Advances and challenges in immunosuppressive antibody drug conjugates

Since the approval of Mylotarg™ in 2000 for acute myeloid leukemia, antibody-drug conjugates (ADCs) have significantly advanced precision medicine, particularly for oncology applications. ADCs combine an antibody, a linker, and a payload to result in a targeted therapeutic that minimizes toxicity resulting from systemic drug exposure. This review explores the innovative application of ADC technology towards immunosuppressive therapeutics, primarily focusing on antibody-mediated delivery of glucocorticoids (GCs). Despite their potent anti-inflammatory effects, the clinical use of GCs is limited by adverse systemic effects including osteoporosis, high blood sugar, adrenal insufficiency, weight gain, and glaucoma. Therefore, targeted delivery via ADCs presents a promising strategy to enhance therapeutic efficacy while reducing toxicity. Herein, we review the current status of immune-suppressing ADC technology, starting with early investigations of CD163-targeted dexamethasone and moving to the design of ADCs employing next-generation ultra-potent GCs. Additionally, we will discuss the current status of anti-inflammatory ADCs that employ non-glucocorticoid immune-suppressive medications. Throughout, we will highlight preclinical and clinical data that serves to derisk and drive investment in this new therapeutic class. In parallel, we will focus on ADC design principles that illustrate the importance of careful selection of payload, linker, and conjugation technology in this emerging field.