Revenge of the ADCs

From complex design challenges to issues with linker stability, ADCs have faced many hurdles, but recent promising developments suggest we may be at a turning point. We ask four gurus if the time for ADCs has arrived – and what advancements are paving the way for their success.

The Gurus
 

Shawn Zhang, Chief Scientific Officer, Ambrx Biopharma

Philipp Spycher, Co-founder and CEO, Araris Biotech

Matt Robinson, Chief Technology Officer, Immunome

Jan Pinkas, Chief Scientific Officer, Pyxis Oncology

Is the term “magic bullets” a fair description of ADCs?
 

Zhang: This description may not be completely fair because of the difficulties of delivering both safety and efficacy with previous ADC technologies. ADCs are designed to be highly targeted therapies that deliver a potent cytotoxic payload directly to cancer cells. In other words, they are a “targeted chemotherapy.” 

However, these treatment modalities are only as good as the conjugation method that holds the chemotherapy and the antibody together. For example, ADCs that have unstable conjugation can prematurely release their toxic payload, which can damage healthy tissues, increase drug resistance potential, and deliver inadequate amounts of the cytotoxin to the tumor. Ultimately a “magic bullet” would have sufficiently stable conjugation technology to enable robust on-target delivery of cytotoxin to cancer, with minimal off-target effects to the patient. 

Spycher: I actually do think that “magic bullet” is a fair description of ADCs. By combining a highly specific antibody with a powerful anti-cancer drug to target and eradicate tumors, we can potentially eliminate unwanted side effects in other parts of the body. With ADCs, we are attempting to deliver the anti-cancer drug in the most targeted manner possible, thereby avoiding the toxicities we often see with traditional cancer therapeutics. Over the years, there have been some development challenges that have prevented ADCs from reaching that “magic bullet” potential, but the field is in a good place now to start seeing results in practice.  

Robinson: Paul Ehrlich’s “magic bullet” term has been thrown around for more than a century, and encapsulated his vision that “we need to learn how to aim chemically.” In other words, Ehrlich saw an opportunity to target chemotherapeutic agents to receptors present on disease-causing agents rather than healthy tissues, thereby improving the therapeutic window of those drugs. In many ways, the modern ADC can be seen as the realization of his theory.

Pinkas: Based on clinical data from numerous ADCs over the past few decades, I feel that a better description could be that ADCs represent a validated approach for “targeted payload delivery.”

Why has it taken so long for the field of ADCs to take off? And are we finally at a turning point?
 

Zhang: ADCs have been a promising class of targeted cancer therapies for over 20 years, but their development has been challenged by several factors. One key challenge has been the complex nature of ADC design, which requires the combination of a cytotoxic drug, an antibody, a linker, and the conjugation technology that connects the components. Each of these components must be optimized in different ways depending on the cancer types or targets. It can take years to develop an ADC with the desired therapeutic profile. 

Despite these challenges, recent advancements in ADC technology have renewed interest in the field. For example, the development of site-specific conjugation technologies has enabled the creation of more precise and stable ADCs, reducing off-target effects and increasing the concentration of the “magic bullet” available to reach tumor sites. In fact, there are a number of promising ADCs now in late-stage clinical trials, as well as plenty more in preclinical development.

Spycher: Tremendous leaps have been made in ADC technology over the last 30 years, and these drugs now have the potential to be highly efficacious cancer therapeutics. However, their limited therapeutic window has been a cause of contention in clinical development (i.e., the balance between clinical efficacy in killing tumor cells and tolerability profile), which explains the lack of broader adoption at the expected pace. Additionally, poorly designed linkers that connect the highly toxic drug payload and the antibody can lead to the inability to efficiently deliver the drug payload to the tumor, thus preventing tumor eradication, or a premature release of the toxic drug in the bloodstream, leading to unwanted toxicities in healthy tissues. 

