Boehringer breathes new life into “don’t eat me” approach

The deal Boehringer Ingelheim signed with OSE Immunotherapeutics late yesterday will not come close to challenging biotech’s most lucrative transactions, but it could breathe new life into an immuno-oncology strategy that had recently been fizzling out.

That approach, targeting the ligand CD47, gained prominence a couple of years ago as a way of preventing tumours from using a so-called “don’t eat me” pathway to evade the immune system. Remarkably, however, there is only one listed company with a clinical asset, and before Boehringer just one large player – Celgene – had given the approach its blessing (see table below).

Even that blessing, a deal Celgene signed with Inhibrx, was struck all the way back in 2012, and its up-front fee was not disclosed, suggesting an insignificant amount. The listed CD47 player, Trillium Therapeutics, has come off heavily in the past three years, and is currently capitalised at under $100m.

Insignificant?

Against this background the signing fee Boehringer paid OSE yesterday – €15m ($18m) for a preclinical asset – is perhaps not as insignificant as it seems. It has certainly endorsed OSE, whose stock surged 50% this morning. The French group had slumped last year when its lead cancer vaccine, Tedopi, was put on clinical hold; its phase III trial only got the go-ahead to resume last month.

The alliance concerns OSE-172, an antibody that targets and inhibits SIRPα, a protein expressed on several cells of the myeloid lineage. The interaction of SIRPα with CD47, its ligand, inhibits destruction of the cell concerned – hence the “don’t eat me” moniker – and some cancers are thought to hijack this pathway by upregulating CD47.

Trillium, like OSE, is trying to inhibit SIRPα in an effort to prevent tumours escaping this type of immune surveillance, though it uses not MAbs but fusion proteins. A lead, TTI-621, is in the clinic, while the follow-up asset TTI-622 sends a more modest activating signal by using an IgG4 rather than an IgG1-derived binding region.

Of course, with this type of interaction either the receptor or the ligand can be targeted, and most groups are in fact aiming to hit CD47. This goes for the private company Forty Seven, whose Hu5F9-G4 is the industry’s most advanced asset, and for CC-90002/INBRX-103, the subject of the Celgene/Inhibrx tie-up.

And the first subject was dosed just last month in a phase I study of Surface Oncology’s SRF231, making this the fifth industry asset targeting SIRPα or CD47 to enter the clinic.

Industry assets targeting the SIRPα/CD47 pathway
Project Company Mechanism of action Note
Phase I
Hu5F9-G4 Forty Seven Anti-CD47 MAb Phase I/II Erbitux & Rituxan combo trials (NCT02953782 & NCT02953509)
CC-90002/INBRX-103 Celgene/Inhibrx Anti-CD47 MAb 2012 deal; phase I in AML (NCT02641002)
TTI-621 Trillium Therapeutics Anti-SIRPα fusion protein Designed as a soluble decoy receptor; Rituxan and PD-(L)1 combos (NCT02663518 & NCT02890368)
ALX148 Alexo Therapeutics Anti-CD47 fusion protein Keytruda, Herceptin or Rituxan combo (NCT03013218)
SRF231 Surface Oncology Anti-CD47 MAb First patient dosed Mar 20, 2018
Preclinical
TTI-622 Trillium Therapeutics Anti-SIRPα fusion protein Uses IgG4 Fc instead of IgG1 Fc to deliver more modest activating signal than TTI-621
NI-1701 Novimmune Anti-CD47/CD19 bispecific MAb Effector arm (anti-CD47) combined with targeting arm (anti-CD19)
NI-1801 Novimmune Anti-CD47/mesothelin bispecific MAb Effector arm (anti-CD47) combined with targeting arm (anti-mesothelin)
OSE-172 Boehringer Ingelheim/OSE Anti-SIRPα MAb Apr 4, 2018 deal worth €15m up front
AUR-104/AUR-105 Aurigene (Dr Reddy's) Anti-CD47 small molecules Decision on which to put into the clinic due by Apr 2019
Anti-CD47 MAb Biocad Anti-CD47 MAb Russian company focused on biosimilars
Anti-CD47 antibodies Arch Oncology Anti-CD47 MAb Company previously known as Tioma (and earlier Vasculox); clinical trial had been planned for 2017
CD47-SIRPα modulators Synthon Anti-CD47 or SIRPα MAbs Patents licensed from Sanquin Blood Supply Foundation in Mar 2017
Source: EvaluatePharma.

So if in the age of immuno-oncology this pathway offers such promise why has it made such slow progress in the clinic? It is nine years since the importance of CD47 was realised by scientists at Stanford Institute.

Part of the problem might stem from a lack of clarity about intellectual property. Forty Seven counts the Stanford team among its scientific founders, but the patent has separately ended up in the hands of Sanquin Blood Supply Foundation, a Dutch organisation that licensed it to Synthon in March 2017.

And, just two weeks later, a US inter-partes review brought by Forty Seven was struck down, prior to this, a challenge by Blink Biomedical to Sanquin's EU patent was rejected in 2016. Analysts have suggested that this casts doubt over other groups patenting MAbs targeting SIRPα or CD47 – something that, if true, could favour Trillium and Alexo, given that these companies focus on fusion proteins rather than MAbs.

The involvement of Celgene, and now Boehringer – both groups must be presumed to have carried out thorough due diligence – should give some hope that the MAb approach might have legs after all.

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