Project Summary: In spite of decades of research, there continues to be a lack of safe and effective treatments that slow the progression of many autoimmune and inflammatory disorders, particularly multiple sclerosis and lupus. Indeed there are currently no effective drugs marketed for the treatment lupus. Glucocorticoids continue to be a mainstay in treatment regimens, in spite of safety concerns that include bone loss, hyperglycemia, hormonal issues, and heart failure. Inhibitors of Interleukin‐1 receptor associated kinase‐4 (IRAK4) have emerged as a promising therapeutic modality that potently block the release of cytokines from lymphocytes, thus ameliorating the effects of various inflammatory disease models. IRAK4 is a key member of the toll‐like receptor (TLR) signaling pathway which plays a vital role in the innate immune response while having little or no role in adaptive immunity. In 2014, my lab (at Pfizer) published a series of highly potent indoloquinoline IRAK4 inhibitors with sub‐nM affinity that suppress LPS‐induced cytokine production both in vitro and in vivo. Development of these inhibitors was halted due to concerns about off‐target activity and poor pharmacokinetic properties. We propose to “resurrect” this series of inhibitors by using antibody‐drug‐conjugate (ADC) technology to selectively deliver them specifically to leukocyte subpopulations. In order to accomplish this, we propose three specific aims: 1) Prepare ADCs which link a potent indoloquinoline IRAK4 inhibitor to a leukocyte‐targeted antibody; 2) Optimize the functional activity and plasma stability of the leukocyte‐targeting indoloquinoline ADCs; 3) Explore alternative ADC delivery systems that target subsets of leukocytes. Successful achievement of these goals will enable intellectual property (IP) generation and rapid translation to a true therapeutic‐development program and will be an important illustration of the use of ADCs for the treatment of autoimmune and inflammatory disorders.