There have also been issues with aggregation of ADCs, which can overall decrease binding of the molecule to the antigen and shorten half-life in the blood. Finally, existing technologies pose challenges of high cost and time to manufacture. With new ADC technologies being developed as well as increased interest in the space, I believe we’re at a turning point for the field to take off.

Robinson: Realizing Ehrlich’s vision has not been simple for many reasons. ADCs are large, complex molecules whose activities are dictated by a number of different parameters, including 1) selectivity and overall uptake of the antibody into tumor versus normal tissues; 2) stability of the ADC in patients; and 3) potency and mechanism of action of the cytotoxic agent being used. Lots of work has gone into understanding how best to attach cytotoxic agents to the antibody delivery vehicles in a way that provides the necessary improvement in therapeutic window versus free drug. In my opinion, the advances made in those areas over the last 10 years or so are what have led to the resurgence in the ADC field.

Pinkas: The ADC field is entering an exponential phase of growth. As the others explained, the technology has taken time to mature because of its complex design and manufacturing when compared with traditional therapeutics. ADCs use payloads that are upwards of 100 times more potent than traditional chemotherapeutics with highly specific antibodies that target and release the drug at the right location. The entire process is a balancing act between safety and activity. Over time, payloads with distinct mechanisms of action have tuned potency, conjugation strategies have become more precise, and linkers have been developed that are more stable in circulation. The improvement of these technologies may yield a new generation of ADCs that will truly transform the cancer treatment landscape.

What have been the biggest milestones for the ADC industry as a whole over the past two years?
 

Zhang: Currently, there are 12 ADCs approved by the US FDA, the most recent being Elahere in 2022 for ovarian cancer and Tivdak for cervical cancer in 2021. I think that one of the key milestones is yet to come – using ADCs to treat solid tumor indications. Most approved ADC therapies target liquid cancers, but there is increasing focus now on solid tumors. 

Spycher: There have been encouraging investments from big pharma into smaller biotech ADC companies, including major deals between Seagen and Pfizer, as well as GSK and Mersana. Investment confidence in the space is very promising to see. 

Robinson: In my opinion, the improvements in linker and conjugation chemistries developed over the last decade have enabled clinical successes that have led to multiple approvals in the space. Perhaps most notably, the approval of Enhertu for the treatment of breast cancer showed how the advances made in the ADC field can be leveraged to substantially improve upon earlier generation therapies and significantly change the standard of care in cancer treatment.

Pinkas: I agree; the approval of Enhertu in people with low expression of HER2 represented a critical moment for the field and showed us that ADCs could go beyond what was possible with traditional therapeutics and reach more patients than previously thought possible. Moreover, Enhertu demonstrates that the potency of the payload is an important component to optimize and that payloads with the highest potency are not always the best.

What are the challenges and biggest discussion points when it comes to optimization?
 

Zhang: The utility of ADCs is significantly hindered by dose-limiting, off-tumor toxicities. Conjugation plays a critical role in controlling the stability, release rate, and efficacy of the drug payload, and instability within this can lead to premature drug release and toxicity, while linker stability can undermine drug release and efficacy. Therefore, pairing optimal linker design, conjugation chemistry, payload class, and tumor target characteristics is necessary to balance stability and release rate appropriately, and is an ongoing challenge in ADC development. Another challenge is achieving optimal antibody-drug ratio (DAR) and conjugation site selection. DAR is critical for maintaining the balance between efficacy and safety. By optimizing the site-specific conjugation of the cytotoxic payload to the antibody with the appropriate linker, then stability and homogeneity can be achieved, reducing dose-limiting, off-site toxicities.

Spycher: All ADC aspects require some optimization, but the optimization of the linker is really most crucial to the therapeutic. Linkers must be stable enough for the ADC to make it to the destination of the tumor without releasing the drug payload prematurely and causing off-target toxicities.

