Related Experiment Video
Updated: May 22, 2026
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
A PBD dimer-containing antibody-drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease
Nour Sabiha Naji1, Taha Soueidatt Ahmedna1,2, Xinghan Zeng1
1Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
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.
Insights
A novel antibody-drug conjugate targeting CCRL2 shows promise for treating high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly TP53-mutated subtypes. This therapy effectively eliminates cancer cells while sparing healthy ones, offering a potential new treatment avenue.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), especially TP53-mutated subtypes, have poor prognoses due to limited therapeutic options.
- The atypical chemokine receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML), with particularly high levels in TP53-mutated MDS/AML and AML with erythroid features.
Purpose of the Study:
- To evaluate the therapeutic potential of CCRL2 as a target in high-risk MDS/AML.
- To develop and assess an anti-CCRL2 antibody-drug conjugate (ADC) for its efficacy and selectivity against MDS/AML cells.
Main Methods:
- Development of an anti-CCRL2 ADC by conjugating an anti-CCRL2 antibody with the cytotoxic pyrrolobenzodiazepine (PBD) payload.
- Assessment of the ADC's cytotoxicity against MDS/AML cell lines and primary patient samples, comparing it to existing therapies.
- Evaluation of the ADC's effects on healthy hematopoietic stem and progenitor cells.
- In vivo studies using xenograft models of TP53-mutated MDS/AML.
Main Results:
- The anti-CCRL2 ADC exhibited potent and CCRL2-selective cytotoxicity against MDS/AML cell lines with TP53 mutations and erythroid features, outperforming gemtuzumab and other ADCs.
- The ADC induced apoptosis and suppressed clonogenicity in primary MDS/AML bone marrow samples without harming healthy hematopoietic stem and progenitor cells.
- In vivo, the anti-CCRL2 ADC suppressed leukemic growth in xenograft models, improved mouse survival, and reduced leukemic burden.
Conclusions:
- CCRL2 represents a promising novel therapeutic target for high-risk MDS/AML, including TP53-mutated subsets.
- The developed anti-CCRL2 ADC demonstrates significant anti-leukemic activity and selectivity, warranting further investigation as a potential treatment for these challenging hematologic malignancies.
