The Evolution Of The ADC Manufacturer – Contract Pharma

Today, with seven commercially approved antibody-drug conjugates (ADCs) on the market and approximately 90 programs in clinical trials, simplifying the complex supply chain to make manufacturing efficient is a necessity. With approximately 70 percent of ADC projects outsourced to contract development and manufacturing organizations (CMDOs),1 a transparent and integrated supply chain is critical for success. Now, this is more important than ever, with more clinical trials with combination therapy expected as more than 200 trials are registered and as ADCs are expected to gain prominence beyond oncology in the areas of anti-infection, anti-inflammatory, cardiovascular diseases and imaging and diagnostic agents.

The typical ADC supply chain is elaborate due to the numerous, specialized processes in their production and the logistical alignment needed between each step. The three main elements of an ADC are:

The benefits of working with established CDMOs on ADC projects are numerous: experience with a variety of constructs and ADC technologies; efficient processes in place for tech transfer and manufacturing; manufacturing expertise, particularly with GMP batches; and understanding of the regulatory pathway for ADCs.

Interspersed with the above manufacturing steps, requisite quality control measuressuch as mAb bioassays and conjugate stability testingcompound an already complicated pathway. Clearly, manufacturers that can simplify this supply chain are doing customers a great service.

Ten years ago, ADC manufacturing took place on a much smaller scale than today. Raw materials, such as mAbs, were only available in clinical rather than commercial-sized batches. Manufacturing was performed as an add-on to other procedures rather than as an optimized, stand-alone process, and few sites were capable of handling high-potency payloads.

Full-length mAbs were humanized IgGs, most often IgG1, conjugated randomly at cysteine or lysine sites, as shown in Figure 1. In these constructs, the payload could bond to the antibody in multiple locations, potentially affecting its activity. With an IgG scaffold containing over 80 lysines,2 conjugation resulted in very heterogeneous ADCs with variable drug-to-antibody ratios (DARs). High DAR species in the final product can impact stability, solubility and cause problems in manufacturing and operations.

To solve the heterogeneity problem, research moved from native IgGs toward site-specific engineered mAbs, including mAbs with engineered cysteines, non-natural amino acids and sequence tagsall of which could be reacted to perform a more homogenous product. The goal was to manipulate the antibody, so it had specific, limited locations where the toxins were to bond. For instance, monoclonal antibodies containing engineered cysteine moieties limit conjugations to positions that do not disturb immunoglobulin folding or assembly or alter antigen binding.3 The structural representation of an ADC made with such an antibody is shown in Figure 2.

Other second-generation developments included modulation of ADC hydrophobicity by using hydrophilic linkers; structure activity relationship (SAR) design relating a molecules structure to function; and enhanced analytical tools such as chromatography. Cytotoxic payloads with greater potency, such as auristatin and maytansine microtube disruptors, also came into play. All these developments helped improve the usefulness of these agents.

More sophisticated, specialized manufacturing techniques and special facilities were also required to handle these powerful toxins safely.

Second-generation linkers had slightly more functionality than earlier linkers. They were also monovalent, but some were cleavable, either enzymatically or via acid exposure inside cells or lysosomes. Examples include linkers based on proteases, hydrazine, polyethylene glycol (PEG) and disulfides. These linkers were expected to help the antibody release the toxin at the right place and the right time and also stabilize the ADC during preparation, storage and systemic circulation.

Todays researchers are exploring additional modes of action and ways to increase activity and specificity. Bi-specific MAbs, both IgG-like and non-IgG-like, contain two dissimilar binding sites. For example, a single ADC may deliver a toxin and activate natural killer cells. One recently constructed agent had four mechanisms of action. Obviously, the conjugation processes and analytics for these agents are non-trivial.

Another up-and-coming technology is utilizing Fabs (antigen-binding fragments) in place of intact mAbs. These are sections of antibodies that include sites for antigen binding and linkage. These Fabs are very stable, may be internalized more readily, are relatively easy to purify, and tend to be less immunogenic than larger ADCs.