Robinson: The optimization process is highly dependent on how each company approaches ADC development. At my company, we believe it's important to keep the focus on novel targets that can enable selective tumor targeting and we have a discovery engine to help with this. Interestingly, our research is revealing novel target classes, such as proteins ectopically (abnormally) expressed on the surface of cancer cells, which we believe are uniquely tumor selective and potentially suitable for development as ADCs. 

Pinkas: Conjugation chemistry is a hot topic right now. Historically, the process for assembling the components of an ADC was imprecise, which contributed to many of the toxicity issues. Today, companies are working on new strategies to approach conjugation in a site-specific manner to generate ADCs with more consistent DAR and to improve stability in circulation. Another major topic of conversation is bystander activity. The challenge with targeted therapeutics in oncology is tumor heterogeneity. All of the cancer cells within a tumor may not express the target, and consequently, treatments may be ineffective at completely eliminating cancer. One way around this is to improve bystander activity. Certain payloads, after being cleaved, can migrate to neighboring cells whether or not they express the target and exert their cytotoxic effect. Novel payloads with enhanced bystander activity have the potential to provide a more holistic antitumor strategy and could potentially lead to more durable responses. 

What innovation is taking place in linkers?
 

Zhang: We are working on an expanded genetic code technology platform for incorporation of synthetic amino acids (SAA). Conjugation to the SAA enables the incorporation of an optimized linker-payload at any selected site in the antibody using industry standard cell lines, thus allowing for the generation of engineered precision biologics with site-specific, homogenous, and stable conjugation.

I’m also seeing the industry exploring a lot of new conjugation technologies, such as enzyme-based or sugar-based chemistries.

Spycher: It’s been shown that in addition to stability of the linker being crucial for ADC success, linkers also play a role in clearance of the ADC. Some of the first innovations used labile and hydrophobic linkers resulting in poor efficacies, pharmacokinetic ADC profiles, and ultimately limited tolerabilities. At my company, we’re working to create hydrophilic and highly stable linkers that allow for straightforward conjugation of the payload drugs, taking off the shelf antibodies and using them in our ADCs. We’re able to retain the biophysical properties of the antibody thanks to the biochemical nature of the linker, which enables us to maximize exposure of the toxic drug to the tumor with only minimal toxicities. In addition, we believe that the release of the payload from the linker should be highly controlled in order to avoid excessive toxicities. This is because for many conventional linkers, once the ADC gets internalizated in whatever tissues, the linker will be cleaved instantly which will then lead to a rapid payload release causing unwanted toxicities.

Robinson: History has taught us that each ADC is bespoke. From my perspective, the biggest advances in linkers are those that provide scientists with the ability to tailor attributes of the therapy, including but not limited to DAR, stability, site-specific conjugation, and solubility. Each of these can then be applied, in a coordinated way, to evaluate their contributions to the efficacy of newly developed ADCs. 

Pinkas: Numerous advances have been made in linker chemistry to improve stability in circulation while maintaining efficient release in the tumor. Clinical data with ADCs comprising linker formats with a range of stability in circulation suggest that payload release contributes to toxicity. The concept of “cleavable” and “non-cleavable” linkers is outdated, and we should describe linkers based on their stability in circulation and the properties of the payload upon release in the tumor. 

Where do you think the priorities should lie when it comes to furthering the ADC field?
 

Zhang: Based on current research and trends in the field, there are several priorities that can be considered, the biggest being improving the safety profile of ADCs. Approved ADCs such as Enhertu have shown promising results, but there is still a lot of room for improvement in terms of minimizing toxicity while maximizing efficacy. This can, and is, being done by further advancing site-specific conjugation technologies to improve the stability and homogeneity of ADCs and minimize off-target effects. In addition, some early research is exploring pro-drug approaches, where an ADC is largely inactive until it enters the tumor site, where it is activated by tumor proteases or other microenvironmental factors. I also believe research efforts should be directed towards understanding the mechanisms of resistance to ADCs and developing strategies to overcome them as well as understanding how they can work with other therapies in combination (i.e., checkpoint inhibitors, to produce the most effective treatment regimens).

