Engineered antibody-lectin hybrids unleash immune cells against cancer by blocking sugar-based checkpoints
AbLecs pair tumour-targeting antibodies with Siglec decoy domains to block glycan immune brakes, boosting killing of cancer cells and shrinking metastases in mice.
Summary
Many cancer patients do not respond to checkpoint inhibitors such as PD-1 blockers. Tumours also coat themselves in sialic-acid sugars that engage inhibitory Siglec receptors on immune cells. Researchers built antibody-lectin chimeras (AbLecs), bispecific molecules that combine a tumour-targeting antibody arm (trastuzumab, anti-HER2) with a Siglec-7 or Siglec-9 decoy receptor arm. The antibody arm concentrates the weak-binding lectin on the cancer cell, where it masks inhibitory glycans. In lab assays, AbLecs enhanced phagocytosis and killing of HER2+ cancer cells by primary human macrophages, NK cells and granulocytes compared with trastuzumab alone. In a humanized mouse lung-metastasis model, they reduced tumour burden. The approach was modular and worked with other antibodies and checkpoints. These are preclinical results.
Detailed Summary
Checkpoint blockade has transformed oncology, yet fewer than 20% of treated patients respond, and a quarter of responders develop resistance. Cancer cells commonly display altered sialic-acid-rich glycans that engage inhibitory Siglec receptors on immune cells, forming 'glyco-immune checkpoints'. These have been hard to drug: high-quality anti-glycan antibodies are scarce, lectin ligands are often multiple and poorly defined, and Fc-fused lectin decoys bind too weakly (µM–mM) to work as therapeutics.
The authors designed antibody-lectin chimeras (AbLecs). Using knobs-into-holes Fc engineering, they co-expressed trastuzumab heavy and light chains with Siglec-7-Fc or Siglec-9-Fc, producing heterotrimeric molecules (T7 and T9) in a single culture. The high-affinity antibody arm anchors the molecule to HER2 on the cell surface, creating a high local concentration that lets the low-affinity Siglec arm bind sialoglycans on the same cell. The authors confirmed assembly by SDS-PAGE, western blot and mass spectrometry, and found melting temperatures of 55–60 °C.
AbLecs bound HER2+ cells with low-nanomolar apparent affinity, similar to trastuzumab, whereas Siglec-Fc decoys alone barely bound. Arginine-mutant AbLecs had roughly 2–3-fold weaker binding, showing that glycan interaction contributes. AbLecs selectively blocked their cognate Siglec decoy binding, nearly to sialidase-treated levels. T7 also competed with an antibody for the Siglec-7 epitope on CD43. A structure-guided computational model estimated that T7 delivers Siglec-7 binding domains about 400-fold more effectively than Siglec-7-Fc, and shifts Siglec-7-Fc from bivalent to mostly monovalent binding, which may disrupt Siglec clustering and inhibitory signalling.
Functionally, AbLecs increased phagocytosis by primary human macrophages and cytotoxicity by NK cells and granulocytes beyond trastuzumab across several donors and cell lines. Activity depended on HER2 and Fcγ receptors, and the enhancement disappeared when the targeted Siglec was blocked or Siglec ligands were removed with sialidase, supporting a dual mechanism of antibody effector function plus glyco-immune checkpoint blockade. In a humanized, immunocompetent mouse model (human Siglec-7/9 and FcγR, murine orthologs knocked out) with B16D5-HER2 lung metastases, AbLecs reduced tumour burden. The authors report that the platform extends to other antigens (HER2, CD20, EGFR) and to dual-blockade designs combining PD-1/PD-L1, CD47/SIRPα or galectin-9 targeting, with synergy over established checkpoints.
Caveats: the work is preclinical, the provided text is truncated before the full in vivo, combination and dual-blockade data, and clinical safety, pharmacokinetics and immunogenicity remain untested.
Key Findings
- AbLecs fuse a tumour-targeting antibody arm to a Siglec-7/9 decoy, binding HER2+ cells at low-nanomolar affinity despite weak lectin binding alone.
- T7 and T9 AbLecs selectively blocked their cognate Siglec binding to cells, reducing it nearly to sialidase-treated levels.
- AbLecs boosted phagocytosis and killing of cancer cells by primary human macrophages, NK cells and granulocytes versus trastuzumab.
- Enhancement required HER2, Fcγ receptors, the targeted Siglec and cell-surface sialoglycans, supporting a dual antibody plus glyco-checkpoint mechanism.
- In a humanized immunocompetent mouse model, AbLecs reduced lung metastatic tumour burden; the platform is modular for other antigens and checkpoints.
Methodology
AbLecs were engineered with knobs-into-holes Fc heterodimerization and characterized biochemically, by flow cytometry binding and competition assays, and by computational binding modelling. Efficacy was tested in primary human macrophage, NK cell and granulocyte co-culture assays with HER2+ cell lines, using Siglec-blocking antibodies, FcγR blockade and sialidase as mechanistic controls. In vivo activity was assessed in transgenic humanized (Siglec-7/9, human FcγR) mice with B16D5-HER2 lung metastases.
Study Limitations
Evidence comes from in vitro assays with cell lines and primary cells, and a single humanized mouse metastasis model with small groups (n=7–8). The supplied text is truncated, so details on combination therapy, other antigens and dual-blockade results were not reviewed in full. Safety, pharmacokinetics, immunogenicity and on-target/off-tumour effects in humans are unknown.
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