ADCs: The next generation of targeted therapies
Antibody drug conjugates (ADCs) are among the hottest properties in pharma, powerful anticancer drugs that target tumours and deliver a lethal payload that destroys them, while leaving healthy tissues untouched. But there’s much more to come from this technology. DDW’s Megan Thomas explores the topic and speaks with experts in the industry.
Early days of ADC drug development
The first ADC was approved around the turn of the century, with Pfizer’s Mylotarg (gemtuzumab ozogamicin) becoming the first such drug approved by the FDA for acute myeloid leukaemia in 2000. Nearly a quarter of a century later, ADCs are among the hottest properties in the cancer drug market following some notable successes after a difficult start for Mylotarg, which failed to live up to its potential because of concerns over its safety.
Mylotarg was ahead of its time in many ways: its novel structure of an antibody to target diseased cells, plus a cancer-killing payload attached via a special linker, is the blueprint for the antibody-drug conjugates (ADCs) that followed.
AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) is a blockbuster-level success, combining the antibody trastuzumab found in Roche’s HER2-targeting cancer drug Herceptin, attached via a special linker to the cancer-killing drug deruxtecan.
Approved in indications including HER-2 expressing breast cancer, Enhertu’s payload is only offloaded once the antibody is bound to the target, where it is absorbed by the cancer cell, which it destroys.
Enhertu is now one of 13 ADCs approved by the FDA, with hundreds of others in development, some of which have been snapped up by big pharma in substantial deals, as is evident in the figures below.
Figure 1: Major deals involving ADCs- 2024
Figure 2: Examples of FDA-approved ADCs – 2024 These include Johnson & Johnson’s $2 billion purchase of ADC specialist Ambrx in January, Genmab’s $1.8 billion buy of ProfoundBio in April, and Ipsen’s $900 million deal with Sutro for anticancer ADC STRO-003, also in April. Medilink’s $1 billion ADC licensing deal with Roche, signed in January 2024, also caught the eye, three months after a $1 billion deal ADC deal with BioNTech.
Challenges for ADCs
There are, of course, challenges for ADCs. They are technically demanding to develop and finding new targets that are expressed only on the surface of cancer cells is a tough task. Development is also, perhaps, hindered by the troubles Pfizer experienced with Mylotarg.
Mylotarg was cleared by the FDA’s accelerated approval process, allowing it to be marketed on the basis of early data in the expectation that a larger trial would confirm its benefits. But Pfizer voluntarily withdrew it from the market in 2010, after post-marketing data failed to confirm its benefits and a lackluster sales performance, although it was reintroduced in 2017 following a reformulation and some further data from investigator-led trials.
Getting new targets for ADCs is a high priority as it could lead to therapies that are more likely to hit cancer cells, allowing for higher doses and greater efficacy with fewer trade-offs needed to ensure an acceptable safety profile.
New targets
Professor Andreas Pahl, CEO of Germany-based ADC specialist Heidelberg Pharma, says: “Finding new targets for ADCs involves several significant challenges. Firstly, identifying tumour-specific antigens that are highly expressed on cancer cells but have limited or no expression on healthy cells is crucial to minimise on-target off-tumour effects and toxicity.
“The heterogeneity of tumours further complicates this process, as different patients, and even different cells within the same tumour, may exhibit varying antigen profiles. Additionally, the dynamic nature of tumour biology means that these targets can change over time, or under treatment pressure, necessitating continuous research and adaptation.”
Stefan Ries is Chief Scientific Officer at DISCO Pharmaceuticals, a German company specialising in finding targets for targeted therapies such as ADCs. DISCO’s approach is to analyse the “surfaceome” of cancer cells – the totality of all proteins expressed on the cell surface – looking for ways that diseased tissue is differentiated from normal tissue. Ries noted that there are other things to think about aside from finding targets expressed only on tumour cells.
He adds: “The target must be internalised efficiently upon antibody binding to ensure the cytotoxic payload is delivered into the cancer cell to trigger cell death. Also, off-target effects of ADCs have to be taken into consideration when selecting the right cytotoxic payloads. This requires extensive preclinical research and validation.”
Advanced genomics and proteomics technologies are being used to discover and validate new targets, Pahl noted, including high-throughput screening techniques and bioinformatics tools. “Collaborative efforts between academic institutions and industry are also accelerating the discovery process,” Pahl said.
According to Ries, one approach is to find targets that tend to be clustered on the surface of cancer cells, allowing for development of bispecific ADCs. These have different binding sites on the tips of the antibody’s “Y-shaped” structure, allowing them to bind with two different targets at once. This increases their chances of hitting a target on the surface of a tumour while reducing side-effects caused by the drugs accidentally killing healthy tissue.
ADC risks
There are risks associated with ADCs, including off-target toxicity, limited efficacy due to drug resistance and complex manufacturing processes.
