Targeting the 5T4 oncofoetal glycoprotein with an antibody drug conjugate (A1mcmmaf) improves survival in patient derived xenograft models of acute lymphoblastic leukemia.

Abstract

Outcome in childhood acute lymphoblastic leukemia is prognosticated on levels of minimal residual disease after remission induction therapy. Higher minimal residual disease levels are associated with inferior results even with intensification of therapy and suggest identification and targeting of minimal residual disease cells as a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient derived xenografts from patients with high minimal residual disease post induction. 5T4 positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier; migrated in vitro on a CXCL12 gradient; preferentially localised to bone marrow in vivo and displayed ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (5T4-Antibody Drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4 positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4 positive patient derived xenograft cells, were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (p=0.0006) over either monotherapy. These data show specifically targeting minimal residual disease cells improved outcomes supporting further investigation of A1mcMMAF in high risk B- cell precursor-acute lymphoblastic leukemia patients identified by 5T4 at diagnosis.