How forward thinking and new approaches will drive up efficiency

 

 

Charlie Johnson, CEO of  biotechnology company ADC Bio, explains how substantial cost savings and faster time to market is achievable through the novel concept of combining the bioconjugation and purification steps.

 

 

 

Charlie Johnson – CEO, ADC Bio

As an advanced manufacturing concept, integrated bioconjugation is highly promising – and is now under development – with the potential to achieve huge efficiencies in the ADC production pipeline.

The key drivers for process innovation

Biopharmaceutical companies seeking suppliers who can transform the efficiency of what has emerged as a highly complex set of manufacturing processes within a multi-faceted supply chain are directly driving the demand for process innovation being brought to the market. Biopharma is under constant pressure to drive down development time and cost of goods, but to still meet demands for increasing amounts of drug required for extended pre-clinical and clinical programs; enabling clinicians to develop the safest and most effective therapeutic regimes prior to drug approval.

At present, the typical antibody drug conjugate (ADC) supply chain involves up to five CDMOs. This includes development and cGMP manufacture of the cytotoxic payload, it’s linker (sometimes combined as a payload-linker), monoclonal antibody (mAb), conjugation of the payload and mAb and finally, the fill finish manufacturing process. Each core element is treated as a discrete activity, which necessitates a fully tested and released product. These elements typically involve material shipments between the different CDMOs across continental borders. The challenge for biopharma is that this approach involves a high degree of redundancy, risk, cost and time penalty for the ADC product concerned. Economic analysis by CDMOs suggests that delivery of multiple elements of the supply chain from a single source location coupled with abbreviated release testing could save months in development time, up to six months for a total clinical supply chain; up to three months for two elements combined (for example mAb manufacturing and bioconjugation) and up to six months for three elements combined (such as mAb production, the bioconjugation and the fill-finish phase). This equates to saving six months in achieving the crucial first-in-man studies and ultimately multiples of that in terms of patent life once an ADC is commercialised.

What could revolutionise the ADC manufacturing industry is a paradigm shift in approach to one in which the entire supply chain is considered as a continuum with only the final ADC considered as a product. This is most likely to be pioneered by early phase specialist CDMOs as adoption of such forward-thinking concepts requires specialist knowledge and engagement at the research and early development phase. CDMO’s specialising in commercial product manufacture arrive too late to drive and develop such innovation for the industry.

One or more promising generic process optimisation solutions could be exploited by CDMO industry innovators; for example single use systems, continuous processing or process analytical technologies or, they could use tools developed specifically for ADC development and manufacturing such as lock-release. This technique streamlines bioconjugation into four simple steps. The technology locks the antibody (mAb) to a resin, performs the conjugation, washes the locked ADC free of residuals and then releases the purified ADC. Originally developed to limit ADC aggregation and improve residual clearance when starting with purified mAbs – problems common with the emerging toxin linker classes – this technology has been a huge step forward for the industry. Moreover, it is also well suited to integrated bioconjugation where mAb purification and conjugation are achieved in one combined process in the development chain.

Integrated bioconjugation – transforming the manufacturing process

The concept of integrated bioconjugation represents a new paradigm in ADC development. The novel approach provides for bioconjugation concurrent with the mAb purification process and dispenses with the need for mAb testing, release, storage and shipping before a conjugate can be made.

The key benefit, and the reason this approach will prove highly disruptive to the manufacturing industry, is that it will generate savings of up to three months of manufacturing time and up to 25% of the overall costs, due to simplified R&D, shorter integrated manufacturing runs and material savings, notably the replacement of protein A. As ever with process innovation, there will be challenges to overcome if the benefits of this method are to be brought to the market. Implementation of this innovative approach will require much of the industry to reevaluate current ingrained manufacturing methods and to establish precisely how it structures the supply chain which, at present, often uses three CMOs.

The starting point for the conjugation will no longer be constrained to the use of purified antibodies as with this new process, it can instead begin anywhere between first capture of the mAb from the cell culture supernatant onto a mimetic lock-release resin and the final stage mAb process operations typically employed. Due to the fact that this involves the handling of highly potent cytotoxins, it will require the conjugation and purification processes to be carried out by integrated bioconjugation contract development and manufacturing organisations with the necessary high containment infrastructure.

The ‘work-horse’ in a mAb downstream process is the protein A capture step. Protein A is a highly specific binder of antibodies and results in a significantly purified mAb bulk and reduction in total process volume in a single step. It is conceivable to consider conjugation of the mAb whilst bound to the protein A resin, but this has several limitations which mean this is not viable. Protein A like the mAb is a protein and as such can be conjugated when employing certain conjugation chemistries. This would render the protein A resin single use and would consume extra toxin linker; both scenarios being cost prohibitive.

An answer has been found – replace protein A with lock-release’s specially developed mimetic resins. These small molecule mimetics retain the beneficial properties of protein A of specificity, capacity and scalability, and have the added and unique benefit of being compatible with conjugation chemistries. Combined with resin costing less than protein A, significant savings in time, complexity and materials are expected. Starting with antibody supernatants, lock-release facilitates both the antibody capture step and subsequent conjugation of the toxin-linker to generate the ADC. The regulatory requirements for viral inactivation, viral clearance and final polishing steps can then be met post-conjugation. However, if an ADC proved not to be stable during certain processes, the innovators are looking into the possibility of carrying out some of these processes prior to conjugation. Conceptually, the developers would capture the antibodies on the mimetic resins, perform the required mAb downstream processing, capture the purified antibody again on the mimetic ligand and then perform the conjugation as the penultimate downstream process. The final process being a simple formulation of the ADC into the correct solution. This approach is not possible with Protein A, even when compatible with the conjugation chemistry, as protein A leaches from the column during mAb release. Protein A is known to cause immunogenic responses in humans and therefore its removal is mandatory and generally requires multiple purification steps to remove it to safe levels. This precludes the use of protein A as the final purification step, unlike when using lock-release mimetic resins.

Taking innovation forwards

A Specialist Process Innovation Group has been established at ADC Bio to assess the viability of its new conjugation process in comparison with conventional approaches. The group’s aim will be to drive and develop technical innovation and its first task is to establish proof of concept for the downstream bioconjugation method – demonstrating that the original antibody production process can be taken and grafted into the new conjugation process, technically how it works and how a sensible amount of product can be recovered from the process – equivalent to what would be amassed from a process which sees production of the antibody first and then the conjugation carried out in a separate step. The group contains experts who possess relevant skills and knowledge in downstream antibody processing, as well as innovations already in use like lock-release – making them well suited to the task in hand. The intention is to carry out a side-by-side case study comparing the traditional antibody first and then conjugation second approach carried out at a different service provider – with the new production process demonstrating significant productivity and economic advantages. The technical proof-of-concept work is being carried out over a 12 to 18 month period.

Conclusion

In essence, the new development process telescopes antibody downstream processing and conjugation – providing just one set of manufacturing, analytical development and release processes. The innovative technique, at the same time, brings in the use of more cost effective and safer resins. As soon as this revolutionary technique is successfully validated, it won’t be long before its benefits will be brought to the market. It would represent a compelling change for the industry, taking manufacturers away from tried and tested conventional techniques through the adoption of a highly beneficial new manufacturing system that better meets industry needs.