In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at  UCL, Dr Sara Aguti highlights her Biologics Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to treat severe neuromuscular disorders. 

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In the next interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Athina Dritsoula and Dr Carlotta Camilli highlight their joint Biologics TIN Pilot Data Fund awarded project focusing on the effect of LRG1 blockade in pancreatic cancer.

How did this joint project come about?

CC: Athina and I both arrived at the Institute of Ophthalmology to do our post-docs where, weirdly enough, we don’t do eye-related research but explore vessel behaviour using ex-vivo models of angiogenesis and in vivo models of solid tumours.

What is the title of your project and what does it involve?

AD: The interest of our lab is focused on the LRG1 protein, which is involved in pathological angiogenesis, but we don’t know much about its normal function. Based on our research, we believe that blocking the function of the LRG1 protein by using a specific monoclonal antibody that we have developed in the lab will be beneficial in conditions with abnormal angiogenesis like cancer. In fact, LRG1 is upregulated in pancreatic cancer, which is a type of cancer with minimal survival that remains untreated. So, Carlotta and I designed this project to study the effect of LRG1 blockade in pancreatic cancer.

What is the motivation behind your project/therapeutic?

CC: Pancreatic cancer is a leading cause of deaths from cancer that kills about half a million people worldwide each year. The current standard of care involves combination cytotoxic chemotherapy, which often fails due to the complex tumour microenvironment. So, there is a great need for developing novel therapeutic strategies that will target new molecules and pathways, and we believe that our anti-LRG1 antibody could be a great novel therapeutic candidate.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

AD: We both thought that the Biologics TIN Programme is a great opportunity to get enough funding to support a short 6-month project that would allow us to a) test our hypothesis and b) generate pilot data to design a bigger project in future if (a) proves right.

Join the Biologics TIN

What do you hope to achieve in the 6 months duration of your project?

CC: Well, we hope that we will manage to prove that our hypothesis is correct, and COVID-19 situation allowing, generate data to apply for more funding and get this project further. Our -very ambitious – aim is to get our antibody into clinical trials for pancreatic cancer in a few years’ time!

What are your next steps from now?

AD: Hope that our orders will be delivered on time and that our experiments will work as planned! We need to complete the project before a second lock down crushes.

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

AD: The 10 minutes Dragons’ Den round felt much longer than it was! Be well prepared for all types of questions, and maybe have a mock interview with your PI, if possible.

CC: Spend enough time to prepare the slide presentation. It might seem easy but it’s not, as it needs to be very concise and straight forward!

About Dr Athina Dritsoula

Dr Dritsoula studied an undergraduate degree in Molecular Biology and Genetics in Greece over a decade ago before arriving in the UK for a Master’s and PhD, and UCL has been home to Dr Dritsoula since. Although human genetics was Dr Dritsoula’s first love, Dr Dritsoula quickly found her “forte” in vascular biology – studying the biology of big human vessels during a PhD, and then smaller vessels stability and angiogenesis during post-doc.

About Dr Carlotta Camilli

After completing a Master’s in Medical Biotechnology, Dr Camilli left Italy to start a PhD at UCL focusing on the use of vascular progenitors for the development of a bioengineered muscle.

However, Dr Camilli’s broad interest in translational medicine pushed her to explore a different pathological context during post-doc, namely the tumour angiogenesis. Dr Camilli found jumping on this new field a difficult but exciting challenge!

In the third interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Gathoni Kamuyu highlights her Biologics TIN Pilot Data Fund awarded project “Identifying monoclonal antibodies for the treatment of Acinetobacter baumannii infections” and presents some advice for future applicants.

Please provide an overview of your Biologics TIN Pilot Data Fund awarded project. 

My project, “Identifying monoclonal antibodies for the treatment of Acinetobacter baumannii infections” will use single B-cell sequencing and cloning techniques to identify monoclonal antibodies targeting A. baumannii [3]. This will involve immunising mice to generate a robust antibody response against selected proteins, obtaining antigen-specific single B cells by fluorescence-activated cell sorting and screening each individual B cell for the production of antibodies effective in controlling the bacterial infection. Once a positive antibody-secreting B cell is identified, the corresponding monoclonal antibody it secretes, can be made in large quantities by recombinant protein expression [4, 5].