Pahl explains: “On-target toxicity can arise from the ADC affecting healthy cells that express low levels of the target antigen, whereas off-target toxicity can arise from premature release of payload in circulation or from unspecific uptake of the ADC in healthy cells. Drug resistance may develop as cancer cells adapt to the ADC treatment, reducing its effectiveness over time.”
Heidelberg Pharma wants to exploit the destructive power of alpha-Amanitin to attack cancer cells, by attaching it to an antibody that binds to tumours, while leaving healthy tissues unaffected. Known to modern science as an inhibitor of RNA polymerase II, alpha-Amanitin is a poison that, when ingested by eating mushrooms such as the death cap (Amanita phalloides), destroys liver cells. The compound targets the transcription process at the heart of all cells, with the accurately antibody section of the drug preventing the poison from damaging healthy tissues.
Pahl says there is a bright future for ADCs, citing the string of high-profile, high value deals where big pharma companies have snapped up rights to pipeline assets. He adds: “The rise of ADCs as a priority for big pharma companies can be attributed to several factors. Firstly, the success of recent ADC approvals and their demonstrated clinical benefits have validated the potential of this therapeutic modality. ADCs offer a targeted approach to cancer treatment, combining the specificity of antibodies with the potency of cytotoxic drugs, which has shown promise in improving patient outcomes.
“Additionally, advancements in ADC technology, such as better linkers and more effective payloads, have addressed some of the earlier limitations, making ADCs more attractive for development. And, last but not least, therapy with ADCs offers physicians the decisive advantage that it can be administered on site at the hospital. Many other new treatment methods, such as CAR-Ts or radio-conjugates, can only be carried out in a few specialised centres.”
Combination therapies
There’s also a growing body of clinical evidence that ADCs could be used in combination with other therapies to enhance their potency.
Combining ADCs with chemotherapy is a well-accepted strategy, with clinical trials showing it can help overcome drug resistance. Many chemotherapies work by damaging DNA in cancer cells, leading to effective combinations with ADCs that target certain parts of the cell cycle. Chemotherapy may also increase the levels of surface antigens targeted by ADCs – for example combining gemcitabine can increase expression of HER2, making it a good choice for combination with ADCs that bind to this receptor.
However, there are issues with overlapping-side effects with chemotherapy, and clinicians have more confidence in the safety profile when used in combination with other drug classes, such as endocrine therapy. It’s also possible to use ADCs in combination with radiotherapy, which can induce cancer cells to produce neoantigens that could be targeted by ADCs, although this has yet to be explored in the clinic.1
Combining ADCs with drugs targeting DNA damage response mechanisms such as poly (ADP-ribose) polymerase (PARP) inhibitors could be another option. The combination approach could be made possible because of fewer overlapping toxicities between these two therapeutic approaches. As our knowledge of cancer biology expands, so does the list of potential targets, with receptors such as Claudin18.2, ROR1, poliovirus receptors (PVR) coming into the frame.2
Immunotherapy potential
An exciting potential combination is with immunotherapy, due to an oft-overlooked property of antibodies. Their Y-shaped structure allows for many different functions: while the tips of the “Y” engage with the surface receptor, the “tail” (Fc) interacts with immune cells.
This includes important interactions with white blood cells and the immune system, encouraging them to destroy cancer cells through a range of mechanisms. These include cytotoxicity, phagocytosis, and attacks from the complement system. This also means that using ADCs in combination with immunotherapy has been shown to create synergies, as immune checkpoint inhibitors.
For example, Astellas and Pfizer’s Padcev (enfortumab vedotin) was FDA approved in April 2023, in combination with Merck & Co’s PD-1 checkpoint inhibitor Keytruda (pembrolizumab), for patients with locally advanced or metastatic urothelial carcinoma, particularly those who could not receive cisplatin-based chemotherapy.
Heidelberg’s Pahl says: “As precision medicine continues to advance, ADCs represent a logical extension of targeted therapies, aligning with the broader trend towards more personalised cancer treatments. Moreover, the substantial commercial potential of ADCs, driven by their high efficacy and the unmet medical needs they address, has incentivized big pharma companies to invest heavily in this area, ensuring a robust pipeline of next-generation ADCs.”
DISCO’s Stefan Ries points out that as our understanding of cell surface proteins increases, there could be the potential to expand ADCs into therapy areas beyond oncology.
ADCs could be used to carry payloads other than cytotoxic drugs, such as anti-inflammatory compounds, antibiotics and siRNAs, Ries said. Any disease where there is a target that clearly differentiates it from healthy tissues could be eligible, he added.
He says: “Infectious diseases, autoimmune disorders, and certain neurological conditions could benefit from the targeted approach of ADCs. By harnessing the precision of the ADC technology, we can develop therapies that more specifically target pathogenic cells or disease-causing proteins.”