A bispecific antibody-drug conjugate targeting CD7 and CD33 shows anti-tumor activity and improved tumor selectivity in an aggressive subtype of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor clinical outcome. Aberrant expression of CD7 in AML patients is linked to shorter overall survival and lack of response to standard of care therapy. CD33/CD7 co-expression on leukemic blasts occurs in approximately one-third of AML patients and is known to be absent in normal myeloid cells. We propose that CD33+CD7+ AML constitutes an aggressive subgroup characterized by poorer prognosis and enrichment in stem-cell associated gene signatures. To address the substantial unmet need in this patient cohort, we developed the antibody-drug conjugate BVX001, a CD33xCD7-targeted bispecific antibody-binding fragment linked to an auristatin payload. Importantly, BVX001 relies on simultaneous binding to CD33 and CD7 in cis through an 'AND-gated' design, for optimal delivery of its cytotoxic payload. Consequently, BVX001 did not affect healthy myeloid progenitors or T cells at concentrations at which its monospecific counterparts showed toxicity. BVX001 induced significant tumor regression in AML cell line and patient-derived xenografts and increased overall survival. Finally, BVX001 showed significant blast ablation and reduced leukemic stem cell frequency in AML patient samples with both high and low target co-expression. Together, our findings support BVX001 as a new and promising approach for the treatment of this aggressive CD33+CD7+ AML subtype, currently lacking targeted therapeutic options.