ADCs present compelling opportunity to deliver crucial drugs, particularly for oncology medications

ADCs offer improved pharmacokinetics, safety profiles, and overall therapeutic efficacy. This capability enables clinicians to navigate within the therapeutic index with greater confidence, minimising concerns about adverse events. Dr Kenneth Barr, Senior Vice President, Discovery Services, Syngene International and Jayashree Aiyar, Vice President, Discovery Biology, Syngene International reveals more

What are the primary drivers behind the growth of the Antibody Drug Conjugates (ADC) market? What makes ADCs so appealing and likely to experience further growth? How has this landscape evolved in recent times?

The side effects and toxicity profiles of a majority of cancer drugs arise due to their lack of specificity in targeting the tumour while sparing healthy cells. ADCs present a compelling opportunity to deliver crucial drugs, particularly for oncology medications, precisely to tumour sites. This process involves synthesising a molecule by merging an antibody with a cytotoxic drug, thereby enabling targeted delivery to the tumour. While the drug alone might lack specificity in action, its fusion with the antibody creates a focussed therapeutic entity.

As the antibody reaches the tumour, it carries the cytotoxic drug, which then acts to eradicate the tumour cells. This mechanism highlights the efficacy of these drugs with lower side effects.

Considering the potency of cytotoxic drugs, their ability to inflict damage necessitates precise targeting of the tumour site, rather than indiscriminate action throughout the body. By achieving this targeted delivery, ADCs offer improved pharmacokinetics, safety profiles, and overall therapeutic efficacy. This capability enables clinicians to navigate within the therapeutic index with greater confidence, minimising concerns about adverse events. Such advantages form the crux of the appeal of the ADC market.

Significant strides have been made in understanding the intricacies of delivering antibody conjugates and refining ADC production. Notably, advancements have focussed on preserving the functional integrity of the antibody’s active site during drug conjugation. Innovations include the development of cleavable conjugates, where the drug detaches upon encountering specific enzymes in the tumour microenvironment, leading to a more localised effect. These developments underscore the ongoing evolution of ADC technology, poised to drive further growth in the market. The introduction of non-toxic payloads, mainly immune modulators, offers an attractive alternative for both cancer and autoimmunity.

While ADCs have been in existence for some time, the market’s expansion has accelerated notably in recent years. Remarkably, nine drugs have garnered approval within the past five years alone, signalling a significant growth trajectory and highlighting the burgeoning opportunities within the ADC market.

What are the outsourcing challenges in this domain?

Key challenges include the identification of targets that are exquisitely specific and selective to the tumour tissue. This often restricts the types of tumours one can target, but great breakthroughs are being made towards the identification of novel targets for specific tumour types. IP around linkers and payloads may be another. And finally, the cost of goods. When considering outsourcing within the context of supply chain management, several critical components come into play. Firstly, there is the need for an organisation capable of producing the payload, the linker, and the antibody, as well as assembling them into a conjugate. Effective supply chain management is paramount to ensure seamless coordination across these various stages.

Moreover, since these drugs often serve as the active component of the small molecule in ADC conjugates, they are classified as highly potent compounds. Consequently, specialised facilities capable of handling such substances, categorised as band 4 or band 5 compounds, are essential within a highly potent API manufacturing environment. These capabilities represent additional requirements beyond the initial set mentioned earlier.

It is also crucial to ponder upon the specific chemistry involved in the process, particularly regarding the introduction of the appropriate linker. Achieving precise delivery of a cell-killing agent demands a deep understanding of bio-conjugation technology. Therefore, a competent CRDMO undertaking this task must possess a diverse skill set encompassing both biology and chemistry. Deserting these aspects could result in unintended behaviour from the ADC due to subpar manufacturing capabilities, accentuating the importance of expertise and experience in this field.

Are there specific regulatory and quality standards to consider for ADC manufacturing?

ADCs intended for clinical trials or commercial use are manufactured as Good Manufacturing Practice (GMP) materials. Hence, the Contract Development and Manufacturing Organization (CDMO) must possess the requisite GMP qualifications and capabilities for producing small molecules, large molecules, and their conjugates. This aspect is essential. Additionally, development organisations involved in the chemistry and bio-conjugation aspects of ADC production must have a solid understanding of the quality control assays necessary for batch release. These assays differ from those typically employed for individual components like small molecules, linkers, or antibodies.

A key consideration in manufacturing is the maintenance of a consistent Drug-to-Antibody (DAR) ratio between batches. This is better achieved through site-specific conjugations or very stringent protocols.

Incorporating these new quality control measures adds complexity to the manufacturing process. Therefore, the CDMO must demonstrate an additional level of capability to meet these requirements effectively. Without these capabilities, outsourcing this component of ADC manufacturing becomes impractical. Hence, adherence to current Good Manufacturing Practice (cGMP) standards is imperative for meeting regulatory expectations in ADC manufacturing.

What are the emerging trends and innovations in ADC outsourcing?

