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Human serum albumin-based drug-free macromolecular therapeutics induce apoptosis in chronic lymphocytic leukemia patient cells by crosslinking of CD20 and/or CD38 receptors.
Li, Jiahui; Gambles, M Tommy; Jones, Brandt; Williams, Justin A; Camp, Nicola J; Shami, Paul J; Yang, Jiyuan; Kopecek, Jindrich.
Afiliación
  • Li J; Center for Controlled Chemical Delivery, University of Utah, 2030 East 20 South, Biopolymers Research Building, Room 205B, Salt Lake City, UT, 84112-9452, USA.
  • Gambles MT; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, 84112, USA.
  • Jones B; Center for Controlled Chemical Delivery, University of Utah, 2030 East 20 South, Biopolymers Research Building, Room 205B, Salt Lake City, UT, 84112-9452, USA.
  • Williams JA; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, 84112, USA.
  • Camp NJ; Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
  • Shami PJ; Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
  • Yang J; Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
  • Kopecek J; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, 84112, USA.
Drug Deliv Transl Res ; 14(8): 2203-2215, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38802679
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Linfocítica Crónica de Células B / Apoptosis / Antígenos CD20 / ADP-Ribosil Ciclasa 1 / Anticuerpos Monoclonales Humanizados Límite: Humans Idioma: En Revista: Drug Deliv Transl Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Linfocítica Crónica de Células B / Apoptosis / Antígenos CD20 / ADP-Ribosil Ciclasa 1 / Anticuerpos Monoclonales Humanizados Límite: Humans Idioma: En Revista: Drug Deliv Transl Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos