Harry Palmer, Royal Commission of 1851 Industrial Fellow and PhD at University of Strathclyde, shares with DDW’s Megan Thomas how antibody-drug conjugates (ADCs) are revolutionising cancer treatment by offering targeted therapies with improved efficacy and reduced side effects, while addressing challenges in their development and paving the way for future innovations.

ADCs vs chemotherapy

Though Palmer acknowledges that traditional chemotherapy has had significant clinical benefits for patients, and that currently around 25% of cancer patients receive some form of chemotherapy, he also references the side-effects patients receiving chemotherapy can suffer from, which stems from the medicine’s inability to distinguish cancer cells from healthy cells.

“Where ADCs can change this downside of cancer treatment is by tethering, or ‘conjugating’, chemotherapeutic medicines to antibodies. These antibodies can recognise and bind to antigens – specific protein structures present on the surface of cancer cells. By leveraging the antibody’s selectivity for cancer cells, the chemotherapeutic medicine can be released at the site or even inside the cancer cell. This drives the chemotherapeutic medicine, or ‘payload’, towards the cancer cell with excellent selectivity, which can lead to improved tolerability and better patient outcomes.”

Advantages and challenges

“ADCs represent a new approach for targeted therapy, through combining existing chemotherapeutics with antibodies that selectively recognise cancer-cells”, says Palmer. “ADCs are more effective at targeting and killing cancer cells, and this greater efficacy allows for a lower dosage compared to traditional chemotherapy, leading to reduced side-effects.”

In addition to using existing chemotherapeutics, Palmer says the reduction in side-effects provided by ADCs has opened the door for the use of anti-cancer medicines with excellent anti-cancer activity but high rates of side effects when not administered as ADCs. He provides the example of ‘auristatins’, which inhibit cell division mechanisms and are now the most commonly used class of payload in clinically approved ADCs.

He concludes: “As patients’ cancers are understood better, ADCs offer an opportunity for a personalised treatment option, employing ADCs that target specific antigens present on a patient’s cancer cells and increasing the chances of a successful treatment.”

While ADCs have already shown great performance in clinical practice, Palmer acknowledges that there is still plenty of research to be done. He says: “In particular, developing and optimising methods to attach the payload to the antibody can be a lengthy process. The nature of the chemical linker between the drug and the antibody, as well as the number of payload drugs conjugated to the antibody, the drug-to-antibody ratio (DAR), are key features of ADCs which underpin many of their resulting pharmacological properties. Given the complexity of ADCs, exploring the impact of each individual component can be a lengthy process and can require making and testing hundreds of ADCs to understand which combination offers the best balance of safety and efficacy.”

Palmer says that scientists are now learning to understand better the process of conjugation, developing techniques to exert greater control over parameters such as the DAR, as well as understanding how the choice of linker structure can tune the properties of the resultant ADC. “Further research in these areas could enable greater chances of success for ADCs to reach and succeed in clinical practice”, he confirms.

Looking forward

“ADCs are one of the fastest growing drug modalities,” Palmer says. “It is always exciting to think where this growth will lead.”

One area which particularly excites Palmer is in developing novel techniques to control the conjugation process. He explains that the DAR is a key property to consider during the development of ADCs, but of growing significance is the precise site of payload conjugation on the antibody. “Research is beginning to unpick how the sites of conjugation can affect the properties of the resultant ADC, such as stability of the conjugation in the blood plasma and payload release rate once inside the cell. My own research is developing new strategies to enable site-selective payload conjugation, to fine-tune both the DAR and site of conjugation and produce ADCs with improved pharmacological properties.”

Another area Palmer hopes to see grow over the next decade is the expansion of ADCs into novel payload formats, such as multi-payload ADCs. He says: “By incorporating two or more payloads with distinct mechanisms of action into a single ADC, multi-payload ADCs could offer greater effectiveness of treatment. For example, by combining traditional payloads with immune-stimulating payloads, the body’s own immune response could be locally boosted at the cancer to work alongside the chemotherapeutic payload. Simultaneously benefitting from multiple different payload mechanisms of action may allow factors such as tumour resistance to be overcome.”

ADCs are also beginning to diversify into payloads beyond cytotoxic molecules, Palmer confirms. He provides an example of an area currently growing is degrader-antibody conjugates (DACs), a class of ADCs which feature PROTAC (proteolysis-targeting chimera) or molecular glue payloads conjugated to the antibody. He says: “Rather than causing cell death directly, these payloads lead to the targeted degradation of specific proteins within the cell, and expansion into novel classes of payload could allow ADCs to treat disease indications beyond oncology.”

Cancer indications

ADCs have already received approval for several different cancer indications. Palmer says: “The great benefit of ADCs as a modality is that by selecting different antibodies, different cancer types can be targeted.”

One form of cancer which has been successfully treated are haematological cancers such leukaemia and lymphoma, which Palmer says is in part due to a greater exposure of these cancers to ADCs circulating in the blood stream. He says: “ADCs have also been clinically approved for several solid tumour indications, and in particular have shown success in treating breast cancer, with three of the thirteen FDA-approved ADCs approved for its treatment.”

According to Palmer, a key target for the field will be the development of new antibodies targeting a wider range of antigens over-expressed by cancer cells, expanding the range of cancers which are treatable by ADCs.

Quality of life

As the development of new ADCs accelerates, and with greater research into understanding how to optimise their properties, Palmer says ADCs could offer a great improvement in the quality of life for patients both during and after receiving treatment. “Targeting cancer cells leads to more effective killing of the cancer cell, and could reduce the risk of long-term tumour relapse through enabling the use of more potent chemotherapeutic payloads.”

He elaborates on this, sharing that the use of ADCs in combination therapies and multi-payload formats offers further opportunities to improve remission rates by treating the cancer through multiple pathways at once, and overcoming cancers resistant to other treatment options.

He continues: “Additionally, selective targeting cancer cells reduces systemic toxicity to healthy cells, and can lead to a large reduction in the adverse effects for patients compared to traditional chemotherapeutics. As the field develops further, the long-term complications and chronic side-effects associated with traditional chemotherapy could be reduced further through improving the selectivity of ADCs for cancer cells, sparing healthy cells in vital organs.”

From DDW Volume 26 – Issue 1, Winter 2024/25 Read the digital issue

Biography:

Harry Palmer is an Industrial Fellow of the 1851 Royal Commission at the University of Strathclyde. He holds a first-class BA and MSci in Natural Sciences from the University of Cambridge, where he won awards, including the Gordon Wigan Prize for his research dissertation with Professor Robert Phipps.