CD19 is an attractive target for immunotherapy. The expression of CD19 is restricted to B cells and follicular dendritic cells. In B cells, expression is initiated at the point of B lineage commitment and continues through the preB and mature B cell differentiation. Expression is lost during the terminal differentiation of B cells to plasma cells. CD19 expression continues in B-lineage cells that have undergone neoplastic transformation, making it a useful marker in diagnosis and treatment of B cell derived lymphomas and leukemias, including non-Hodgkin’s lymphoma (NHL), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). We have generated human antibodies to CD19 in transgenic mice, and selected for high binding affinity as well as the ability to rapidly internalize for drug delivery. Anti-CD19 conjugates have been made with highly potent cytotoxic drugs of the DNA minor groove-binding alkylating agent class. Conjugates which contain either a stable hydrazone linkage or a peptide linkage have been made, and both conjugates have been characterized with respect to cyotoxicity, stability, selectivity and in vivo behavior.

Well-characterized, monomeric anti-CD19 conjugates have been produced and tested in vivo for the treatment of (a) established Raji subcutaneous tumor xenografts and (b) a Raji cell systemic tumor model. The anti-CD19 conjugate at a single dose of 0.3 μmole/kg resulted in regression of established subcutaneous tumors with no associated weight loss, or other overt toxicity. Efficacy was substantially superior to that of naked CD19 antibody and non-specific control antibody conjugates. Conjugates were also highly active in a Raji systemic model. Two weekly doses of the anti-CD19 conjugate at 0.3 μmole/kg were well-tolerated and mice were tumor-free for the four-month study period.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA