to distinguish between self and non self. It is able to do this through the use of self-markers, which are proteins or other molecules that are expressed on the surface of cells and tissues. These self-markers serve as a sort of “identity card” for the body’s cells, allowing the immune system to distinguish them from foreign cells or substances.

These identity cards can be major histocompatibility complex (MHC) molecules which are expressed on the surface of cells. MHC molecules present pieces of proteins from inside the cell to immune cells called T cells. T cells are able to recognise the MHC-presented protein as either self or non-self based on its sequence. If the protein is recognised as non-self, the immune system will mount an immune response against the cell expressing the non-self protein. Another mechanism that helps the immune system recognise self from non-self is through the expression of self-antigens, which are proteins that are specific to an individual and are expressed on the surface of cells. The immune system can recognise self-antigens and differentiate them from non-self-antigens, which helps to prevent the immune system from attacking the body’s own cells.

Cells are continuously mutating into cancer cells but they are normally recognised by the immune system and destroyed but some evade recognition by the immune system and form tumours by several mechanisms:

Down regulation or loss of expression of MHC molecules: Tumour cells can down regulate the expression of MHC molecules on their surface, making them less visible to T cells and less likely to trigger an immune response.

Production of immunosuppressive molecules: Tumour cells can secrete immunosuppressive molecules such as TGF-beta and IL-10 that can inhibit the immune response and prevent the activation of immune cells such as T cells and natural killer (NK) cells.

Formation of an immunosuppressive microenvironment: The microenvironment surrounding the tumour can also be immunosuppressive, with the presence of immune cells such as regulatory T cells and myeloid-derived suppressor cells that can inhibit the immune response.

Hijacking of immune checkpoints: Tumour cells can also exploit immune checkpoint pathways to evade detection and attack by the immune system. Immune checkpoint pathways are regulatory pathways that help to prevent the immune system from attacking the body’s own cells.

These “cold tumours” tend to have a low mutational burden and a lower infiltration of immune cells. They also tend to express higher levels of immune checkpoint molecules, which can inhibit the immune response and prevent the activation of immune cells.

“Hot tumours”, on the other hand, tend to have a higher mutational burden, which means that they have a larger number of genetic mutations that can be recognised as non-self by the immune system. They also tend to have a higher infiltration of immune cells, including T cells and natural killer (NK) cells. In addition, hot tumours tend to express lower levels of immune checkpoint molecules, which can allow the immune response to be activated. In immunotherapy it’s the goal to switch a tumour from cold to hot to achieve destruction of the tumour by the immune system.

Scancell has developed four proprietary technology platforms – viz. Moditope®, ImmunoBody®, GlyMab™ and AvidiMab® – that could potentially treat a whole range of cancers using immunotherapy. We briefly detail them in the following paragraphs – a more detailed explanation is provided in Appendix 1: Understanding the science behind Scancell’s platforms

1 – Moditope® – The first vaccine platform is called Moditope. Scancell currently has 2 Moditope vaccine candidates, which are, in the simplest form, multi-epitope peptide vaccines that aim to boost naturally accruing cancer specific CD4 T-cells to such a high level they have therapeutic potential.

One of the hallmarks of cancers is an altered metabolism, due to the uncontrolled growth and proliferation of cancer cells. For this, they require a constant source of energy and one way a cancer cell can meet this energy need is through autophagy, the process whereby proteins within a cell are broken down and recycled to provide energy. Cancer cells use 2 methods – citrullination and homocitrullination – which label proteins at specific locations and when these labelled proteins enter the autophagy pathway, to be broken down, the labelling changes the location within the protein where it will be digested, which produces cancer-specific epitopes or neoantigens. In the process of the protein being broken down into epitopes, some epitopes are loaded onto the major histocompatibility class II molecules (MCH-II) and presented on the cell surface. This should allow immune cells to recognise the tumour cells and target them for destruction. However, cancer cells under normal conditions have a down-regulated expression of the MHC-II molecules and therefore the cancer cells are not recognised by the immune system.

By using the Moditope vaccines, Scancell hopes to break the cycle of down-regulated MHC-II expression and immune cell avoidance. When Moditope vaccines are administered, the peptides will be taken up by antigen-presenting cells (APCs) and presented to CD4 T cells.  These CD4 T cells will then enter the tumour where they will again encounter the peptides expressed on the surface of APCs and, as a result, the CD4 T cells become activated and secrete interferon-gamma (IFNγ) which in turn induces the up-regulation of MHC class II on the cancer cells, making them visible to the CD4 T-cells which can then kill the cancer cells.

2 – ImmunoBody – Scancell’s ImmunoBody platform is a technology in which a DNA plasmid encodes a human antibody engineered to express tumour-specific epitopes (that are over-expressed by cancer cells), which can present the epitope to the immune system and train it to recognise (and thus kill) cancerous cells possessing these epitopes.

Antibodies are ideal vectors for carrying t-cell epitopes as they have a long half-life and can target APCs via their Fc receptors allowing efficient stimulation of both helper CD4 T-cells and killer CD8 T-cell responses. The helper CD4 T-cells overcome the immunosuppressive tumour environment and greatly increase the population of killer CD8 t-cells, which attack the tumour.

Scancell is developing two products using its ImmunoBody platform the SCIB1 and SCIB2. The ImmunoBody is designed to activate both CD4+ and CD8+ T-cells in two distinct ways: directly and via cross-presentation.

3 – Glymab – Scancell has two antibody platforms in development, GlyMab and AvidiMab. The first, GlyMab, are novel monoclonal antibodies (mAbs) that recognise glycans with high specificity and affinity.

Glycans are complex carbohydrates that are found on the surface of cells and play a variety of important roles in the body. They can be involved in processes such as cell-cell recognition, immune system function, and the development and progression of diseases.  There are several different types of glycans, and some of them have been the focus of research for the development of new therapies. For example, cancer cells often have abnormal glycans on their surface, and targeting these glycans with therapies such as monoclonal antibodies has shown promise as a potential cancer treatment.

Scancell currently has five lead anti-glycan mAbs within the GlyMab portfolio, that recognise and directly kill cancer cells. These mAbs also have multiple potential uses such as drug delivery, chimeric antigen receptor (CAR) T cells or redirected T cell killing.

4 – AvidiMab – is a technology platform acquired in 2018 from the University of Nottingham. AvidiMab antibodies have the potential for greater avidity – which improves the ability to kill cancerous cells. The AvidiMab technology can potentially be applied to any antibody-based therapy to enhance its efficacy and Scancell has already applied it to their ImmunoBody vaccine candidates (iSCIB1+ and iSCIB2) and its COVID-19 vaccine as well as its anti-glycan mAbs shown above, with proof of concept in preclinical studies.

OVERALL CANCER MARKET

The global oncology market was valued at US$ 286.04 billion in 2021 and is expected to reach over US$ 581.25 billion by 2030, growing at a CAGR of 8.2% from 2022 to 2030.

