2. Academic Validation
  3. Precision targeting of CXCR4+ leukemia cells by a humanized MMAE-nanoconjugate in an AML mouse model

Precision targeting of CXCR4+ leukemia cells by a humanized MMAE-nanoconjugate in an AML mouse model

  • Biomed Pharmacother. 2025 Sep 23:192:118573. doi: 10.1016/j.biopha.2025.118573.
Annabel Garcia-León 1,  Julián I Mendoza 2,  Ariana Rueda 2,  Lorena Alba-Castellon 2,  Josep F Nomdedéu 3,  Alberto Gallardo 4,  Jorge Sierra 3,  Ana Garrido 3,  Esther Vázquez 5,  Antonio Villaverde 5,  Ramon Mangues 2,  Ugutz Unzueta 6,  Isolda Casanova 7
Affiliations

Affiliations

  • 1 Institut de Recerca Sant Pau (IR SANT PAU), Barcelona 08041, Spain; Josep Carreras Leukaemia Research Institute, Barcelona 08916, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain; University of Barcelona, Barcelona 08007, Spain.
  • 2 Institut de Recerca Sant Pau (IR SANT PAU), Barcelona 08041, Spain; Josep Carreras Leukaemia Research Institute, Barcelona 08916, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain.
  • 3 Josep Carreras Leukaemia Research Institute, Barcelona 08916, Spain; Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain.
  • 4 Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain.
  • 5 CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
  • 6 Institut de Recerca Sant Pau (IR SANT PAU), Barcelona 08041, Spain; Josep Carreras Leukaemia Research Institute, Barcelona 08916, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain. Electronic address: uunzueta@santpau.cat.
  • 7 Institut de Recerca Sant Pau (IR SANT PAU), Barcelona 08041, Spain; Josep Carreras Leukaemia Research Institute, Barcelona 08916, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain. Electronic address: icasanova@carrerasresearch.org.
PMID: 40991987 DOI: 10.1016/j.biopha.2025.118573
Abstract

Acute myeloid leukemia (AML) presents major clinical challenges due to chemoresistance and high relapse rates, primarily driven by therapy-resistant leukemic stem cells (LSCs) within the bone marrow. To address this issue, we developed T22-HSNBT-H6-MMAE, a novel humanized nanoconjugate designed to target CXCR4⁺ cells while delivering the cytotoxic payload monomethyl Auristatin E (MMAE). CXCR4 signaling pathway plays a critical role in LSC survival by preserving stem-like properties and activating protective mechanisms that promote treatment resistance. Moreover, CXCR4 is overexpressed in approximately 50 % of AML patients and is associated with poor prognosis and high relapse rates. We evaluated the therapeutic potential of T22-HSNBT-H6-MMAE using in vitro assays with AML cell lines and primary patient samples, as well as in vivo studies in a disseminated AML mouse model. Our results demonstrated that T22-HSNBT-H6-MMAE exerts a CXCR4-dependent cytotoxic effect through mitotic catastrophe and Apoptosis induction in CXCR4⁺ AML cell lines. In vivo evaluation in a disseminated CXCR4⁺ AML mouse model showed potent antineoplastic activity, with complete suppression of leukemic dissemination and significantly prolonged survival, all without systemic toxicity. Notably, the nanoconjugate remained effective even in models with extensive bone marrow involvement and exhibited activity against diverse patient-derived CXCR4⁺ AML blasts, while sparing healthy donor bone marrow and peripheral blood mononuclear cells (PBMCs) from significant toxicity. Collectively, these findings highlight T22-HSNBT-H6-MMAE as a promising therapeutic candidate for a broad range of AML patients, offering selective antineoplastic activity against CXCR4⁺ leukemic cells.

Keywords

Acute myeloid leukemia; CXCR4; Humanized nanoconjugate; MMAE; Targeted therapy.

Figures
Products