Engineering novel cancer treatments: ADCs and radioconjugates

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At AstraZeneca, we have the ambition to redefine the backbone of current cancer treatment – chemotherapy and radiotherapy regimens – with our discovery platform that delivers highly targeted antibody-drug conjugates (ADCs) and radioconjugates directly into cancer cells. 

Developing targeted cancer treatments

For decades, radiotherapy and chemotherapy have been the mainstays of cancer treatment. While these approaches can be effective, they also affect healthy tissue, causing off-target effects.

There is an urgent need to develop more targeted cancer treatments that act like a guided missile, delivering a powerful payload directly into cancer cells. Utilising our robust in-house capabilities and proprietary discovery platforms, we are developing advanced therapies to meet this need.

One promising approach we are working on is antibody-drug conjugates (ADCs). These molecules consist of an antibody attached via a chemical linker to a chemotherapy payload. When administered, the antibody part of the molecule homes in on tumour cells that express a specific tumour associated or overexpressed protein on their surface. The ADC is then taken into the cancer cell, where appropriate cleavage mechanisms release the cytotoxic payload. This process kills the cancer cell in a more targeted way than traditional chemotherapy, sparing healthy cells.

Alongside this, we are also developing radioconjugates, where targeting vehicles such as antibodies or their fragments, and small molecules or peptides are linked with radiotherapy agents. This approach delivers the radiation therapy to tumour cells, enabling cancer cells to be destroyed in a more targeted manner than traditional external beam radiation, offering more tailored treatments for patients.

Since the first US Food and Drug Administration (FDA) approvals of ADCs in 2000 and radioconjugates in 2018, the development of these modalities has progressed rapidly. Our vision is to see them redefine cancer therapy regimens into the future.

Improving target specificity for ADCs and radioconjugates

For ADCs and radioconjugates to be able to redefine the cancer treatment space, there is still work to be done – such as making them better at homing in on cancer cells and reducing off-target effects, and thus enhancing tumour specificity.

To achieve this, our focus is on continuous improvement of the design and engineering process. This includes how we identify novel targets using state-of-the-art multi-omics approaches, and using screening approaches which prioritise identifying drug candidates with functional effects early on in the drug discovery process. By combining diverse antibody generation approaches with advanced automation technologies, we are now able to identify novel antibody therapeutics at unprecedented speed and scale.

We also use sophisticated protein engineering to enhance tumour specificity by combining two different antibodies into one molecule, known as bispecific antibodies. Bispecific antibodies can bind to two different tumour associated antigens on the same cell simultaneously. By harnessing this unique property, ADCs and radioconjugates can be made more selective to cancer cells than their traditional counterparts. This is because bispecific ADCs or radioconjugates can potentially deliver the payload to tumour cells that express both target antigens, leaving normal peripheral cells and tissue (which often only express one of the two antigens) unharmed.

We are also engineering better linkers to make our ADCs and radioconjugates more targeted. Unstable linkers can lead to ADCs dropping their payload prematurely in places where they can affect healthy tissue. Making them more stable ensures they carry their payloads all the way into tumour cells. Another focus is to ensure that linkers can only be cleaved in tumour cells, so the payload is only activated in cancer cells, and that they remain inactive if the drug is taken up by healthy tissue.

Building a toolbox of payloads to match disease biology

No matter how precise an ADC or radioconjugate is, it can’t treat cancer without an effective payload, and not all payloads affect all tumours equally. Therefore, we are working on matching ADC and radioconjugate payloads to the biology of the cancer cells, with the aim of making the cancer treatments more efficient.

A common challenge with matching payloads to cancers is that tumours can be highly complex and diverse. Therapies that target just one biological mechanism can temporarily treat the cancer, but often resistance emerges, and the tumour recurs. To tackle this problem, we are exploring using multiple different payloads on one ADC. By using different mechanisms of action at the same time, it could be possible to reduce drug resistance in tumours and provide more durable benefits for patients.

We have also engineered ways to expand the targeted, cytotoxic impact of ADC payloads in a heterogenous tumour through the so-called bystander effect. This occurs when a payload is designed to kill nearby target negative cancer cells that could not initially be targeted by the ADC treatment.

A world of potential for ADCs and radioconjugates

Our ADC and radioconjugate platforms are only the first step in our journey to redefine cancer therapies. We are excited about the potential of combining these platforms with other treatment modalities.  

For example, we are exploring delivering them with therapies with different mechanisms of action such as cancer immunotherapies or molecules targeting the DNA damage response pathway, or even combinations of different ADCs and/or radioconjugates that will be dosed sequentially.

Our transformational technologies such as proteomics, artificial intelligence and computational pathology are also helping us to accelerate the development of these novel treatment combinations. In some cases, they let us investigate which antibody target is most likely to work for a particular cancer or which patients are most likely to benefit.

We aim to continue to leverage these technologies in a way that in the future we can address multiple aspects of development simultaneously. As our ability to engineer our ADC and radioconjugate platforms evolve, so will our ability to develop precision medicines which target the right medicine, to the right patient, at the right time.

We look forward to seeing how our programmes deliver over the coming years, and remain committed to continued innovation in this space.

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