{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:38:05Z","timestamp":1785404285825,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,14]]},"group-title":"Cancer Biology","reference-count":102,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["U01 CA232563"],"award-info":[{"award-number":["U01 CA232563"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 CA232563-S3"],"award-info":[{"award-number":["U01 CA232563-S3"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32 GM 135131"],"award-info":[{"award-number":["T32 GM 135131"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T2018-014"],"award-info":[{"award-number":["T2018-014"]}],"id":[{"id":"https:\/\/ror.org\/00kbbk236","id-type":"ROR","asserted-by":"publisher"}]},{"award":["886246066"],"award-info":[{"award-number":["886246066"]}],"id":[{"id":"https:\/\/ror.org\/04537p149","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,26]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  While CD19- and BCMA-directed immunotherapies have improved outcomes for B-lymphoid and plasma cell malignancies, frequent relapses with antigen loss\/downregulation highlight the need for new targets. Here, using transcriptomic datasets and newly-developed monoclonal antibodies, we show that\n                  <jats:italic>P2RX5<\/jats:italic>\n                  , long considered a pseudogene in humans, encodes a stable protein in 80% of individuals of African descent carrying the ancestral haplotype. Like CD19, P2RX5 displays B-cell lineage-restricted expression in normal tissues. Unlike CD19, P2RX5 is expressed not only in B-cell neoplasms, but also in T-cell leukemia (T-ALL) and multiple myeloma (MM). We developed P2RX5-directed bispecific T-cell engagers and CAR T cells, which killed T-ALL cells with no evidence of T-cell fratricide. These agents were non-inferior to FDA-approved CD19- and BCMA-directed immunotherapeutics in cell culture and xenograft models of Burkitt lymphoma and MM, while maintaining potency against CD19- and BCMA-negative variants. Hence, P2RX5 is a unique multi-lineage target for frontline or salvage immunotherapy.\n                <\/jats:p>","DOI":"10.64898\/2026.01.14.698748","type":"posted-content","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:35:14Z","timestamp":1768437314000},"source":"Crossref","is-referenced-by-count":0,"title":["The ancestral haplotype of P2RX5 yields a B-cell surface marker and a multi-lineage immunotherapy target"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-4733","authenticated-orcid":false,"given":"Zhiwei","family":"Ang","sequence":"first","affiliation":[{"name":"Division of Cancer Pathobiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Castro","sequence":"additional","affiliation":[{"name":"Division of Cancer Pathobiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-0194","authenticated-orcid":false,"given":"Luca","family":"Paruzzo","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA"},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;"},{"name":"Division of Hematology\/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Schimdt","sequence":"additional","affiliation":[{"name":"Division of Cancer Pathobiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-089X","authenticated-orcid":false,"given":"Zainul 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