Spycher: Further enhancing linker technologies that allow for fine tuning of stability and conjugation of the payload to the antibody should be at the forefront of ADC development. A strong linker foundation sets up the ADC for success, but I feel that  linkers have been greatly undervalued in the ADC space. For example, depending on the amino acid sequence used for the linker, potential dose-limiting toxicities can be much better controlled. In my view, there is no such story as a “one-size fits all linker.” For each antibody and payload combination,  linker optimization is necessary to maximize payload delivery to the tumor. Thus, linker performance sets the stage for the efficacy, safety, and tolerability of ADC therapeutics. 

An additional consideration for the development of ADCs is the beneficial impact of high drug-to-antibody ratio (DAR). As we advance ADCs, we may find that high DARs are not necessary when using a low potency warhead. Ratios of 4 or less may be beneficial, and allow for high dosing and achieve high tumor penetration.

Robinson: While I believe future advances in linker, drug, and conjugation chemistry will continue to progress the ADC field, I also believe that a better understanding of the target landscape is going to be critical to fully realize Ehrlich’s vision of the “magic bullet.” Ehrlich postulated the need for receptors that are selective for disease versus normal tissues. The currently approved ADCs are focused on a small subset of targets, and hence small subset of cancers, with significant room to expand. The data we are generating at my company – through the interrogation of patients’ antibody responses against their disease – has uncovered unique areas of biology that highlight novel target classes with the potential to provide increased tumor selectivity as compared to current targets. The better we understand those target classes, the more we will be able to select the right targets with potential to have the greatest benefit for patients, hopefully across multiple cancers. 

Pinkas: While innovation is needed on all fronts, the biggest impact will come from improvements in conjugation strategies, since this can broadly translate to improvements across ADCs. The second priority is payloads. Not all payloads are created equally, and each employs a different mechanism of action, which may be more effective against certain types of cancers. Excitingly, newer payloads have been shown to induce immunogenic cell death, meaning that the drug kills the cancer cell and primes the immune system. This has major implications, especially in a combination treatment setting with other immuno-oncology drugs like checkpoint inhibitors.

Please make a bold prediction for the coming years…
 

Zhang: We will one day see ADCs replace standard chemotherapy treatment and become the standard-of-care for cancer treatment. With the approval of newer and more effective ADCs, and with the ongoing development of next-generation ADCs with improved targeting, potency, and safety profiles, the field is poised for significant growth. Additionally, as personalized medicine becomes more tailored as we gain a wealth of individualized data, ADCs with the ability to target specific cancer subtypes could become an increasingly important tool in the fight against cancer. This will include the identification and validation of new cancer targets, which would be invaluable for our field, industry, and most importantly, for patients with solid tumors who have long awaited consistently reliable treatment options.

Spycher: When looking at how ADCs have already altered the treatment paradigm for certain cancer indications, essentially re-defining how patients are treated and the impact on their quality of life, it seems to me that ADCs are primed to play key roles for many cancer indications. Eventually, they may replace conventional chemotherapy and live up to their initial promise of being “magic bullets.”

Robinson: Leveraging modalities, such as ADCs, may provide a more linear clinical translation in drug development. I expect that better understanding of cancer biology and the expression of targets on the surface of solid tumor cells, specifically in the context of the tumor microenvironment, will expand the landscape of tumor targets addressable by ADCs, leading to multiple clinical milestones and additional approvals in the coming years. 

Pinkas: ADCs will become first-line treatments for many different indications. In oncology, we’ve seen the rise of many new treatment modalities, but we don’t often see drugs breaking into first-line treatments. As the industry becomes more sophisticated in the design and development of ADCs, we’ll start to see them become more prevalent first-line options.

Further down the road, I could envision ADCs being used outside of oncology. The beauty of this technology is that it’s really a delivery system for highly potent small-molecule drugs. In fact, we could potentially apply this strategy to deliver different agents that, for example, suppress the activity of cells responsible for autoimmune disease.