 (https://www.precedenceresearch.com)

(https://marketresearchcommunity.com)

DEVELOPMENT PIPELINE

Scancell R&D pipeline is comprised of 11 lead products, two from the Moditope platform, three from the ImmunoBody platform and 5 antibodies from the GlyMab platform. The company’s products are targeting cancers with unmet needs, except for COVIDITY. During the pandemic Scancell utilized its knowledge in vaccine design to produce, COVIDITY, a vaccine against SARS-CoV-2, the virus that causes COVID-19.

Scancell’s R&D pipeline (Source Scancell)

In 2022 Scancell announced that the first patient for a Phase 1 Modi-1 clinical trial (ModiFY) had been enrolled and dosed. The ModiFY study is a first-in-human clinical trial in patients with triple negative breast cancer, ovarian cancer, head and neck cancer, and renal cancer. In the trial, Modi-1 will be administered alone or in combination with checkpoint inhibitors (CPIs) in patients with head and neck, triple negative breast and renal tumours. This study will recruit up to 125 patients in up to 20 clinical trial sites across the UK to assess the safety.

SCIB1 is the most advanced product from the Scancell’s ImmunoBody platform, a five-year survival and proof of concept Phase 1/2 clinical trial has already been completed, with 14 out of 16 patients (89%) surviving for more than the 5 years following vaccination. A new phase 2 trial is now underway at multiple centres in the UK, the trial will include a cohort of melanoma patients who will receive SCIB1 plus checkpoint inhibitors. The updated protocol also allows all patients to receive the SCIB1 vaccine as a needle-free injection. To date, SCIB1 has been delivered using electroporation to enhance the uptake and presentation of the DNA vaccine to the immune system and, although electroporation is a proven delivery method, Scancell believes that needle-free injection could provide enhanced patient acceptance. Scancell is currently using PharmaJet Needle-Free Injector Systems in its COVIDITY trial being carried out in South Africa.

SCIB2 Scancell’s second vaccine candidate from the ImmunoBody platform, for the treatment of patients with solid tumours and was due to be in a phase 1/2 clinical trial, funded and sponsored by Cancer Research UK, however due to the impact of the COVID-19 pandemic, Cancer Research UK reassessed their collaboration model and have ended their partnership with Scancell. Scancell will now explore their options to advance the programme either in house or with another partner.

COVIDITY is Scancell’s COVID-19 vaccine and in collaboration with University of Cape Town (UCT) Lung Institute in South Africa they are running a phase 1 trial. The objectives of the trial are to assess the safety and immunogenicity of COVIDITY, with study data expected to be available in H1 2023.

SCANCELL’S ADDRESSABLE MARKET OPPORTUNITY

As stated earlier, the overall cancer immuno-therapy market was estimated at $86bn in annual revenues in CY2021 – forecast to increase to $272bn by CY2030 – a 13.6% CAGR – substantially ahead of the 8.2% CAGR for the overall oncology market.  From a financial perspective, one of the factors with the greatest appeal is the wide number of solid cancers the company could potentially address across its 4 platforms – over 10 – ranging from head and neck cancer, to triple negative breast cancer, colorectal cancer, renal cancer, ovarian cancer, malignant melanoma, non-small cell lung cancer, prostate cancer, bladder cancer, pancreatic cancer, small cell lung cancer, et al. If one considers the incidence rate of these various indications across just 7 key markets – the United States, United Kingdom, France, Germany, Switzerland, Australia and Japan – and after appropriately adjusting for expression rate, diagnosis rate, compliance rate, the addressable patient population is between 550,000 – 600,000 patients (across these 7 markets). Translating this into a revenue opportunity depends on the mode of treatment elected – for instance chemotherapy and radiation is much cheaper than using check point inhibitors and antibody drug conjugates. Our revenue estimates have been built up by indication with estimates for the United States, versus other markets.

To illustrate an example, we estimate the revenue opportunity for Modi-1 alone would be around $9bn in annual revenue (across the 4 indications of head and neck cancer, triple negative breast cancer, renal cancer and ovarian cancer). Depending on the market share assumed – every 10-percentage point market share equates to $900m in annual revenue – just on the Modi 1 platform alone. As stated in the investment summary, we think there is potential (if all ducks line up) for the peak annual revenue opportunity (across platforms / indications) to be around US$12 bn.  From an opportunity perspective, the biggest value drivers are Modi – 1 and Modi – 2, given that they target so many indications, followed by the mAbs (SC129, SC134, SC88 and SC27). Both Modi – 1 and Modi – 2 could potentially deliver $3bn in peak annual revenues, if all goes well. Adjusted with even a 10% chance of success, this implies around $600m – more than 3x the current market capitalization of the company.

Source: Vulpes

PATENTS GRANTED / PENDING – BUTTRESS COMPETITIVE POSITIONING

Despite the company’s modest scale of operations (thus far) it has a fairly wide patent portfolio. The key patents which have either been granted, or are pending, are detailed in the table below.

COMPETITIVE LANDSCAPE

Immuno-oncology is an emerging field that has developed in great strides in the fight against cancer, bolstered by a refined understanding of how tumours evade the natural immune response and the discovery of checkpoint inhibitors there has been an increased imputes. Leading immuno-oncology researchers are leveraging next-generation sequencing (NGS) to study immunotherapy response factors, discover biomarkers, and apply genomics to personalised immunotherapy.

Scancell has many competitors in the oncology vaccine field ranging from the likes of BioNTech, CureVac and Moderna who are utilising their mRNA platforms for the expression of neoantigens to the numerous small biotech companies each with their own unique platforms. One thing that sets Scancell apart from the rest is that they have three different platforms, to create vaccines and monoclonal antibodies against glycans.

There are numerous companies developing anti-glycan antibodies, in every stage of development, how Scancell differentiates is the number of different glycan molecules they are targeting, opening up the opportunity to many licensing deals.  

We put together a list of companies that we believe are some of Scancell’s biggest competitors, though there are likely more, in the oncology vaccine field and companies producing anti-glycan antibodies for oncology therapy. 

Companies working on anti-cancer vaccines

OncoPep founded in 2010 are developing PVX-410, a multi-peptide vaccine that targets multiple tumour-associated antigens and is currently in a Phase 2 clinical trial for triple-negative breast cancer.

Curevac, BioNTech and Moderna Therapeutics all three mRNA companies are leaders in their field and two are now almost household names, after the pandemic. All three are focusing on the future and the development of cancer vaccines using their RNA technology platforms to express neoantigens.

Inovio Pharmaceuticals vaccines are DNA plasmids encoding for cancer specific epitopes, delivered intramuscularly by needle fee technology. The companies’ lead therapies are targeting HPV cancers and are currently in phase 3 clinical trials. 

Hubro Therapeutics is a private company developing therapeutic and prophylactic cancer vaccines. Their lead vaccine candidate, FMPV-1 targets frameshift mutation in the transforming growth factor β receptor 2 gene (TGFβR2) and is currently in phase 1 clinical trials. Frameshift mutant TGFβR2 is present in 44% of Microsatellite instability (MSI) related cancers and particularly in more than 77% of MSI-H colorectal cancer and 80% of MSI-H gastric cancer.

