An Antibody-Drug Conjugate Targeting CCRL2 to Improve Outcomes in High-risk MDS and MDS-related AML

About This Grant

PROJECT SUMMARY Patients with myeloid neoplasms with loss-of-function TP53 mutations or deletions have a very short overall survival due to lack of effective and safe therapies. Novel approaches with high efficacy and low toxicity are urgently needed. We reported that the atypical chemokine receptor C-C motif receptor-like 2 (CCRL2) is overexpressed in hematopoietic progenitor cells from patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) arising from MDS and that its deletion suppresses MDS/AML cells growth and sensitizes them to hypomethylating agents making CCRL2 an attractive target in myeloid neoplasms. We discovered that TP53 mutated MDS/AML samples express the highest levels of CCRL2 across AML subtypes. Thus, we developed an anti-CCRL2 antibody-drug conjugate (ADC), which shows significant anti-leukemic activity against TP53 mutated MDS/AML cell lines and primary samples in vitro and in cell line- and patient-derived TP53 mutated AML xenograft models without any effect against healthy hematopoietic cells and systemic toxicity in healthy mice. Moreover, screen of 171 anti-cancer agents that are either FDA approved or under investigation in clinical trials revealed that the PARP1/2 inhibitors talazoparib and stenoparib have the highest synergistic effect when combined with the anti-CCRL2 ADC against TP53 mutated MDS/AML cells. However, additional patient-derived xenograft studies and assessment of the efficacy and safety of anti-CCRL2 ADC in an immunocompetent TP53 mutated syngeneic AML model are needed for the validation of the anti-leukemic activity and safety of this agent before its transition to early phase clinical trials. Moreover, the synergistic or additive effect of the addition of PARP1/2 inhibitors to anti-CCRL2 ADC need to be validated in in vitro and in vivo studies. In the first aim of this study, we will analyze the efficacy of recurrent doses of anti-CCRL2 in patient-derived TP53 mutated MDS/AML xenografts following a successful approach engrafting these samples and in lethally irradiated CD45.1 recipients of bone marrow cells from Jak2V617F/+ Trp53−/− and Jak2V617F/+ Trp53+/− mice. In the second aim of this study, we will analyze the additive or synergistic effect of combining the anti-CCRL2 ADC with the PARP1/2 inhibitors talazoparib and stenoparib both in vitro by treating TP53 mutated MDS/AML cell lines and primary samples and in vivo using our established cell-line derived TP53 mutated MDS/AML xenograft models. Murine models are scientifically justified because they permit evaluation of the anti‑CCRL2 ADC and its combination with PARP1/2 inhibitors in vivo using both xenograft and immunocompetent TP53‑mutated AML models that closely recapitulate human myeloid neoplasm biology and drug responses, which cannot be achieved in vitro or with non‑mammalian systems. These studies are essential to establish efficacy, define on‑ and off‑target toxicity, and generate the preclinical data required by NIH and regulatory agencies before initiating early‑phase clinical trials in patients with TP53‑mutated myeloid neoplasms. Our studies have the potential to introduce a new targeted therapy with low off- and on-target toxicity and a novel combinational strategy that can improve the remission depth urgently required for patients with TP53 mutated myeloid neoplasms to achieve longer survival.