What is the motivation behind your project/therapeutic?

Acinetobacter baumannii has been referred to as the perfect predator in the media [6] and is number one on a recent WHO list of antimicrobial resistant (AMR) pathogens to which alternative therapies are urgently required [7, 8].

Through many different mechanisms, A. baumannii can survive and spread rapidly within hospitals, causes approximately 6-24% of nosocomial bacteraemia and pneumonia (particularly within intensive care units) and is associated with high morbidity and mortality rates [8-10]. Current treatment options uses complex antibiotic combinations to overcome the AMR profile, and there is an increase in reports on the incidence of infections caused by pan-drug resistant A. baumannii (non‐susceptibility to all agents in all antimicrobial categories) [11].

Monoclonal antibodies (MAbs) are a viable alternative to antibiotics that avoids the problem of drug resistance [12].  A carefully selected MAb offers multiple advantages over antibiotics that include rapid development with low toxicity, have minimal effect on the human microbiome, do not drive resistance to antimicrobials and can be conjugated to additional molecules to enhance antimicrobial effects.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

The biologics TIN pilot data fund was specifically interested in funding projects by early career researchers (ECR), on biologics (including monoclonal antibodies), that were between the discovery and translational phases. This would allow the ECR to generate pilot data that could be used to apply for larger grants. My current research work had identified potential protein targets that elicited protective antibody responses against Acinetobacter baumannii making them ideal targets for monoclonal antibody development.

In addition, it was an opportunity to identify, interact and establish collaborations through the TINs, with groups within UCL that have similar research questions or have specialised research techniques.

What do you hope to achieve in the 6 months duration of your project?

I hope to have identified a subset of monoclonal antibodies targeting A. baumannii for further validation. I would also like to establish the pipeline I would use to identify monoclonal antibodies against additional antigens of interest that we would identify.

What are your next steps from now?

Hit the lab and generate data…

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

Read the application instructions carefully, keep within the word count on your application and keep your 2 min pitch, simple, straightforward and to the point.

Learn more about and join the TINs

About Dr Gathoni Kamuyu

Dr Gathoni Kamuyu obtained a BSc. in Biochemistry (1^st Class Honours, University of Nairobi, Kenya) and MSc. in Molecular Biology of Infectious Diseases (Distinction, LSHTM,United Kingdom). Dr Kamuyu’s research career started at the KEMRI-Wellcome Trust Research Programme (Kilifi, Kenya), evaluating the link between exposure to parasitic central nervous system infections and epilepsy [1].

In 2017, Dr Kamuyu obtained a PhD from the Open University/KEMRI-Wellcome Trust programme, which focused on identifying the targets of protective antibodies against Plasmodium falciparum, one of the causative agents for Malaria [2]. During her initial post-doctoral training at University Hospital Heidelberg, Germany, Dr Kamuyu used in vivo models to evaluate a panel of P. falciparum proteins as targets of protective antibodies.

Currently, Dr Kamuyu is a Research Fellow within Prof. Jeremy Brown’s group in the Department of Respiratory Medicine, Centre for Inflammation and Tissue Repair (CITR), UCL. Her research focus includes understanding acquired immunity to Acinetobacter baumannii (A. baumannii), identifying the potential targets of protective antibodies and the mechanisms employed by A. baumannii to evade the effector functions mediated by the complement system.

References

1. Kamuyu, G., et al., Exposure to multiple parasites is associated with the prevalence of active convulsive epilepsy in sub-Saharan Africa. PLoS Negl Trop Dis, 2014. 8(5): p. e2908.

2. Kamuyu, G., et al., KILchip v1.0: A Novel Plasmodium falciparum Merozoite Protein Microarray to Facilitate Malaria Vaccine Candidate Prioritization. Front Immunol, 2018. 9: p. 2866.