BrightPath Biotherapeutics, lead vaccine GRN-1201 is a novel cancer peptide vaccine and targets four novel tumour-associated antigens that are shared across major cancer types. The peptides of GRN-1201 are restricted to HLA-A2, which includes approximately 50% of the populations of the USA and Europe, as well as 40% of the population of JP. An open-label phase I clinical study on melanoma and a phase II clinical study in combination with an immune checkpoint inhibitor on non-small cell lung cancer are ongoing in the USA.

Achilles Therapeutics plc is developing precision T-cell therapies that target clonal neoantigens, they utilise the neoantigens to stimulate T-cells Ex Vivo. With their two lead products Chiron for advanced small cell lung cancer and Thetis for melanoma are both in place 1/2 clinical trials.

Geneos Therapeutics are using personalised therapeutic cancer vaccines (PTCV), their vaccine consists of a DNA plasmid that can target 80+ neoantigens in the same patient specific formulation. Their lead vaccine, GT-30, is currently in phase 2 clinical trials for Hepatocellular Carcinoma. 

Gritstone bio, their lead oncology product candidate, GRANITE, is an individualised neoantigen-based immunotherapy. It is being evaluated in multiple studies, including a Phase 2/3 study evaluating GRANITE as a maintenance treatment in patients with newly diagnosed, metastatic microsatellite-stable colorectal cancer (MSS-CRC) who have completed FOLFOX- bevacizumab induction therapy.

Sellas Life Sciences Group lead peptide vaccine, Galinpepimut-S (GPS), is an immunotherapeutic which targets the Wilms Tumour 1 (WT1) protein which is present and over-expressed in an array of haematological malignancies and solid tumours and is currently in a phase 3 clinical trial for Acute Myeloid Leukemia and phase 2 clinical trials for Malignant Pleural Mesothelioma, Multiple Myeloma, and Ovarian cancer.

ISA Pharmaceuticals B.V. platform is based on Synthetic Long Peptides (SLP®) combined with AMPLIVANT® which comprises a proprietary and synthetic Toll-Like Receptor (TLR)1/2 ligand to enhance immune-stimulatory activity. The companies lead vaccine ISA101 consists of 12 synthetic long peptides (25 to 35 amino acids long) derived from the E6 and E7 oncogenic proteins of the HPV 16 virus, a strain responsible for over 50% of human cervical cancers and cervical intra-epithelial neoplasias, more than 85% of HPV-positive head and neck cancers and is in a phase 2 clinical trial. The companies has several vaccine candidates under investigation for multiple cancers.

Ultimovacs ASA lead vaccine, UV1, consists of three long synthetic peptides, representing 60 amino acids of the reverse transcriptase subunit of human telomerase (hTERT). The UV1 peptides contain several CD4 and CD8 epitopes, shown to be promiscuous in terms of Human Leukocyte Antigen (HLA) allele type for presentation and is five phase 2 studies in five different indications.

Sumitomo Pharma Oncology lead cancer vaccine Ombipepimut-S Emulsion (DSP-7888) contains 2 peptides that induce WT1-specific cytotoxic T lymphocytes (WT1-CTLs) and helper T cells to attack WT1-expressing cancerous cells found in various types of hematologic malignancies and solid tumours and is currently in a phase 1/2 clinical trial.

Ose-immuno most advanced product, Tedopi®, a therapeutic neoepitope-based vaccine, is a proprietary combination of nine optimised neoepitopes, selected and optimised from 5 tumoral antigens to activate specifically T-cells, plus one epitope giving universal helper T-cell response targeting T -cell activation. A phase 3 clinical study has been completed for NSCLC.

Invectys Inc lead vaccine VS-2001 is a DNA vaccine targeting cancer human telomerase complex (named hTERT) which is over expressed in 90% of human tumours, but is virtually absent from normal cells. VS-2001 completed its Phase I trial in various advanced cancer indications in June 2018, demonstrating satisfying safety and immune responses.

RhoVac AB is developing an antigen-based cancer therapy, RV001, that is designed specifically for preventing or eliminating metastatic cancer cells, irrespective of cancer type. The peptide vaccine target is RhoC expressed in all metastatic cancer and is currently in phase 2 clinical trials.

Nykode Theraputics is developing a DNA plasmid vaccine platform named Vaccibody™. The DNA is delivered by needle-free jet injector into the muscle cells. The newly encoded Vaccibody™ proteins are then secreted from the cells and target and recruit the APC. The Vaccibody™ protein may bridge and APC and a B cell and thus form an APC-B cell synapse, which may lead to rapid and strong B cell activation responsible for mediating the production of antigen-specific antibodies. Their lead product VB10.16 is currently in phase 2 clinical trials for HPV16 cervical cancer, they also have a vaccine, VB10.NEO, in phase 2 clinical trials that encodes neoantigens for Melanoma, lung, bladder, renal, head & neck cancer, developed in collaboration with Genentech.

ImmunityBio are using a Human adenovirus 5 (hAd5) vaccine vector to deliver neoantigens to the immune system to activate CD4+ and CD8+ T cells, along with antibody (humoral) responses. Their hAd5 technology has produced several product candidates that have been studied in Phase 1 and 2 clinical trials as potential vaccines for certain cancers; these candidates have shown an ability to overcome previous adenovirus immunity in cancer patients and preclinical models.

Evaxion Biotech A/S has three cancer vaccines in its portfolio. The first EVX-01 is peptide-based for the treatment of a variety of metastatic and unresectable melanomas. Evaxion is now conducting a large phase 2b clinical trial with this candidate. EVX-02 is a DNA-based cancer therapy intended for the adjuvant treatment of patients with advanced resectable melanoma. EVX-02 is currently being investigated in a phase 1/2a clinical trial. EVX-03 is an DNA-based cancer therapy, intended for the treatment of non-small cell lung cancer (NSCLC). Evaxion is expecting to conduct a clinical trial phase 1/2a in NSCLC.

Companies working on anti-Glycan antibodies

Glycotope GmbH a private company founded in 2008 and aims to develop tumour-specific monoclonal anti-glycan antibodies. Their pipeline costs of 6 antibodies which are all in pre-clinical development, their lead product is GT-001 which targets the tumour-associated LewisY (LeY, CD174), GT-001 binds to a high percentage of breast cancers non-small cell lung cancer, colorectal cancer, head and neck cancer, small cell lung cancer and ovarian cancer patient samples. Their second product, GT-002 is an IgG1 mAb targeting LYPD3 (C4.4A), LYPD3 is expressed in various cancer indications with high medical need, including squamous cell carcinoma of the head and neck (HNSCC). They recently spun-off their services business, FyoniBio GmbH, and are now entirely focused on drug discovery and development. They have partnerships with Byondis B.V, LegoChemBio and a licence agreement with Daiichi Sankyo.

Y-mAbs Therapeutic, founded in 2015 is focused on immunotherapies, radio immunotherapies, and companion diagnostics. Their lead product Naxitamab has FDA approval and is a mAb that can bind the tumour target glycan GD2, which is abundantly found on neuroblastoma and other related tumours.

