Generation of human monoclonal antibodies for the treatment of emerging infections in low- and middle-income countries (LMICs)

Abstract

Effective therapies to counter the threat from emerging and re-emerging viruses are urgently needed. Due to their relative safety and specificity, monoclonal antibodies are an attractive approach for deployment in future outbreaks and several monoclonals have been approved or are in clinical development. Despite LMICs experiencing the major burden of these infectious threats, access to approved (either full or for emergency use) therapeutic antibodies is limited. There is significant opportunity for LSTM to establish a pipeline for isolation and eventual in-country manufacture and clinical development of therapeutic fully human mAbs – either against new targets or biosimilars for existing targets. This PhD will establish a human mAb discovery platform focussing initially on targets where access to high quality well-characterised sources of B cells is available (e.g., SARS-CoV2 and Rabies post-vaccine samples). By using a range of virus antigens as bait we will optimise the discovery process to identify broadly reactive mAbs (e.g., pan-phylogroup or even pan-genus) targeting different epitopes. Identifying suitable antibody cocktails, whilst potentially complicating the manufacturing process, limits downstream problems due to virus escape. Monoclonal isolation will be achieved using single B-cell sorting and antibody variable gene cloning and subsequent antibody expression. Alternative methods, such as antigen-labelled single-cell transcriptomics (scRNA-Seq) will also be explored. Antibody potency and breadth will be assessed using appropriate immunoassays and virus neutralisation assays, with the most promising mAbs being advanced into preclinical in vivo protection studies.

Where does the project lie on the Translational Pathway?

T1 – Basic Research

T2 Human / Clinical Research         

Expected Outputs

• The project will deliver shortage skills training, high-impact publications, establish a much-needed monoclonal antibody discovery platform and deliver candidate therapeutic antibodies for subsequent production and delivery in low- / middle-income countries. Clinical development will be facilitated through collaborations with SMEs with expertise in antibody process optimisation (Synthetic Genetic Systems Ltd. (Syngensys), Sheffield) and biomanufacture in low/middle-income settings (Univercells, Brussels).

Training Opportunities

Training will be available in the laboratory techniques outlined above. They will also be encouraged to develop translational skills and project management skills relevant to the project outlined.

Skills Required

The student should have good competency in a molecular biology lab learned either through placement or via an extended UG/PGT project.

Key Publications associated with this project

Gieselmann L, Kreer C, Ercanoglu MS, Lehnen N, Zehner M, Schommers P, Potthoff J, Gruell H, Klein F. Effective high-throughput isolation of fully human antibodies targeting infectious pathogens. Nat Protoc. 2021 Jul;16(7):3639-3671. doi: 10.1038/s41596-021-00554-w. Epub 2021 May 25. PMID: 34035500.

Urbanowicz RA, Tsoleridis T, Jackson HJ, Cusin L, Duncan JD, Chappell JG, Tarr AW, Nightingale J, Norrish AR, Ikram A, Marson B, Craxford SJ, Kelly A, Aithal GP, Vijay A, Tighe PJ, Ball JK, Valdes AM, Ollivere BJ. Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection. Sci Transl Med. 2021 Sep;13(609):eabj0847. doi: 10.1126/scitranslmed.abj0847. Epub 2021 Aug 5. PMID: 34376569; PMCID: PMC9835846.

Kramer KJ, Wilfong EM, Voss K, Barone SM, Shiakolas AR, Raju N, Roe CE, Suryadevara N, Walker LM, Wall SC, Paulo A, Schaefer S, Dahunsi D, Westlake CS, Crowe JE Jr, Carnahan RH, Rathmell JC, Bonami RH, Georgiev IS, Irish JM. Single-cell profiling of the antigen-specific response to BNT162b2 SARS-CoV-2 RNA vaccine. Nat Commun. 2022 Jun 16;13(1):3466. doi: 10.1038/s41467-022-31142-5. PMID: 35710908; PMCID: PMC9201272.

Paciello R, Urbanowicz RA, Riccio G, Sasso E, McClure CP, Zambrano N, Ball JK, Cortese R, Nicosia A, De Lorenzo C. Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb. J Gen Virol. 2016 Jan;97(1):82-94. doi: 10.1099/jgv.0.000330. Epub 2015 Oct 29. PMID: 26519290; PMCID: PMC5478175.

Liu X, Li Y, Li J, Zhou J, Guo J, Pu Y, Jiang Y, Zhou Y, Jiang Z, Shu Q, Wang C, Wang J, Zhao Y, Zhao W, Wang H, Wei J, Yu H, Gao J, Li X. Comparing recombinant human rabies monoclonal antibody (ormutivimab) with human rabies immunoglobulin (HRIG) for postexposure prophylaxis: A phase III, randomized, double-blind, non-inferiority trial. Int J Infect Dis. 2023 Sep;134:53-62. doi: 10.1016/j.ijid.2023.05.017. Epub 2023 May 19. PMID: 37211270.