Research Objective: Design and develop a novel category of immunomodulatory proteins, both as tools to study the immune response and as targeted disease therapeutics.

Technology Outcome: Newly designed and validated antibody fusion proteins that selectively bias immune response toward immunostimulatory or immunosuppressive activities.

TR&D 3 aims to engineer novel, innovative fusion proteins that enhance functionality of naturally occurring molecules and serve as effective targeted treatments to modulate the immune response and for disease treatment. Our approach will integrate structural immunology, chemical biology, and molecular engineering to design and validate antibody fusion proteins that selectively bias the immune response toward immunostimulatory or immunosuppressive activities. This aim is motivated and driven by the need within the immunoengineering community for targeted molecular agents that manipulate the immune response. The specific aims of TR&D 3 are:

• Specific Aim 1: Demonstrate the therapeutic efficacy of immune-biasing IL-2 ICs.
• Specific Aim 2: Extend single-chain cytokine/anti-cytokine antibody fusion ICs to IL-7.
• Specific Aim 3: Target a biased IL-2 IC to tumor-resident Tregs to enhance cancer immunotherapy.

Our versatile cytokine/anti-cytokine antibody fusion protein (IC) platform represents a major advance for the study and treatment of immune diseases by providing powerful and safe off-the-shelf therapies that selectively activate immune cells directly in patients. The targeted nature of our platform circumvents the pleiotropy and toxicities of current clinical cytokine drugs, and the modular design of ICs allows for application to any cytokine system and target antigen. As the importance of the immune system is becoming apparent for many diseases (e.g., cardiovascular, inflammatory, and neurodegenerative),65 the potential impact of ICs is tremendous.