Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster III
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Antibody Therapy, Translational Research, Drug development, Bispecific Antibody Therapy, Diseases, Treatment Considerations, Biological therapies, Immunotherapy, Myeloid Malignancies
Methods: We conducted assays using cancer cell lines expressing CD39 and peripheral blood mononuclear cells (PBMCs) derived from healthy donors to evaluate T cell activation and cytotoxicity. Additionally, we assessed CD39 expression in blasts from AML patient bone marrow cells treated with venetoclax, a standard chemotherapeutic agent. Flow cytometry was used to quantify CD39 expression levels and phenotypic shifts in AML blasts. We investigated the depleting effect of BP1223 on blasts from multiple AML patient samples using both in vitro cytotoxicity assays and ex vivo bone marrow cultures. To assess safety, we investigated the impact of BP1223 on normal bone marrow cells, including hematopoietic stem cells and progenitor cells. We also examined on human umbilical vein endothelial cells (HUVECs), given the known expression of CD39 on endothelial cells.
Results: BP1223 induced robust T cell activation, characterized by increased PD-1 expression, and potent cytotoxicity against CD39-positive cancer cell lines, resulting in significant tumor cell lysis confirmed by flow cytometry. In ex vivo studies using clinical samples, venetoclax treatment enriched the AML blast population for CD39 positive cells by selectively eliminating CD39-negative cells. BP1223 effectively depleted these CD39-positive blasts ex vivo, and this effect was further augmented by the combination with venetoclax and azacitidine, resulting in nearly complete depletion at clinically relevant concentrations. Moreover, BP1223 also exerted bystander effects that eliminated CD39-negative blasts in co-culture systems, indicating the engagement of a broader anti-leukemic immune response. Normal bone marrow cells and HUVECs showed minimal cytotoxicity when exposed to BP1223, suggesting a favorable safety profile.
Conclusions: BP1223 demonstrates potent antitumor activity against both CD39-positive and -negative AML blasts, mediated through effective T cell engagement and activation. The bispecific antibody's ability to induce bystander cytotoxicity enhances its therapeutic potential, addressing both primary and resistant leukemic populations. The minimal impact on normal bone marrow cells and endothelial cells underscores BP1223’s high safety profile. These findings suggest that BP1223 could serve as a promising novel therapeutic option for AML, potentially improving outcomes in patients with CD39-expressing and chemotherapy-resistant disease.
Disclosures: Yuda: BMS: Research Funding; Takeda: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Chugai: Research Funding; Daiichi Sankyo: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Genmab: Research Funding; Sumitomo Pharma: Research Funding; MSD: Research Funding; Mitsubishi Tanabe: Research Funding; BrightPath Biotherapeutics Co.,Ltd.: Research Funding. Aramaki: BrightPath Biotherapeutics Co.,Ltd.: Current Employment, Patents & Royalties. Matsumura: BrightPath Biotherapeutics Co.,Ltd.: Current Employment, Patents & Royalties. Nakajima: BrightPath Biotherapeutics Co.,Ltd.: Current Employment, Patents & Royalties. Mie: BrightPath Biotherapeutics Co.,Ltd.: Current Employment, Patents & Royalties.
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