ADC Antibody drug conjugates CDMO Market

Antibody-Drug Conjugates (ADCs) – known as ‘the guided missiles of cancer therapy’ – are forecast to drive robust double-digit growth in contract development and manufacturing over the coming years, positioning them as a pivotal force in the biopharmaceutical landscape. This trajectory is propelled by their enhanced targeting capabilities in cancer treatment and the increasing prevalence of oncological disorders worldwide.

ADCs represent a cutting-edge class of biopharmaceutical drugs that combine the specificity of monoclonal antibodies with the potent cell-killing activity of cytotoxic small molecule drugs. They are ‘guided missiles’ due to their precise targeting of cancer cells whilst minimising damage to healthy tissues, addressing one of the longstanding challenges in oncology treatment.

The surging interest in ADCs is evident from the flurry of recent high-profile acquisitions and partnerships in the sector. Pfizer’s $43 billion acquisition of Seagen in late 2023 underscores the immense potential and value attributed to ADC technology. This deal, along with other significant transactions such as AbbVie’s $10 billion acquisition of ImmunoGen and Johnson & Johnson’s $2 billion purchase of Ambrx Biopharma, signals a transformative phase in the biopharmaceutical industry’s approach to cancer therapeutics.

However, the path to bringing ADCs to market is fraught with complexities. The intricate manufacturing process, involving the production of antibodies, cytotoxic payloads, and their subsequent conjugation, presents significant challenges.

These hurdles, coupled with stringent regulatory requirements and the need for specialised expertise, have led to an increased reliance on Contract Development and Manufacturing Organisations (CDMOs) within the ADC space.

This report provides an overview of ADC contract manufacturing, the growth opportunities that are driving investment and innovation in this field and the challenges that both drug developers and manufacturers must navigate.

This infographic highlights contract development and manufacturing organisations who provide Antibody-Drug Conjugate services to biopharma customers:

 

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What are Antibody-Drug Conjugates?

Antibody-Drug Conjugates (ADCs) represent a pioneering class of biopharmaceutical drugs that combine the specificity of monoclonal antibodies with the potent cell-killing activity of cytotoxic small molecule drugs. 

These complex molecules are designed to deliver highly potent cytotoxic agents directly to cancer cells whilst sparing healthy tissues, thereby potentially improving the therapeutic index of anticancer treatments.

At their core, ADCs consist of three primary components:

1. Monoclonal antibody: This serves as the targeting mechanism, designed to recognise and bind to specific antigens expressed on the surface of cancer cells.

2. Cytotoxic payload: This is a potent small molecule drug, often too toxic for systemic administration on its own, which is responsible for killing the cancer cells once internalised.

3. Linker: This chemical structure connects the antibody to the cytotoxic payload, playing a crucial role in the stability of the ADC in circulation and the controlled release of the payload once inside the target cell.

The seamless integration of these components results in a ‘magic bullet’ approach to cancer treatment, aiming to overcome the limitations of traditional chemotherapy by enhancing efficacy and reducing systemic toxicity.

How do ADCs work?

The mechanism of action for ADCs involves several key steps, each critical to their therapeutic efficacy:

1. Targeted Binding: The monoclonal antibody component of the ADC selectively binds to specific antigens overexpressed on the surface of cancer cells. This targeting mechanism is crucial for the precision of ADC therapy.

2. Internalisation: Once bound to the target antigen, the ADC-antigen complex is internalised into the cancer cell through endocytosis. This process effectively delivers the entire ADC inside the cell.

3. Lysosomal Processing: Inside the cell, the ADC-antigen complex is typically trafficked to lysosomes, where the acidic environment and specific enzymes begin to break down the complex.

4. Payload Release: The linker, designed to be stable in circulation but labile under specific intracellular conditions, is cleaved. This releases the cytotoxic payload within the cancer cell.

5. Cell Death: The free cytotoxic drug then exerts its cell-killing effects, typically by disrupting critical cellular processes such as DNA replication or microtubule assembly, leading to apoptosis of the cancer cell.

6. Bystander Effect: In some cases, depending on the nature of the payload and linker, the released cytotoxic drug may also diffuse into neighbouring cells, potentially killing nearby cancer cells that may not express the target antigen.

This multi-step process allows ADCs to deliver potent cytotoxic agents specifically to cancer cells, potentially maximising efficacy whilst minimising systemic toxicity.

 

Conditions treated with ADCs

The versatility of ADCs lies in the ability to target various tumour-associated antigens, allowing for potential application across a wide range of cancer types.

ADCs have shown particular promise in the treatment of various cancers, both haematological malignancies and solid tumours.

