本研究探讨了基于人血清白蛋白 (HSA) 的无药大分子治疗 (DFMT) 治疗慢性淋巴细胞白血病 (CLL)（一种常见的成人白血病亚型）的疗效。 DFMT 是一种新颖的策略，采用恶性 B 细胞上 CD20 和 CD38 受体的仿生交联，而不需要低分子量药物。细胞凋亡通过两步过程启动：i) 细胞表面抗原识别双特异性接合剂，即与吗啉代寡核苷酸缀合的 Fab' 片段 (Fab'-MORF1)；随后ii)将MORF1修饰的细胞与多价效应物、持有多个互补MORF2拷贝的HSA、HSA-(MORF2)x交联。在此，我们评估了基于 HSA 的 DFMT 对从诊断为 CLL 的患者中分离出的 56 个样本的治疗效果。 Obinutuzumab (OBN) 和 Isatuximab (ISA) 的 Fab' 片段用于合成抗 CD20 (Fab'OBN-MORF1) 和抗 CD38 (Fab'ISA-MORF1) 双特异性接合剂。 CD20和CD38受体的表达水平显着影响DFMT的功效。双靶点 DFMT 策略 (CD20  CD38) 比单靶点方法更有效，特别是在受体表达升高的样本中。用吉西他滨或ricolinostat预处理患者细胞分别显着增加细胞表面CD20和CD38表达。 62.5% 的 CD20 靶向样本和 42.9% 的 CD38 靶向样本中细胞凋亡被有效启动。我们的研究结果证明了 DFMT 在个性化 CLL 治疗中的潜力。需要进一步的研究来在大量患者样本中验证这些结果，并探索 DFMT 对其他恶性肿瘤的适用性。© 2024。控释协会。

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.© 2024. Controlled Release Society.