A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML

Naji, N. S.; Ahmedna, T.; Peske, J. D.; Zeng, X.; Perkins, B.; Thompson, Z.; Nichakawade, T. D.; Lee, B. S.; Watson, E.; Chatzilygeroudi, T.; Luo, L.; Paun, B.; Klausner, M.; An, Y.; Supeanu, T.; Gojo, I.; Ghiaur, G.; DeZern, A. E.; Levis, M. J.; Resar, L.; Jones, R. J.; Karanika, S.; Paul, S.; Karantanos, T.

doi:10.1101/2025.08.17.670714

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bioRxiv · 10.1101/2025.08.17.670714

A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML

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Abstract

Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations and deletions have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to 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. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients 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. Statement of significancePyrrolobenzodiazepine(PBD)-conjugated anti-CCRL2 ADC shows anti-leukemic effect in MDS/AML models including TP53-mutated disease without affecting healthy hematopoietic cells supporting that it is a promising candidate for single-agent or combination therapies in high-risk MDS/AML.

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Naji, N. S., Ahmedna, T., Peske, J. D., Zeng, X., Perkins, B., Thompson, Z., Nichakawade, T. D., Lee, B. S., Watson, E., Chatzilygeroudi, T., Luo, L., Paun, B., Klausner, M., An, Y., Supeanu, T., Gojo, I., Ghiaur, G., DeZern, A. E., Levis, M. J., Resar, L., Jones, R. J., Karanika, S., Paul, S., Karantanos, T.. 2025-08-21. A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML. https://doi.org/10.1101/2025.08.17.670714

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