Araris Doubles Down With Dual-payload ADC
A conversation with Philipp Spycher, Araris Biotech AG
Swiss antibody-drug conjugate (ADC) maker Araris Biotech is approaching a multifaceted disease with a multifaceted drug.
The company is developing novel ADCs with two oncolytic payloads, a unique approach for the trendy modality that captured the attention of biotech companies of all sizes and commanded enormous investment.
Araris is aiming to take its first multi-payload ADC, which uses a combination of payloads including topoisomerase 1 inhibitor (TOP1i) payloads, to the clinic sometime in late 2025, says cofounder and Chief Scientific Officer Philipp Spycher, Ph.D.
Araris' work provides valuable insights into enhancing the performance of ADCs and mitigating their side effects, a major challenge hindering the widespread adoption of this promising modality. Spycher has been actively sharing this innovative approach at conferences throughout the year and he recently spoke with us in detail about it. His answers have been edited for clarity and length.
Can you give us an overview of this novel delivery approach?
Spycher: We’re trying to address one of the major challenges in the oncology field. Cancer is not a homogeneous moiety or mass. It’s very heterogeneous with differential target expression profiles across tumors.
All the ADCs in development so far deliver one type of payload. Of course, you see resistance occurring over time. You may not be able to address the heterogeneity.
Chemotherapy traditionally has been about combination therapy. Chemotherapy has always been a mixture of agents having different modes of action. For the past 30 years, it has been the gold standard in many cancer indications.
When we deliver multiple payloads with one ADC we can address the shortcomings of cancer heterogeneity and resistance much better and also in a more targeted fashion than chemotherapy. It allows us to eliminate those cancer cells and reduce the number of surviving cells very efficiently. It is clear that cancer cells may not be susceptible to just one payload but require a combination of drugs to be eliminated.
This is the overarching idea of multi-payload ADCs. I think it’s a truly novel concept in the ADC space as people are thinking about what’s next. This is how we see the ADC space: one avenue for delivering multiple payloads with ADCs, and not just one type of payload — two or even three different payloads — to better address this scourge of cancer heterogeneity and resistance.
You’ve said this multi-payload ADC has the pharmacokinetics of a monoclonal antibody. Can you explain why that’s a good thing?
Spycher: We think that an ADC should retain the pharmacokinetic profile of the naked antibody. On one hand, it enables the ADC to circulate in the blood for a long time.
We want to redistribute the specific uptake of the ADC evenly in the human body to avoid excessive toxicity, which may happen when the pharmacokinetic profile is not like that of the unconjugated antibody.
The ADC will go somewhere and accumulate there. When there is accumulation of the ADC in a healthy tissue, it means you also deliver more payload to that tissue, and you may end up with excessive cytotoxicity.
That’s why we want to make sure the ADC circulates long in the blood and that we can expose the tumor to the ADC as much as possible, which is key for its efficacy. I think ADCs have failed a lot in clinical development previously because the payload delivery to the tumor was not maximized.
It’s important to add that because we’re engineering linkers that connect the payload to the ADC, we also want to make sure that the ADC only releases the payload in the tumor. We can design the linker such that it’s only released in the lysosome and not in the endosome.
Many linkers that are used to date release the payload in the endosome, before reaching the lysosome, where endosomal enzymes cleave off the drug and cause toxicity.
We want to distinguish an endosomal delivery from a lysosomal delivery to improve cancer cell targeting, particularly for the more potent payloads. That goes hand-in-hand with the pharmacokinetic profile of this ADC.
How does it work that way?
Spycher: First, it’s that we don’t lose the payload in circulation, which improves tolerability. When you lose the payload in circulation, this leads to toxicities in the blood.
You see it across all ADCs. No matter what the target is, patients suffer from neutropenia, leukopenia, or anemia. When you have high-potency payloads and high DAR (drug-antibody ratio), then it’s even more pronounced.
So, we have a stable attachment of the payload. Second, there’s the pharmacokinetic profile as mentioned. Ideally, the ADC accumulates unspecifically, everywhere. It’s evenly distributed. That would be the goal, so that no certain tissue is causing toxicity.
That’s why the pharmacokinetic profile needs to be antibody-like.
Third, we have a very good ADC exposure (no loss of payload in the blood) because of the attachment site. We have a protected site on the antibody very close to the glycosylation site asparagine 297. We attach the linker/payload on the glutamine 295, which is just two residues apart. We think that helps shield the linker/payload from exposure and premature enzymatic cleavage.
Also, the linkers that we use are hydrophilic, which helps to ensure a good pharmacokinetic profile. Hydrophilicity helps to avoid unspecific uptake.
Then there’s the stability of the linker. We have linkers that are more stable in an endosomal environment and thus are not immediately cleaved. Often you have Fc-mediated recycling of the ADC, which may mostly happen through endosomal recycling.
Cathepsin B and other enzymes cleave conventional linkers in the endosome. Of course, when they are cleaved in those cells, and you lose the payload, it will cause toxicity issues. Our linkers are designed to preferentially release more in a lysosomal fashion.
This is particularly true for payloads that are very potent, like MMAE (monomethyl auristatin E). High-potency payloads, we think, really should be stably attached on the antibody to avoid premature cleavage once the ADC is taken up unspecifically.
ADCs are complex. There are many tools to optimize an ADC to avoid toxicity issues. We even think we can potentially address on-target, off-tumor toxicity by using linkers that are stable in the endosomes, i.e., they are not immediately cleaved when they enter cells.
What bottlenecks or other opportunities are you running into as you advance this novel approach?
Spycher: So far, at least on the technical side, we have not encountered any problems attaching these payloads onto antibodies. We have shown that with our linkers, it’s possible to hook up any payload or payload combination onto antibodies very efficiently.
The question is, of course, what payloads do you choose and why?
We like topoisomerase inhibitors because they’re active in many cancer indications.
Of course, we can think about other payload combinations and maybe using non-cytotoxic payloads. But then the question is whether they will be active in those indications because there’s no clinical data that would support activity in those cancer indications.
You could also think of novel combinations — combining a PARP inhibitor with a TOP1i — but then the question is, is it possible to give the PARP inhibitor systemically together with the ADC? That’s also being done in clinical development.
We have shown that, at least with TOP1i and MMAE, the codelivery is really important. Interestingly, MMAE and TOP1i given as a combination of ADCs was not effective, showing that synergistic activity can be achieved through codelivery.
Ultimately, clinical data will tell whether codelivery would be superior to systemic delivery. At least from a rational perspective, I think that’s something to consider.
About The Expert:
Philipp Spycher has an extensive background in bioconjugation and ADCs. He obtained his master’s degree and Ph.D. from ETH Zurich in material science and protein engineering. During his post-doctoral work at Paul Scherrer Institute, he introduced the novel approach of using transglutaminases for antibody conjugation, which led to the discovery of what is now called Araris linker technology.