Bristol-Myers Squibb is developing a monoclonal antibody, BMS-986012, targeting fucosyl-GM1, and is currently in phase 2 clinical trials for Small Cell Lung Cancer.

OBI Pharma was founded in 2002. Their lead antibody, OBI-999, targets Globo H which is highly expressed in various types of cancer, such as breast, prostate, and lung. OBI-999 was granted Orphan Drug Designation (ODD) for its use in gastric cancer in January 2020 and is currently in a Phase I dose-escalation study. OBI Pharma also have a vaccine, OBI-866, targeting SSEA-4, a tumour-associated carbohydrate antigen highly expressed in many cancers that is currently in a phase 1 dose escalation study.

BioNTech in 2019 acquired MabVax Therapeutics, and with it they got the antibody MVT-5873, now called BNT-321, which targets the Lewisa antigen. It is under development for the treatment of metastatic adenocarcinoma of the pancreas, cholangiocarcinoma, pancreatic ductal adenocarcinoma, and metastatic colorectal cancer and is currently in phase 2 clinical trials.

Recepta Biopharma founded in 2006 has an anti-glycan antibody portfolio consist of RebmAb100 which recognises the LewisY antigen. LewisY has a pronounced expression in tumour tissues, especially in epithelial carcinomas, when compared to its expression in non-tumour tissues. Phase I clinical trials in patients with ovarian and breast and Colorectal cancer were completed in 2022. They have two other anti-glycan antibodies in development, RebmAb300 targeting LewisB antigen expressed on several types of carcinomas of epithelial origin, such as colorectal, lung, ovary, and breast, among others and RebmAb400 targeting A34, a glycoprotein belonging to the family of adherent junction molecules. Its expression is particularly high in gastric and oesophageal adenocarcinomas.

Tacalyx a private company founded in 2019, and raised €7m seed funding in 2019, develops therapeutics targeting cancer-specific carbohydrate antigens on the surface of metastatic malignant tumours where no satisfactory treatments exist. Currently there isn’t any information publicly available on their pipeline.

GlykoGen a private company founded in 2016 aims to develop high-affinity class-switched (IgG) antibodies targeting carbohydrates found on the surface of cancerous cells. Currently there isn’t any information publicly available on their pipeline.

Ihp Therapeutics a private company founded in 2020 is a drug discovery company targeting difficult to treat diseases with limited therapeutic options. They have an anti-glycan antibody in preclinical studies, IHP-101, which targets Sialyl Lewis4 that is over expressed on tumours.

Wyeth started a phase 1 clinical study in 2020 for their antibody, CMD-193, targeting the LewisY antigen, for the treatment of Neoplasms, however it was terminated due to abnormal distribution and lack of tumour targeting.

GlycoNex founded in 2001 is focused on anti-glycan antibody development. Their lead antibody GNX102, targets the LewisY antigen and they received IND from US FDA. Their first-in-human phase 1 clinical trial started in 2020.

Palleon Pharmaceuticals was founded in 2016 and has raised over $140m. Palleon’s lead program, E-602, is a first-in-class engineered genetic fusion of human sialidase with a monoclonal antibody. E-602 is designed to desialylate both immune cells and tumour cells, which could remove immune evasion of the cancer. It is currently in Phase 1 clinical studies.

BOARD OF DIRECTORS AND SENIOR MANAGEMENT TEAM

Chairman – Dr Jean-Michel Cosséry

Scancell recently announced the appointment of Dr Jean-Michel Cosséry as Non-Executive Chairman of the Board. Dr. Cosséry replaces Dr John Chiplin who announced in October 2022, for personal reasons, his intention to step down as Executive Chairman and Non-Executive Director. Dr. Cosséry has over 25 years of experience in the pharmaceutical and biotechnology industries and has held several senior management roles at Eli Lilly and GE Healthcare. Additionally, he has served on the boards of various companies such as Kymab (acquired by Sanofi) and Immunocore. At present he is on the boards of Malin PLC, Exact Therapeutics AS, Eracal Therapeutics, and Sophia Genetics SA.

Chief Executive Officer, Chief Scientific Officer – Professor Lindy Durrant

Professor Durrant is an internationally recognised immunologist in the field of tumour therapy and co-founder of Scancell. She has worked for over 25 years in translational research, developing products for clinical trials including monoclonal antibodies and cancer vaccines. She has a personal Chair in Cancer Immunotherapy in the Department of Clinical Oncology at the University of Nottingham.

Chief Development Officer – Dr. Sally Adams

Dr. Adams has worked on many complex projects over the past 25 years including anti-infective vaccines and cancer immunotherapies. She has previously held Development Director positions in life science companies and, prior to her appointment as Development Director at Scancell, she worked as a development consultant to Scancell providing guidance on the development of SCIB1.

Non-Executive Director – Mr. Martin Diggle Mr. Diggle is a founder, director and partner of Vulpes Investment Management, which manages a number of funds including the Vulpes Life Sciences Fund.

He has over 30 years’ experience in investment banking and fund management and has been an investor in life sciences and biotech for nearly 20 years. His other directorships are Oxford Biomedica plc, Proteome Sciences plc, Chronos Therapeutics Limited, Oxford Endovascular and Leucid Bio.

Non-Executive Director – Dr. Ursula Ney

Dr. Ney has over thirty years’ experience in the pharmaceutical and biotechnology industry, including twenty years in senior leadership roles that also encompassed Executive and Non-Executive Board positions. She has broad experience of biologic and small molecule drug development across a range of therapeutic areas having been Director of Drug Development and on the Board of Celltech plc and later Chief Operating Officer and Executive Director of Antisoma plc. Most recently, she was Chief Executive Officer of Genkyotex SA. She was a on the board of Discuva Ltd and is currently a Non-Executive Director of Proteome Sciences plc and a member of the Board of Governors of the University of Plymouth.

Non-Executive Director – Susan Clement Davies

Ms. Davies is an experienced life sciences financier with over 25 years of capital markets and investment banking experience, including Managing Director of Equity Capital Markets at Citigroup Global Markets Limited/Salomon Smith Barney and most recently until 2018, Managing Director at Torreya Partners. She is currently Non-Executive Director of MiNA Therapeutics, Non-Executive Director of Exploristics and Non-Executive Director and Chair of the Audit Committee of Evgen Pharma plc, Advisor at Oxford Science Enterprises and Member of the CW+ NHS Hospital Innovation Advisory Board. Ms. Davies has a BSc in Economics from University College London and a MSc in Economics from the London School of Economics.

Director of Finance & Admin, Company Secretary – Keith Green

Mr. Green trained and qualified as a chartered accountant with Peat Marwick (now KPMG). He has taken on many consultancy and interim finance roles for private and AIM listed companies in the life sciences sector. He started working for Scancell on a part-time basis in January 2010 and took up a full-time role in September 2016.

