Cytokine players keep the faith

It would be logical to think that the discontinuation this year of the cytokine poster child, Nektar and Bristol Myers Squibb’s bempegaldesleukin, might have discouraged others from pursuing this mechanism. Think again: there are plenty of companies still developing cancer therapies based on IL-2 and the related cytokine IL-15, an analysis by Evaluate Vantage shows.

And all these groups must believe that their approach will be the one that finally cracks the cytokine conundrum. With many of the projects still at an early stage, however, investors and potential acquirers alike will be forgiven for approaching this space with a healthy dose of scepticism.

Bristol now looks foolish for parting with $1.85m up front to license bempegaldesleukin – and Radek Špíšek, the chief executive of one of the next-generation cytokine developers, Sotio, admits that big pharma has been burnt.

“With respect to their appetite for this sort of molecule, bigger players will now wait for more advanced clinical data, in my opinion,” he tells Evaluate Vantage.

Combo or mono

Despite this admission, Sotio is pinning its hopes on a basket trial of its lead project, SOT101, in combination with Merck & Co’s Keytruda.

Mr Špíšek concedes that the uncontrolled nature of this study, Aurelio-04, will make it difficult to ascertain whether SOT101 has any additional benefit over the PD-1 blocker; this was an issue that dogged bempegaldesleukin.

But he hopes that Sotio will prevail by focusing on patients who have previously failed checkpoint inhibitors and cancers in which these drugs have not worked.

Leaders of other cytokine developers, meanwhile, say they have learnt from the Nektar experience.

“We think it's very important, particularly given the lessons in this field, that we show our drug has independent activity before we add checkpoint inhibitors,” says Aron Knickerbocker, the chief executive of Aulos.

Medicenna’s Fahar Merchant agrees. “We want to demonstrate single-agent activity first. That’s crucial. Until we are able to demonstrate that it's premature to say: we'll now combine it.”

Although these two chief execs are aligned on that point, they disagree on another: each reckons that his molecule could be best in class.

Not alpha and beyond

No doubt the other groups listed below are also confident that they will come out on top. And despite the setbacks to the broader cytokine space, Aulos and Medicenna are just two of the contenders that have entered the clinic since the last time Vantage carried out this analysis (Cytokine interest shows no sign of waning, August 26, 2021).

Developers of the current crop of cytokines are looking to improve on Proleukin, a recombinant human IL-2 that has anticancer activity – but which carries the high cost of serious adverse events, including capillary leak syndrome.

“The reason why there's still a lot of enthusiasm for IL-2 is that Proleukin works. And, when it works, it can be quite striking,” says Aulos’s Mr Knickerbocker. “If anybody can widen that therapeutic index, and make it safer and even more effective – that's tantalising.”

One problem with Proleukin is that it activates T regulatory cells (Tregs), making it hard to find a therapeutic window for the drug. And binding to vascular endothelial cells is thought to drive capillary leak.

A way of combating Treg activation could be the so-called “not-alpha” approach: avoiding binding to the alpha chain of IL-2. This is found on the high-affinity trimeric receptor, which is expressed on Tregs and vascular endothelial cells.

Meanwhile, the beta and gamma IL-2 subunits are found on the intermediate-affinity dimeric receptor, which tends to be seen on CD8+ T cell and NK cells. Selectively hitting this receptor should therefore lead to a stronger anticancer effect.

Still, bempegaldesleukin was a “not-alpha” project. So is Sanofi’s SAR444245, an asset gained via Synthorx that has so far disappointed, and Alkermes’s nemvaleukin alfa, which initially impressed as monotherapy before excitement dwindled.

Aulos and Medicenna are both pursuing “not-alpha” approaches, but neither group is disheartened by the bempeg blow-up.

Beta and albumin

Medicenna’s Mr Merchant has an explanation, saying that previous methods to “mask” IL-2 – including pegylation and fusing the IL-2 protein to another molecule – did reduce binding to the alpha subunit, but also diminished binding to beta.

