Antibody drug conjugates (ADCs) represent a promising new generation of cancer therapeutics and a significant advance in targeted drug delivery. Frequently referred to as biological “missiles” or “bullets”, ADCs are typically composed of a monoclonal antibody (mAb) attached to a chemotherapy agent. Once the mAb binds to the specific target protein on the patient’s cancer cells, the ADC delivers the cytotoxic payload needed to cause cell death. This targeted approach aims to minimise damage to the healthy cells nearby, helping to reduce the side effects caused by traditional chemotherapy agents. 

According to GlobalData figures, the antibody drug conjugate market was valued at $8.6 billion in 2023, with expectations to exceed $45 billion by 2030. There are already several blockbuster drugs on the market such as Roche’s Polivy, Gilead Science’s Trodelvy, and Daiichi Sankyo/Astra Zeneca’s Enhertu. The latter was the first FDA-approved tumour-agnostic ADC and is now being used to treat a range of HER-2 expressing metastatic cancers, with sales more than doubling last year from $1.25 billion in 2022 to $2.5 billion in 2023. According to GlobalData, this made Enhertu the highest grossing ADC of the year. With potential to gain approval for all HER-2 tumours, its annual sales could surpass $10 billion by 2028.

There are 17 marketed ADCs in the GlobalData Drugs database (12 of which have been marketed in the US), while an additional 13 are currently in the pre-registration phase. Hundreds more candidates are making their way through the drug development pipeline, with 360 products in clinical trials. Meanwhile, the majority of drugs (580) are currently in pre-clinical development, indicating a market that is poised to explode over the next decade.

The ADC deal landscape is taking off

Various high-profile deals show the growing trend. In late 2023, Pfizer completed the largest ADC-related deal, acquiring Seagen for $43 billion. Seagen had multiple licensing agreements with major pharmaceutical companies and an advanced ADC portfolio, with five marketed drugs. Earlier this year, Johnson & Johnson purchased ADC specialist Ambryx for $2 billion while Genmab acquired ProfoundBio for $1.8 billion, gaining access to a promising portfolio of ADCs including Rina-S, an ADC currently undergoing clinical trials for ovarian cancer and other FRα-expressing solid tumours.

Industry wide, the number of ADC licensing agreements grew 462% from 2018 to 2023, while acquisition volumes more than tripled. Meanwhile, the total value of ADC licensing agreements reached a record high in 2023, at $32.3 billion.

Drug development challenges

Yet while there is a lot to pin hopes on, ADC developers are facing challenges. This manifests in the data, which shows 110 discontinued candidates and 820 that are currently inactive. Moreover, according to GlobalData’s clinical trials data, there have been 387 completed trials since 1 Jan 2014 but just as many – 389 studies – suspended, terminated, or withdrawn.

Toxicity issues have been at the heart of the market’s challenges, with serious side effects remaining a significant hurdle to the clinical success of ADCs. This is partly due to the nature of the cytotoxic payloads, some of which have specific toxicities that can lead to severe adverse events (AEs) such as interstitial lung disease, ocular disorders, serious organ dysfunction, anaphylaxis, and neutropenia – a drop in white blood cells.[i] As such, the ratio of drug to antibody must be carefully balanced but this presents a major challenge in itself, since higher ratios have the power to improve the ADC’s therapeutic effects while simultaneously worsening the chance of AEs.

“Despite the availability of increasingly more tumor-selective monoclonal antibodies, ADCs are still associated with significant and dose-limiting toxicities, based on their cytotoxic warheads,” says Dr Bernd Seizinger, leading ADC expert and independent board member for Turbine Simulated Cell Technologies. “The side effect profile of ADCs is still dominated by the side effect profile of their respective cytotoxic payloads.”

Another significant hurdle lies in the stability of the chemical ‘linker’ needed to connect the antibody to the payload. When these linkers are unstable, payload may be released prematurely in healthy tissues.

The toxicity issues and off-target effects associated with the first generation of ADCs are now limiting the therapeutic benefits of today’s candidates. Essentially, many ADCs have not been safe enough to be delivered at sufficient strengths. This translates to poor efficacy, since if the payload is too sensitive it may degrade or lose efficacy before reaching the tumour site, thus compromising the drug’s therapeutic effect. Resistance is a further challenge, with most cancers eventually becoming resistant to the cytotoxic payloads of ADCs.

New technologies offer hope

As funding pours into the ADC industry, novel technologies are now being developed to help overcome drug development challenges. This includes some alternative ‘cytotoxic’ payloads, says Dr Seizinger.

“The combination with anti-cancer drugs such as DDR-(DNA damage response) inhibitors could improve the key challenge of resistance development,” he adds. “This may include a new generation of ADCs which carry a DDR inhibitor within the same construct as an additional linker arm.”

The industry is also focused on designing linkers that cleave with specificity in order to reduce off-target effects. Recent developments in this space such as the use of enzyme-cleavable linkers, photo-responsive linkers, Fe(II)-responsive linkers, dual-responsive linkers, and bioorthoganol linkers have good potential to bring more control to payload release.[ii]

But there is still a high level of unpredictability when it comes to payload sensitivity levels, and more understanding is needed of payload biology in order to effectively resolve toxicity and resistance-related issues. This is where computational cell models can be of value, since they have the power to help researchers at the cutting edge of science gain a more accurate understanding of how a novel combination will function in human cells and tissue.

Turbine Simulated Cell Technologies is currently pioneering this approach. The Hungarian company has developed an advanced computational model which translates transcriptomatic, genomic and interactomic (protein-protein interaction) data into virtual cells, which it calls “avatars”. These avatars are then trained to capture patterns of phenotypic cell states under various perturbation conditions, opening new avenues for researchers to test payload combinations at scale while highlighting genetic drivers of response or resistance.

The company recently presented a scientific poster at ADC World, sharing details from several experiments it had conducted in order to assess the model’s ability to capture payload biology. This capability was challenged from three angles. First, can the model predict payload sensitivity in never-seen cell lines? Secondly, can the model predict the synergistic effects of payloads combined with a different mechanism of action drug? And finally, can the model differentiate drivers of response from biologically meaningless correlations? To find out more, please download the poster below, or visit https://www.turbine.ai/demo to pre-register for Turbine’s upcoming Payload Predictor platform launch!

[i] Treatment-related adverse events of antibody-drug conjugates in clinical trials: A systematic review and meta-analysis. https://doi.org/10.1002/cai2.97

[ii] Recent advances in ADCs. https://njbio.com/antibody-drug-conjugates/