Improving the Therapeutic Index of ADCs with a Peptide Linker Technology

Although a growing number of antibody–drug conjugates (ADCs) have been approved as cancer therapeutics, the full promise of ADCs has yet to be fully realized, owing to issues with stability and the resulting toxic side effects. In this Q&A, Philipp Spycher, Ph.D., Chief Executive Officer and founder of Araris Biotech, discusses his company’s new peptide linker technology, which has been shown in preclinical studies to enable highly targeted delivery of payloads with minimal loss during circulation, with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): Can you start the discussion off with a concise historical overview of Araris Biotech, particularly how the company has evolved over the few years since we last featured you in Pharma’s Almanac?

Philipp Spycher (PS): I incorporated the company at the end of January 2019 after I completed my postdoctoral studies. My vision was to cure cancer with antibody–drug conjugates (ADCs). It was a big vision and is still the same vision, but during our journey over the last three and a half years, we achieved several milestones. We raised a significant financing round in October of 2020 with mainly UK- and Swiss-based investors, built out the team with additional experts from various fields, expanded the advisory board, and significantly grew and strengthened the company overall.

On the technology side, we have also further evolved the company to the point where we believe that we are getting close to realizing that vision. The more data that come out from the lab, the more excited the team and everybody gets, especially since the data is highly consistent. The vision was to generate a technology that enables us to deliver on the promise of site-specific ADCs and their expansion of the therapeutic index. By doing so, it would mean that we can go for targets and indications not possible with conventional ADCs and thus expand on their applications and deliver on the promise of curing cancer.

DA: How would you characterize the present moment in the overall trajectory of the ADC sector?

PS: There has been significant evolution in the ADC space accompanied by real learning. The key focus now is on the ability to design effective ADCs with a high therapeutic index, particularly having stable payload attachment on the antibody and selecting the right payload — not necessarily the most potent ones. We have seen that less potent payloads can actually help deliver compelling data, and those successes have triggered more interest in the ADC space. People now really appreciate the ability of ADCs to deliver toxins to the tumors and kill them.

Recent clinical data have been unbelievable showing that applying new linkers and payloads can make a huge difference. There are great opportunities for Araris, because we can generate really stable ADCs directly from ‘off-the-shelf’ antibodies and virtually hook up any payload there is in a very simple and efficient way. In general, renewed interest in ADCs was triggered by the numerous acquisitions of small biotechs, such as VelosBio by Merck and NBE Therapeutics by Boehringer Ingelheim, as well as Immunomedics by Gilead and the licensing deal between Daiichi Sankyo and AstraZeneca.

DA: With respect to addressing some of those key challenges, such as stability, heterogeneity, and development timelines and costs, what general solutions are in play in the industry, and, more specifically, what approach has Araris taken?

PS: Addressing the stability of the overall molecule and how to efficiently deliver high amounts of payloads to the tumor are still the key issues. It is also crucial to ensure that attaching a payload to an antibody does not affect the properties of the antibody or the payload release. Conventional ADCs suffered because the properties of the antibodies were altered once the payload molecules were attached, which limited their ability to deliver the cytotoxic compound to the target tumors. Additionally, when the payload isn’t stably attached to the antibody, it can be released too early, leading to side effects and a lower therapeutic index as well. Those issues were very common.

With the technology that we have developed at Araris Biotech, we can generate stable ADCs that have pharmacokinetic (PK) profiles similar to the antibody; they provide high exposure of the cytotoxic agent to the tumor tissue. We have data showing high activity at low doses combined with high tolerability, and, as a result, our candidates have significantly higher therapeutic indices compared with conventional ADCs.

DA: Can you elaborate on what is unique about Araris’ linker technology and how it enables those benefits?

PS: There are multiple aspects to our technology, but what is really key is that the payload is attached to a privileged attachment site on the antibody so that the pharmacokinetic profile of the resulting ADC is essentially identical to the unmodified antibody. That enables the delivery of high amounts of payload to the tumors. Also important is the design of the linker to ensure that the payload is stably attached to the antibody while traveling to the tumor but then is released specifically at the targeted site. With our technology, once the ADC is internalized into the tumor cell, the degradation of the linker happens very efficiently.

The reason we can achieve such behavior is because we use hydrophilic peptides as linkers. They enable site-specific conjugation and efficient release of the payload within the target cell. In addition, this approach ensures biocompatibility, which we think is a critical factor that has mostly been overlooked. There is a particular enzyme in the body that may be involved in neutropenia, a dose-limiting toxicity for many ADCs. The enzyme thereby recognizes certain sequences in the linkers, causing its cleavage and thus loss of the payload, eventually killing neutrophils.

With Araris’ technology, we have data showing that we have significantly reduced neutropenia compared with other ADCs. We can achieve this performance because we have optimized the linkers so that they are not cleaved by this enzyme but are metabolized at the target site and result in the release of the payload. We believe that our ability to design such stable linkers that enable efficient release only at the targeted site is unique in the entire ADC space.

DA: What impact does your technology have on the manufacturability of ADCs?

