The applicant has made the observation that homodimers of several anti-human B cell monoclonal antibodies (Mabs) signal significant growth arrest and/or death in lymphoma cells. Indeed, Mabs which signal poorly as (IgG) monomers make highly effective antitumor agents when they are used as (IgG-IgG) dimers. The applicant will now also study how and under what conditions Mab monomers/dimers act in conjunction with chemotherapy and immunotoxins (ITs) to give increased anti-tumor effects. She will determine whether: 1) """"""""second generation"""""""" signaling antibodies have anti-tumor activity. These include both homo- and heterodimers and new apoptosis-inducing MAbs, 2) signaling Mabs can increase the sensitivity of cells to chemotherapeutic agents plus or minus ITs; 3) her best signaling antibodies can cure SCID/Daudi mice of advanced disease when combined with chemotherapy or ITs and what the optimal way to combine these agents is. If Mabs make cells more sensitive to chemotherapy, she will determine whether lower doses of chemotherapy can be used. 4) She will also develop methods to grow primary lymphomas (from fresh patient material) in SCID mice. To this end, she is using techniques which prevent normal B cells (which contaminate lymphoma specimens) from generating lymphoproliferative disease in these animals so that the monoclonal B lymphoma cells grow out. These tumors will be used as targets for therapy. To this end, she has initiated collaborations at her institution and at two other institutions for the acquisition of fresh lymphomas.