3. Lu, R.M., et al., Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci, 2020. 27(1): p. 1.

4. Carbonetti, S., et al., A method for the isolation and characterization of functional murine monoclonal antibodies by single B cell cloning. J Immunol Methods, 2017. 448: p. 66-73.

5. von Boehmer, L., et al., Sequencing and cloning of antigen-specific antibodies from mouse memory B cells. Nat Protoc, 2016. 11(10): p. 1908-1923.

6. Patterson, S.S.a.T., The Perfect Predator: A Scientists’s Race to Save Her Husband from a Deadly Superbug: A Memoir.

7. (WHO), W.H.O., Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotic. 2017.

8. Tacconelli, E., et al., Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis, 2018. 18(3): p. 318-327.

9. Allegranzi, B., et al., Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet, 2011. 377(9761): p. 228-41.

10. Cerceo, E., et al., Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options. Microb Drug Resist, 2016. 22(5): p. 412-31.

11. Magiorakos, A.P., et al., Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect, 2012. 18(3): p. 268-81.

12. McConnell, M.J., Where are we with monoclonal antibodies for multidrug-resistant infections? Drug Discov Today, 2019. 24(5): p. 1132-1138.

In the second interview as part of the new Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Anais Cassaignau highlights her Biologics TIN Pilot Data Fund awarded project “Developing an scFv binder against nascent huntingtin” and presents some advice for future applicants.

Please provide an overview of your Biologics project.

This project entitled “Developing an scFv binder against nascent huntingtin” is looking to exploit the unique features of nascent proteins, i.e. the shapes they form while they are being made. I am currently pursuing the novel disease angle that is the focus of this award.

Relative to the fully formed protein, the nascent protein is typically protected against misfolding /aggregation. We are looking to show that this entity may be a tractable therapeutic target in Huntington’s Disease.

What is the motivation behind your project/therapeutic?

I am interested in understanding how proteins fold while they are being synthesised by the ribosome, and how the ribosome itself regulates and modulates this process¹. The correct folding of proteins in the cell is vital to all forms of life, and scientists are increasingly recognising that many diseases bear protein misfolding hallmarks including devastating neurodegenerative illnesses, several cancers and also diabetes.

Huntington’s is a devastating neurodegenerative disease, designated as an incurable disease with only symptomatic treatment currently available, and which often involves invasive delivery e.g. via spinal chord injections.  This is despite seminal work in the field that underpins much of what we understand regarding the pathological underlying processes and in particular how the causative agent, huntingtin, forms aggregates. I hope to be part of devising new therapeutic strategies that involve targeting the mutant form of huntingtin at the earliest point of biosynthesis – an angle which has not previously been explored in this manner.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

I wanted to initiate a crucially needed orthogonal extension to the research I have been undertaking; building upon the wealth of collective knowledge that the entire lab and myself have been building together over years about how proteins are made and how they fold, and applying these paradigms to develop relevant disease-related models.

What do you hope to achieve in the 6 months duration of your project?

I want to demonstrate that targeting a nascent protein is possible, through binding an antibody and scFv to a nascent huntingtin during biosynthesis and monitoring how this modulates the folding/misfolding outcomes for this protein.

What are your next steps from now?

Finessing of assays and the production of samples of the nascent huntingtin. The protein will be translationally-arrested (a “snapshot” of biosynthesis) and then we will test the interaction of our antibody and scFv to it, and see how this influences the fate of this aggregation-prone protein.

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

I would strongly encourage prospective applicants to reach out to the members of their respective TIN as the first step; their expertise will help you to appropriately refine your initial ideas and define the key questions in order to apply. Finally… Make a list of all the things you don’t know and read about them one by one.

Join the UCL Therapeutic Innovation Networks

About Dr Anais Cassaignau

Dr Cassaignau became interested in protein folding on the ribosome during her final year of BSc Biochemistry at UCL. Following this, Dr Cassaignau initiated a project within the Research department of Structural and Molecular Biology and has not left since, undertaking a Wellcome Trust-funded PhD and postdoc with John Christodoulou.

