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Novel antibody-nanoparticles for drug-based therapies

Primary Supervisor: Professor Zoe Pikramenou, School of Chemistry

Secondary supervisor: Professor Dagmar Scheel-Toellner, Professor Mike Hannon

PhD project title: Novel antibody-nanoparticles for drug-based therapies

University of Registration: University of Birmingham

Project outline:

Antibody based therapies targeting specific surface structures on target cells are a very successful therapeutic modality. To increase therapeutic potency of antibodies, antibody-drug conjugates have also been identified as efficient systems for drug delivery, targeting the drug intake to the desired cells, proving specificity and minimising side effects. Nine conjugates are approved in clinical trials with many more in preclinical tests.1 The design of drug conjugates are limited by the efficiency of covalent and directed attachment of the drug to the antibody by selected linkers.

In this project, we are interested to develop novel antibody-drug conjugates based on gold nanoparticles for treatment of malignant and anti-inflammatory diseases.

Gold nanoparticles provide an inert scaffold for localised delivery and attachment of a choice of antibodies and drugs. The versatility of antibody attachment as well as drug loading on the gold nanoparticle allows flexibility in delivery of more than one agent and monitoring of delivery success by choosing luminescent labels on the gold for imaging and detection. Gold nanoparticles are relatively inert based on the gold properties, they are used in very small quantities (pM to nM) and have inserted clinical trials for phototherapy applications.

At Birmingham we have developed water soluble nanoparticles (13 nm in diameter) with attachment of selective targeting agents and demonstrated the delivery of cytotoxic drugs using nanoparticle scaffold (Scheme 1).2,3 We use a suite of luminescent agents based on metal complexes with sensitive luminescent signals that allow detection sensitive to nanoparticle localisation in cells. We will use our nanoparticle designs to

attach antibodies by selectively modifying the Fc region for gold attachment. We will use platinum and iridium complexes with known cytotoxicity to attach to nanoparticle.

Scheme 1

We have previously shown the release of platinum drugs in cancer cells using our nanoparticle constructs.2

We will study antibodies with therapeutic action towards malignant and inflammatory diseases involving B cell-responses such as rheumatoid arthritis. A key example is rituximab, a monoclonal antibody that triggers B cell depletion. To establish the activity of nanoparticles loaded with metallodrugs and antibodies we will use rituximab and establish the change in cytotoxicity in the new designs. Following this we will move to alternative B cell targeting therapy targeting FcRL4 an IgA receptor, which is specifically expressed on a pathogenic B cell population. This will overcome the potential depletion of all circulating B cells associated with rituximab.

The Scheel-Toellner have generated highly specific human recombinant monoclonal antibodies to FcRL4 and tested this antibody in a series of assays exploring their ability to kill FcRL4-expressing target cells through complement activation, antibody dependent cellular cytotoxicity using NK cell and antibody mediated phagocytosis by macrophages.

We will optimise our novel platform by testing a range of particle sizes and antibody concentrations as well as the selection of the cytotoxic drugs on the particles.

References:

  1. Drago, J.D., Modi, S., Chandarlapaty, S., Nat. Rev. Clin. Oncol. 2021, 18, 327-344.
  2. Caballero, A.B., Cardo, L., Claire, S., Craig, J.S., Rochford, L.A., Hodges, N.J., Pikramenou, Z., Hannon, M.J., Chem. Sci., 2019, 10, 9244.
  3. King, S., Teixeira, R., Dosumu, A., Dehghani, H., Ward, A., Hodges, N., Botchway, S., Bicknell, R., Pikramenou, Z. J. Am. Chem. Soc., 2018, 140, 10242.
  4. Amara K, E Clay, L Yeo, D Ramsköld, J Spengler, N Sippl, JA Cameron, L Israelsson , PJ Titcombe, C Grönwall , I Sahbudin , A Filer, K Raza , V Malmström , D Scheel-Toellner. J Autoimmun. 2017 Jul;81:34-43.
  5. Yeo L, H Lom, M Juarez, M Snow, CD Buckley, A Filer, K Raza, D Scheel-Toellner.. Ann Rheum Dis. 2015 May;74(5):928-35. Highlighted in Nature Reviews in Rheumatology

BBSRC Strategic Research Priority: Integrated Understanding of Health:Pharmaceuticals

Techniques that will be undertaken during the project:

The project will involve interdisciplinary training in the areas of synthetic molecular chemistry, nanoscience, cell culture, imaging and analytical detection techniques.

Contact: Professor Zoe Pikramenou, University of Birmingham