The long range goal of these studies is to develop criteria for predicting which B cell-reactive monoclonal antibodies will have anti-tumor effects 1) by themselves, 2) in combination with each other and 3) in combination with B cell-reactive immunotoxins and/or chemotherapy. There is accumulating evidence that potent antibody-mediated anti-tumor effects can be achieved by either apoptosis and/or cell cycle arrest. In a human Burkitt's lymphoma line, anti-CD19 induces lyn-dependent cell cycle arrest. In contrast, the crosslinking of IgM induces apoptosis. We will use these two different effects to screen monoclonal antibodies against epitopes on four candidate antigens that appear to transmit negative signals to tumor cells, i.e., CD20, 21, 23 and 24. Our major objective is to identify an antibody that causes apoptosis (since anti-mu cannot be used clinically) and to determine whether there are additive effects among these signalling antibodies based on their categorization in vitro. The objective is to develop an in vitro paradigm for predicting the efficacy of combinations of antibodies by themselves or with chemotherapy and/or immunotoxins so that clinical trials can be designed rationally rather than on a hit-or-miss basis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064679-02
Application #
2107309
Study Section
Experimental Immunology Study Section (EI)
Project Start
1994-09-30
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ghetie, Maria-Ana; Marches, Radu; Kufert, Stephanie et al. (2004) An anti-CD19 antibody inhibits the interaction between P-glycoprotein (P-gp) and CD19, causes P-gp to translocate out of lipid rafts, and chemosensitizes a multidrug-resistant (MDR) lymphoma cell line. Blood 104:178-83
Meng, Ruiqi; Smallshaw, Joan E; Pop, Laurentiu M et al. (2004) The evaluation of recombinant, chimeric, tetravalent antihuman CD22 antibodies. Clin Cancer Res 10:1274-81
Ghetie, M A; Bright, H; Vitetta, E S (2001) Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin. Blood 97:1392-8
Ghetie, M A; Ghetie, V; Vitetta, E S (1999) Anti-CD19 antibodies inhibit the function of the P-gp pump in multidrug-resistant B lymphoma cells. Clin Cancer Res 5:3920-7
Thrush, G R; Lark, L R; Clinchy, B C et al. (1996) Immunotoxins: an update. Annu Rev Immunol 14:49-71
Uhr, J W; Marches, R; Racila, E et al. (1996) Role of antibody signaling in inducing tumor dormancy. Adv Exp Med Biol 406:69-74
Ghetie, V; Engert, A; Schnell, R et al. (1995) The in vivo anti-tumor activity of immunotoxins containing two versus one deglycosylated ricin A chains. Cancer Lett 98:97-101