A PBD dimer–containing antibody-drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53 -mutated disease
Year: 2026
Type: article
Abstract: ABSTRACT: Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes because of the lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML compared with healthy hematopoietic cells, and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks, leading to cancer cell death. Anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity associated with DNA damage against cell lines derived from patients with MDS/AML with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation, and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML, including TP53-mutated subsets.
Source: Blood Advances
Authors: Nour Sabiha Naji, Taha Ahmedna, Xinghan Zeng, Yuju An, Yashvi Hemani, Brandy Perkins, Zanshe Thompson, Tushar D. Nichakawade, Yanyan Wang, Bum Seok Lee, Evangeline Watson, Theodora Chatzilygeroudi, Li Luo, Bogdan Paun, Melanie Klausner, Teodora Supeanu, Ivana Gojo, Gabriel Ghiaur, Amy E. DeZern, Mark J. Levis, Linda Resar, Richard J. Jones, J. David Peske, Styliani Karanika, Suman Paul, Theodoros Karantanos
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Awards: Mechanisms of a therapeutic DNA vaccine targeting Mycobacterium tuberculosis persisters, T32: Predoctoral and Postdoctoral Training Program in Nanotechnology for Cancer Research, TCR Targeting Antibodies for the Treatment of T cell Cancers, CCRL2 as a Regulator of Growth and Novel Target in Myelodysplastic Syndrome
OpenAlex ID: W7161816256