Abbvie takes its Treg cue
The big pharma becomes the latest to look at IL-2 to harness regulatory T cells, but plenty of others have the same idea.
IL-2 therapies for cancer might be going through an existential crisis, but interest is building on the flip side of the equation: using IL-2 to stimulate T regulatory cells (Tregs) to treat autoimmune diseases.
Abbvie is the latest to get involved here, yesterday gaining an option to license Cugene’s candidate CUG252 for $49m up front. This is the latest in a long line of deals, the latest being Merck & Co’s $1.85bn purchase of Pandion last year for its IL-2 project, and a look at the pipeline shows plenty more activity in this space.
Using IL-2 to treat both cancer and autoimmune diseases might seem counterintuitive, but the cytokine plays a role in both stimulating and damping down the immune system. While high doses of the cytokine are thought to activate pro-inflammatory T and NK cells, low doses are said to selectively activate Tregs.
To overcome concerns that simply administering low dose IL-2 might not be enough to treat autoimmune diseases, many groups have engineered IL-2 to achieve selective targeting of Tregs.
Abbvie reckons that Cugene’s CUG252 could be best in class, but this is far from proven – the project is still in phase 1 in healthy volunteers and lupus patients. During the option period Cugene will carry out phase 1b in an undisclosed autoimmune/inflammatory disease; if Abbvie chooses to exercise the option it will become responsible for further development.
|IL-2 projects designed to stimulate Tregs for autoimmune use (excludes IL-2 inhibitors)|
|NKTR-358/ LY3471851||IL-2 alpha agonist||Lilly/ Nektar||Island-SLE & Instruct-UC|
|Efavaleukin alfa/ AMG 592||IgG Fc-IL-2 mutein fusion protein||Amgen||NCT04680637 (lupus) & NCT04987307 (UC)|
|ILT-101||Low-dose IL-2||Servier/ Iltoo||Diabil-2 (type 1 diabetes)|
|mRNA-6231||LNP mRNA encoding mutein IL-2||Moderna||NCT04916431|
|SAR444336/ THOR-809||Pegylated IL-2||Sanofi (ex Synthorx)||Ph1, per Sanofi annual report (no CT.gov entry)|
|MK-6194/ PT101||IgG Fc-IL-2 mutein fusion protein||Merck & Co (ex Pandion)||NCT04924114 (UC)|
|CUG252||Treg-selective IL-2 mutein||Abbvie/ Cugene||NCT05328557 (lupus)|
|XmAb564||Monovalent IL-2-Fc fusion protein||Xencor||NCT04857866|
|RG7835/ RO7049665||IgG Fc-IL-2 mutein fusion protein||Roche||Autoimmune hepatitis & UC studies terminated|
|CC-92252/ DEL 106||IgG Fc-IL-2 mutein fusion protein||Bristol Myers Squibb (ex Celgene [ex Delinia])||Psoriasis study terminated|
|Project B4 (SLIT)||Sublingual IL-2||Biolingus||NA|
|MDNA209||IL-2 mutein with increased affinity for IL-2Rβ||Medicenna||NA|
|ASKG222||Fc-IL-2 fusion protein||Askgene Pharma||NA|
|Unnamed||IL-2 mutein with increased affinity for IL-2Rα||Bright Peak Therapeutics||NA|
|Source: Evaluate Pharma, company communications & clinicaltrials.gov.|
Other groups are further along, including Nektar, whose Lilly-partnered NKTR-358 is now one of its brightest hopes following the blow-up of the cancer-targeting IL-2 bempegaldesleukin. A key autoimmune test is approaching, with the phase 2 Island-SLE trial in lupus due to complete in November. However, Lilly said during its first quarter that it had dropped the asset in ulcerative colitis, where the mid-stage Instruct-UC study is still listed on clinicaltrials.gov as recruiting.
Sanofi, through its $2.5bn takeout of Synthorx, is also looking at both sides of the IL-2 equation, as is Medicenna, although that company’s autoimmune project MDNA209 is preclinical.
Despite all the interest, there are some less rosy signs: Roche dropped its IL-2 mutein RG7835 in February, while a phase 1 study of Bristol Myers Squibb’s CC-92252, an asset gained via Celgene, was stopped after failing to meet progression criteria.
The remaining groups involved in this burgeoning field will hope that it does not go the same way as IL-2 for cancer.
This story has been updated to reflect NKTR-358's status in ulcerative colitis.