Third-generation payloadspotent cytotoxins such as PBDs and tubulysin, which require special facilities and handlingare not that different than second-generation payloads.

The most unexpected aspect of third-generation development is the revolution in the general understanding of what linkers can do. SAR studies show that linkers change antibody properties, including changes in toxicity and pharmacokinetic profiles. It is now known that if a linker is altered, these parameters must be reevaluated.

New linker categories still include cleavable and non-cleavable, but they also encompass entities such as the Fleximer platform, a polyvalent and biodegradable molecule that can carry multiple payloads. Additionally, hydrophilic linker modulation such as pegylation can mask a larger molecule from the immune system and decrease renal clearance to increase longevity in the circulation. This is a very useful concept as PBDs are very hydrophobic and, once conjugated, are prone to aggregation.

Todays complex, multifaceted ADCs place substantial demands on drug developers and manufacturers, and these challenges are compounded by this sense of urgency in a crowded field and need for life-saving therapies:

Established CMDOs in the ADC business will need to keep pace with future technological advances in this fast-growing industry. Companies that will be successful in the bioconjugation space are providing dedicated facilities for high-potency biologicals, establishing platform operations and developing a workforce with the advanced and specialized expertise to meet the expectations of customers and regulatory agencies. Next-generation bioconjugation will not only be challenged by new and novel chemical unit operations, but will also require novel analytical technologies to provide a more granular understanding at the molecular level. Techniques and tools will need to provide answers for the control strategy of complex products and will need to evolve to support sophisticated release strategies for on-line and at-line in-process testing.

Along with comprehensive laboratory services and expert assistance, the following technologies are particularly helpful for successful ADC manufacturing:

SUS technologies add simplicity and are available for all steps throughout the ADC manufacturing process. Having a complete, single-use process in place can make a big difference: no cleaning studies are needed, reducing costs. The components are designed to be scalable. Extractables and leachables documentation is available to meet regulatory requirements. Operator safety is increased, particularly when handling highly potent ingredients. Implementation of single-use reactor along with a full line of single use equipment for all unit operations is expected be the preferred platform of choice for all bioconjugation processes.

The advancement of PAT allows real-time testing during a GMP process to gather rich, real-time data about the physical and chemical parameters during active processes. It can be used to ensure the process is going as planned and it can also be used to monitor trends in process iterations.

Purification strategies have been expanded to include large-scale chromatography and an increased number of constructs have chromatography. The major reasons to integrate chromatography include: to clear lipophilic drugs that are not amenable to TFF clearance; to remove aggregates and to refine conjugated species distribution, as in removing unconjugated mAb; and to ensure the best possible ADC therapeutic index and specificity, an important function since 60% of constructs require this type of purification.

Potential customers are also evaluating services beyond preparation of the materials, such as formulation support and studies to support the regulatory filing.

Ten years ago, ADCs were a relatively simple concept: use an antibody to target a cell and precisely deliver a biologically active agent. Now, the mission is much more complicated. CDMOs with long-range plans for ADC manufacturing are setting up processes to handle challenging supply chains and investing in facilities and processes to ensure efficiency, quality and security for their customers. Companies that can help deliver multiple constructs to enable a well-designed clinical program are providing customers the opportunity to advance in the field at a fast pace. CDMOs are uniquely positioned to see a wide variety of best practices and can provide solutions based on what has been observed in the industry. In addition, as more commercial products enter the market, there is an acute need for companies that understand how to execute late-stage studies to support a filing strategy. The growth of ADCs in the clinical and commercial API space is a testament to the ability of manufacturers to evolve the technologies required to handle complex molecules.

Whether its understanding the structure-activity relationships around the antibody, linker and drug, or managing a complex supply chain, a CDMO with experience should have the skills and tools needed to help ADC developers navigate these challenges.

Sources

Jyothi Swamy is associate director, ADC/bioconjugation contract manufacturing at MilliporeSigma.

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The Evolution Of The ADC Manufacturer - Contract Pharma