At ILC Therapeutics (ILCT), we are pioneering a novel drug class called hybrid interferons, Dawn Firmin, Chief Operating Officer, tells Dr Kevin Robinson.
This is being driven by our platform technology, which has so far delivered two engineered cytokine candidates that are progressing towards the clinic. This article explores the journey so far, some of the specific challenges that have arisen and how we have faced them.
An introduction to hybrid interferons
Natural interferons (IFNs) are the body’s first defence against pathogens. They work in multiple ways, such as by activating immune cells, upregulating antigen presentation, acting as a signalling bridge between the innate and adaptive immune system, and modulating multiple inflammatory pathways.
To date, there have been 17 distinct natural IFN subtypes identified, each with different biological properties generating different modes of action.
Some specific IFN subtypes (primarily IFNa2 and IFNb) have been used effectively in the clinic for almost 40 years; however, they can cause significant side-effects, including autoimmune disorders and cytokine release syndrome, which can be fatal.
At ILCT, we have developed a first-in-class technology platform whereby we can rationally select attributes from different natural interferons, producing a novel drug class: hybrid interferons.
These chimeras are designed to improve the efficacy of natural interferons and reduce their side-effects, demonstrating pleiotropy by tackling a disease through multiple pathways.
Hybrid interferons can be engineered for specific activities in defined indications; and, using our platform approach, we have identified two candidates: our lead candidate Alfacyte, a broad-spectrum antiviral for the treatment of upper respiratory tract infections, and Dermacyte, which has shown early preliminary efficacy signals in a model of psoriasis.
The journey so far
ILCT’s hybrid interferon platform can rationally design, select and develop novel candidates, engineering highly specific proteins that are differentiated from the natural interferons that have previously been used in the clinic.
We are building a diverse pipeline of innovative first-in-class hybrid interferons with differentiated modes of action in indications with unmet medical need.
Our preclinical work in the development of Alfacyte has included a range of models to better understand the biological properties of our lead candidate … and to see whether the intended pleiotropy of hybrid interferons was being observed.
These included in vitro immunology and cytokine assessment to explore Alfacyte’s influence on immune cell activity and the inflammatory response, and surface plasmon resonance (SPR) to evaluate the binding interactions between Alfacyte and its target receptor (compared with its natural interferon counterparts).
When developing a new drug class, during this early work to understand a (potential) candidate, biology is critical. And, given the pleiotropy of hybrid interferons, with multiple pathways being targeted, we are continuing this work to gain a full picture of how these candidates interact with their target cells and affect immune activity and inflammation.
Beyond assessing how a novel drug class binds to targets and impacts downstream pathways, it is key to assess a candidate’s other characteristics — such as its pharmacokinetics (PK) — which, given the lack of available data for a new drug class, is particularly important.
Of course, it is also key to look at your drug’s efficacy in models that accurately reflect the intended human indication. We conducted viral screening to determine Alfacyte’s antiviral activity against a range of pathogens, including RSV, COVID-19, Zika, Dengue, influenza, HCMV, HBV and Hep C.
Viruses were selected based on in vitro efficacy and market landscape research, then followed by in vivo efficacy studies to assess Alfacyte’s potential to manage viral load.
Alfacyte was assessed in vivo against RSV and COVID-19, two high-priority indications for a broad-spectrum antiviral, for which we used cotton rats and hamsters, respectively, which are gold-standard models for these disease indications.
However, specific reagents for these species are not typically commercially available, which necessitated the creation of the reagents from scratch using specialist CROs. The results encouragingly showed that Alfacyte is active against RSV, COVID-19, Zika and Dengue, with further results pending.
These studies have helped us to develop a deeper understanding of how these hybrid interferons differ biologically from their natural constituent counterparts while also assessing their efficacy in models that reflect human disease.
These early results have been essential as we continue to pursue breakthroughs to treat indications with significant unmet medical need and validate our hybrid interferon platform.
Scaling-up
When developing a novel class of biologics, there is specific legislation and guidelines from competent authorities that helps to provide a framework to guide the manufacturing process — which we are doing with the support of an expert CMC consultant.
We have now begun work towards the scaled manufacture of Alfacyte and progression towards GMP, with preliminary characterisation and the drug substance manufacturing process development now complete.
When considering the scale-up of a manufacturing process, there are some key challenges to consider — including the selection of an appropriate expression system for the synthesis of the protein (considering that these proteins are engineered chimeras not found in nature).
At ILCT, we investigated several expression systems to produce Alfacyte in E. coli, assessing the viability of cytoplasmic and periplasmic production.
Feasibility and optimisation studies confirmed that the cytoplasmic route of protein production, via inclusion bodies (IB), was the most appropriate.
The development of the upstream process (USP) to extract Alfacyte focused on selecting the best conditions needed to generate maximum protein recovery.
This has been optimised, as has the downstream development process (DSP), which focusses on the selection of the key parameters required to produce Alfacyte with specifications that are appropriate for Phase I (purity and yield).
Any protein produced by E. coli is subject to potential process contaminants, including the presence of host cell proteins (HCPs) and residual host cell DNA (resDNA).
Both of these can contribute to the presence of impurities beyond the agreed specification and should be monitored carefully to ensure product purity and reduce the risk of adverse clinical events.
ILCT has developed a manufacturing process that includes a step that's specifically designed to remove host cell impurities.
ILCT has conducted an extensive feasibility and optimisation study to identify suitable drug product formulations for use at Phase I.
Initially assessing 35 formulation candidates, two have been selected for long-term stability studies, of which the 9-month timepoint has recently been assessed and showed little to no degradation under real-time conditions (4 °C).
Another key consideration when transitioning from small-scale lab production to commercial production is the capacity of the GMP suite being used to manufacture your product.
Consideration should include buffer volumes, ability to maintain purity at a larger scale, the economics of a larger-scale process and the comparability of equipment used during development with that used at scale-up.
Ultimately, the manufacturing process has to be transferrable to a GMP environment; and, for a small biotech, it is here when an expert CRO consultant can provide invaluable advice as the business grows and scales its production.
In addition, when scaling the manufacture of a biologic as a platform company, ILCT’s chemistry, manufacturing and controls (CMC) processes must be flexible and ready for multiple hybrid interferon candidates.
As an example, we needed to ensure that our manufacturing and analytics processes are universal enough to accommodate multiple hybrid interferons — including specific antibodies to detect and distinguish different candidates.
This and other steps have helped to “future-proof” our CMC and helped to make it platform-ready: not only able to manufacture our lead candidate efficiently and consistently, but also able to adapt quickly to future candidates.
What’s next?
During the coming months, we will produce an engineering batch of Alfacyte and generate stability data to supplement and support our characterisation records. We will also continue the long-term stability study of our candidate drug product formulations, for intended use in Phase I as an intravenous administration.
In conclusion, developing a complex new drug class can present a host of challenges — whether that be developing a manufacturing process suitable for GMP production or designing in vivo studies in species that typically do not have commercially available reagents.
If a company also has a platform technology, as we do at ILCT, this also brings a new range of considerations to ensure that you are ready to accommodate new assets.
However, regulatory guidelines provide a framework to direct the drug development pathway; and, for a small biotech such as ILCT, working with expert consultants and other specialist partners can make the journey a success.
At ILCT, we work to the highest standards, allowing us to leverage the most value out of our hybrid IFN platform and our lead candidate.