Introduction to ADC Technology and Development Trends

Antibody-Drug Conjugates (ADC) are a novel class of therapeutic drugs formed by chemically coupling an antibody with a small molecule toxin through chemical or enzyme-mediated linkers (as shown in Figure 1). ADCs combine the tumor-targeting specificity of antibodies with the potent cytotoxic activity of toxins, enabling highly effective and targeted killing of tumor cells while having minimal impact on normal cells. This gives ADCs high safety and notable therapeutic efficacy.

ADC has undoubtedly become one of the hottest areas in innovative drugs in recent years. From Pfizer’s acquisition of ADC biotech company Seagen for $43 billion to the recent surge of Chinese ADC innovation projects expanding overseas, the number of new business development projects have been continually breaking records. Compared to standard chemotherapy, ADCs have shown better clinical efficacy in multiple indications. It is expected that by 2028, the total revenue from approved ADC projects and those in Phase III clinical trials will reach at least $26 billion.

Supplementary | Forecasted revenue for antibody-drug conjugates on the market or in phase lldevelopment.
'Other includes 10 approved and phase ll ADCs with <$1 bilion of forecasted sales between 2023-2028Source: EvaluatePharma (October 2023); BCG analysis.

ADC Purification Process

With the increasing popularity of ADC and the launch of new R&D projects, the challenges encountered in ADC process development have become more prominent, such as the control of DAR (Drug-to-Antibody Ratio), aggregation control, removal of free toxins, and process scale-up stability. Among these, the removal of free toxins is particularly critical. In the conjugation process, to ensure complete reaction and a certain DAR value, excess toxin molecules are often added.

1.Ultrafiltration Process

The ultrafiltration process is an important component of the ADC purification steps, as it can achieve liquid exchange and impurity removal. It is widely used in various stages of ADC production. For instance, ultrafiltration is employed in processes such as liquid exchange before conjugation, preparation of crude ADC products, and post-conjugation purification.

Among these, the ultrafiltration step after conjugation is particularly critical.

• Free toxin residue affects the safety of the drug and needs to be removed to within a safe limit.

• Due to the unique characteristics of free toxins (including small molecule toxins and toxins from conjugation linkers), their removal efficiency is often low, requiring an increased number of dialysis/exchange cycles (e.g., over 20 times). Additionally, other measures such as quenching can be employed to enhance the removal efficiency of the ultrafiltration step to some extent,  but their applicability is limited.

• The starting material in the ultrafiltration step contains a certain proportion of organic solvents, which may have an impact on some antibodies/ADCs, thus requiring extensive optimization of the ultrafiltration process.

For certain projects, based on product characteristics and process development considerations, chromatography methods may also be chosen for toxin removal.

2.Chromatography Process

Compared to the ultrafiltration process, the chromatography process operates under milder conditions and has a smaller impact on the ADC product. It can remove free toxins as well as impurities such as aggregates. However, traditional chromatography media are often costly, and considering the impact of organic solvents on the media's lifespan, the process typically requires larger chromatography systems, which increases costs and places more demands on plant design and space.

Therefore, the current trend both domestically and internationally is to replace traditional media with membrane chromatography. Membrane chromatography offers higher capacity, faster flow rates, and reduced consumable needs, resulting in shorter process times. Additionally, it eliminates the need for column packing and unpacking steps, making the operation more convenient and flexible, while also requiring less space.

3.Activated Carbon Depth Filtration Process

Process optimization is always an ongoing endeavor. In addition to the application of ultrafiltration and membrane chromatography technologies, is there a more convenient, cost-effective, versatile, and efficient method?

The answer is yes. Activated carbon, a widely used traditional technology, also demonstrates unique advantages in ADC processes. It is gradually becoming a "dark horse" in ADC purification processes.

Activated Carbon

Activated carbon (AC) is a carbon-based material obtained through a series of processing treatments. It appears black or jet black in color and has a highly developed internal pore structure. With its large specific surface area and strong adsorption capacity, activated carbon is an excellent adsorbent.

Activated carbon can be classified based on its source into: wood-based activated carbon, fruit shell-based activated carbon, and reactivated carbon; and based on its physical form into: wood-based activated carbon, fruit shell-based activated carbon, and reactivated carbon.

And based on its physical form into: powder, granular, spherical, etc. Activated carbon itself has stable chemical properties, high mechanical strength, resistance to acids, alkalis, and high temperatures, and does not have any adverse effects on the product. Therefore, it is widely used in air purification, water treatment, decolorization and purification steps in the food, pharmaceutical, and MSG chemical industries, among others.

In the pharmaceutical field, activated carbon depth filters can not only be used for decolorization and endotoxin removal but also effectively remove free toxins and other related impurities in ADC processes. According to testing experience, a single step of activated carbon depth membrane filtration can effectively reduce toxin levels by tens to hundreds of times, with a wide range of process control parameters. Feedback from various projects indicates that activated carbon depth filtration also has broad applicability and can be effectively used for the removal of various toxin-related impurities.

With the increasing use of activated carbon and considerations such as the scale-up of the ADC process in later stages, the application validation documents for activated carbon in the ADC purification process differ from the conventional requirements. For example, the compatibility of certain organic solvents at higher concentrations and extractables need to be separately validated.

To address this need, Cobetter has conducted compatibility studies of activated carbon depth filters based on common reagents used in ADC processes, such as DMSO, DMF, etc. Additionally, we have also performed related validations for products commonly used in ADC processes, such as ultrafiltration membrane cassette, single-use products and related components, filter cartridges, etc.

Based on the potential risks of extractables/leachables, Cobetter has conducted relevant verifications in accordance with USP 665. Please contact Cobetter for the relevant documents and certificates.

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