1. How does the ribosome fold the proteome? Cassaignau, AME, et al Ann. Rev. Biochem, 2020, 89, 389-415.  https://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-062917-012226 

In the first interview as part of the new Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Giulia De Rossi highlights her Biologics TIN Pilot Data Fund awarded project “LRG1 antibody for diabetic macular oedema” and presents some advice for future applicants.

Please provide an overview of your Biologics project. 

There are currently 4.8 million people in the UK living with diabetes and over 300,000 of these have their sight threatened by a severe ocular complication called diabetic macular oedema (DMO), which has now become the most common cause of blindness in the working population.

Clinical studies have shown that leucine-rich alpha-2-glycoprotein 1 (LRG1) is enriched in the eyes of diabetic patients and we showed in other settings that it can drive vascular dysfunction. My hypothesis is that LRG1 is an early pathological switch in DMO and I believe that it may represent a novel/alternative pathway we could target therapeutically.

My project “LRG1 antibody for diabetic macular oedema” will test the efficacy of function-blocking antibody against LRG1 using murine models of diabetes. Specifically, I will be looking at the effects of this biologic on vascular homeostasis and permeability.

 

What is the motivation behind your project?

Currently, if you are diagnosed with DMO, you will receive monthly intra-ocular injections of VEGF-neutralizing antibodies. Unfortunately, this line of treatment has only a 50% chance of working and often responses are short-lived. As a result, despite the NHS spending £116m/annum, 2000 people go blind every year.

With diabetes reaching epidemic proportions, there is an urgent unmet need and market for developing new treatments for this devastating condition.

I believe targeting LRG1 with a function-blocking antibody has the potential not only to treat patients who are refractory to current therapies, but also to achieve earlier and therefore better outcomes in all patients.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

I had an interesting set of preliminary data that I felt was suitable for applying for a pilot proof-of-concept grant.

The TIN pilot data fund was also my first opportunity to apply for and manage a grant as the lead applicant, which I hope will be a first stepping stone towards independent research and career development.

What do you hope to achieve in the 6 months duration of your project?

With the funding requested I plan to answer 3 critical questions: 1) Is LRG1 a pathological switch in DMO? 2) Is a Lrg1-deficient mouse protected from DMO? and 3) Can anti-LRG1 antibodies prevent the onset of DMO?

What are your next steps from now?

My planned experiments will support the preclinical dataset necessary to take the anti-LRG1 antibody into clinical trials, by establishing whether LRG1 is a valid target, and, together with the available supporting literature from clinical studies, will constitute the foundation for a translational grant application next year.

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

Make sure you clearly describe: what the problem is, your proposed solution, why your approach is better, what you want to do next if successful (clear career and translational path).

As with every application with a limited word count, you might end up with an extremely abridged version of your initial text and some key concepts might become cryptic. Have someone from a different field review your application and tell you if they can still understand the key message you want to convey.

There is no space to describe the experiments in detail, so just explain the scientific questions you want to answer, you will have the opportunity to wear your scientist hat if you get to the Q&A stage.

Good luck future applicants!

Dr Giulia De Rossi will be discussing her Biologics TIN Pilot Data Scheme application process experience in the upcoming ACCELERATE Success event, “Grant Writing for Translational Research” on Tuesday 6th October.  This is an educational, translational training event to help UCL researchers write impactful applications by recognising the important elements of a translational research/innovation grant application and increase chances of funding success. Register here.

About Dr Giulia De Rossi

Dr Giulia De Rossi is a research fellow at the UCL Institute of Ophthalmology in the lab led by Professor Stephen Moss and Professor John Greenwood. Dr De Rossi’s training was in Biotechnology and the main focus of her PhD and post-doctoral work has been understanding the mechanisms underpinning vascular dysfunction and new blood vessel formation.

Dr De Rossi joined UCL in July 2019 to work on a Diabetes UK-funded project aimed at identifying new targets and mechanisms to treat the microvascular complications of diabetes.