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ADP-ribosylation is important in many cellular processes, including DNA replication and repair, maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. Poly-ADP-ribose is important in a number of critical physiological processes such as DNA repair, cellular differentiation, and carcinogenesis. Until recently, only one human enzyme, PARG, had been identified that degrades the ADP-ribose polymer.

The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of autoimmune diseases and T cell malignancies. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. The toxin portion of the immunotoxin is genetically engineered to maintain bioactivity when recombinantly produced in Pichia pastoris.

This technology identifies twenty five (25) new alternatively spliced transcripts of the BORIS gene. The transcripts lead to the expression of seventeen different protein isoforms with variable N- and C-termini encoded by BORIS gene locus. Differential expression levels of BORIS isoforms were observed in different cancers. While some BORIS alternative splice variants were expressed at different levels in all types of cancers, other expressed forms are specific to particular cancer(s).

The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of rejection response in a patient, including graft-versus-host disease and transplantation of organs, tissues and cells into a host. In a specific embodiment of the invention, the transplant involves pancreatic islet cells. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of resting T cells, resulting in an accentuation of immune tolerizing responses and an increased tolerance to transplants and grafts.

The invention concerns immunotoxins and methods of making the immunotoxins. Targeting of the immunotoxins occurs via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. As a result, the immunotoxin can be used to treat autoimmune disease, malignant T cell-related cancers, and graft-versus-host disease.

T lymphocytes play an important role in the immune system by recognizing foreign protein motifs on cells. T lymphocytes are stimulated to recognize these motifs through their interactions with peptide-MHC complexes (pMHC). Thus, studying pMHC is an important aspect of understanding how the immune system works, particularly with regard to the development of vaccines. Unfortunately, the detection of pMHC is largely dependent on indirect assays, due to the difficulty of producing antibodies for specific pMHC.

The ubiquitin-proteasome system has recently been recognized to play a central role in tumor biology. Bortezomib, an inhibitor of the chymotrypsin-like activity of the proteasome, has clinical activity in a variety of hematologic malignancies and is FDA approved for use in Multiple Myeloma and Mantle Cell Lymphoma.

NIH inventors, in collaboration with Scott and White Memorial Hospital inventors, have developed new immunotoxins comprising a mutant diphtheria toxin linked to an anti-prostate specific membrane antigen (PSMA) fold-back diabody. The fold-back diabody construct has a shortened linker region between the heavy and light chains of the antibody variable domain. This construct allows interactions between the longer-linked variable domains while preventing interactions between the shorter-linked variable domains.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory disease, and their anti-inflammatory effects are believed to result from their ability to inhibit the formation of prostaglandins by prostaglandin H synthase (COX). Two forms of prostaglandin H have been identified, COX-1 and COX-2. The former seems to be constitutively expressed in a variety of tissues while the high expression of the latter has been reported in colorectal tumors. NSAIDs have been shown to be effective in reducing human colorectal cancers and possibly breast and lung cancers.

Scientists at the National Institutes of Health have developed mouse monoclonal antibodies against the human spindle assembly checkpoint protein, MAD1. The spindle assembly checkpoint in mitotic cell division regulates the fidelity of chromosome segregation during cell division. MAD1 is an important component of this checkpoint control, which if compromised, can lead to the initiation of cancer cell growth. These monoclonal antibodies are the first available antibodies against MAD1 and can be used in laboratory research and diagnostics.