As promising therapeutic agents for treating oncology indications, antibody-drug conjugates (ADCs) have become prominent in the biopharmaceutical market in recent years. The approval of the first ADC in 2000 by the Food and Drug Administration (FDA) to treat acute myeloid leukaemia prompted a move in the oncology space toward targeted cancer therapy.1 As of June 2023, 11 ADCs are available on the market, having gained the FDA approval for treating a range of cancers, including leukaemia, lymphoma, and cervical and ovarian cancer.2 With the global ADC market valued at $8.6 billion in 2022, and forecast to reach $23.9 billion by 2032, research into this promising drug method will continue to transform the therapeutic landscape.3 However, the complexity of ADCs means their design, development, and manufacturing are multifaceted, with many challenges that must be overcome to successfully deliver these therapies to the patients who need them.
In this article, Louise Duffy, Chief Technical Officer (CTO), and Campbell Bunce, Chief Scientific Officer (CSO) at Abzena, explore how innovation in the biopharma sector is driving the development of novel ADCs to treat indications beyond cancer. They also examine the difficulties that drug developers and manufacturers must overcome to ensure ADC development and manufacturing success.
Constructing an ADC
ADCs contain three separate components, including:1
• The antibody: Traditionally a monoclonal antibody (mAb), this part of the ADC is key to specifically binding the target antigen with high binding affinity.
• The linker: This component connects the toxic payload to the antibody. Ensuring that it remains bound during circulation, the linker is specifically designed to maintain the stability of ADC in circulation and release the payload at the target site. A cleavable linker will take advantage of the environmental differences between the systemic circulation and the tumour cells to accurately release the drug. Alternatively, a non-cleavable linker will rely on the catabolic digestion of the whole ADC by proteases to release the payload.
• The toxic payload: These highly potent materials (HPAPI) exert cytotoxicity onto the cells targeted.
The design of these innovative therapies demands extensive teamwork and innovation across various disciplines and areas of expertise, to ensure the ADC is designed for optimal function and stability while enabling scalability, manufacturability, intellectual property, and funding.
Navigating the ADC Development
ADCs represent a promising option when developing drugs for oncology. As a result of the rising interest in this drug method within the biopharmaceutical sector, there are currently over 100 ADCs in clinical trial studies.4
The design and development of ADCs begins following the identification of a suitable molecular target. Typically, the drug target is chosen based on its differential expression on the cells of interest, e.g. tumour cells that will allow them to be pinpointed by the ADC. Drug developers will then conduct a comprehensive evaluation of the safety implications of aiming at that particular target or pathway before initiating ADC design.
In addition to the careful design of each element, the assembly of all components is a key part of the ADC development and will significantly impact the drug performance. The antibody, the linker and the payload, all three elements need to be brought together in a way that produces an optimal form of the ADC, one that is stable, can be manufactured at scale, and is capable of delivering the required therapeutic effect safely. The key to achieving this is considering the target product profile (TPP) of the final ADC product when designing each element. As a result, the developers with a holistic overview of the end objective from the earliest development stages are best positioned for success.
