TOLERANCE INDUCTION BY THERAPEUTIC MONOCLONAL ANTIBODIES

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The long-term goal of this Project is to develop means for achieving selective immunosuppression and tolerance to hematopoietic stem cell grafts in man. Three approaches will be evaluated. Specific aim 1 will determine whether selective donor-recipient T-cell deletional tolerance can be induced in vivo by administering a nonmitogenic anti-CD3 epsilon mAb to prevent or treat GVHD. The immuno- suppressive potency of nonmitogenic murine anti-human CD3 epsilon mAb BC3 will be tested in two clinical settings. The first trial will evaluate mAb BC3 used in combination with glucocorticoids to prevent GVHD in recipients of marrow from HLA-compatible unrelated donors. The second trial will evaluate mAb BC3 used for first-line treatment of acute GVHD. The hypothesis to be tested is that in the presence of limited HLA mismatch between donor and recipient, treatment with mAb BC3 will induce clonal deletion of allospecific cytotoxic and possibly helper T lymphocytes. Host-reactive donor T-cells will be characterized and quantified before and after anti-CD3 epsilon mAb therapy to determine whether treatment is associated with T-cell clonal deletion. Specific aim 2 will determine whether acute GVHD can be prevented by treatment with a highly potent IL-2R alpha-specific immunotoxin administered on days 1-4 after transplantation, when donor T-cells are first activated by recipient alloantigen. This study will test whether the RFT5 mAb coupled to deglycosilated ricin A chain (RFT2.dgA) can be administered safely on days 1-4 after unrelated marrow transplantation and whether a dose of RFT5.dgA can be found where the risk of grades III-IV GVHD is 15-25% or less. Specific aim 3 will determine whether donor-recipient T-cell costimulation by a monovalent CD28-ligand. We propose to engineer a full-size "humanized" IgG that has only a single CD28-combining site with the ultimate goal of testing its immunosuppressive activity in human marrow transplantation.