He believes that activating beta is crucial, and to this end Medicenna has introduced mutations to IL-2 to shift binding from alpha to beta. Another feature of MDNA11 is that is it fused to albumin to extend its half-life.

This could have a couple of advantages, Mr Merchant says: first, an albumin-fused product could be easier to manufacture than pegylated products, which have had issues with heterogeneity; second, albumin tends to accumulate in tumours, which could help drive MDNA11 where it needs to go.

Whether MDNA11 is actually better than what has come before needs to be proven, however.

Medicenna recently claimed that the first clinical outcomes data from its phase 1/2 Ability study showed "preliminary evidence" of MDNA11's single-agent activity, pointing to signs of tumour control in four of 10 evaluable patients; however, no responses were seen. 

The company is currently testing higher doses, and a combination with PD-(L)1 inhibitors is slated for later.

The most similar approach to Medicenna’s comes from Synthekine, which is no surprise as the technology for both originated at Dr Chris Garcia’s lab at Stanford University. But Synthekine is shunning the gamma subunit and has instead created an alpha/beta-biased IL-2 agonist, STK-012, designed to avoid activation of NK cells.

CD25 blocking

Meanwhile, Aulos, a private company, also aims to avoid alpha, but in a completely different way. The group’s lead asset, AU-007, is not an IL-2 therapy itself, but a monoclonal antibody that binds to IL-2 and prevents this from binding to CD25 – another name for the alpha chain of the receptor.

With AU-007 present, IL-2 can still bind to the dimeric receptor – thereby activating CD8+ T cell and NK cells, but not Tregs.

As well as dialling down Treg activation in the first instance, Aulos believes that AU-007 could prevent a negative feedback loop whereby activated T-effector cells make more IL-2, which eventually brings Tregs into play.

“This is a normal yin and yang that occurs biologically,” Mr Knickerbocker explains. “When we have an infection, we control it, and then our body restores our immune system to a less activated state, so we don't have autoimmunity. But in the context of cancer, that's not helpful.”

He adds that other projects, even if they do not bind to Tregs themselves, can initiate this feedback loop.

Aulos has not yet nailed down whether AU-007’s action on a patient’s own IL-2 will be enough to have an anticancer effect, or whether exogenous IL-2 will be needed. This is something the group is looking at in its phase 1/2 study, which has three arms: AU-007 monotherapy; AU-007 plus a single dose of Proleukin “to jumpstart that positive feedback loop”; and AU-007 and Proleukin dosed concomitantly.

Mr Knickerbocker is quick to note that the dose of Proleukin will be “significantly lower” than the one used historically, hoping that this will allow AU-007 plus Proleukin to sidestep the toxicity previously seen with the approved drug.

He also points to the lack of immunogenicity of a MAb, plus the ease of manufacturing versus some other approaches that involve engineering proteins. Aulos expects to start the phase 2 portion of its trial next year, so it will be some time before these issues become important. 

Cis targeting

Not all the companies in this analysis are taking a not-alpha approach. One of these is another private preclinical player, Asher Bio, which has a so-called cis-targeted IL-2, AB248.

In a nutshell, this involves “targeting IL-2 selectively to CD8+ T cells and no other cell type”, Asher’s chief executive, Craig Gibbs, says. He believes that activation of even NK cells could be problematic.

“One, it's contributing to toxicity, because NK cells will release cytokines in response to IL-2 therapy, even if there's no danger signal present. Two, because NK cells are so prevalent they form a very large pharmacological sink and soak up IL-2 molecules, preventing them from accessing CD8 cells in the tumour.”

He says this could explain why efficacy with not-alpha approaches has so far been disappointing, “and why they still have residual toxicities”.

Asher says it has achieved this precise targeting by first attenuating IL-2’s activity, “so we have this weak IL-2 that really doesn't bind any cell type at all very effectively”. This molecule is then attached to an antibody that binds to a target present only on the cell type of interest. In the case of AB248, the antibody binds to CD8.

This provides a modular approach by which Asher could in theory attach any cytokine to any antibody.

