{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:33Z","timestamp":1785411393014,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,21]]},"group-title":"Cancer Biology","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["K08HL168777"],"award-info":[{"award-number":["K08HL168777"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Leukemia Research Foundation New Investigator Research Grant Program"},{"name":"MacMillan Pathway to Independence Program Award"},{"award":["HBMT pilot grant"],"award-info":[{"award-number":["HBMT pilot grant"]}],"id":[{"id":"https:\/\/ror.org\/02nfzhn33","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NCI","award":["K08CA270403"],"award-info":[{"award-number":["K08CA270403"]}]},{"name":"Leukemia Lymphoma Society Translation Research Program"},{"name":"American Society of Hematology Scholar"},{"name":"Swim Across America Translational Cancer Research"},{"name":"NCI","award":["T32 CA153952"],"award-info":[{"award-number":["T32 CA153952"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Patients with myelodysplastic syndrome (MDS)\/acute myeloid leukemia (AML) with high-risk features including\n                  <jats:italic>TP53<\/jats:italic>\n                  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\n                  <jats:italic>TP53<\/jats:italic>\n                  -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\n                  <jats:italic>TP53<\/jats:italic>\n                  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\n                  <jats:italic>TP53-<\/jats:italic>\n                  mutated MDS\/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived\n                  <jats:italic>TP53<\/jats:italic>\n                  -mutated MDS\/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS\/AML.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of significance<\/jats:title>\n                  <jats:p>\n                    Pyrrolobenzodiazepine(PBD)-conjugated anti-CCRL2 ADC shows anti-leukemic effect in MDS\/AML models including\n                    <jats:italic>TP53<\/jats:italic>\n                    -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.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.17.670714","type":"posted-content","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T01:30:21Z","timestamp":1755826221000},"source":"Crossref","is-referenced-by-count":1,"title":["A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS\/AML"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4761-7435","authenticated-orcid":false,"given":"Nour Sabiha","family":"Naji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taha","family":"Ahmedna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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