Antibody Fusion Proteins with Disrupted Heparin- Binding Activity

Heparin sulfate is found throughout all tissues and commonly bound to the cell surface.  Many signaling molecules such as  growth factors, chemokines and cytokines bind to heparin present at the  cell surface and in the  extracellular matrix of all tissues.  While this local heparin binding is an advantage when the cytokine is secreted in its normal environment to be locally retained, it may be a drawback when the cytokine is being delivered by a targeting device such as an antibody fusion protein.   In a therapeutic antibody-cytokine fusion protein, the antibody provides the specificity to a tumor antigen and the fused cytokine provides an enhanced immune response to the tumor, thus concentrating the cytokine in the tumor microenvironment.

Although the initials studies are focused on one antibody-cytokine fusion protein containing IL-12 and targeting HER2/neu, there are a number of other therapeutic approaches involving targeted delivery of a broad spectrum of heparin-binding cytokines and chemokines that might also benefit from a reduction in non-specific tissue/heparin binding. It is possible that there could be major improvements in targeted anti-cancer immunotherapy in general that result from the proposed studies.