Medical Director – Dr. Robert Miller

Dr. Miller has over 32 years of experience in drug development. He has worked in the pharmaceutical industry for Zeneca (now AstraZeneca) and Protodigm. Robert was a founding member of the consultancy Fulcrum Pharma Developments and worked as Chief Medical Officer until its merger and subsequent sale to ICON. He is a founder and managing partner of the drug development consultancy Artemida Pharma Ltd. As a consultant, he has acted as Chief Medical Officer/Medical Director for several companies especially in the oncology and immuno-oncology field. He trained and worked as a cardiothoracic surgeon at the London Hospital Medical College before moving into the pharmaceutical industry. He is a Fellow of the Royal College of Surgeons and Fellow of the Faculty of Pharmaceutical Medicine and Royal Society of Medicine.

Head of Translational Research – Dr. Samantha Paston

Dr. Paston joined Scancell from Immunocore where she held several positions including Head of T Cell Cloning and Group Leader. While at Immunocore, she was responsible for the generation of the in-house T cell cloning method and biological molecule discovery which made significant contributions to the current Immunocore oncology pipeline. Prior to this, she held several positions at Medigene, Avidex, NIBSC and GSK. She holds a PhD from University College London in Immunology/Haematology, following an BSc Honours Degree in Microbiology from the University of Sheffield.

Head of Manufacturing – Dr Adrian Parry

Dr. Parry joined Scancell from Mereo BioPharma where he was Head of Small Molecule CMC (Chemistry, Manufacturing and Controls), managing outsourced GMP manufacturing activities. Prior to this, he was New Product Development Director at Juniper Pharmaceuticals and has previously held further CMC positions at Circassia, Shire Pharmaceuticals, Prosidion, Evotec and OSI Pharmaceuticals, totalling 20 years of development expertise including the delivery of multiple, complex GMP drug products. He holds a PhD in Physical Organic/Analytical Chemistry from The Open University, following a MSc in Advanced Analytical Chemistry from the University of Bristol.

Head of Quality – Akua Asare

Ms. Asare joined Scancell in 2020 to implement the Company’s Quality Management System, ensuring that trial participants and data are safeguarded in compliance with global regulatory requirements. She has nearly 20 years of operational experience within contract research organisations, pharmaceutical and biotech businesses, including Gilead Sciences and Bionical Emas.

Head of Clinical Operations – Fayaz Master

Mr. Master joined Scancell from Allergy Therapeutics where he was the Head of Clinical Development, responsible for the clinical development of a mosaic virus-like particle. Prior to this he held senior oncology Clinical Development/Operation roles at ClinMed and BTG, a UK based specialty pharmaceutical company. He led the clinical operations team responsible for generating clinical evidence for TheraSphere, a radioembolisation therapy in patients with primary and metastatic colorectal cancer. Mr. Master has just under 20 years of clinical operations experience in early and late-stage global oncology clinical development.

FINANCIAL STATEMENTS

• Scancell is a pre-revenue early-stage biotechnology company and thus there is little to highlight from a revenue perspective.
• From an expense perspective, the company’s overall expense for FY2023 is forecast at around £18m (including interest expense), whilst FY2024 expenses are forecast at around £20m.
• The balance sheet had £24m cash as at Oct’22
• We expect that Scancell’s convertibles of £19.6m will either be converted, or rolled forward.
• We provide historical financials for data, rather than analytical, purposes

Scancell Ltd: Profit and Loss Statement, FY ended 30 April, Currency £ ‘000

Source: Company

Scancell Ltd: Balance sheet, FY ended 30 April, Currency £ ‘000

Source: Company

Scancell Ltd: Cash Flow Statement, FY ended 30 April, Currency £ ‘000

Source: Company

Scancell Ltd: Half yearly Profit and Loss Statement, and cash levels, Currency £ ‘000

Source: Company

APPENDIX 1: UNDERSTANDING THE SCIENCE BEHIND SCANCELL’S PLATFORMS

1 – Moditope

The Moditope vaccines are in the simplest form, multi-epitope peptide vaccines that aim to boost naturally accruing cancer specific CD4 T-cells to such a high level they have therapeutic potential. Scancell has two Moditope vaccine candidates in development that have been designed to take advantage of two similar cellular pathways that both generate stress-induced post-translational modifications (SIPTMs) to proteins and ultimately cancer-specific peptides, which are now commonly referred to as neoantigens, that CD4 T-cells can recognise. Why Scancell may succeed where others have failed is their discovery and use of these specific neoantigens in their vaccines.

Meditope mechanism of action (Source: Scancell)

Cancer, Citrullination and Homocitrullination

One of the hallmarks of cancers is an altered metabolism, due to the uncontrolled growth and proliferation of cancer cells they require a constant source of energy and one way a cancer cell can meet this energy need is through autophagy, this is the process where proteins within a cell are broken down and recycled to provide energy.

Autophagy Processes (Source: https://theconversation.com)

Scancell has shown that cancer cells up-regulate two pathways, citrullination and homocitrullination. Both of these pathways label proteins at specific locations and when these labelled proteins enter the Autophagy pathway, to be broken down, the labelling changes the location within the protein where it will be digested, which produces cancer-specific epitopes or neoantigens. In the process of the protein being broken down, into epitopes, some epitopes are loaded onto the major histocompatibility class II molecules (MCH-II) and presented on the cell surface. This should allow immune cells to recognise the tumour cells and target them for destruction, though cancer cells under normal conditions have down-regulated expression of the MHC-II molecules and therefore the cancer cells won’t be recognised by the immune system.

Moditope mechanism of action

By using the Moditope vaccines, Scancell hopes to break the cycle of down-regulated MHC-II expression and immune cell avoidance. When Moditope vaccines are administered, the peptides will be taken up by antigen-presenting cells (APCs) and presented to CD4 T cells.  These CD4 T cells will then enter the tumour where they will again encounter the peptides expressed on the surface of APCs and, as a result, the CD4 T cells become activated and secrete interferon-gamma (IFNγ) which in turn induces the up-regulation of MHC class II on the cancer cells, making them visible to the CD4 T-cells which can then kill the cancer cells.

Modi-1

The Modi-1 peptides are generated within cancer cells by the process of citrullination.  Citrullination is the enzymatic conversion of positively charged arginine residues to a polar but neutral citrulline, by the enzyme peptidyl arginine deaminases (PAD) in a Ca2+-dependent manner.

Under physiological conditions, the intracellular cytosolic calcium concentrations are around 100-fold lower than that required for PAD activity, however, under pathological conditions PAD enzymes become active with high calcium concentrations being present in the autophagy pathway. This change in the overall charge of the protein, due to citrullination, can result in the destabilisation of the protein and modification of protease cleavage sites, altering the peptide repertoire presented by antigen-presenting cells (APCs). A beneficial feature of using citrullinated peptides as vaccines is that inflammatory cytokines have been shown to induce citrullination creating a positive feedback loop.

