Imagine if you could take a highly toxic anticancer drug, and have it delivered at the cellular scale just where it needs to go, so that it doesn’t destroy healthy cells. This is the promise and the realm of Antibody Drug Conjugates (ADCs). ADCs are a type of drug therapy produced by conjugating a monoclonal antibody (the “antibody”) to a cytotoxic payload (the “drug”), designed to be able to specifically target cancer cells, and then deploy the payload directly to the target, reducing off-target effects and systemic exposure to the cytotoxic molecules. ADCs represent one of the fastest-growing regimes of oncology drugs, owing to their effectiveness in vivo.

Features of ADCs

Paul Ehrlich, the Nobel Prize-winning German scientist, and the one who coined the term “chemotherapy,” had the percept of an idea for targeted therapies more than a hundred years ago. It wasn’t until the 1980s that the first ADC trials were conducted, from which an incredible amount of knowledge was amassed. The very first ADC approved was gemtuzumab ozogamicin in the year 2000 for acute myeloid leukemia. It was a CD33 antibody conjugated to calicheamicin, which is a cytotoxic antibiotic.

ADCs have three main components: the antibody, the cytotoxic payload, and the linkers. While the antibody molecule and cytotoxic small molecule have been described, the linkers represent an additional challenge as part of the anatomy of an ADC. The linker is designed to make sure that the cytotoxic chemical stays attached to the antibody until its release at the site of the tumor cells. These are typically characterized in two forms: cleavable and non-cleavable linkers. The former linkers are “cleaved” through mechanisms such as hydrolysis, proteolysis, or reduction. While non-cleavables remain intact until lysosomal degradation has occurred. While the non-cleavable molecules can produce better potential safety profiles by not releasing too early, but one feature that theoretically occurs is “bystander killing,” where the cytotoxic payload is released near or around the tumor microenvironment, which can destroy cells supporting the tumor environment (potentially a helpful effect), and non-cleavable linkers seem to be associated with a lower theoretical potential for bystander killing.

Because of their monoclonal antibody (mAb) backbone, ADCs are regulated by the FDA as biologics, as opposed to small molecules or other types of molecules.

Even though ADCs are designed to have high specificity of targeting of cancer cells, there are risks of premature release of the cytotoxic element into the body, generating what are called off-target off-tumor adverse events. Indeed, the principal goal of ADCs is high specificity targeting of the correct environment, high deployed functional toxicity of the payload, and low overall toxicity systemically.

Amenability of ADCs to outsourcing

Most developers of ADCs elect to outsource the production of their therapeutic molecules, due to the rigorous challenges with this type of drug. For example, bioconjugation represents a critical component of the ADC molecule, and companies that don’t have the expertise and capacity to do this would need to outsource the development to effectively get this right. There are estimates that the outsourcing of ADCs to contract development and manufacturing organizations (CDMOs) will grow over the next decade with a compound annual growth rate (CAGR) of 13 percent, which is about twice the anticipated CAGR of the CDMO industry itself. If we run the math to its forecast limit, that will leave CDMOs with a higher proportion of ADCs overall (relative to other drugs) than they have now.

Below are some pros and cons that exist within the outsourcing realm for antibody drug conjugates.

Pros
•  Technical expertise – Outsourcing ADCs to CDMOs can help if the Sponsor doesn’t have the pre-existing infrastructure to do the complex manufacturing or testing that is required. ADCs have some challenging chemistry associated with them, and they require appropriate analytical expertise.
•  Regulatory expertise – As mentioned above, outsourcing ADCs helps to offset some of the needed expertise in the regulatory domain; ADCs are regulated as biologics, but are nevertheless different. CDMOs who do this work have the regulatory expertise to help ensure the production and testing are conducted appropriately to streamline a new drug’s path to successful approval.
•  Complex supply chain – ADCs have a relatively more complex supply chain, and outsourcing their manufacturing allows the CDMOs to take on this work, which can be a core competency of theirs, leading to the potential for a higher success rate, and reduced overall costs to the Sponsor by reducing the potentials for internal errors.

Cons
•  Quality – It should be noted that the major players in the CDMO market continue to produce overall with very high quality; the drawback is monitoring and overseeing quality from afar when outsourcing to a CDMO. It adds logistical challenges compared with ensuring quality for internally produced drugs, particularly for a molecule as complex to manufacture as an ADC.
•  Formulation and manufacturing challenges – Platforms may not work, because of the idiosyncrasies of each ADC, and at the same time, manufacturing may involve a complex coordination and orchestration of several organizations handling intermediates. This necessarily ties into the quality element above.

Conclusion

Complex situations require innovative solutions. As Albert Einstein once opined, “The significant problems we face cannot be solved at the same level of thinking we were at when we created them.” ADCs are a complex production challenge but have offered, and demonstrated, great promise as a therapeutic agent. For this reason, they’re worth the effort to surmount formulation and production challenges, as well as clinical challenges. They also offer an approach to treatment that’s mechanistically different from the other treatments in the landscape, and this increases our overall odds of success in treating patients with various forms of disease.

Outsourcing doesn’t always represent the solution, but depending on the challenge, it can be a very effective solution for a number of reasons. And this has proven particularly true for antibody drug conjugates, which represent a novel treatment modality in our pharma armamentarium.

What remains true is that “Different isn’t always better, but better is always different.” 

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Contributing Editor Ben Locwin is a biotech executive and has worked on the development and developability of ADCs, and is optimistic about the expansion of this modality, both for its impacts on the industry for the better, as well as its direct benefit to patients in need. Ben writes Contract Pharma’s Clinically Speaking column, and has been featured in The Wall Street Journal, the Associated Press, Forbes, USA Today, NPR, and other top-tier media outlets.