Delays fail to Quell Treg interest
Astrazeneca’s $85m Quell collaboration comes after Regeneron’s tie-up with Sonoma and Lilly’s deal with Trex.
Until recently engineered T regulatory cell (Treg) approaches have largely been the preserve of small biotechs, but a trio of 2023 deals has seen big players muscle into the space. The latest agreement came this morning, with Astrazeneca’s collaboration with Quell Therapeutics in type 1 diabetes and inflammatory bowel disease.
Still, the Treg field has not exactly moved quickly. Quell itself has yet to start dosing patients in the first-in-human trial of its lead project, QEL-001 – something it had originally planned to do in 2022.
Luke Henry, Quell’s chief business officer, tells Evaluate Vantage that the delay stemmed from manufacturing improvements “that gave us a meaningful change in the quality of the final Treg cells”. The company then had to get “version 2.0” through regulators before dosing could begin. The first patient has yet to receive therapy, but this is expected soon, with initial safety data due this year.
In any case QEL-001, which is being evaluated in liver transplant, is not covered by the Astra deal. Quell reckons it can commercialise this asset itself, Henry says, whereas it might need some help in bigger diseases. “There’s this whole suite of autoimmune diseases that we could go after. We can't as a small company prosecute that all ourselves.”
The Astra deal does include an option under which Quell can later choose to co-develop the type 1 diabetes programme in the US “if Quell wants to have more skin in the game”.
Henry will not speculate on when the Astra-partnered projects might reach the clinic, saying only that the companies are “going to move as fast as we can”. The IBD work is currently a little further behind, he says.
Tregs are naturally found in the body and have a role in immunosuppression; it is therefore hoped that they could be used to treat autoimmune and inflammatory diseases. However, unmodified Tregs have previously fallen short.
With the next generation of Treg therapies companies are engineering the cells, for example by adding a Car construct to direct Tregs to a specific antigen found at the organ or site of interest.
With QEL-001, Quell is using a Car construct specific for HLA-A2, designed to direct the Tregs to an HLA-A2-positive donor liver in mismatch transplant recipients.
In type 1 diabetes and IBD, Quell and Astra are not yet disclosing the targets they are looking at.
As well as Car constructs, Quell can also add other “modules”, giving a mix-and-match approach that could be tailored by disease, Henry says. One such module is a safety switch, “not dissimilar” to the ones used in Car-T, while another is a “phenotype lock”. The latter involves engineering the cells to express high levels of FoxP3 to keep them in the Treg state and prevent a flip back to a pathogenic effector T cell phenotype.
Referring to the phenotype lock, Henry says: “I think the Astrazeneca team saw that as a piece of our platform that's quite differentiating.”
Meanwhile, Astrazeneca's head of biopharmaceuticals R&D, Mene Pangalos, described Quell's scientific approach as "both leading and highly innovative" in an emailed statement.
Quell is also developing other modules, including ones to improve persistence or promote tissue repair. Henry sees the latter having particular potential in IBD.
Astra and Quell are not the only companies working on Tregs for bowel disorders. A few months ago Regeneron signed a deal with Sonoma covering ulcerative colitis and Crohn’s disease.
At the time, Matt Sleeman, vice-president of immunology and inflammation at Regeneron, pointed to a particularly strong link between Tregs and inflammatory bowel disease, but told Vantage: “I wouldn't rule out other indications.”
|Recent deals involving engineered Tregs|
|Large partner||Small partner||Scope of deal||Up-front fee||Potential milestones||Date|
|Astrazeneca||Quell Therapeutics||Type 1 diabetes & inflammatory bowel disease||$85m*||$2bn||Jun 2023|
|Regeneron||Sonoma Biotherapeutics||Ulcerative colitis, Crohn’s & 2 undisclosed indications, plus Regeneron option for 5th indication||$75m**||$45m||Mar 2023|
|Lilly||Trex Bio||Undisclosed; covers TRB-051, TRB-031 & TRB-041||$55m||$1.1bn||Jan 2023|
|*Undisclosed mix of cash & equity; **$45m cash, $30m equity. Source: company releases.|
He said that Regeneron had been interested in Tregs “for some time”, highlighting Sonoma’s “similar philosophy” and “strong scientific capabilities” as factors in the choice of partner.
Asked why Regeneron had not plumped for another popular approach, which involves using IL-2 to harness endogenous Tregs – an area where Merck and Abbvie have struck deals – Sleeman replied: “IL-2 expands the overall [Treg] population. I think you need to focus the Tregs in the target tissue.”
As with Astra and Quell, the Regeneron deal does not affect Sonoma’s lead project, which is being developed for rheumatoid arthritis.
Lilly also took a step into the Treg arena early this year with a deal with Trex Bio, although details are thin on the ground.
The most advanced engineered Treg player is Sangamo, which has already dosed three patients in the phase 1/2 Steadfast study of TX200 in kidney transplant. That company's chief scientific officer, Jason Fontenot, admitted to Vantage in April that progress had been slower than hoped, a fact he put down to the pandemic.
With big pharma having signalled its intent, perhaps momentum will pick up.
|Selected companies developing engineered Treg projects|
|Company||Lead Treg project||Indication||Details||Trial details|
|Sangamo Therapeutics||TX200||HLA-A2-mismatched kidney transplant||Autologous HLA-A2-specific Car-Tregs||Ph1/2 ex-US Steadfast, 3 pts dosed|
|Quell Therapeutics||QEL-001||HLA-A2-mismatched liver transplant||Autologous HLA-A2-specific Car-Tregs with Foxp3 phenotype lock module & safety switch||Ph1/2 Liberate recruiting in UK; safety data due H2 2023|
|Teraimmune||TI-168||Haemophilia A with inhibitors||FVIII-specific TCR-engineered Tregs||IND cleared for ph1/2 study Oct 2022|
|Sonoma Biotherapeutics||SBT-77-7101||Rheumatoid arthritis||Autologous Car-Tregs targeting citrullinated protein||To enter clinic end 2023/early 2024|
|Abata Therapeutics||ABA-101||Multiple sclerosis||Autologous TCR-engineered Tregs recognising immunogenic myelin fragments||To enter clinic 2024|
|Gentibio||GNTI-122||Type 1 diabetes||Autologous engineered Tregs (EngTregs) from T effector cells, incorporating Foxp3 & IL-2 signalling support||Preclinical|
|Kyverna Therapeutics||Undisclosed||Undisclosed||"Reprogrammed" synReg T cells||Preclinical|
|Source: Evaluate Pharma & clinicaltrials.gov.|