Genetic Engineering of T Cells Resistant to Oxidative Stress

Provided is a method to genetically engineer human lymphocytes, to enable expression of an antioxidant enzyme, which can render the cells resistant to immune suppression mediated by reactive oxygen species (ROS).

Adoptive immunotherapy of patients with advanced cancer or viral infections has so far met with positive, but limited success. This limited therapeutic effect of adoptively transferred lymphocytes may be attributable in part to elimination of Natural Killer cell and T cell activities by oxidative stress. Systemic administration of drugs that strengthen the patient's resistance to ROS is limited by several factors: Drugs have difficulty penetrating into tumors, can cause toxicity due to the relatively high dosages needed to reach the necessary concentration in the tumor or virus infected tissue, and most drugs have a limited half-life.

Dr. Nishimura (Medical University of South Carolina) and his collaborators at the Karolinksa Institutet have developed a method to overcome these problems through "arming" the patients lympocytes (the so called T-cells and NK-cells) through genetic modification with an antioxidant enzyme (catalase) which can neutralize ROS. A patient's own lymphocytes are transduced with a viral construct coding for catalase. This procedure is done ex vivo in a test tube. The modified lymphocytes can then be transferred back to the patient.

Because the modified lymphocytes are now more resistant to ROS, they are protected from cell death and have an enhanced capacity to recognize virus-expressing target cells. They will be able to actively migrate into tumor tissues and have the potential of replicating and remaining in the host for prolonged periods of time.

Recombinant fusion proteins consisting of complement inhibitors and fragments of soluble P and E-selectin glycoprotein ligand-1 that taret to cell adhesion molecules

Disclosed are methods to produce novel fusion proteins, which rely on different targeting mechanisms, to bind to E-selectin and P-selectin with higher affinity and specificity then any prior construct. Historically the proteins were difficult to express recombinantly, however inventors at MUSC found that coexpression of enzymes allows them to produce the functional protein in reasonable quantities.

Phage-Based Therapeutic System

The disclosed invention relates to the discovery, identification and characterization of toxic agents with are lethal to drug-resistant pathogens and drug-resistant diseased cells (such as cancerous cells). Further, the invention provides a novel system by which multiple targets may be simultaneously targeted to cause the death of a diseased cell.

This application relates to multi-ribozymes and their use to target RNA in a tissue-specific or target-specific manner, for the treatment of cancers and bacterial, viral and parasitic infections.

In Vitro Production of Potentially Therapeutic Human Monoclonal Antibodies

The invention provides for a novel method of developing human monoclonal (mAb).

Researchers at the Medical University of South Carolina recently demonstrated that isolation of B cells from healthy humans can be transformed using a novel technique and manipulated to continuously proliferate in vitro. Using this technique, the investigator was able to produce millions (theoretically all possible) of transformed B cells which were then screened for the mAbs with specificity against desired cancers, pathogens, toxins and viruses.

Protection Against Lung Fibrosis by Up Regulating the Function or Expression of Caveolin-1

The invention provides for a novel approach of treating lung fibrosis related diseases (including scleroderma lung disease, idiopathic pulmonary fibrosis, interstitial pneumonia, asbestosis). Currently, there are no effective treatments available for these diseases.

Lung fibrosis involves an excessive accumulation in lung tissue of extracellular matrix proteins, particularly collagen I, which might be due to depletion of the signaling molecule caveolin-1 in lung fibroblasts. Caveolin-1 is one of the three members of the caveolae coat proteins. Upregulating caveolin-1 expression and/or function may prove to be a novel therapy for scleroderma and other causes of lung fibrosis.

Upregulation of caveolin-1 was achieved by a) infection of cells with adenovirus encoding the full-length caveolin-1 molecule, or b) using a membrane-permeable peptide containing the caveolin-1 scaffolding domain (CSD). Control bleomycin-treated mice showed severe lung damage, whereas mice receiving CSD showed only slight to moderate lung damage.

The results indicate that CSD peptide provides protection against the progression of lung fibrosis through several distinct mechanisms. A variety of insults trigger a common pathway involving several processes that culminate in lung fibrosis. The inventors have shown the ability of caveolin-1 to block these processes.

Generation of An Anti-EGF Receptor Antibody

Available for licensing is a hybridoma producing monoclonal antibody 6C7. These monoclonal antibodies were raised in mice against a glycosylation variant of EGF receptor from cervical carcinoma cell line ME-180.

Overexpression of EGF receptor is associated with advanced disease and poor prognosis. Monoclonal antibodies could potentially be used for the detection and therapeutic treatment of cervical cancer. Tumor EGF receptors are differentially glycosylated compared to normal tissues, therefore, it would be possible to selectively target the tumor EGF receptor using an antibody directed against the glycan portion of this protein.

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