Some of the key conditions where ADCs are currently used or under investigation include Haematological Cancers (such as Lymphomas and Myeloma), Solid Tumours, Melanomas and other cancer types. As research progresses, the list of conditions treatable with ADCs is likely to expand.

 

Recent M&A and deal-making in the ADC market

The ADC market has witnessed a surge in mergers, acquisitions, and strategic partnerships in recent years, underscoring the growing importance and potential of this therapeutic approach. Some of the most significant deals include:

Pfizer’s Acquisition of Seagen (December 2023):

   In a landmark deal valued at $43 billion, Pfizer acquired Seagen, a leader in ADC technology. This acquisition significantly bolstered Pfizer’s oncology portfolio, adding four approved medicines, including three ADCs: Adcetris (brentuximab vedotin), Padcev (enfortumab vedotin), and Tivdak (tisotumab vedotin). This deal represents one of the largest acquisitions in the pharmaceutical industry in recent years and highlights the strategic importance of ADCs in the oncology space.

AbbVie’s Acquisition of ImmunoGen (February 2024):

   AbbVie’s $10 billion acquisition of ImmunoGen marked another significant move in the ADC market. This deal brought AbbVie Elahere (mirvetuximab soravtansine-gynx), an FDA-approved ADC for platinum-resistant ovarian cancer, along with a promising pipeline of ADC candidates.

3. Johnson & Johnson’s Acquisition of Ambrx Biopharma (March 2024):

   In a $2 billion deal, Johnson & Johnson acquired Ambrx Biopharma, gaining access to several clinical and preclinical ADC programs targeting multiple cancer indications. This acquisition underscores J&J’s commitment to expanding its presence in the ADC market.

Merck and Daiichi Sankyo Partnership (October 2023):

 This $22 billion global development and commercialisation agreement focuses on three of Daiichi Sankyo’s ADC candidates: patritumab deruxtecan, ifinatamab deruxtecan, and raludotatug deruxtecan. The deal structure, including a $4 billion upfront payment and potential additional payments of up to $16.5 billion, reflects the high value placed on promising ADC candidates.

Bristol-Myers Squibb and Systimmune Partnership (2024):

 A projected $8.4 billion deal to co-develop and co-commercialise Systimmune’s BL-B01D1 for treating metastatic or unresectable non-small-cell lung cancer, further demonstrating the industry’s confidence in ADC technology.

These deals, among others, illustrate the intense interest and substantial investments being made in the ADC space, reflecting the industry’s recognition of ADCs as a key growth area in oncology therapeutics.

 

Recently launched products and pipeline candidates

The ADC market has seen several successful product launches in recent years, with a robust pipeline promising further advancements. Recently launched products include: 

• Elahere (mirvetuximab soravtansine-gynx) – ImmunoGen/AbbVie: Approved in 2022 for platinum-resistant ovarian cancer.
• Tivdak (tisotumab vedotin) – Seagen/Pfizer: Approved in 2021 for recurrent or metastatic cervical cancer.
• Trodelvy (sacituzumab govitecan) – Gilead Sciences: Approved in 2020 for triple-negative breast cancer and urothelial cancer.

The pipeline for ADCs remains robust, with over 260 candidates currently in clinical trials across various stages of development. This pipeline diversity spans a wide range of cancer types and targets, promising continued innovation and potential breakthroughs in cancer treatment.

Promising pipeline candidates include:

• Datopotamab deruxtecan – Daiichi Sankyo/AstraZeneca: In late-stage development for breast and lung cancers.
• ARX517 – Ambrx Biopharma/Johnson & Johnson: In development for prostate cancer.
• STRO-002 – Sutro Biopharma: In clinical trials for ovarian and endometrial cancers.
• RC88 (camidanlumab tesirine) – ADC Therapeutics: In development for Hodgkin lymphoma.

 

ADC Contract Manufacturing growth factors

The Antibody-Drug Conjugate (ADC) contract manufacturing market is poised for significant growth in the coming years, driven by increasing demand for targeted cancer therapies and advancements in ADC technology.

Several key factors are propelling the growth of the ADC contract manufacturing market:

1. Rising cancer prevalence

The global increase in cancer cases is driving demand for more effective and targeted therapies. According to the World Health Organization, cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. This growing disease burden is creating a strong market for ADCs, which offer a more targeted approach to cancer treatment.

2. Advancements in ADC technology

Ongoing innovations in antibody engineering, linker technology, and payload development are expanding the potential applications of ADCs. These advancements are improving the efficacy and safety profiles of ADCs, making them more attractive to both pharmaceutical companies and regulatory bodies.

