2013 – CONTROLLING CLONAL HEMATOPOIESIS-DRIVEN ATHEROSCLEROSIS BY TARGETED CONDITIONING AND STEM CELL TRANSPLANTATION

Clonal hematopoiesis (CH) is an age-related phenomenon linked to increases in cardiac mortality, all-cause mortality and myeloid malignancies. The magnitude of risk rivals that of known risk factors like high cholesterol or hypertension. Unlike those settings, CH has no ready intervention to mitigate it. Theoretically, bone marrow transplantation (BMT) might impact the abundance of disease driving clones, but the risks of that therapy as currently practiced are too extreme. Further, it is not clear that this intervention would impact atherosclerosis. We have defined antibody drug conjugates (ADC) against CD45 that enable high levels of chimerism in transplant settings. These ADC have been well tolerated in pre-clinical models and do not involve genotoxins that might incur long term risks. We therefore tested if CD45-ADC could be used to deplete Tet2 deficient HSPCs and their mature progeny and if that in turn could impact atherosclerotic disease. CH-related atherosclerosis was modeled in LDLR knockout mice bearing wild-type (WT) or 20% Tet2-/- hematopoietic cells. After week 6 of 12, the mice received one dose of isotype- or CD45-ADC followed by WT bone marrow infusion. 6 weeks later there was a 3-fold reduction of Tet2-/- cells and 75% of peripheral blood was derived from the WT graft. Notably, a single dose of ADC reduced the number of CD11b+ myeloid cells in the atherosclerotic plaques of both the WT and Tet2 mutant hosts. In the Tet2-/- hosts, the area of the aortic plaques strikingly regressed. These data indicate that ADC treatment can deplete plaque macrophages associated with disease. It can enable regression of atherosclerosis while replacing the disease causing mutant clones. If ADC conditioning proves itself clinically, the potential for extending BMT to clonal hematopoiesis may have broad based health benefits.