An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia

B-lineage acute lymphoblastic leukemia (B-ALL) therapy is being transformed by therapies targeting antigens such as CD19, CD20, and CD22 on the surface of B-ALL cells. Moreover, having therapies targeting these different B-ALL antigens has helped address challenges associated with both intra- and inter-patient variability in targeted antigen expression levels and antigen loss as mechanisms of therapy resistances. To further expand the range of targetable antigens in B-ALL therapy, we developed a novel antibody-drug conjugate (ADC) that targets the VpreB1 (CD179a) component of the surrogate light chain. VpreB1 is expressed across most B-ALL molecular subtypes but otherwise has expression limited to precursor B cells, but not mature B cells. Our VpreB1 antibody demonstrated high affinity for its target protein and when conjugated to the toxin calicheamicin (VpreB1-ADC) exhibited significant in vitro toxicity against B-ALL cells harboring a range of genomic alterations. In vivo, the VpreB1-ADC was well tolerated in mice, with modest weight loss and decreased white blood cell counts. When tested against a B-ALL cell line and multiple B-ALL patient-derived xenograft models, the VpreB1-ADC significantly reduced leukemia burden, prolonged survival, and cured a subset of mice. These promising results support further investigation of the VpreB1 component of the surrogate light chain as a therapeutic target, including the VpreB1-ADC in preclinical and clinical trials, with the goal of expanding the arsenal of immunoconjugates available for the treatment of B-ALL.