An ancestral haplotype of P2RX5 yields a B-cell surface marker and a promising multi-lineage immunotherapy target
Ang, Z.; Castro, A.; Paruzzo, L.; Schimdt, C.; Hasanali, Z. S.; Hayer, K. E.; Stella, F.; Soldan, S. S.; Diz, M. T.; Kwok, C.; Sainos, P. K.; Ji, K.; Krohl, P. J.; Fine, J.; Sehgal, P.; Martinez, D.; Spangler, J. B.; Riley, J. L.; Vogl, D. T.; Porazzi, P.; Pillai, V.; Lieberman, P. M.; Allman, D.; Ruella, M.; Thomas-Tikhonenko, A.
Show abstract
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 P2RX5, 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.
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