3. Increasing FDA approvals

The growing number of FDA approvals for ADC therapies is boosting market confidence and driving further investment in this area. As of 2023, there were over a dozen FDA-approved ADCs on the market, with many more in late-stage clinical trials.

4. Rising outsourcing trend

The complex nature of ADC manufacturing, coupled with the high costs associated with establishing in-house capabilities, is driving pharmaceutical companies to outsource ADC production to specialised CDMOs. This trend is a significant growth driver for the contract manufacturing market.

5. Expanding application in solid tumours

While early ADCs were primarily focused on haematological cancers, recent advancements have expanded their application to solid tumours. This broadening of the therapeutic scope is opening up new market opportunities and driving growth.

6. Increasing investment and funding:

The flurry of high-value mergers, acquisitions, and partnerships in the ADC space, as detailed in the previous section, is injecting significant capital into the market. This investment is fuelling research, development, and manufacturing capabilities.

7. Growing preference for targeted therapies:

There is an increasing shift towards personalised medicine and targeted therapies in oncology. ADCs, with their ability to deliver cytotoxic payloads directly to cancer cells, align well with this trend.

 

Manufacturing challenges

Despite the positive growth outlook, the ADC contract manufacturing market faces several challenges including:

1. Manufacturing complexity

ADC production is a highly complex process involving multiple steps, each requiring specialised expertise and facilities. The complexity of manufacturing presents challenges in scale-up and can lead to high production costs.

Olon Group’s CEO, Paolo Tubertini, explains that “ADC class is highly promising and extremely challenging as well, as they require specific capabilities to handle different modalities with strict containment regulations.”

“This required high level of control ensures the safest environment for ADC payload-linker production and product integrity, that can only be reached leveraging over decades of expertise in containment for cytotoxic anticancer production, focusing on full control of cross-contamination, operator protection and extensive training” 

Olon Group recently acquired GTP Bioways, a French Biotech CDMO specialising in R&D Services, process development and production of mAbs, enzymes, proteins, nanodrugs, ADCs and F&F. Now part of Olon’s Biotech division, this integration enables the company to expand and diversify its technological offerings, supporting every stage of the product lifecycle.

 

2. Regulatory hurdles

The regulatory landscape for ADCs is complex, given their hybrid nature as both biologic and small molecule drugs. Navigating these regulatory requirements can be time-consuming and costly, potentially slowing market growth.

 

3. High development and production costs

The specialised nature of ADC manufacturing, coupled with the need for high-containment facilities for cytotoxic payload handling, results in significant costs. These high costs can be a barrier to entry for smaller companies and may limit the number of ADC projects that pharmaceutical companies can pursue simultaneously.

Firelli Alonso explained on a recent episode of the PharmaSource podcast that “ADC manufacturing is very challenging for CDMOs because they have to work in OEB-5 level facility because the toxin is so poisonous.”

“To work under OEB-5 manufacturers conditions, they have to be certified by company’s such as SafeBridge who can verify management and control of potent compounds. They need OEB capable facilities all the way from drug substance to drug product.”

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4. Technical challenges in ADC design:

Optimising the three components of an ADC (antibody, linker, and payload) to achieve the desired efficacy and safety profile remains a significant challenge. Issues such as payload attachment site selection, linker stability, and managing drug-to-antibody ratio can impact the success rate of ADC development.

5. Limited number of specialised CDMOs:

While the number of CDMOs offering ADC manufacturing services is growing, there is still a limited pool of organisations with the necessary expertise and facilities. This could potentially create bottlenecks in the manufacturing pipeline as demand increases.

Herman Bozenhardt explained that is his view “‘only five CDMOs are fit for purpose” when it comes to Antibody-Drug Conjugates. He said:

“The real issue is handling a highly potent compound. The process is no problem, it’s how you bring it into the facility and how you handle it.”

He highlights several critical considerations, including:

• Proper material handling and storage
• Contamination prevention
• Effective cleaning and neutralization procedures
• Facility design and air handling systems

6. Potential for off-target toxicity:

Despite their targeted nature, some ADCs have shown off-target toxicity in clinical trials. Addressing these safety concerns is crucial for the continued growth and acceptance of ADC therapies.

7. Competition from other emerging cancer therapies:

ADCs face competition from other innovative cancer treatments, such as cell therapies, cancer vaccines, and bispecific antibodies. The success of these alternative approaches could potentially impact the growth of the ADC market.

8. Intellectual property challenges:

The complex nature of ADCs often involves multiple patents covering various aspects of the molecule. Navigating this intellectual property landscape can be challenging and may lead to legal disputes, potentially slowing market growth.

 

Overview of the ADC manufacturing process

The manufacturing process for ADCs is highly complex and requires specialised facilities, equipment, and expertise due to the toxicity of the payload.

