Generating new therapeutics for cervical cancer treatment
The Debbie Fund team have generated many millions of antibodies using high-throughput bacteriophage display technology and selected the best ones to treat cervical cancer. A protein called B7-H3 was chosen as target. It is present at high density on cervical cancer cells, particularly on tumours from patients with aggressive disease, but it has little expression on healthy tissues.
Dr Magdalena Buschhaus is a Debbie Fund researcher at UCL Cancer Institute who joined the project in November 2018. Magdalena’s role in the project is discovering novel antibody candidates targeting human B7-H3 protein and their development for clinical application in treatment of cervical cancer.
Magdalena’s work has created new and unique antibodies that have potential to help patients with cervical cancer by targeting treatment to the cancer cells and sparing healthy tissues.
ADC Approach
An antibody drug (ADC) uses the exceptional specificity of an antibody to its target to deliver a highly potent toxic payload for accurate and efficient killing of cancer cells. Below left is a monoclonal antibody shown with a conjugated warhead in red. The green arrows indicate the target-binding arms of the antibody.
On the right, a microscope image showing fluorescently tagged Debbie Fund antibodies (in green) targeting to B7-H3 on the surface of HeLa cells, a world-famous immortal cancer cell line human derived from a patient with cervical cancer (The Immortal Life of Henrietta Lacks by Rebecca Skloot – 9781509877027 – Pan Macmillan)
The new Debbie Fund antibodies can deliver extremely toxic drugs specifically to cancer cells.
Cellular Therapies
B7-H3 is present at high levels on many cancer types, which has enabled Debbie Fund to learn about the potential for different types of cancer therapy with the antibodies.
One of our B7-H3 antibodies was developed as a cellular therapeutic for a rare paediatric cancer in an exciting piece of work carried out by a clinical PhD student, Dr Kathleen Birley, and recently published in the Journal Molecular Therapy Oncolytics. (https://doi.org/10.1016/j.omto.2022.08.008)
Debbie Fund is acknowledged in this paper and although the project was cost neutral for Debbie fund, it added enormous value. The focus of Kathleen’s research fellowship was to develop one of the antibody libraries we have access to for Debbie Fund work. Professor John Anderson, Consultant Paediatric Oncologist at Great Ormond Street Institute of Child Health, who was one of the principal investigators in the work said “CAR-T therapy clinical trials for this antibody are being planned in children’s brain tumours. These studies could open up the door for other B7-H3 expressing tumours like cervical cancer”.
More about Kathleen’s work and B7-H3 as a target can be seen in this short video from Children with Cancer UK (What is immunotherapy? | Easy explanation - YouTube)
Graphical abstract from Birley et al., A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers. Journal Molecular Therapy Oncolytics, September 2022.
The antibodies Kathleen developed can direct the body’s own immune cells to kill cancer cells in paediatric cancer. This could open the door for new cervical cancer treatments using Debbie Fund antibodies.
Cervical cancer discovery led by Debbie Fund offers major new clue to better understand the disease
The Debbie Fund Genomics Team recently published an integrated molecular analysis of cervical cancer in the journal Nature Communications.
This was the largest study of its kind in cervical cancer and was based on a collaboration that included scientists and clinicians from across Europe. The study afforded key new insights into the molecular changes that occur during cervical cancer development and their clinical significance. Of particular interest for development of new therapies was the finding that B7-H3 (a promising therapeutic target against which the Debbie Fund team is developing antibody-based drugs), is found at increased levels in the tumours of women that experience particularly aggressive disease and poor survival outcomes. This gives us hope that our antibodies will benefit women for whom current treatments display very limited efficacy.
Dr Ankur Chakravarthy
Dr Ian Reddin
Dr Tim Fenton
The genomic study increased global understanding of changes that occur during cervical cancer development, and it provides evidence that our new antibody treatments will target cancers in patients with aggressive disease.
Clinical Development
The exceptional tumour killing potential of the ADCs has led to a partnership with a pioneering ADC company, Iksuda Therapeutics, (We build superior ADCs | Iksuda Therapeutics) Iksuda are evaluating the antibodies with an aim to develop them as ADC treatments for the clinic. Debbie Fund and UCL Business have agreed that to keep cervical cancer in constant consideration given the provenance of the funding for the molecules.
Dr David Simpson, the Chief Executive Officer of Iksuda remarked that “Iksuda is delighted to be working with the UCL Debbie Fund team in the development of new therapies for cervical cancer patients. Iksuda is focused on the design and development of first- and best-in-class ADCs for hard-to-treat cancers, especially those which are associated with high rates of relapse and resistance and where few effective treatment options are available. B7-H3 is over-expressed in numerous tumours including colorectal, gastric, pancreatic, oesophageal, lung and renal cell. We believe that it represents a promising target for an ADC therapeutic approach and have been following Kerry’s research with interest.”
Dr Ian Evetts, Iksuda’s Chief Business Officer added “Importantly, B7-H3 is also involved in the development and progression of cervical cancer, being particularly relevant to aggressive disease. The lack of adjuvant therapy following chemoradiation for locally advanced disease results in around half of treated patients relapsing, and on relapse, prognosis is poor with a low probability of long-term survival. In particular, recurrence rates are higher by disease stage making aggressive forms difficult to treat. We are excited about the potential to combine the new B7-H3 antibodies with Iksuda’s technologies to deliver a best-in-class B7-H3-directed ADC. Iksuda’s ADCs benefit from tumour-activated release of payloads, selected for the most appropriate cancer-cell killing mechanisms for the tumour that is targeted. We believe that this approach should drive an effective and well-tolerated treatment option for patients”.
Linking up with Iksuda provides a real opportunity to develop a new antibody-based drug that could one day help patients with cervical cancer.
Professor Kerry Chester, who has been overseeing the Debbie Fund work since the beginning of the project said “It’s been quite remarkable to see the antibody and genomics arms of the project, these very different disciplines, independently coming to recognise B7-H3 as the target for therapeutic intervention. We are thrilled to be working with Iksuda to further develop the Debbie Fund antibodies, their technology is great - it’s the right way forward”.