Mod-1 cancer vaccine consists of a combination of three citrullinated peptides from two different proteins. The first protein vimentin is a major constituent of the intermediate filament family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Vimentin is over-expression in various epithelial cancers, including prostate cancer, gastrointestinal tumours, breast cancer, malignant melanoma, and lung cancer. Vimentin’s over-expression in cancer correlates well with accelerated tumour growth, invasion, and poor prognosis. Due to its over-expression in cancer and its association with tumour growth and metastasis, vimentin serves as an attractive potential target for cancer therapy. The second target protein is the metalloenzyme α-enolase, which is involved in the process of glycolysis. Many tumours tend to favour metabolism via glycolysis even in normal oxygen conditions. The α-enolase enzyme mediates this metabolic process and plays an important role in the process of cancer development, it is over-expressed in a variety of cancers.

On their own peptide vaccines fail to induce a strong T-cell response; to overcome this Scancell has conjugated each peptide to a toll-like receptor agonist (AMPLIVANT®), which acts as an adjuvant, allowing lower dosing at higher efficacy, through better dendritic cell antigen processing and presentation as well as enhanced T cell priming. Scancell has entered into a worldwide licensing and collaboration agreement with ISA Pharmaceuticals (Leiden, the Netherlands) to use the AMPLIVANT® adjuvant technology for the development and commercialisation of Modi-1. Preclinical data demonstrates that conjugation of the citrullinated Modi-1 peptides to AMPLIVANT® enhances anti-tumour immune responses and results in highly efficient tumour eradication, including protection against tumour re-challenge.

In Vivo preclinical study using the B16 tumours expressing HLA-DR4 under the control of an IFNγ inducible promoter in HLA-DR4 transgenic mice, Scancell show the survival of the mice against the aggressive tumour model up to 50 days after the mice receive a single immunisation. Modi-1 provided 100% protection in the mice and the single citrullinated peptide of either α-enolase or vimentin still achieved a quite remarkable 90 and 80% survival.  This data demonstrates that Mod-1 can mediate a potent anti-tumour response through CD4 T-cells against citrullinated epitopes on tumour cells and combining two citrullinated vimentin peptides with a citrullinated enolase peptide should also minimize tumour escape.

Modi-1 vaccinated mice (Source: Scancell)

Modi-1 is currently in a proof-of-concept clinical trial in humans, designed to explore the safety and immunological activity of Modi-1 via a dose escalation study across four tumour types. The preliminary efficacy of the vaccine in patients with solid tumours, including those with advanced head and neck, ovarian, triple-negative breast and renal carcinomas. Modi-1 will be administered as a combination therapy with checkpoint inhibitors, such as anti-PD1, in patients with head and neck, triple-negative breast or renal tumours. With Efficacy data anticipated during 2023/24.

Modi-1 in Phase 1/2 trial (Source: Scancell)

Modi-2

The second asset of the Moditope platform is Modi-2 which utilises, a slightly different post-translational modification pathway to Modi-1, homocitrullination occurs via a process known as carbamylation, leading to a change in the molecular charge of a protein and as with citrullination this leads to change in protease digestion and the generation of unique CD4 T-cell activating epitopes.

Scancell has identified homocitrullinated epitopes derived from the proteins -vimentin, aldolase, cytokeratin 8 and immunoglobulin binding protein (BiP), which have been shown to generate potent a CD4 T-cell response in preclinical models across a wide range of cancer types.

As with Modi-1, Modi-2 requires an adjuvant to make a strong immune response and this time Scancell has licensed a novel technology called SNAPvax from Vaccitech to boost Modi-2. The SNAPvax technology makes peptides form virus-like particles, which are also conjugated to a TL7/8a adjuvant, this powerful technology will promote strong T-cell responses.

SNAPvac technology (Source: Scancell)

Modi-2 vaccinated mice (Source: Scancell)

Initial preclinical results look promising, using 4T1 tumour cells in Balb/c mice, Scancell shows that over 70% of animals immunized with the Modi-2 SNAPvax particles, 4 days post tumour implant, survive, compared with 20% of unvaccinated mice. The use of SNAPvac could lead to a potentially superior therapeutic vaccine candidate and Scancell aims to initiate a Phase 1 clinical study in cancer patients in 2023.

ImmunoBody vaccine design (Source: Scancell)

2 – ImmunoBody

Scancell’s ImmunoBody technology is a DNA plasmid that encodes a human antibody engineered to express tumour-specific epitopes that are over-expressed by cancer cells, which can present the epitope to the immune system. Antibodies are ideal vectors for carrying t-cell epitopes as they have a long half-life and can target APCs via their Fc receptors allowing efficient stimulation of both helper CD4 T-cells and killer CD8 T-cell responses. The helper CD4 T-cells overcome the immunosuppressive tumour environment and greatly increase the population of killer CD8 t-cells, which attack the tumour. Scancell is developing two products using its ImmunoBody platform the SCIB1 and SCIB2.

ImmunoBody mechanism of action

The ImmunoBody is designed to activate both CD4+ and CD8+ T-cells in two distinct ways: directly and via cross-presentation.

The direct presentation pathway sees the ImmunoBody DNA transfecting directly into antigen-presenting cells (APCs). The ImmunoBody DNA is then transcribed and translated and the antibody is synthesised within the APC. The tumour-specific epitopes within the antibody are then presented on the external surface of the APC by MHC-I and MHCII molecules. When a T-cell interacts with an MHC presenting the tumour epitope, the T-cell is subsequently activated and an anti-tumour response is initiated. Due to the highly immunosuppressive tumour microenvironment, the direct presentation alone is not enough to generate the high T-cell avidity necessary for the desired anti-tumour effect.

ImmunoBody Mechanism of action (Source: Scancell)

Scancell’s ImmunoBody platform also leverages the cross-presentation pathway, where ImmunoBody antibodies are synthesised in other cell types such as smooth muscle. The antibody is secreted and then binds to the APCs via the Fc-binding CD64 receptor. Once internalised, the antibody is degraded and the tumour-specific epitopes are again presented by MHC-I and MHC-II molecules in the same way as the direct presentation pathway. Although on their own, the direct and the cross-presentation pathways result in an immune response of low T-cell potency, it is ImmunoBody’s ability to synergise two distinct T-cell activation pathways which allows ImmunoBody to produce a powerful CD4+ and CD8+ T-cell response.

SCIB1 Five-year survival data (Source: Scancell)

SCIB1& iSCIB1+

SCIB1 is Scancell’s lead candidate using the ImmunoBody platform and codes for two epitopes from TRP-2 and gp100 proteins which are found on malignant melanoma cells. Scancell initiated a phase I/2 trial of SCIB1 in malignant melanoma in July 2010 and later published promising five-year survival data in 2018. The trial enrolled 35 patients with stage III or IV disease (15 patients had tumours present and 20 had fully-resected disease at study entry). Stage III melanomas are tumours that have spread to regional lymph nodes.

SCIB1 was delivered using electroporation, which is a method of vaccine delivery that uses an electrical pulse to increase cell membrane permeability and help increase SCIB1 uptake into APCs. All patients received five injections of SCIB1 over 5.5 months. At the discretion of the investigator, patients could continue to receive SCIB1 at 3–6-month intervals. T. Patients were followed up for five years after the completion of the trial.