The process can be broadly divided into several key steps:

1. Antibody Production:

   – The process begins with the production of the monoclonal antibody, typically using mammalian cell culture techniques.

   – This involves cell line development, upstream processing (bioreactor cultivation), and downstream processing (purification).

   – The antibody must be produced to meet specific quality attributes that will allow for efficient conjugation later in the process.

2. Cytotoxic Payload Manufacturing:

   – The cytotoxic payload is typically a small molecule drug synthesised through complex organic chemistry processes.

   – This step requires high-containment facilities due to the potent nature of these compounds.

   – Payload manufacturing often involves multi-step syntheses and extensive purification processes.

3. Linker Production:

   – Linkers are synthesised through chemical processes and are designed to be stable in circulation but labile under specific conditions within target cells.

   – The choice of linker can significantly impact the pharmacokinetics and efficacy of the final ADC.

4. Conjugation:

   – This critical step involves attaching the cytotoxic payload to the antibody via the linker.

   – Conjugation methods can vary (e.g., lysine conjugation, cysteine conjugation, site-specific conjugation) and significantly impact the final product’s characteristics.

   – This step requires precise control of reaction conditions to achieve the desired drug-to-antibody ratio (DAR).

5. Purification of the ADC:

   – After conjugation, the ADC must be purified to remove any unconjugated antibodies, free drug, and other process-related impurities.

   – This typically involves chromatography techniques and may include ultrafiltration/diafiltration steps.

6. Formulation:

   – The purified ADC is formulated into a stable liquid or lyophilised form suitable for administration.

   – This step involves careful selection of buffer components and excipients to ensure product stability.

7. Fill-Finish:

   – The final formulated product is filled into vials or syringes under aseptic conditions.

   – This step may include lyophilisation for some ADC products.

8. Analytical Testing and Release:

   – Throughout the manufacturing process, extensive analytical testing is performed to ensure product quality and consistency.

   – Final product testing and release involve a comprehensive panel of tests to confirm identity, purity, potency, and safety.

Each of these steps requires specialised expertise and equipment, making ADC manufacturing one of the most complex processes in the biopharmaceutical industry.

 

Key considerations when choosing an ADC CDMO partner

When selecting a CDMO partner for ADC manufacturing, pharmaceutical companies should consider several critical factors:

1. Technical Expertise: The CDMO should have demonstrated experience in ADC manufacturing, including expertise in antibody production, payload synthesis, conjugation chemistry, and analytical methods specific to ADCs.

2. Regulatory Compliance: The CDMO must have a strong track record of regulatory compliance, including successful inspections by agencies like the FDA and EMA.

3. Quality Systems: Robust quality management systems are crucial, given the complexity of ADC manufacturing and the potential impact on patient safety.

4. Capacity and Scale-up Capabilities: The CDMO should have the capacity to meet current needs and the ability to scale up production as the ADC progresses through clinical trials and towards commercialisation.

5. Containment Capabilities: Given the high potency of ADC payloads, the CDMO must have appropriate containment facilities and safety protocols in place.

6. Analytical Capabilities: Comprehensive analytical services are essential for characterising ADCs and ensuring product quality and consistency.

7. Supply Chain Management: The ability to manage complex supply chains, including the sourcing of specialised raw materials, is crucial for ADC manufacturing.

8. Flexibility and Responsiveness: The CDMO should be able to adapt to changes in project requirements and respond quickly to challenges that may arise during development and manufacturing.

9. Intellectual Property Protection: Strong systems and protocols for protecting proprietary information and technologies are essential.

10. Geographic Location: The location of the CDMO can impact logistics, regulatory considerations, and the ability to oversee operations effectively.

11. Financial Stability: The long-term financial stability of the CDMO is important to ensure continuity of manufacturing operations throughout the product lifecycle.

12. Technology Transfer Capabilities: Efficient technology transfer processes are crucial for smooth transitions between development stages or from in-house to outsourced manufacturing.

13. Fill-Finish Capabilities: If end-to-end services are desired, the CDMO’s capabilities in formulation development and fill-finish operations should be evaluated.

14. Track Record in ADC Development: Previous success in bringing ADC products through clinical development and to market can be a valuable indicator of a CDMO’s capabilities.

15. Collaborative Approach: A CDMO that fosters open communication and acts as a true development partner can add significant value beyond mere manufacturing services.

By carefully evaluating these factors, pharmaceutical companies can select a CDMO partner that aligns with their specific needs and objectives in ADC development and manufacturing.

For more advice on outsourcing to contract manufacturers, make sure to take our Outsourcing Fundamentals eLearning course.