For a novel antibody drug conjugate (ADC) to progress to the clinic many challenges need to be addressed before reaching the final ADC drug product meant for patients. While much focus is given to complex conjugation chemistry and purification processes for ADC production, the linker-payload presents its own unique challenges that need to be overcome for the successful assembly of ADCs and their use as valuable therapeutics.
The linker-payload, which generally consists of a highly potent chemotherapy attached to linker has the multipurpose of attaching the payload to the antibody, providing stability to the structure and enabling release of its payload at the target site of disease. The current landscape of linkers and payloads used in ADCs continues to expand meaning there is no single solution to the development and manufacture of these highly complex chemical compounds. Linker-payloads typically fall into two categories; those produced by semi-synthesis from payloads derived from natural sources such as fermentation, and those resulting from total synthesis beginning with less complex commercially available building blocks. Both paths have unique challenges which should be carefully considered to ensure the right molecular approach and design is applied to meet the target product profile of the ADC. Both strategies for creating a linker-payload deal with common problems, and both have proven successful. These approaches will be covered in this seminar exploring how they were used and why.
Once a novel linker-payload is designed, a rational development plan should be put in place to ensure effective linking to the small molecule (cargo) in a scalable process. Many factors contribute to the chosen strategy to balance issues such as exposure of the drug to degradation pathways and high drug loading leading to insolubility and clearance. Different tools, reagents, processes and resources can be applied to optimal linker-payload and design and manufacture.
Once the linker payload has been designed, developed and a synthetic route for an efficacious conjugate is established, the research-based process needs be transferred and scaled-up for IND enabling tox studies and first in human clinical trials. Consideration of the planned manufacturing scale and critical quality attributes needed for the ADC at the start of development will help define the necessary unit operations. Expertise and experience play a crucial role in the journey to the clinic which we hope to convey our learnings as part of this seminar.
In this webinar, we will review the pros and cons of semi-synthetic and synthetic linker payloads as well as discuss the considerations that should be taken when conjugating your linker payload to its antibody, with the ultimate goal of generating successful clinical material. Examples that illustrate how to overcome the challenges of linker payloads will be presented.
Key Learning Objectives
- Discover the pros and cons of semi-synthetic linker payloads
- Discover the pros and cons of synthetic linker payloads
- What to consider in conjugating your linker payload to your antibody
- Considerations in combining small and large molecules in the GMP environment leading to successful clinical material.