T-cell responses were seen in 90% of patients with no vaccine-related serious adverse events or dose-limiting toxicity. Overall, 18 of 20 stage III/IV melanoma patients with resected disease were alive at the time of reporting. In addition, of the 16 resected patients who received 2-4 mg doses of SCIB1, only six patients had a recurrence of their disease and only two recorded deaths. All 14 surviving patients in this group passed the five-year time point. The five-year overall survival was 87.5% and the recurrence-free survival is 62.5%, this shows vast improvement over standard care.

SCIB1 + Checkpoint Inhibitors

Scancell sees the potential of a synergistic approach by combining SCIB1 with checkpoint inhibitors, which have been highly successful as immunotherapy. As 60- 80% of melanoma patients treated with checkpoint inhibitors do not generate an anti-tumour response capable of ttumour suppression, SCIB1 in combination with the checkpoint inhibitors may induce a high enough immune response for tumour suppression in these non-responding patients.

In preclinical studies Scancell has already shown this synergy, HLA-DR4 mice with B16F1-DR4 tumours were vaccinated with SCIB1 resulted in the survival of 45% of mice and when combined with the checkpoint inhibitor PD1 antibody they showed an increase in survival to 85% and an enhanced number and proliferation of tumour infiltrating CD8 T-cells.

Following this successful preclinical result Scancell initiated a phase II study designed to assess SCIB1 in combination with either of the checkpoint inhibitors anti-PD-1, CTLA4 or PD-L1 in August 2019. The study is designed to investigate whether SCIB1 can show an improvement in the tumour response rate, progression-free survival, and overall survival in 25 patients with advanced inoperable melanoma. Patient recruitment has been impacted by the COVID-19 pandemic. Scancell expects to complete the study by 2024.

iSCIB1+ is the second-generation version of SCIB1 and includes the AvidiMab Fc region modification to increase vaccine efficacy and iSCIB1+ contains more immune-stimulating epitopes. The epitopes that were inserted into SCIB1 were HLA-A2 restricted which meant that only 40% of patients would be suitable for vaccination, with the incorporation of more tumour-specific epitopes that aren’t HLA-A2 restricted into iSCIB1+ increases the population that is available for vaccination and therefore increasing the market opportunity significantly.

In a preclinical study, Scancell vaccinated C57BI mice at 3-, 11- and 18-days post B16 tumour establishment with either iSCIB1+ or SCIB1 (no AvidiMab). The addition of the AvidiMab increased the survival of the mice to 50%.

SCIB2 & iSCIB2

iSCIB2 is the second cancer vaccine based on the ImmunoBody platform and encodes for the tumour antigen NY-ESO-1. Expression has been shown across several cancer types including synovial sarcomas, oesophageal, liver, gastric, prostate and lung cancers, with studies reporting that approximately 40% of cancer patients express this antigen. It is highly immunogenic and has the potential to generate the desired highly potent immune response. However, due to the tumour microenvironment being highly immunosuppressive, previous studies have failed to induce effective tumour control using this epitope.

Scancell utilising its ImmunoBody platform has shown in a mouse model that the first generation SCIB2 in HLA-A2/DR1 mice with B16F10 tumours increased survival to 40% and combining the checkpoint inhibitor antibody anti-PD-1 with iSCIB2 further increased survival to 100%. This second generation SCIB2 named iSCIB2 contains the addition of AvidiMab, further boost the efficacy of the vaccine.

Covidity

Scancell has utilised its ImmunoBody platform in a proof-of-concept study testing a vaccine against COVID-19. While it may never reach the market Scancell has been able to use the pandemic to its advantage, securing funding to show the significance of the novel Immunobody platform and AvidiMab Scancell designed a DNA vaccine encoding for antigens against the SARS-CoV-2 nucleocapsid (N) protein and spike (S) protein. The N protein is highly conserved amongst coronaviruses; therefore, the vaccine has the potential to generate protection against other variants of coronavirus. This Immunobody COVID vaccine has been named COVIDITY and encodes the AvidiMab sequence, to increase the killing potential of the vaccine. The first in human clinical study will explore the safety, tolerability and immunogenicity of COVIDITY when administered by needle free injection, by either the intrademeral or intramuscular route, participants will receive four doses of the vaccine. The phase1 clinical study is currently enrolling patients at a single centre in South Africa and is expected to be completed in H1 of 2023.

Antibodies

Scancell has two antibody platforms in development, GlyMab and AvidiMab. The first, GlyMab, are novel monoclonal antibodies (mAbs) that recognise glycans with high specificity and affinity. Scancell currently has five lead anti-glycan mAbs within the GlyMab portfolio, that recognise and directly kill cancer cells. These mAbs also have multiple potential uses such as drug delivery, chimeric antigen receptor (CAR) T cells or redirected T cell killing.

The second platform, AvidiMab, has briefly been mentioned before, Scancell has identified specific antibody modifications that enhance the avidity of target recognition technology and has been used to increase the direct killing ability of Scancell’s own anti-glycan mAb portfolio but also has the potential to enhance the efficacy of other mAbs or antibody-based therapies currently in development or available commercially.

3 – GlyMab

Glycans are complex carbohydrates that are found on the surface of cells and play a variety of important roles in the body. They can be involved in processes such as cell-cell recognition, immune system function, and the development and progression of diseases.  There are several different types of glycans, and some of them have been the focus of research for the development of new therapies. For example, cancer cells often have abnormal glycans on their surface, and targeting these glycans with therapies such as monoclonal antibodies has shown promise as a potential cancer treatment.

In the past this has been challenging to produce anti-glycan antibodies as they tended to have a low affinity or low specificity for their targets, resulting in off-target toxicity. However, Scancell has managed to overcome this limitation and is now able to produce high-affinity anti-glycan mAbs with direct killing properties. Scancell has five mAbs in preclinical development with four directly targeting different glycans expressed on tumour cells and one mAb targeting a checkpoint molecule present on T cells.

Scancell preclinical anti-glycan mAbs; SC129, SC134, SC2811 SC88 and SC27 target a range of different cancer types. The mAbs SC129, SC88 and SC27 target Lewis glycans. Lewis glycans are a type of carbohydrate that is found on the surface of cells and is involved in processes such as cell-cell recognition and immune system function. They are classified as “blood group” glycans because they are named after the Lewis blood group system, which is used to classify individuals based on the presence or absence of certain glycans on their red blood cells. They are ideal candidates for mAb therapy as they have a very limited distribution on normal tissues and are over-expressed on many carcinomas, including those of the colon, lung, breast, prostate and ovary and are essential co-accessory molecules for cell survival pathways. Blocking these pathways could lead to direct tumour cell killing.

Current GlyMab assets (Source: Scancell

SC129 is Scancell lead GlyMab candidate and it has already been licensed to Genmab, it targets sialyl-di-Lewis^a which is expressed on approximately 90% of pancreatic cancers, as well as on colorectal and gastric cancers at a high level. Scancell has shown that SC129, binds to its target and is internalised allowing delivery of a toxin and killing of the cancer cells at sub nanomolar concentrations. In a xenograft mouse model, the administration of SC129 resulted in effective tumour control.

