TY - JOUR

T1 - Precision Glyco-Modulated GcMAF2.0 Targets CLEC10A to Bidirectionally Re-Wire Macrophage States: Cross-Species Evidence, Mechanistic Omics and Translational Horizons

AU - Pokushalov, Evgeny

AU - Kudlay, Dmitry

AU - Bogachev, Sergey

AU - Johnson, Michael

AU - Snegireva, Julia

AU - Miller, Richard

N1 - Precision Glyco-Modulated GcMAF2.0 Targets CLEC10A to Bidirectionally Re-Wire Macrophage States: Cross-Species Evidence, Mechanistic Omics and Translational Horizons / E. Pokushalov, D. Kudlay, S. Bogachev [et al.] // Immunology. – 2026. – V. 178. - N. 4. - Pp. 561-581. – DOI 10.1111/imm.70132. – EDN XYHVWU.

PY - 2026/8

Y1 - 2026/8

N2 - Macrophages orchestrate inflammation, tissue repair and tumour surveillance, yet macrophage-targeted strategies such as CSF1R inhibition, CD47 blockade or TLR7/8 agonists have so far yielded only modest, context-restricted benefit. The C-type lectin CLEC10A (MGL/CD301) recognises a single terminal α-N-acetylgalactosamine (α-GalNAc) and couples this minimalist glycan cue to context-dependent inflammatory or reparative programmes, making it an attractive target for precision macrophage re-programming. This review synthesises mechanistic, pre-clinical and clinical data on Gc protein-derived macrophage-activating factor 2.0 (GcMAF2.0), a mono-α-GalNAc derivative of vitamin-D-binding protein that engages CLEC10A with high avidity. We summarise lessons from heterogeneous “GcMAF1.0” products, outline GMP workflows that yield EF-M1/EF-M2, and review CLEC10A-centred signalling and metabolic re-wiring, including SYK versus STAT6/PPARγ cascades and shifts in arginine, glucose and fatty-acid metabolism. Cross-species data from rodent inflammation models, human and canine myeloid cells, barrier-tissue and tumour models, and mesoscopic platforms indicate that α-GalNAc ligands and EF-M2 bias macrophage profiles and attenuate joint and barrier-tissue inflammation. A randomised double-blind placebo-controlled trial of EF-M2 in canine osteoarthritis links macrophage repolarisation to pain relief, gait restoration and serum ARG1/iNOS and IL-10/TNF-α shifts, providing disease-modifying proof of concept. We also review the small, uncontrolled human experience with analytically characterised GcMAF2.0 (≈120 patient-courses), noting favourable short-term tolerability but low certainty of benefit and a need for randomised, lot-traceable trials with mechanistic endpoints. Overall, we position the α-GalNAc–CLEC10A axis as a tunable handle on macrophage plasticity and outline the experimental and regulatory priorities needed to translate GcMAF2.0 into evidence-based immunotherapy.

AB - Macrophages orchestrate inflammation, tissue repair and tumour surveillance, yet macrophage-targeted strategies such as CSF1R inhibition, CD47 blockade or TLR7/8 agonists have so far yielded only modest, context-restricted benefit. The C-type lectin CLEC10A (MGL/CD301) recognises a single terminal α-N-acetylgalactosamine (α-GalNAc) and couples this minimalist glycan cue to context-dependent inflammatory or reparative programmes, making it an attractive target for precision macrophage re-programming. This review synthesises mechanistic, pre-clinical and clinical data on Gc protein-derived macrophage-activating factor 2.0 (GcMAF2.0), a mono-α-GalNAc derivative of vitamin-D-binding protein that engages CLEC10A with high avidity. We summarise lessons from heterogeneous “GcMAF1.0” products, outline GMP workflows that yield EF-M1/EF-M2, and review CLEC10A-centred signalling and metabolic re-wiring, including SYK versus STAT6/PPARγ cascades and shifts in arginine, glucose and fatty-acid metabolism. Cross-species data from rodent inflammation models, human and canine myeloid cells, barrier-tissue and tumour models, and mesoscopic platforms indicate that α-GalNAc ligands and EF-M2 bias macrophage profiles and attenuate joint and barrier-tissue inflammation. A randomised double-blind placebo-controlled trial of EF-M2 in canine osteoarthritis links macrophage repolarisation to pain relief, gait restoration and serum ARG1/iNOS and IL-10/TNF-α shifts, providing disease-modifying proof of concept. We also review the small, uncontrolled human experience with analytically characterised GcMAF2.0 (≈120 patient-courses), noting favourable short-term tolerability but low certainty of benefit and a need for randomised, lot-traceable trials with mechanistic endpoints. Overall, we position the α-GalNAc–CLEC10A axis as a tunable handle on macrophage plasticity and outline the experimental and regulatory priorities needed to translate GcMAF2.0 into evidence-based immunotherapy.

KW - C-type lectin receptor

KW - CLEC10A

KW - GcMAF2.0

KW - dial-a-bias

KW - macrophage re-programming

KW - precision glyco-immunomodulation

KW - vitamin D-binding protein

KW - α-GalNAc

UR - https://www.scopus.com/pages/publications/105033102406

UR - https://elibrary.ru/item.asp?id=90269369

UR - https://www.mendeley.com/catalogue/75e45738-b5b1-3e68-bc9d-90f965776b23/

U2 - 10.1111/imm.70132

DO - 10.1111/imm.70132

M3 - Article

C2 - 41854501

VL - 178

JO - Immunology

JF - Immunology

SN - 0019-2805

IS - 4

M1 - 561-581

ER -