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A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML
Theodoros Karantanos, Nour Naji1, Taha Ahmedna1
1Johns Hopkins University.
Abstract:
Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations 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.
Insights
A new antibody-drug conjugate targeting CCRL2 shows promise for treating high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly those with TP53 mutations. This targeted therapy effectively kills cancer cells while sparing healthy ones.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), especially those with TP53 mutations, have poor prognoses due to limited effective therapies.
- The atypical chemokine receptor CCRL2 is overexpressed in MDS and secondary AML (sAML), with highest levels found 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 treating these conditions.
Main Methods:
- Development of an anti-CCRL2 ADC by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD).
- Assessment of the ADC's cytotoxicity against MDS/AML cell lines and primary bone marrow samples, comparing it to existing therapies.
- Evaluation of the ADC's effects on healthy hematopoietic stem and progenitor cells.
- In vivo studies using xenografts of TP53-mutated MDS/AML cell lines and patient-derived samples to assess anti-leukemic activity and survival benefits.
Main Results:
- The anti-CCRL2 ADC exhibited potent, 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 samples without harming healthy hematopoietic stem and progenitor cells.
- In vivo, the ADC suppressed leukemic growth in xenografts, improved mouse survival, and reduced leukemic burden in patient-derived models.
Conclusions:
- CCRL2 represents a promising novel therapeutic target for high-risk MDS/AML.
- The developed anti-CCRL2 ADC demonstrates significant potential as a targeted therapy for TP53-mutated MDS/AML and related leukemias.
