Chimeric ANTI-CD19 Monoclonal Antibodies for the Treatment of Precursor B Cell Acute Lymphoblastic Leukemia

Thousands of people are diagnosed with B cell malignancies every year, yet the only FDA-approved immunotherapies for them are based on anti-CD20 monoclonal antibodies (MAbs). However, CD20 is not expressed on precursor B cell acute lymphoblastic leukemia (pre-B ALL), and CD20 expression is often lost following anti-CD20 immunotherapy. CD19 is a pan B cell membrane antigen that is restricted to the B cell lineage and expressed on B cell lymphomas and pre-B ALLs. Previous studies have shown that a murine anti-human CD19 MAb, HD37, has efficacy in SCID mice with human B cell tumors. Furthermore, homodimers consisting of two conjugated IgG molecules of HD37 are more effective than monomers at inducing tumor cell death. Yet, their large size prevents effective tumor penetration, and normal Fc effector funtions are often not retained. Murine antibodies are also highly immunogenic. Therefore, the objective of this study was to construct, express, and test the in vitro and in vivo activities of chimeric divalent and tetravalent HD37 MAbs. Both chimeric HD37 MAbs and the murine HD37 MAb were equally effective at mediating antibody dependent cellular cytotoxicity (ADCC) with mouse effector cells. The anti-tumor activities of all three MAbs were identical in SCID mice xenografted with human B cell tumors. However, the chimeric tetravalent MAb has a higher binding affinity and a longer half-life of dissociation than either of the divalent MAbs. Moreover, the chimeric tetravalent MAb mediated ADCC and complement dependent cytotoxicty (CDC) more efficiently than the divalent MAbs when human effector cells and human complement were used. None of the MAbs were cytotoxic to target cells in the absence of effector cells or complement. These data suggest that 1) the HD37 MAbs effectively extend the mean survival time of SCID mice engrafted with human B cell tumors; 2) more than two of the tetravalent HD37 MAb's binding sites are active; and 3) because in vitro results show that the chimeric tetravalent MAb is more effective than the divalent MAbs at mediating ADCC and CDC with human effector cells and complement, the chimeric tetravalent HD37 MAb could be superior to the divalent MAbs in humans.

Author dc:creator

• Tsai, Lydia Kar-Yuk

Contributors dc:contributor

• Vitetta, Ellen S.

• Antibodies, Monoclonal
• Antigens, CD19
• Antineoplastic Agents
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

Language dc:language

en

Identifier

760909253

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/612