An Antibody-Drug Conjugate Targeting VpreB1 for the Treatment of B-cell Acute Lymphoblastic Leukemia Open Access

• VpreB1 is a unique component of the pre-B-cell receptor and is expressed by most B-ALLs, but not by mature lymphocytes.

• An antibody-drug conjugate targeting VpreB1 showed preclinical efficacy against B-ALL cell lines and patient-derived xenograft models.

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 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 showed high affinity for its target protein and when conjugated to the toxin calicheamicin (VpreB1-ADC) exhibited significant in vitro toxicity against B-ALLs 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 (PDX) 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, and the VpreB1-ADC in preclinical and clinical trials, with the goal of expanding the arsenal of immunoconjugates available for the treatment of B-ALL.