TORONTO - GlycoDesign Inc., which focuses on glycobiological research, has further expanded its potential product portfolio following the signing of a licensing deal with the Samuel Lunenfeld Research Institute (SLRI) of Mount Sinai Hospital.

The agreement is for access to recently issued patents covering a new class of inhibitors of transforming growth factor-beta (TGF-beta) and will involve research that could lead to new therapies for cancer, infectious diseases, inflammation and fibrosis.

The SLRI, established in 1985 in Toronto, is one of Canada's premier research facilities. It operates programs in the areas of the genetic basis of disease and embryological and fetal development.

GlycoDesign, of Toronto, will provide SLRI milestone payments and royalties on any drugs commercialized from the research.

TGF-beta has fascinated the biotechnology industry since its initial identification and characterization just over a decade ago. TGF-beta refers to a subgroup of a multifunctional cytokine growth factor super family of approximately 30 proteins known to play an important role in embryogenesis, tissue development and wound healing.

For example, in cell cultures, TGF-beta suppresses proliferation of most non-transformed cells, induces formation of extracelluar matrix and also induces cell differentiation. On the flip side, however, elevated levels of TGF-beta are associated with fibrosis in multiple human afflictions, including atherosclerosis and scarring of skin wounds.

TGF-beta also has been implicated in promoting the growth of tumors by suppressing certain components of the immune system, and in chronic inflammation associated with asthma and arthritis.

The potential of this molecule, therefore, lies in methods of enhancing its beneficial effects and discovering specific inhibitors to block the pathological consequences of excess or inappropriate expression.

Jeremy Carver, CEO of GlycoDesign, told BioWorld International that technology has tremendous potential and the company will be building upon SLRI's discovery of a novel binding domain that regulates the interaction of the TGF-beta cytokine with its ligand. This interaction can be targeted for detailed research to design specific regulators of TGF-beta.

Regulators of TGF-beta may be used to treat a number of diseases and conditions, including kidney disease, diabetic nephropathy, vitreoretinopathy, immunosuppression in cancer and scarring in wound healing. Inhibitors of TGF-beta may also be useful in the treatment of atherosclerosis, Carver said.

A leading scientist in the discovery of TGF-beta antagonists is Jim Dennis, one of the founders of GlycoDesign. His group at SLRI has identified the major TGF-beta cytokine binding domain in the type II TGF-beta receptor, a short peptide sequence designated TRH1, that prevents TGF-beta from binding to its receptor.

In addition, Dennis' group has identified a functional TRH1 sequence in the serum glycoprotein fetuin that antagonizes TGF-beta activity in several experimental models, including epithelial cell proliferation and kidney cell differentiation.

TGF-Beta Research Complements Cancer Drug

Carver said the SLRI research is an excellent fit with GlycoDesign's ongoing cancer research program, which involves the lead drug candidate GD0039, a carbohydrate processing inhibitor. GD0039 is based on technology also licensed from the SLRI that blocks the formation of tumor cells.

GD0039 is entering Phase II trials aimed at treating renal cell carcinoma. Later this year, GlycoDesign intends to file investigational new drug applications in Canada for evaluation of GD0039 in the treatment of lung, breast, melanoma, head-and-neck and colorectal cancers. The company has discovered the drug candidate not only has indications in cancer, but in inflammation and infectious diseases.

Since TGF-beta plays a pivotal role in the immune system by preventing, in certain situations, the development of a protective cell-mediated immune response, antagonist agents could potentiate the activity of such drugs as GD0039. The key is to find suitable therapies designed to enhance the cellular response to destroy tumor cells, Carver added.

The main thrust of the research with SLRI will be on engineering recombinant inhibitors and optimizing them for TGF-beta antagonist activity. They will then be tested in animal models for indications in cancer, fibrosis and wound healing. *

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