Development of MGD007, a gpA33 x CD3-Bispecific DART Protein for T-Cell Immunotherapy of Metastatic Colorectal Cancer.

We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART protein designed to redirect T cells to target gpA33 expressing colon cancer. The gpA33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. MGD007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T cells.

Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity.

Purpose: The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens.

Experimental Design: Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes.

Depletion of mammalian target of rapamycin (mTOR) via siRNA mediated knockdown leads to stabilization of beta-catenin and elicits distinct features of cardiomyocyte hypertrophy.

Cardiac myocyte growth is under differential control of mammalian target of rapamycin (mTOR) and glycogen-synthase-kinase-3beta (GSK3beta). Whereas active GSK3beta negatively regulates growth and down-regulates cellular protein synthesis, activation of the mTOR pathway promotes protein expression and cell growth. Here we report that depletion of mTOR via siRNA mediated knockdown causes marked down-regulation of GSK3beta protein in cardiac myocytes.

Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins.

The interactions of the selectin family of adhesion molecules with their ligands are essential for the initial rolling stage of leukocyte trafficking. Under inflammatory conditions, the vascular selectins, E- and P-selectin, are expressed on activated vessels and interact with carbohydrate-based ligands on the leukocyte surface. While several ligands have been characterized on human T cells, monocytes and neutrophils, there is limited information concerning ligands on B cells.

Type 1 sphingosine 1-phosphate G protein-coupled receptor signaling of lymphocyte functions requires sulfation of its extracellular amino-terminal tyrosines.

The type 1 sphingosine 1-phosphate (S1P) G protein-coupled receptor (S1P1) transduces signals from S1P that mediate thymocyte emigration, T cell transmigration of lymph nodes, and T cell chemotaxis in tissues. Alterations in expression of functional S1P1 receptors by lymphocytes are the major mechanisms controlling their responses to S1P and were thought to be solely a consequence of the balance between surface down-regulation and insertion. However, results now show that lack of sulfation of tyrosines 19 and 22 of the extracellular N terminus of S1P1 diminishes high-affinity S1P binding and decreases S1P signaling of T cell migration and other functions.