Anti-CD64(scFv)-SNAP-Auristatin F: An in vitro proof of concept study for a recombinant antibody conjugate targeting CD64+ acute monocytic leukemia

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Acute monocytic leukemia (AML-M5) is a rapidly progressing hematological malignancy characterized by limited therapeutic options and poor survival outcomes. Conventional therapies, such as intensive chemotherapy offer limited efficacy due to their lack of tumor specificity, significant systemic toxicities, and high risk of disease relapse after initial treatment, underscoring the need for more targeted therapeutic approaches. CD64 (FcγRI) is highly expressed on monocyte-derived myeloid leukemia cells and has been identified as a promising therapeutic target for the treatment of AML-M5. We have previously demonstrated that recombinant immunotoxins and their humanized counterparts (human cytolytic fusion proteins) can selectively target and eliminate CD64 + AML-M5 cells. However, their clinical efficacy is might be limited by immunogenicity and endosomal degradation. In this study, we developed a next-generation antibody-drug conjugate (ADC) consisting of an anti-CD64 single-chain variable fragment (H22(scFv)) conjugated to the anti-mitotic agent auristatin F in a 1:1 stoichiometry via a site-selective chemistry. This novel ADC demonstrated selective cytotoxicity against CD64 + monocytic leukemia cells in vitro, providing first compelling preclinical evidence for further clinical exploration of CD64-targeted therapies in treating aberrant myeloid leukemias. • Acute monocytic leukemia (AML-M5), an aggressive hematological malignancy require target-specific therapies to improve (pre) clinical outcomes • CD64 is a prime antigen for targeted biotherapeutics in anti-leukemia immunotherapy. • Monomethyl auristatin F (MMAF) is a cytotoxic drug inducing cell death via microtubule assembly disruption. • SNAP-tag technology allows auto-labelling of MMAF with CD64-specific antibodies to generate novel CD64-ADC. • CD64-ADC, containing chemically synthesized MMAF offers improved preclinical potential compared to degradable antibody toxins/fusion proteins in vitro.