QLS2309, a trifunctional NKp46/CD16a-NK cell engager targeting CD70 enhances efficacy against acute myeloid leukemia via mitigating the refraction to therapeutic antibody-dependent cytotoxicity

Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is characterized by clonal expansion of myeloid precursors in the bone marrow (BM) and peripheral blood. Despite advancements in treatment, unmet medical needs persist in AML, with up to 50% of patients relapsing after initial chemotherapy and older patients facing a poor prognosis. CD70, a member of the tumor necrosis factor family, is expressed in over 80% of AML blasts and exhibits high specificity for leukemia stem cells (LSCs), while normal hematopoietic stem cells (HSCs) and immune cells show minimal or no expression. This makes CD70 an attractive therapeutic target for AML. However, approximately one-third of AML patients express the high-affinity Fc receptor CD64, which may impair the tumor-killing efficacy caused by Fc-mediated ADCC of therapeutical monoclonal antibodies. To address this challenge, we generated a trifunctional natural killer cell engager (NKCE), QLS2309, which targets AML blasts via binding to CD70 and engages NK cells via binding to NKp46/CD16a on NK cells. QLS2309 is a human IgG1 bispecific antibody featuring an anti-NKp46 nanobody (VHH) and an anti-CD70 antigen-binding fragment (Fab). Unlike anti-CD70 monoclonal antibodies, QLS2309 retained potent antitumor activity against primary AML blasts regardless of CD64 expression. Additionally, it selectively induced NK cell activation and cytokine secretion only in the presence of AML cells. In vivo studies demonstrated dose-dependent tumor growth inhibition with QLS2309, showing superior efficacy compared to cusatuzumab (an ADCC-enhanced monoclonal antibody). Single-dose pharmacokinetics in non-human primates (NHPs) revealed linear exposure, while multiple-dose toxicokinetics showed no significant accumulation. A GLP toxicity study in cynomolgus monkeys (QW × 4) confirmed favorable safety, with QLS2309 well-tolerated up to 100 mg/kg and minimal cytokine release. In conclusion, QLS2309 combines excellent efficacy, favorable pharmacokinetics, and a strong safety profile, outperforming cusatuzumab. These data support QLS2309 as a promising novel therapy for AML. A Phase 1 dose-escalation study in CD70+ relapsed/refractory hematologic malignancies is currently ongoing (NCT07173595).