Department of Pharmaceutical Chemistry
University of Kansas
Antigen-drug Conjugates as Potent Antigen-specific Immunotherapies (2015-2016)
Clinical researchers attempting to desensitize patients to autoantigens have historically focused on either altering antigen exposure or immunosuppressing patients, which leads to serious side effects. The proposed antigen-drug conjugates will target the highly specific antigen-capture system of autoantibodies and B cell receptors to guide immunosuppressant drugs to immune cells, thus selectively treating cells responsible for the autoimmune disease.The long-term goal of this proposal is to create an entirely new class of therapeutics called Antigen-Drug Conjugates (AgDCs) to treat autoimmune diseases. Similar to the concept of Antibody-Drug Conjugates, disease-causing autoantigen will be used as a guide molecule to deliver immune modulating drugs directly to the antigen-specific cells responsible for disease, in an effort to reverse autoimmunity. We propose to synthesize 4 AgDCs using combinations of 2 antigens (ovalbumin; OVA and proteolipid protein; PLP) conjugated with 2 immunosuppressant drugs (dexamethasone; DEX and rapamycin; RAPA). OVA and PLP are known to activate an antigen-specific immune responses in primary splenocyte cultures derived from mice sensitive to these antigens (OT.II and experimental autoimmune encephalomyelitis; EAE, respectively). Our central hypothesis is that OVA AgDCs and PLP AgDCs delivering DEX or RAPA will decrease inflammatory markers in their respective ex vivo splenocyte cultures when compared to controls or to treatments with autoantigens (OVA or PLP). Thus, the objective of this pilot project is to synthesize, characterize, and identify AgDCs that skew antigen-sensitive primary splenocyte populations towards autoantigen tolerance.
The project has two Specific Aims:
Specific Aim #1: Characterize AgDC binding specificity.
Specific Aim #2: Determine immune response to AgDCs in antigen-sensitive primary splenocytes.
AgDCs that specifically tolerize the immune response to disease-causing autoantigen would create a new paradigm for autoimmune disease treatment. Project completion would yield multiple papers on the structure, binding, and immunological activity of AgDCs and would position our group for in vivo studies in EAE mice. Our team is well positioned to complete the proposed protein structure and function studies with support from collaborations with multiple core laboratories and investigators.