T-cell engagement with a difference

In8bio's pivot this week towards the development of antibodies that specifically seek to recruit γδ T cells should ring a few bells. The same approach, though perhaps using a slightly different technology, is being taken by Lava Therapeutics, a listed biotech whose key pipeline projects boast Pfizer and Johnson & Johnson as licensors.

It's clear that T-cell engagers, which use CD3 targeting as part of a bispecific MAb, have already made a big splash, but In8bio is the latest to try homing in on a much more specific cell population. That said, neither it nor Lava have found the going easy; the market capitalisations of both groups have fallen well below $50m over the past year.

In In8bio's case the fall was prompted by loss of investor faith in the company's original focus on cell therapies based on the γδ T cell subtype. The lead of these, an unmodified product coded INB-100, was last year hit by an FDA requirement to run a controlled trial before approval, and a concomitant halving of the company's workforce.

Fresh focus?

INB-100 and several other cell therapies remain in the pipeline, but the γδ T-cell engager technology, disclosed at this week's TD Cowen healthcare conference, offers In8bio a fresh focus. 

The lead asset here has been revealed as INB-619, which hits CD19 and has potential in oncology and autoimmune indications. The precise structure of INB-619, and the way it binds to γδ T cells, hasn't been disclosed, but the project is said to expand and activate Vδ1+ and Vδ2+ cells, which are key types of γδ T cells.

In contrast, typical T-cell engagers such as Roche's Columvi and J&J's Tecvayli use binding to CD3, a protein expressed on all T cells, to activate these lymphocytes broadly.

For its part Lava too has been secretive, but an ASH 2024 poster covering JNJ-89853413, an anti-CD33 project licensed to J&J, revealed that this bispecific MAb uses a high-affinity Vδ2 binder to engage γδ T cells. Presumably the same approach is used by the anti-EGFR project LAVA-1223, licensed by Lava to Seagen in 2022 and now in clinical development at Pfizer as PF-08046052.

Despite the presence of J&J and Pfizer as big pharma partners, Lava was last year forced to restructure to cut costs, and last month, with cash down to $77m, it moved to evaluate "strategic options", including a sale or acquisition. In8bio has only enough cash to last through this year, and Lava's struggles won't fill investors with confidence about raising more.

Multispecific MAbs that engage T-cell subpopulations or other cell types

Notes: *assumption from patent filings; **has myeloid-engager discovery deal with Novartis. Source: OncologyPipeline.

Still, it can't be denied that there is interest among several companies to develop MAbs that engage very specific populations and subpopulations of cells, and In8bio is the latest to do so.

Away from T lymphocytes, for instance, at least two private groups, LTZ Therapeutics and Dren Bio, are looking to develop MAbs that engage myeloid cells, such as macrophages. Again, information is scant on the precise approaches, but patent filings suggest that the former hits the protein CLEC5A (also known as MDL-1), while the latter targets CLEC7A (Dectin-1), in addition to a tumour-targeting moiety.

Also notable is AstraZeneca's so-called Titan technology, which has yielded multispecific MAbs that the company claims specifically recruit CD8+ (rather than CD4+) T cells. This is achieved thanks to two "nanobody" domains, one of which hits CD8 and the other the T-cell receptor, and two such CD8-guided T-cell engagers, one against CD20 and the other against GPC3, are now in the clinic.