Considerable interest is currently focussed on exploring novel linkers and payloads, representing a significant area of research and development. New ADC modalities, including Ab-PROTAC molecules, Ab-oligo and Ab-peptide conjugates, along with non-toxic payloads, are expanding the horizons of ADC modalities to areas beyond cancer. Syngene, as an organisation, collaborates with ADC manufacturers and developers across the entire spectrum, from research to development to manufacturing.

On the antibody front, there is ongoing exploration into utilizing bi-specific antibodies to enhance specificity and antitumor activity at lower thresholds. Additionally, various novel linker technologies are being explored, including multi-linker technologies, quaternary ammonium linkers, peptide linkers, and cleavable linkers to name a few. These linkers are designed to either carry higher payloads or enable localised release within the tumour environment through enzymatic activity or other mechanisms.

Furthermore, advancements in conjugation technology are driving innovation in ADC outsourcing. Novel conjugation technologies are being explored to address issues related to potency, solubility, and metabolism. For instance, approaches like Hydrazides and ThioBridges utilisze disulfide bonds within antibodies for conjugation, resulting in a more targeted placement of the linker and payload away from the antibody’s active site.

Overall, innovation is underway in both linker technologies and conjugation methods, reflecting a dynamic landscape within ADC outsourcing.

Are there specific therapeutic areas within oncology where ADC outsourcing is particularly prevalent?

The prominence of ADC outsourcing is less about the type of antibody used and more about the application of chemistry and biology. Numerous approved antibody-drug conjugates target conditions such as leukaemia, multiple myeloma, cervical cancer and ovarian cancer, showcasing a broad spectrum of targeted tumour types.

From a contract manufacturing standpoint, the emphasis lies in ensuring the availability of capabilities for the desired conjugation processes rather than focusing on the specific tumour being targeted. This approach underscores the importance of versatile manufacturing capabilities that can accommodate diverse therapeutic areas within oncology.

How does the cost-effectiveness of ADC outsourcing compare to in-house development and manufacturing?

Comparing the cost-effectiveness of developing and manufacturing ADCs involves considering various perspectives. Firstly, there is the development of technologies, where investments are required to establish small-scale or pilot-scale processes for manufacturing antibody conjugates and their components. While this initial phase does not demand a Good Manufacturing Practice (GMP) facility, significant setup costs are incurred. Transitioning to routine manufacturing in a GMP facility entails substantially higher capital expenditure (CapEx) and operating costs. This phase involves conducting supporting studies such as quality controls, payload assessments, and purification analyses, adding to the overall expenses.

Moreover, setting up an in-house high-potency Active Pharmaceutical Ingredient (API) facility imposes substantial investments due to the stringent containment requirements and specialised equipment involved. The decision to invest in such facilities hinges on the anticipated utilisation, as low utilisation rates may render in-house production economically unviable.

Comparatively, outsourcing ADC manufacturing presents an attractive option due to the lower initial investment required. The level of investment for ADC production exceeds that for manufacturing antibodies or routine small molecules. Leveraging the expertise and infrastructure of CDMOs allows for more efficient utilisation of facilities and cost savings.

In addition to this, there is potential in the biosimilar market, with players exploring opportunities in ADCs. This avenue offers an appealing opportunity for newcomers to enter the ADC space by collaborating with established CDMOs, thus avoiding the need to build the technology from scratch. Therefore, while in-house development may offer control over the entire process, outsourcing provides a cost-effective alternative, particularly for organisations seeking to minimise upfront investments and leverage existing expertise and infrastructure.

Has Syngene done any work on ADC? Anything you like to share?

Syngene has been actively involved in the development of ADCs, a field showing great promise in targeted cancer therapy. ADCs consist of monoclonal antibodies engineered to bind specifically to cancer cells, coupled with potent chemotherapy agents through a linker. This targeted approach enables the selective destruction of cancer cells while minimising damage to healthy tissue, thereby enhancing treatment efficacy and reducing adverse effects.

In our pursuit of advancing ADC technology, Syngene has focused on developing next-generation ADCs tailored to meet the evolving needs of cancer treatment. One key aspect of our innovation involves the design of dual-binding sites on antibodies. This modification enhances the precision with which ADCs target cancer cells and facilitates the internalisation of cytotoxic drugs, ultimately improving treatment outcomes.

Additionally, Syngene has pioneered the incorporation of non-cytotoxic immunologic payloads into ADCs. These payloads are designed to stimulate the body’s innate immune system, empowering it to mount a more robust response against cancer cells. This innovative approach holds promise for enhancing the body’s natural defences against cancer and augmenting the effectiveness of ADC therapy.

Furthermore, we have made significant progress in improving the stability of ADC molecules in circulation. Through innovative linker chemistry and site-specific conjugation strategies, we have achieved homogeneous ADCs with heightened stability, ensuring consistent and effective tumour targeting.

Our collaborative efforts with clients on the above strategies helped deliver a first-in-class ADC that is currently in Phase I trials in patients with advanced solid tumours. This novel ADC is anticipated to offer improved dosing accuracy and a superior safety profile compared to traditional ADCs, representing a significant leap forward in cancer treatment.