Refining and targeting exatecan with ADC technology

Antibody-drug conjugates (ADCs) hold immense promise for targeted cancer therapy, but challenges remain in maximising their efficacy and minimising toxicity. ADC Therapeutics (ADCT) is tackling these challenges head-on with its next-generation ADC development programme, focused on a novel exatecan-based platform.

This interview with Dr Patrick van Berkel, Chief Scientific Officer at ADC Therapeutics, explores the company’s innovative approach, highlighting the unique features of its exatecan-based platform, its potential advantages over existing therapies, and the exciting preclinical pipeline targeting a range of solid tumours. Berkel also discusses the strategic rationale behind target selection, the company’s competitive positioning, and the future direction of ADC Therapeutics’ research and development efforts.

Can you describe ADCT’s exatecan-based platform?

Our exatecan-based platform uses a novel hydrophilic linker that enables traceless release of the chemotherapeutic drug exatecan and offsets the toxin’s hydrophobicity, which has posed a challenge to its use in the past.

This way, we believe we can harness the full potency of exatecan. Our platform has clear advantages over other approved Topoisomerase-1 (Topo-1) inhibitors, such as durextecan, including:

• Higher potency
• Increased bystander effect
• Lower risk of multi-drug resistance, as exatecan is not an MDR1 substrate
• No signs of interstitial lung disease in preclinical data so far
• Superior therapeutic index.

Topo-1 inhibitors are a broad class of drug compounds that offer potential for sequencing and combination. These possibilities would need to be validated but could include sequencing with other members of the Topo-1 class if exatecan can provide benefit in patients who have been exposed to commercially approved Topo-1 inhibitors like DXd and SN38. Exatecan is not a PgP substrate and has the potential to show benefit in patients who are resistant to these other Topo-1 inhibitors.

What are the potential benefits of the exatecan-based platform?

A lot goes into designing an ADC beyond selecting a payload. The process involves the intelligent choice of antibody, linker, payload and conjugation technology. The choices we have made with our exatecan platform have resulted in a therapeutic index >10 regardless of the target we use, from validated targets like PSMA to less validated targets like ASCT2, which is also expressed at low levels on certain healthy tissues.

What are the advantages of exatecan-based ADCs versus a radioligand or bispecific approach?

ADCs combine the cytotoxicity of chemotherapy with the target specificity of antibodies and, with an optimised therapeutic index, can offer a unique advantage over bispecific monotherapy alone. Moreover, bispecific and biparatopic antibodies can also be used to improve the targeting potential of ADCs, combining the advantages of both modalities. Radioligands have not been established as an ADC competitor outside of prostate cancer yet, with the strongest data being against a ‘clean’ target with almost exclusive expression in prostate tumour cells.

ADCs, however, have demonstrated efficacy even in targets without a clean expression profile, such as HER2 and Trop2. Moreover, widespread adoption of radioligands may be limited, especially in community centres that may not have the infrastructure to administer them. With an optimised therapeutic index, ADCs can be used in academic and community centres, as well as combined with standard of care across care settings. As we’ve seen traditionally with radiation and chemo being backbone therapies, ADCs, antibodies and radioligands will continue to be used in sequence or in combination in the future.

What are ADCT’s exatecan-based candidates targeting in preclinical studies?

ADC Therapeutics is advancing next-generation preclinical candidates targeting Claudin-6, NaPi2b, PSMA and ASCT2 to treat solid tumours. These candidates are based on an innovative proprietary approach that utilises exatecan with a novel hydrophilic linker as a highly potent and differentiated payload. Progress continues with the IND-enabling studies and we expect to announce this year which target will progress to IND submission in 2025. We also plan to highlight our progress in preclinical trials evaluating these at upcoming scientific conferences in the first half of 2025.

What cancers could these preclinical candidates treat?

Claudin-6 and NaPi2b are overexpressed in a large proportion of patients with non-small cell lung cancer (NSCLC), ovarian and endometrial cancer. ASCT2 is expressed in both small cell lung cancer and NSCLC, including squamous NSCLC, colorectal as well as head and neck cancer. PSMA is over-expressed in metastatic castrate-resistant prostate cancer.

Why were these selections made?

We are focused on differentiated targets that are overexpressed in patients with tumours known to be sensitive to Topo-1 inhibition and are one of the first companies going after these prioritised targets using this approach. We believe each of our four lead ADC targets – Claudin-6, PSMA, NaP2b and ASCT2 – offers the potential to improve the standard of care for cancer patients in an area of high unmet need.  

Why focus on larger oncology indications where there is greater competition?

As outlined in our research strategy, our first step was to focus on areas where we see significant unmet need and have therefore focused on tumour types with the highest potential patient impact. While there is also greater competitive intensity in these larger tumour types, we are going after less competitive targets where we believe we can take innovative approaches to address this unmet need.

How are you uniquely positioned to compete in a dynamic and evolving ADC space with other competitor exatecan-based platforms?

Development of ADCs is very complex but over the last decade we have gained a lot of experience. We have validated end-to-end capabilities with an approved ADC, two novel compounds in clinical development and multiple INDs filed since 2015. While there are other Topo-1 inhibitor-based ADCs in development, most are not late-stage and we believe our unique capabilities combined with the strong features of our ADC candidates will prove successful.

How does the exatecan-based platform align with ADCT’s commercial-stage portfolio?

In solid tumours, we aim to pursue multiple ADC candidates in parallel and increase our shots on goal through our novel exatecan-based research platform.

Does ADCT plan to advance its preclinical selection alone or with a partner?

In addition to the candidate we take forward to IND, we will determine on a case-by-case basis whether we wish to progress additional candidates internally or seek to partner to share the development and financial risk. 

Is ADCT planning to move into other technology or other indications beyond its current scope?

We will continue to diversify our payloads. There is still a significant amount of chemotherapy use and our objective is to replace all chemo use with more targeted therapy. We need to have a more expanded toolbox with different toxins to achieve this.

How confident are you in your IP on the new platform? Have any of your patent applications been approved?

Each of the exatecan programmes has a composition of matter patent application pending for the antibody-drug conjugate per se. These patents would have a potential base expiration up to 2049. We also have a pending application for our proprietary hydrophilic linker technology in combination with exatecan with a potential base expiry up to 2044.