Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin’s lymphoma

Targeting cytotoxic drugs to cancer cells using antibody-drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b comprise the hetrodimeric signaling component of the B-cell receptor (BCR), and are attractive targets for the use of ADCs since they are B-cell specific, expressed in non-Hodgkin’s lymphomas (NHLs), and trafficked to a lysosomal-like compartment as part of antigen presentation. We show here that the stablelinker ADCs anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are capable of target-dependent killing of NHL cell lines in vitro. Further, these two ADCs are equally effective at low doses in xenograft models of follicular, mantle cell, and Burkitt’s lymphomas, even though several of these cell lines express relatively low levels of CD79b in vivo. In addition, we demonstrate that anti-CD79b ADCs were more effective than anti-CD79a ADCs and that, as hypothesized, antiCD79b antibodies down-regulated surface BCR and were trafficked to the lysosomal-like compartment MIIC. These results suggest that anti-CD79b-MCCDM1 and anti-CD79b-MC-MMAF are promising therapeutics for the treatment of NHL.