No sooner had cytokine therapies been labelled an area to watch in 2018 than Bristol-Myers Squibb paid a massive $1.85bn for rights to Nektar’s NKTR-214, a project working specifically to stimulate signalling via the cytokine interleukin-2.
This might seem ironic, since IL-2 is already an established though now infrequently used melanoma therapy, sold since the 1990s; but it comes with serious side effects, which have driven the industry’s efforts to develop a new wave of IL-2-based therapeutics (see table below). However, as Alkermes’s 13% share price slide last week shows, there are fears that not all these therapies hold equal promise.
Much of Alkermes’s fall had to do with a downgrade from Jefferies, which reckons that the company’s ALKS 4230 might have weaker efficacy than NKTR-214. “A closer look at IL-2 science suggests not all IL-2s are the same,” the analysts opined.
At play is a highly complex series of interactions that are only just starting to be understood. Cytokines are potent signalling proteins that, broadly speaking, stimulate cells in the immune system.
But there are problems, such as the fact that general IL-2 stimulation can cause severe vascular toxicity. Nevertheless, the 1998 launch of Novartis’s Proleukin, a recombinant IL-2, following years of work by the NCI’s Dr Steven Rosenberg, arguably represented the industry’s first cancer immunotherapy, and Evercore ISI’s Umer Raffat calls IL-2 a “good old immune therapy with safety baggage”.
The promise of IL-2-based therapeutics lies partly in combination with checkpoint blockade, thanks to the potential of highly specific stimulation to turn cold tumours immunogenic – the approach that scored Nektar its $1.85bn up-front payment (Nektar delivers the sweetest deal, February 14, 2018).
Nektar’s NKTR-214 is an agonist of the IL-2 receptor’s β chain. This highlights the complexity of IL-2’s interaction with its receptor, and the fact that the receptor can have either a heterodimeric or heterotrimeric form, depending on its composition of the chains α (CD25), β (CD122) and/or γ (CD132) (see diagram).
CD122-biased activation causes proliferation of effector T cells rather than immune system-suppressing T regulatory cells, whereas CD25 bias triggers the opposite effect. Another possible benefit of avoiding CD25-mediated stimulation is that this has been suggested as the reason behind IL-2's vascular leak toxicity.
In a similar vein Roche is pursuing development of two assets, RG7461 and cergutuzumab amunaleukin, which are both fusion proteins that include an IL-2 variant meant to reduce binding to CD25 to avoid stimulating Tregs. And Medicena’s MDNA109 is designed to bind 200 times more effectively to CD122 than to CD25.
Meanwhile, Alkermes’s ALKS 4230 is a fusion protein comprising IL-2 and, paradoxically, CD25. This is also an attempt to reduce binding of IL-2 with CD25, via steric hindrance.
However, the jury is out as to which is the best approach. Jefferies analysts say that preclinically ALKS 4230 seems to generate a lower effector T cell/Treg ratio than NKTR-214. And safety is still unknown, so hard evidence will not come until clinical studies read out.
Alkermes’s phase I trial could yield some data around the mid-year, and Jefferies say vascular safety events were seen in one patient. Evercore’s Mr Raffat additionally cites slow recruitment into Alkermes’s study, something he puts down to five continuous days’ IV infusion, which requires inpatient treatment.
|Selected oncology projects based on IL-2 signalling|
|Pulmoleukin||Immunservice||Phase III||Biomimetic inhaled IL-2||Inhaled therapy for lung metastases in renal cell carcinoma|
|NKTR-214||Nektar Therapeutics||Phase II||CD122 (IL-2Rβ)-biased pegylated IL-2||Keytruda and Opdivo combo trials under way|
|DI-Leu16-IL2||Alopexx/Provenance Biopharmaceuticals||Phase II||CD20 MAb/IL-2 fusion protein||Possible preference for CD20-expressing tumour cells|
|RG7461||Roche||Phase II||FAP/IL-2v fusion protein||Diminished CD25 (IL-2Rα) binding; two Tecentriq combo trials under way|
|Teleukin||Philogen||Phase II||F16 Ab/IL-2 fusion protein||F16 Ab is a targeting moiety|
|ALT-803||Altor Bioscience||Phase II||Mutant IL-15/IL-15Rα fusion protein||Stable heterodimer aiming to increase half life of IL-15|
|ALKS 4230||Alkermes||Phase I||IL-2/CD25 (IL-2Rα) fusion protein||Diminished CD25 (IL-2Rα) binding by virtue of steric hindrance|
|Cergutuzumab amunaleukin (RG7813)||Roche||Phase I||CEA MAb/IL-2v fusion protein||Diminished CD25 (IL-2Rα) binding; Tecentriq combo trial under way|
|Camidanlumab tesirine||ADC Therapeutics/Genmab||Phase I||Anti-CD25 antibody-drug conjugate||Targets CD25-expressing laukaemia/lymphoma cells|
|NHS-IL2-LT/EMD 521873||Merck KGaA||Phase I||IL-2/Ab fusion protein||Ab portion meant to direct agent to regions of tumour necrosis and apoptosis|
|NIZ985||Novartis||Phase I||IL15/soluble IL-15Rα dimer||Through 2015 acquisition of Admune; PDR001 combo trial under way|
|MDNA109||Medicenna Therapeutics||Preclinical||Enhanced version of IL-2||PD-1 combo mouse data; clinical trial expected late 2018|
|Angeloxin||Angelica Therapeutics||Preclinical||Mutated diphtheria toxin/IL-2 fusion protein||Improved version of Ontak|
|PB101||Pivotal Biosciences||Preclinical||Low-toxicity IL-2 analogue||Aims to circumvent Proleukin's vascular leak syndrome toxicity|
|Anti-IL-2 Program||Xoma||Preclinical||IL-2/MAb complexes||MAb directs IL-2 to enhance effect; potential in PD-1 combo|
|NKTR-255||Nektar Therapeutics||Preclinical||IL-15Rα-specific agonist||Aims to engage IL-15Rα (CD215)/IL-2Rγ (CD132) complex|
|CYP 0150||Cytunepharma||Preclinical||IL-15 linked to Sushi+ domain of IL-15Rα||Aims to circumvent IL-15Rα (CD215) cleavage from presenting cells|
|AM0015||Armo Biosciences||Preclinical||rhIL-15||Future development of AM0015 in combination with AM0010|
|Source: Clinicaltrials.gov and EvaluatePharma.|
The list above also includes projects targeting IL-15 because this cytokine is structurally similar to IL-2. In fact, its receptor’s β and γ chains are identical to IL-2’s. The leading project here appears to be Novartis’s NIZ985, which works on the principle that combining IL-15 with its α chain can cause superagonist activity and spur proliferation of effector memory T cells.
This suggests a stark difference versus IL-2, with the IL-15 receptor's α chain stimulating rather than damping down effector T cells. Nektar’s NKTR-255 and Cytunepharma’s CYP 0150, both preclinical projects, also aim to make use of this finding.
Michael Gladstone, a partner at Atlas Venture, recently called 2018 the year of the cytokine, and the Nektar deal certainly suggests that this is how things are shaping up. However, despite the availability of Proleukin, next-generation IL-2 agents are still in their infancy.
As such it is hard for investors to look to specific data readout points, and interest will likely focus on the initiation of further trials, and the settings in which these agents will be studied. It goes without saying that more deals would not do sentiment any harm.
This story has been updated to add Altor, Philogen, ADC, Merck KGaA and Xoma assets.