Novel IgM-derived antibody-drug conjugate selectively kills chronic lymphocytic leukemia cells through binding of Fc mu-receptor leading to rapid internalization and intracellular cytotoxic payload delivery

The IgM Fc receptor (FcμR) is a previously unexploited target for monoclonal antibody therapy and antibody drug conjugate (ADC) therapy of B-cell chronic lymphocytic leukemia (CLL). While anti-FcμR IgG binding does not cause FcμR internalization, IgM bound to FcμR are rapidly internalized (>80% internalized within 5 minutes). FcμR is overexpressed in CLL with only limited expression on normal B, T, and NK cells. In our study, 29 out of 30 CLL patient samples (97%) evaluated by flow cytometry had high FcμR expression by CLL cells (mean(SD)=89.1(7.1)%) and the remaining patient had moderate CLL FcμR expression (57.9%). In contrast, FcμR expression by T cells (mean(SD)=8.9(5.2)%) was significantly lower (p<0.0001). We developed a FcμR targeting ADC consisting of the CH2-CH3-CH4 IgM regions conjugated to monomethyl auristatin F. Flow cytometric analyses of CLL patient samples showed potent ADC mediated killing of CLL cells (mean(SD)=78.8(10.1)%, p< 0.0001 versus scaffold treated control) but not T cells (mean(SD)=8.4(3.8)%, p=0.3210 versus scaffold treated control). The ADC also greatly reduced tumor burden in NOD/SCID/IL-2Rγnull mice xenografted with 4 CLL patient samples (mean reduction(SD)=74(20)% in blood and 65(19)% in spleen, n=30). In summary, FcμR is a promising new target for therapy of CLL and possibly other malignancies. Our preclinical results provide translational evidence for the clinical utility of IgM-derived protein scaffolds to target FcμR expressing cells.