“MOR” engineering of antibodies in ALL

In this issue of Blood, Schewe and colleagues identify a novel Fc-engineered CD19 antibody with significant activity in a xenograft model of patient-derived mixed lineage leukemia (MLL)–rearranged acute lymphoblastic leukemia (ALL).¹ 

Although the majority of children with ALL are cured, infants with B-cell precursor (BCP) ALL have an extremely poor outcome, with a 4-year event-free survival <50%.²  The MLL gene represents the most frequent cytogenetic abnormality in infants.³  Therefore, novel treatment strategies are clearly needed in this patient subgroup. CD19 is expressed almost universally on the cell surface of all BCP ALLs, making it an attractive therapeutic target.⁴  Over the last decade, there has been success in using the anti-CD19 bispecific T-cell–engaging antibody blinatumomab and chimeric antigen receptor T cells targeting CD19 in the treatment of relapsed/ refractory ALL.^5,6  However, the possibility of other side effects (eg, neurologic, cytokine release syndrome) makes these agents potentially more challenging in the treatment of infant ALL.

Native unconjugated CD19 immunoglobulin G1 antibodies are not able to mediate effector functions well.⁷  Previous attempts to modify the Fc (fragment crystallizable) domain have been successful. The humanized CD19 antibody MOR208 carries the amino acid mutations S239D/I332E in the CH2 region of its Fc region.⁸  Here, Schewe and colleagues evaluate the efficacy of CD19-DE, an Fc-engineered antibody carrying the MOR208 V-regions and S239D/ I332E mutations in the Fc domain in xenograft models of aggressive MLL-rearranged pediatric ALL (see figure).

In their experiments, the authors use pediatric-derived leukemia cells in their xenograft models. They are able to demonstrate that CD19-DE prolongs the survival of xenografts in a minimal residual disease model of infant BCP ALL.¹  These results are confirmed in a randomized preclinical phase 2–like xenograft trial using 13 patient samples. In addition, they demonstrate that CD19-DE in combination with chemotherapy is superior to antibody or chemotherapy alone in an overt leukemia model of infant BCP ALL. Finally, the dependence of CD19-DE on macrophages to phagocytize and kill ALL cells is shown by depleting macrophages using liposomal clodronate. This also led to a significant reversal of the beneficial effects of CD19-DE.¹ 

This work by Schewe and colleagues elegantly demonstrates the activity of a novel antibody, CD19-DE, in a xenograft model of MLL-rearranged leukemia. Clinical trials will be needed to evaluate the efficacy of this antibody in patients. CD19-DE may have potential applications in the treatment of adult ALL and other pediatric ALLs in various settings, such as newly diagnosed ALL (in combination with chemotherapy), relapsed/refractory ALL (in combination with chemotherapy), and minimal residual disease (as a single agent). Future work will be needed to determine its place in the current treatment armamentarium. This paper is illustrative of the exciting era we have entered and of “MOR”e ways we have to engineer antibodies in the treatment of various human malignancies.