SC134 targets the glycan, fucosyl GM1. Which is be expressed on as many as 90% of small-cell lung cancer cases. Scancell has shown that SC134 efficiently binds to its target in xenograft models, can deliver drugs specifically to cells with high expression of fucosyl GM1 and when linked with scFv fragment of a CD3 mAb it can bring in T-cells to engage the cancer cells, with preliminary data proving the concept and showing T-cell activation and direct tumour killing.

SC2811, targets glycolipid stage-specific embryonic antigen 4 (SSEA4), a glycan over-expressed in many cancers, however, Scancell has also shown that T-cells express SSEA4 and that SC2811 can stimulate T-cell proliferation and increase survival of mice with a tumour model to 40%.

SC88 targets Lewisacx expressed on 100% of colorectal tumours. The cell-based studies again showed highly specific target binding with little off-target effects making it an attractive candidate for ADC, CAR-T or T cell bi-specific development.

SC27 targets Lewis^y which is expressed on a broad range of tumours, with 55% colorectal, 86% gastric, 38% ovarian and 46% of breast cancer tissues shown to express this glycan. Preclinical studies have shown SC27 exhibits strong anti-tumour activity.

While each GlyMabTM mAb has its own set of characteristics and intricate details, the key common similarity across the panel how the mAbs appear to target their respective target glycans in a highly specific manner. This, combined with the selection of glycan targets whose expression is almost exclusively limited to tumour cells, makes the GlyMabTM platform a very good prospect for the development of new and innovative mAb-based therapies.

4 – AvidiMab

In the development of Scancell’s anti-glycan antibodies, they identified unique sequence residues found within the murine version of their mAbs in the Fc region that enable mAbs to self-associate upon target recognition, resulting in more potent, high avidity antibodies. Scancell transferred these murine residues to human Fc versions of the anti-glycan mAbs, which resulted in the promotion of non-covalent Fc-Fc interactions that enhanced the direct tumour cell-killing ability.

The AvidiMab technology can potentially be applied to any antibody-based therapy to enhance its efficacy and Scancell has already applied it to their ImmunoBody vaccine candidates (iSCIB1+ and iSCIB2) and its COVID-19 vaccine as well as its anti-glycan mAbs shown above, with proof of concept in preclinical studies.

AvidiMab antibody direct killing (Source: Scancell)

Overall strengths

Scancell has patent protection on the use of citrullination and homocitrullination peptides to be used as cancer vaccines (Modi-1/2) this alone makes then unique as they have identified a pathway and multiple epitopes, they are now combining the epitopes with the licensed SNAPvac to make, potentially, a more immunogenic and therefore better vaccine that has potential to make Scancell stand out from their competitors.

Though Scancell is a lean biotech, it certainly isn’t a one trick pony, in fact it could be argued that they have too many platform technologies, but sometimes strength is in numbers, and their Immunobody technology (SCIM1/2) is one of great interest. In contrast to cellular approaches such as chimeric antigen receptor transduced T-cells (CAR-T-cells) which are patient specific, costly, and time consuming to manufacture, Immunobody is rapid, inexpensive, and applicable to a wide range of patients. Different T-cell epitopes can be grafted into the engineered ImmunoBody antibody framework allowing rapid customization for different tumour types to produce a pipeline of therapeutic vaccines. ImmunoBody is suitable for use as monotherapy for early-stage cancers in order to eliminate micro-metastases, but also as combination therapy with a checkpoint inhibitor for late-stage disease.

Their GlyMab platform is more about the individual antibodies Scancell identifies and manages to prove their use case; these we imagine will be licensed off as and when the company has a data package suitable to convince pharma to take the risk, as Scancell has already managed to do with Genmab. The anti-glycan antibody field is relatively new and how Scancell select for high avidity antibodies is their ‘trade secret’. 

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All information, estimates, forecasts and opinions included in this document may be subject to change without notice. Changes in market conditions or in any assumptions may have a material impact on any estimates or opinion stated. In any event, past performance is no guarantee of future results, and future results may not meet expectations due to a variety of economic, market and other factors. Any information relating to past performance, or any future forecast based on past performance or other assumptions, is not necessarily a reliable indicator of future results. If the Information has been distributed by electronic transmission, such as e-mail, then such transmission cannot be guaranteed to be secure or error-free as information could be intercepted, corrupted, lost, destroyed, arrive late or incomplete, or contain viruses. The sender therefore does not accept liability for any errors or omissions in the contents of the Information, which may arise as a result of electronic transmission. The Information is not directed to, or intended for distribution to or use by, any person or entity who is a citizen or resident of or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation. Without prejudice to the foregoing, the reader is to note that additional disclaimers, warnings or qualifications may apply based on geographical location of the person or entity receiving this report.

Country Specific Notices

United Kingdom: This document does not constitute an offer or invitation to purchase or subscribe for any securities, and neither this document nor anything contained herein shall form the basis of or be relied upon in connection with or act as an inducement to enter into any contract or commitment whatsoever.

This document is only addressed to and directed at persons resident in the United Kingdom and who are “Qualified Investors” within the meaning of article 2(e) of The Prospectus Regulation (EU) 2017/1129 (as it forms part of UK domestic law by virtue of the European Union (Withdrawal) Act 2018) (“Qualified Investors”). In addition, in the United Kingdom, this document has not been approved by an authorised person pursuant to section 21 of the Financial Services and Markets Act 2000 (“FSMA”) and, as such, this document is being distributed only to, and is directed only at, qualified investors (i) who have professional experience in matters relating to investments falling within article 19(5) of the Financial Services and Markets Act 2000 (Financial Promotion) order 2005 (the “Order”) or are Qualified Investors falling within article 49 of the Order, and (ii) to whom the information may otherwise lawfully be communicated (all such persons together being referred to as “Relevant Persons”). The information in this document must not be acted on or relied on in the United Kingdom, by persons who are not relevant persons. This document must not be acted on or relied on in the United Kingdom, by persons who are not both Relevant Persons and Qualified Investors.

United States of America: This document is not intended as an offer or solicitation for the purchase or sale of any securities, financial instrument or product or to provide financial services. It is not intended to create legal relations on the basis of information provided herein.
Singapore: If this document is distributed in Singapore, it is made available through general information circulation only it is not intended as an offer or solicitation for the purchase or sale of any securities, financial instrument or product or to provide financial services. It is not intended to create legal relations on the basis of information provided herein. The contents of the Materials have not been reviewed by in the Monetary Authority of Singapore.

South Africa: This publication is not, nor is it intended to be, advice as defined and/or contemplated in the (South African) Financial Advisory and Intermediary Services Act, 37 of 2002, or any other financial, investment, trading, tax, legal, accounting, retirement, actuarial or other professional advice or service whatsoever. The views in this publication are those of the author(s) and are subject to change and “Vulpes” has no obligation to update its opinions or the information in this publication. If this publication contains recommendations, those recommendations reflect solely and exclusively those of the author(s) and such opinions were prepared independently of any other interests. This publication does not constitute personal investment advice.