Innovations contributing to the reemergence of antibody drug conjugates

Antibody-drug conjugates (ADCs), agents formed by linking cytotoxic payloads to monoclonal antibodies, hold immense potential to target a wide range of hematologic and solid tumors. Paul Ehrlich first proposed the concept for ADCs in 1904, shortly after antibodies were discovered. He imagined developing “magic bullets” composed of pathogen-targeted antibodies bound to toxins, which could eliminate a pathogen without harming healthy tissues. Subsequently, ADCs emerged from adapting Ehrlich’s ideas to the field of chemotherapy. If chemotherapies were linked to cancer-targeted antibodies, they could deliver treatment specifically to cancer cells, eradicating the cancer while sparing healthy tissue.

However, ADC development has since been complicated by several overarching challenges: (1) the lack of universal, cancer-specific antibodies; (2) the challenge of balancing an ADC’s tolerability and efficacy; (3) ADC provocation of a patient’s immune response; and (4) cancer developing mechanisms of resistance. At first, these challenges appeared to be nearly insurmountable. After the first ADC approval in 2000, only two additional ADCs received approval until 2017. Meanwhile, over 90 ADC candidates have failed during clinical trials.

Now, however, ADCs are experiencing a reemergence in oncology therapeutic development. Of the 15 ADCs now approved, 12 received approval by the United States Food and Drug Administration in the last seven years, and over 150 ADCs are presently in clinical development. Accelerated approvals of ADCs reflect a continuing advancement of ideas and techniques that are helping to overcome the challenges faced by first-generation ADCs.

For example, one challenge faced by ADC developers involves balancing a payload’s ability to eradicate cancer cells with an ADC’s stability and tolerability while in the bloodstream or when taken up by healthy cells. A key recent breakthrough has been an improved comprehension of linker chemistry. A new class of linkers that cleave only under conditions found within tumor microenvironments can now minimise off-target effects.

Refined manufacturing processes have also improved ADC’s stability and efficacy. Traditional manufacturing methods utilise bioreactors, which must be cleaned between batches and risk introducing viral and bacterial contamination. In turn, contamination can provoke an immune response to the ADC, reducing its stability in the bloodstream. The sector is now moving away from multi-use bioreactors toward presterilised, disposable, component-based toolsets, which reduce contamination risk while allowing for faster and more flexible production.

The intersection of advances in ADC development brightens the drug class’s future. ADC developers are now combining innovations that optimise ADC’s discrete components — the antibody, the linker, the target, and the payload — to make therapies that are safer, more targeted, and more potent. In addition, developers are experimenting with new methods of ADC manufacturing, administering ADCs earlier in a patient’s treatment pathway, and developing ADCs in combination with other targeted and immunotherapies. With ADCs emerging as one of the fastest-growing segments of pharmaceuticals in 2024, the number of FDA approvals are likely to accelerate, revealing new treatment pathways and new problems to solve along the way.

Learn more about ICON’s services and how we can support your ADC clinical development, please contact us.

This article was first published on Clinical Oncology Daily on 3 June 2024.

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