RE: University of Turku28 May 2026 11:19
Excellent post Vares and the summary gives the reason why some of us are here and invested. Certain others like BD🤡🤡🤡 , just come across as a tad simple and never ever contribute anything whatsoever. Just the same old drivel and grabbing the odd sandwich money here and there 🤣. Thanks for the chart PD, you were bang on the money and the volume told the story !!
Summary of thesis :
Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) are characterised by therapy resistance and relapse risk, reflecting immune dysfunction within the bone-marrow niche and the metabolic adaptability of malignant myeloid cells. This thesis establishes the biological and clinical relevance of the scavenger receptor Clever-1 (STAB1) in myeloid malignancies and evaluates therapeutic targeting with the anti–Clever-1 antibody bexmarilimab.
Clever-1 was consistently detected in malignant myeloid populations in AML cell lines and primary AML/MDS samples, including leukaemic blasts and CD34+ progenitors, with marked inter-patient heterogeneity. Expression was enriched in AML with monocytic differentiation (FAB M4–M5) compared with less differentiated AML and MDS, a pattern reproduced in independent transcriptomic cohorts.
Ex vivo Clever-1 blockade did not induce uniform cytotoxicity but promoted myeloid phenotypic modulation, most notably HLA-DR upregulation in antigen-presenting monocyte-like populations, and modified responsiveness to azacitidine and venetoclax in selected resistant settings. In a phase I/II clinical study with bexmarilimab treatment combined with azacitidine, the regimen demonstrated a manageable safety profile without dose-limiting toxicities and achieved sustained in vivo target engagement, evidenced by high receptor occupancy on circulating CD14+ monocytes and shifts away from an immunoregulatory phenotype. Clinical responses occurred across dose levels in high-risk MDS and relapsed/refractory AML, with activity associated with baseline immune composition rather than blast burden.
Mechanistically, we identify a previously unrecognised intracellular trafficking axis whereby AML cell–intrinsic Clever-1 translocates from the cell surface to mitochondrial compartments and regulates delivery of modified lipoprotein-derived cargo.
Disruption of this pathway reduced mitochondrial lipid incorporation, impaired complex IV assembly, and diminished respiratory capacity, particularly in models reliant on mitochondrial energy metabolism and under lipid-restricted conditions. Collectively, this PhD thesis establishes Clever-1 as a context-dependent immunometabolic regulator in malignant myeloid cells and justifies continued clinical development of Clever-1–targeted therapy in myeloid malignancies
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