PS: We have made a lot of progress on the manufacturing side. Payload attachment used to require multiple steps, but today we have reduced that down to just one. In addition, we don’t need to do any engineering of the antibody to prepare it for use as an ADC. We can work with off-the-shelf antibodies and attach payloads in a single step.

Another advance was a reduction in the amount of payload used. Earlier processes required the use of large excesses of the payloads, which are quite expensive, since they are complicated chemical compounds. Now, we only need to use a minimal quantity, which significantly reduces purification requirements and costs.

Finally, the linker we use is quite hydrophilic, and the location of the payload attachment is not as exposed as is typically the case for other conjugation sites, which in combination results in ADCs that have very good hydrophilicity — much better than that seen for conventional ADCs. Hydrophilicity is important for solubility and bioavailability.

DA: When we last spoke, Araris Biotech was pursuing a hybrid, two-pronged business model including both partnering and in-house development of your own ADCs. How has your internal pipeline evolved?

PS: We have made a lot of progress developing our own ADC assets in liquid and solid tumor types. Our lead product is an anti-CD79b ADC now in preclinical development. The discovery phase for this molecule has been completed, and we hope to advance into clinical development by early 2024. It is a very exciting candidate, because we think we can go into an indication that has previously not been possible for conventional ADCs.

A second program is underway that aims to go for solid tumor targets with a focus on difficult-to-treat solid tumor indications, which makes it especially exciting.

DA: When it comes to partnerships, are you looking for specific types of companies or are you more agnostic to whatever is possible?

PS: We are open to partnering with any pharma companies that are looking to develop effective ADC-based therapies. Our goal is to enter into high-value partnerships.

In that regard, we are seeing significant interest, because ADCs are a very hot topic at the moment, and we think that creating stable linkers is the crucial element for achieving success. The ability to attach multiple payloads on the same antibody is also of real interest. Araris Biotech’s linker technology can address both issues — including the attachment of up to four of the same or different payloads — and we are discussing this with many different pharma companies.

DA: Is that something that has been possible before — linking multiple payloads to a single antibody?

PS: When we talk to people in the field, it seems that everyone is working on developing a solution, but only very few have yet published any data demonstrating a real benefit. It is early right now, but I do think that in the next few years we will see very exciting progress published.

I am very excited about this development of attaching more than just one type of payload on the antibody. I think it really offers a completely new avenue for ADC design. Araris Biotech is very well positioned, because we can chemically control the attachment of the payload nicely, and we can create such ADCs quite easily.

DA: Is there anything else that you’d like to share about how the company has evolved over the last couple of years in terms of investors, funding, or expansion of the team?

PS: We started as a spin-off company from the Paul Scherrer Institute (PSI) and ETH Zurich and are presently still located at the original incubator site in Zurich. But Araris Biotech has matured sufficiently, and we are excited to be moving during the summer to a new location and becoming fully independent. Our team now comprises 10 people, and we will soon be hiring additional members. Growth in that regard will continue over the months and years to come. In addition, our advisory board has been expanded to include experts with experience designing clinical trials and supporting target identification.

In terms of financing, we are currently active with Series A fundraising. It is very good to be in the ADC space, but we are seeing lots of interest in our technology in particular because of the exciting data that we have generated thus far. For instance, our lead molecule has shown remarkable tolerability in monkeys where conventional ADCs would have shown significant toxicities or even deaths.

DA: How do you anticipate the ADC sector evolving further over the next few years? Are any big developments expected? And what contribution do you think Araris will make to that evolution?

PS: Our vision is to provide a functional cure for some cancers. If we can show in clinical development that the compelling preclinical tolerability results in monkeys and activity results in mice translate well into humans, I think we could potentially set the new benchmark in ADC linker technology. The overall result should be a significant improvement in the therapeutic index that would really enable us to deliver on the promise of site-specific ADC technology. We should be able to expand into indications or applications that have previously not been possible with conventional ADCs.

That is the key focus: improving the therapeutic index. But doing so has traditionally been very challenging, because the payloads are lost while the ADCs are in circulation. If the linker-payload is too exposed, the linker may be cleaved prematurely or the ADC may have an altered PK-profile, leading to decreased toxin delivery to the tumor and a narrow therapeutic index. With the Araris linker technology, we believe that we can achieve an improvement in the therapeutic index because of the greater stability, unchanged PK-profile, and cleavage mechanism of our linkers.

For this reason, I hope that with the technology we will make a real impact on treating cancer patients. At Araris, the whole team, as well as our scientific advisory and investor board members, also share this vision.

As with all novel pharmaceutical technologies, the effectiveness of the technology will be shown in the clinic. I think that Araris Biotech has every reason to believe that the molecules that we are developing with our new ADC linker technology are very strong candidates that will be safe and efficacious and have good therapeutic indexes.

Philipp Spycher

As the inventor of the Araris Linker Technology, Philipp has a profound background in Bioconjugation and ADCs. He obtained his master’s degree and Ph.D. from ETH Zurich at the interface of material science and protein engineering. During his post-doctoral work at PSI, he introduced the novel approach using transglutaminases for antibody conjugation that led to the discovery of the Araris Linker Technology.