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SIGLECs go from homing beacons to next-generation checkpoints

Why SIGLECs are rising in the landscape of next-generation checkpoint targets

Propelled by growing understanding of their biology, and an expression pattern that goes well beyond T cells, SIGLEC proteins are rising as the next set of checkpoint targets to challenge PD-1. The sugar-binding proteins could prove useful outside of cancer as well.

Two members of the family, CD22 (SIGLEC2) and CD33 (SIGLEC3), have already spawned commercial products as cell-surface markers that direct antibody-based therapies to kill B cell and myeloid cancers, respectively.

That strategy gained momentum last year when shares of Allakos Inc. (NASDAQ:ALLK) more than tripled in value on takeout rumors following positive Phase II GI data from its SIGLEC8-targeting mAb AK002. The therapy triggers antibody-dependent cytotoxicity (ADCC) against SIGLEC8-expressing eosinophils and mast cells that drive inflammatory diseases like eosinophilic gastritis (see "Allakos Sustains Gains on Strength of GI Readout").

Advances in chemical tools and disease models have paved the way for a new set of therapies that use SIGLECs (sialic acid-binding immunoglobulin-like lectins) as switches to boost or dampen the activity of immune cells, rather than deplete them (see Figure: "SIGLECs: More than GPS Coordinates").

“This is a broader spectrum checkpoint pathway than the first generation.”

Jim Broderick, Palleon

The majority of SIGLECs suppress immune activation via mechanisms similar to the T cell checkpoint PD-1,

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