Development of a bispecific Antibody–Drug Conjugate targeting CD7 and CD33 to treat Acute Myeloid Leukaemia

Abstract

AbstractAcute myeloid leukemia (AML) is a heterogeneous malignancy of the bone marrow associated with poor outcomes and limited treatment options available to patients. Recent developments have demonstrated that patient stratification based on disease classification (e.g. somatic mutations) allows for selective treatment regimens and greatly improved outcomes. AML patients can also be stratified based upon the heterogeneous immunophenotype of surface antigen expression on leukemic blasts and stem cells. Here we present data identifying a sub-population of AML patients showing expression of both CD33 and CD7 on their tumour cells, using mass cytometry. This combination of antigens is disease-specific, and is not expressed on healthy haematopoietic cells in patients. We developed a bispecific antibody–drug conjugate (ADC) targeting both CD7 and CD33 and demonstrate that these bispecific ADCs are cytotoxic to AML cells in vitro. Importantly, the anti-CD33/CD7 bispecific ADCs are more selective than single-antigen targeting ADCs and safely discriminate tumour from healthy cells (either myeloid or lymphoid). These anti-CD33/CD7 bispecific ADCs are well tolerated and selectively target AML cells in pre-clinical in vivo studies in mice. This study presents the first proof-of-principle for targeting specific and unique combinations of surface antigens on tumour cells with potential to overcome observed toxicities with current ADCs.