Early Career Innovators: Treating Antimicrobrial Resistant Pathogens with Monoclonal Antibodies, Biologics TIN

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.