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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

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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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Acknowledgements

The authors thank core facilities, Flow Cytometry and Confocal Fluorescence Microscopy, for support.

Funding

The research was supported by NIH grant R01 CA246716 from the National Cancer Institute (to JK). We acknowledge support of funds in conjunction with grant P30 CS042014 awarded to Huntsman Cancer Institute.

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Authors and Affiliations

  1. Center for Controlled Chemical Delivery, University of Utah, 2030 East 20 South, Biopolymers Research Building, Room 205B, Salt Lake City, UT, 84112-9452, USA

    Jiahui Li, M. Tommy Gambles, Jiyuan Yang & **dřich Kopeček

  2. Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, 84112, USA

    Jiahui Li, M. Tommy Gambles, Paul J. Shami, Jiyuan Yang & **dřich Kopeček

  3. Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Brandt Jones, Justin A. Williams, Nicola J. Camp & Paul J. Shami

  4. Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, 84112, USA

    **dřich Kopeček

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  1. Jiahui Li
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  2. M. Tommy Gambles
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  8. **dřich Kopeček
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Contributions

Conceptualization, JK, JY, JL; methodology, JL, MTG, BJ, JAW, NJC; validation JK, JL, JY; investigation, JL, MTG, BJ, JAW; data analysis, JL, JK, JY, PJS; writing– original draft preparation, JL, JK; writing– review and editing, JK, JL, JY, PJS, NJC; funding acquisition, JK, NJC; supervision, JK, JY, NJC. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Jiyuan Yang or **dřich Kopeček.

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All patients gave informed consent through a research protocol by the University of Utah Institutional Review Board (IRB# 45880).

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Competing interests

J.Y. and J.K. are co-inventors on US patents assigned to the University of Utah related to this work. Otherwise, the authors declare no competing financial interests.

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Li, J., Gambles, M.T., Jones, B. et al. 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 Deliv. and Transl. Res. 14, 2203–2215 (2024). https://doi.org/10.1007/s13346-024-01629-3

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