The group also has a CD8-targeted IL-21 project, AB821; one aim is eventually to combine this and the IL-2 for a potentially synergistic effect – with the obvious caveat that it is very early days for both assets.

Asher plans to take AB248 into the clinic by the end of this year, and to look at monotherapy as well as a checkpoint inhibitor combo. With the latter, however, “we're selecting a couple of tumours where PD-1 monotherapy is well benchmarked, so we can determine the contribution of the IL-2 to the combination”, Mr Gibbs says.

The IL-21 project, meanwhile, is about a year behind. 

One company doing something similar is Roche, with RG6279, an IL-2 targeted to PD-1-expressing cells. “It's kind of like cis targeting,” Mr Gibbs says. “But PD-1 is expressed on a range of cell types, including Tregs, which you wouldn't want to activate.”

He adds that, in addition, Roche “hasn’t done the attenuation step”, which could also decrease selectivity as RG6279 might bind to and activate other cells on the way to its target. Roche is further ahead though, with its project already in a phase 1 trial.

Mr Gibbs is disparaging about the not-alpha approach, including the new entrants.

But Aulos’s Mr Knickerbocker argues: “I think the challenges with other so-called non-alpha approaches were that they weren't really non-alpha, and they didn't necessarily contain the negative feedback loop.”

IL-15

There is yet another way that some companies hope to harness the power of this cytokine pathway: by targeting IL-15, which is structurally similar to IL-2. The trimeric receptors for both cytokines share the beta and gamma subunits.  

For IL-15 to function “there also needs to be a third component, the alpha subunit of the IL-15 receptor, that normally is expressed on antigen-presenting cells”, explains Sotio’s Mr Špíšek. However, “in the tumour microenvironment the alpha subunit is very often missing because you don't have antigen-presenting cells”.

To get around this, Sotio, which is headquartered in the Czech Republic, has fused wild type IL-15 to the alpha subunit of the IL-15 receptor to create its most advanced asset, SOT101.

“This gets you a fusion protein that, by design, is specific for the IL-2/IL-15 beta gamma receptor; there's no way it could bind to anything else. And it already contains the alpha subunit that is critical for signalling,” Mr Špíšek says.

As with the not-alpha projects above, this approach should therefore activate only CD8+ T cell and NK cells, and avoid stimulating Tregs.

Regarding potential advantages, Mr Špíšek highlights the simplicity of SOT101, noting that the asset is not engineered, aside from a short peptide linker. He also notes SOT101’s relatively short half-life of around four hours, which he says could avoid the exhaustion of T cells that can be seen with long-term receptor occupancy.

Finally, he reckons that IL-15 is a better cytokine to start from, given that it is the “true T-cell cytokine. With IL-2 you need a little bit more engineering. And, to my knowledge, there's always some leakage of function to Tregs, which we don't have.”

Data presented at Asco from the dose-finding Aurelio-03 trial detailed one partial response among 30 patients receiving SOT101 monotherapy. A combination of SOT101 and Keytruda yielded one confirmed complete response and four partial responses among 19 patients, all in either tumours for which the PD-1 inhibitor is not approved – thyroid cancer and mesothelioma – or in patients who had previously failed on a checkpoint inhibitor alone.

Data from the basket trial of the SOT101/Keytruda combo, Aurelio-04, should be available in late 2023. 

Near-term readouts

In the meantime, other cytokine projects are set to yield data in the nearer term: in the fourth quarter Ascendis is to report topline data with TransCon IL-2 β/γ monotherapy.

And Sanofi has not given up on SAR444245, with initial results from basket trials also expected during this period – and Innovent obviously sees potential here, having recently signed up to co-develop the project.

Meanwhile, results with Neoleukin’s not-alpha contender, NL-201, as monotherapy have been delayed until next year; they had previously been expected in the second half of 2022. The group has also started dosing in a Keytruda combo arm of the same trial.

If any of these disappoint, this could further dent the hopes for the many other players in this space, which have already taken a battering after the bempeg debacle.

The table in this story has been updated to include CUE-102.