Human serum albumin-based drug-free macromolecular therapeutics induce apoptosis in chronic lymphocytic leukemia patient cells by crosslinking of CD20 and/or CD38 receptors - Drug Delivery and Translational Research

This study explores the efficacy of human serum albumin (HSA)-based Drug-Free Macromolecular Therapeutics (DFMT) in treating Chronic Lymphocytic Leukemia (CLL), a prevalent adult leukemia subtype. DFMT, a novel strategy, employs biomimetic crosslinking of CD20 and CD38 receptors on malignant B cells without the need for low molecular weight drugs. Apoptosis is initiated via a two-step process: i) Recognition of a bispecific engager, Fab’ fragment conjugated with morpholino oligonucleotide (Fab’-MORF1), by a cell surface antigen; followed by ii) crosslinking of the MORF1-decorated cells with a multivalent effector, HSA holding multiple copies of complementary MORF2, HSA-(MORF2)x. Herein we evaluated the efficacy of HSA-based DFMT in the treatment of 56 samples isolated from patients diagnosed with CLL. Fab’ fragments from Obinutuzumab (OBN) and Isatuximab (ISA) were employed in the synthesis of anti-CD20 (Fab’OBN-MORF1) and anti-CD38 (Fab’ISA-MORF1) bispecific engagers. The efficacy of DFMT was significantly influenced by the expression levels of CD20 and CD38 receptors. Dual-targeting DFMT strategies (CD20 + CD38) were more effective than single-target approaches, particularly in samples with elevated receptor expression. Pretreatment of patient cells with gemcitabine or ricolinostat markedly increased cell surface CD20 and CD38 expression, respectively. Apoptosis was effectively initiated in 62.5% of CD20-targeted samples and in 42.9% of CD38-targeted samples. Our findings demonstrate DFMT’s potential in personalized CLL therapy. Further research is needed to validate these outcomes in a larger number of patient samples and to explore DFMT’s applicability to other malignancies. Graphical Abstract

Vivo-Morpholinos | Gene Tools, LLC

A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

A monthly journal publishing high-quality, peer-reviewed research on all topics related to RNA and its metabolism in all organisms

Structural insights into the morpholino nucleic acid/RNA duplex using the new XNA builder Ducque in a molecular modeling pipeline

Abstract. The field of synthetic nucleic acids with novel backbone structures [xenobiotic nucleic acids (XNAs)] has flourished due to the increased importance o

Noncanonical function of folate through folate receptor 1 during neural tube formation - Nature Communications

Neural tube defects are common birth defects that have been shown to be reduced through periconceptional folate supplementation, though the mechanism for this effect is unclear. Here they show that FOLR1 is necessary for neural tube formation in human neural organoids and Xenopus laevis embryos, and that this role is independent of its folate transport function.