Fighting the superbugs – Centauri Therapeutics antibacterial program featured in article published in Chemistry & Industry magazine
Centauri has developed an immunotherapeutics platform that can direct a potent natural immunity to target disease, via multifunctional molecules called Alphamers™. The Alphamer molecules are versatile structures consisting of three separate parts.
- A targeting domain which allows the Alphamer to bind specifically to the target of interest. We have exemplified antibodies, antibody fragments, peptides, oligonucleotides and chemicals within our IP estate
- An effector domain which comprises a variable number of natural carbohydrate structures which are recognised by pre-existing antibodies in humans. These antibodies are present at high titre in all humans, they are polyclonal consisting of a number immunoglobin subclasses and are able to trigger a potent immune response engaging both innate and adaptive immune mechanism concurrently
- The third part of the molecule is a proprietary Linker molecule, which covalently links effector and targeting domains. Linkers are stable, non-cleavable, and can be used in a modular fashion to link a targeting domain (the cell-binding component) to our effector molecules and engage the potent natural immune system mechanism. Linkers are critical to Alphamer properties and optimisation of functionality.
It is possible to select structurally diverse domains, for example a small molecule, peptide, aptamer, antibody or antibody fragment and use a linker to connect the targeting moiety to our effector domain.
Centauri’s approach is novel; unique in the anti-infective space and difficult to replicate by other ‘bi-specific’ modalities in oncology applications. Alphamer differentiation stems predominantly from four important features:
- The effector domain in an Alphamer is a natural sugar which is inherently non-toxic (an immunological hapten)
- Alphamers can be systemically delivered and repeatedly dosed
- Activation of the immune system only occurs on the target of interest driven by the targeting domain
- Alphamers, as a single agent, can engage multiple important immune mechanisms concurrently, including target cell killing and neo-antigen presentation, leading to a durable memory cell response (via complement activation, antibody dependant cellular toxicity, target cell phagocytosis)
Aptamer Discovery Capability
The Aptamer Discovery Team focuses on the discovery and development of aptamers for therapeutic applications.
Aptamers are short oligonucleotide sequences that bind with high affinity and selectivity to diverse biological targets. Aptamers are selected using a methodology known as SELEX (Systematic Evolution of Ligands by EXponential enrichment). Centauri has developed SELEX into a technology platform that is reliable, robust and amenable to the discovery of the nuclease stable aptamers required for therapeutics. Aptamer libraries are typically comprised of 10E14 unique molecules, so delivering unprecedented diversity compared to phage display (10E10) and small molecule (10E6) libraries. The combination of Next Generation Sequencing and bioinformatics enables the identification of hundreds of potential lead aptamer sequences from a single SELEX campaign in a very short timeframe and low cost.
Aptamer binding sites are not restricted to the hydrophobic pockets associated with small molecule interactions or the immunogenic epitopes of antibody therapeutics and so this innovative technology is uniquely placed for the discovery of novel interactions with target molecules.
See Partnering RNA Aptamers as Targeting Agents for Novel Immunotherapeutics, by clicking here
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Founding and Platform Development
2010: Alphamer IP acquired from Nobel Laureate Dr Kary Mullis and initial investment from high net worth individuals
2011: R&D begins, collaboration with USCD (Prof. Victor Nizet)
2015: Publication of first in vitro proof of concept that alphamers have the potential to redirect pre-existing antibodies and trigger an immediate antibacterial immune response ( J MolMed DOI 10.1007/s00109-015-1280-4).
2015: Current Executive Management team formed with Mike Westby as CEO and Clive Dix as Chairman
2016: Avvinity collaboration with initiated with Horizon Discovery PLC, including an initial £2.8m investment to progress oncology R&D
2017: Innovate UK’s Biomedical Catalyst (BMC) programme award to co-fund research focused on antimicrobial resistance
2018: Additional investment by Horizon Discovery following achievement of oncology milestones
ONCO1 is a systemically-delivered Alphamer targeting EGFR over expression on solid tumours. Injected, Alphamers will circulate throughout body searching for metastases. The specific targeting domain of the Alphamer will lead to a high density of carbohydrate presentation on the cell surface leading to inflammation, lysis and phagocytosis of diseased cells. Our technology works on the cell surface and is unaffected by EGFR driven cell signalling and escape mechanisms. As a result, we expect our agent to be active against TKI resistant and sensitive tumours.
ABX01 targets drug-sensitive and Multi-Drug Resistant (MDR) Gram-negative bacteria, including clinically-relevant strains of Enterobacteriaceae, P. aeruginosa, and A. baumannii. The novel features of this approach are: broad spectrum efficacy against Gram-negative bacterial infections; a dual mechanism of action (direct and immune-mediated action) to kill bacteria; and an ability to harness and re-direct naturally occurring effector antibodies.