Ben Locwin, Contributing Editor10.11.16
Antibody-drug conjugates (ADCs) represent a particularly important class of drug therapies with specialized effects. They enact their therapeutic benefits by their combination of antibody effects and drug chemistry effects. The antibody portion allows for rapid and very efficient site targeting, and the drug portion allows for a precise insertion of a drug molecule that otherwise couldn’t avoid causing more systemic effects. For example, the linkers between the antibody and drug components allow the cytotoxic drug molecules (payload) to be released in precise ways. These linkers include: hydrazones—releasing the drug in acidic conditions within lysozomes of the target cells; peptides—hydrolyzed enzymatically by lysosomal proteases; and disulfides—undergo intracellular reduction reactions.
Think about ADCs as a satellite deployment vehicle with booster rockets. When the booster has fulfilled its duty bringing the satellite close to orbit, the booster stage separates to allow the insertion of the satellite into orbit. Similarly, the ADC antibody allows for precise targeting of certain cells in the body for treatment, then the linker detachment allows the drug payload to precisely effect its treatment.
Challenges undergoing resolution
While the developability of ADCs retains many of the macro-scale features of typical antibodies, other nuances such as the drug-to-antibody (d2a) ratio, delivery efficacy in vivo, and conjugated stability must be properly approached. Advancing analytical methods are providing much more information about the molecules, and can often be properly specified by knowing which type of linker molecule is used, the site of the conjugation, and the qualities of the drug molecule. The typical heterogeneity of ADCs has been a target of fairly recent refinement, where site-specific conjugation of the drug to the antibody would lead to more homogenous ADCs, which have in some cases shown benefits in vivo compared with nonspecific modification of antibodies.
Outsourcing of ADCs
When looking for outsourcing of antibody-drug conjugates, it’s important to understand if the contract organization has competence with Quality by Design (QbD) principles. The proper approach to manufacturability necessarily has in its structure QbD, so that repeatability can be achieved because the process steps and substeps are well and properly characterized.
Also critical is to understand if the outsourcing organization has a well-established de-risking framework embedded in the fabric of their approach to ADC developability. This allows discussions to focus more on the long-term strategy of the drug and the market, as the minutiae that represent incremental risks would be already identified, characterized, and modeled in order to take the path of highest likely success. For example, newer methods of high-throughput screening have been able to produce demonstrable probabilistic improvements in finding antibody candidates less-likely to aggregate, which poses immunological risks in vivo.
De-risking ADCs and partnerships
The aggregate risk of the ADC plus the outsourcing relationship leads to the overall risk profile of successfully developing and producing an ADC. There is no way to separate and fully isolate processing steps of manufacturing an ADC from the partnership and relationship considerations. These include: aligning strategic goals between host and supplier, ensuring coherent relations, frequent and open feedback bi-directionally from host to supplier and supplier to host) as well as up and down both organizations.
Many technical and process-developmental issues have had at their root cause something as simple as communication gaffes between organizations, documentation mishaps, or misinterpretation of particular business or operational outcomes. Many of these are very subjective and incredibly consequential. Stepping back and ensuring the relationship is what was expected, that the people are doing what is intended and have proper vehicles through which to elevate concerns or defects such as through standardized work and a real-time defect alert and resolution system, can lead to outsourcing of complex ADCs that is very successfully undertaken. The focus can then be put back on the ADC processes themselves to ensure they are as efficient and effective as possible, and are constantly evolving and improving to provide patients access to safer, more efficacious drug treatments.
Ben Locwin
Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com.
Think about ADCs as a satellite deployment vehicle with booster rockets. When the booster has fulfilled its duty bringing the satellite close to orbit, the booster stage separates to allow the insertion of the satellite into orbit. Similarly, the ADC antibody allows for precise targeting of certain cells in the body for treatment, then the linker detachment allows the drug payload to precisely effect its treatment.
Challenges undergoing resolution
While the developability of ADCs retains many of the macro-scale features of typical antibodies, other nuances such as the drug-to-antibody (d2a) ratio, delivery efficacy in vivo, and conjugated stability must be properly approached. Advancing analytical methods are providing much more information about the molecules, and can often be properly specified by knowing which type of linker molecule is used, the site of the conjugation, and the qualities of the drug molecule. The typical heterogeneity of ADCs has been a target of fairly recent refinement, where site-specific conjugation of the drug to the antibody would lead to more homogenous ADCs, which have in some cases shown benefits in vivo compared with nonspecific modification of antibodies.
Outsourcing of ADCs
When looking for outsourcing of antibody-drug conjugates, it’s important to understand if the contract organization has competence with Quality by Design (QbD) principles. The proper approach to manufacturability necessarily has in its structure QbD, so that repeatability can be achieved because the process steps and substeps are well and properly characterized.
Also critical is to understand if the outsourcing organization has a well-established de-risking framework embedded in the fabric of their approach to ADC developability. This allows discussions to focus more on the long-term strategy of the drug and the market, as the minutiae that represent incremental risks would be already identified, characterized, and modeled in order to take the path of highest likely success. For example, newer methods of high-throughput screening have been able to produce demonstrable probabilistic improvements in finding antibody candidates less-likely to aggregate, which poses immunological risks in vivo.
De-risking ADCs and partnerships
The aggregate risk of the ADC plus the outsourcing relationship leads to the overall risk profile of successfully developing and producing an ADC. There is no way to separate and fully isolate processing steps of manufacturing an ADC from the partnership and relationship considerations. These include: aligning strategic goals between host and supplier, ensuring coherent relations, frequent and open feedback bi-directionally from host to supplier and supplier to host) as well as up and down both organizations.
Many technical and process-developmental issues have had at their root cause something as simple as communication gaffes between organizations, documentation mishaps, or misinterpretation of particular business or operational outcomes. Many of these are very subjective and incredibly consequential. Stepping back and ensuring the relationship is what was expected, that the people are doing what is intended and have proper vehicles through which to elevate concerns or defects such as through standardized work and a real-time defect alert and resolution system, can lead to outsourcing of complex ADCs that is very successfully undertaken. The focus can then be put back on the ADC processes themselves to ensure they are as efficient and effective as possible, and are constantly evolving and improving to provide patients access to safer, more efficacious drug treatments.
Ben Locwin
Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com.
