Abstract
Non-Hodgkin’s lymphoma (NHL) is an attractive indication for the use of antibody-drug conjugate (ADC) therapeutics since NHL is responsive to conventional chemotherapeutic and antibody treatments. Additionally, experience with rituximab indicates that depletion of normal B-cells can be tolerated without untoward side effects, suggesting that B-cell specific surface proteins that are also prevalent in NHL are potential ADC targets. ADCs with stable linkers have lower toxicity than ADCs containing the same drugs with less stable linkers, however, for these ADCs to be effective the antibody must be degraded to release the active drug. This limits potential targets to surface antigens that upon antibody binding are highly internalized and subsequently degraded. We hypothesized that components of the B-cell receptor (BCR) would be excellent targets for stable-linker ADCs since, when cross-linked, the BCR is targeted to the lysosomal-like compartment MIIC as part of B-cell antigen presentation. In particular, CD79, the signaling component of the B-cell receptor, comprised of two peptide chains CD79a (Igα, mb-1) and CD79b (Igβ, B29), seemed a promising target for ADC treatment of NHL. CD79’s expression is restricted to the B-cell lineage and is on the surface of almost all NHLs. Unlike surface-Ig targeted therapies, which require a new drug for each cancer clone, CD79 sequences are invariant and a single drug is appropriate for the entire population. We found that ADCs targeted to CD79b were more effective than those targeted to CD79a. Furthermore, excellent efficacy is demonstrated with ADCs containing stable linkers and our data indicate in particular, that both anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are effective at low doses in subcutaneous cell-line xenograft models of follicular lymphoma, mantle cell lymphoma, Burkitt’s lymphoma and disseminated Burkitt’s lymphoma. Mechanism-of-action experiments show that anti-CD79b antibodies down regulate surface BCR expression and internalized antibody accumulates in the lysosomal-like MIIC compartment as hypothesized. We evaluated a number of ADCs targeted to other B-cell antigens and found that they were not effective if the ADC had a stable linker, indicating that CD79 has special properties as a target for ADCs. Our results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are particularly promising therapeutics for the treatment of NHL.
Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma
