Xi Li, Yu Zhang, Bing Li and Haiqing Hua, Duality Biologics, Shanghai, China
Background/Purpose: Small molecule immune modulators, such as glucocorticoids (GCs), are highly effective in treatment for various inflammatory diseases. However, prolonged systemic administration of GCs is associated with significant adverse effects such as osteoporosis, metabolic disturbances and central nervous system suppression. Biologics, such as anti-TNFα monoclonal antibody, have achieved great success in treating autoimmune diseases. Nevertheless, a large population of patients are still in need of more efficacious medicine. In order to enhance biologics' clinical efficacy and minimize GCs systemic adverse effects, a platform named as Duality Immune Modulating Antibody Conjugate (DIMAC) has been developed. The aim of DIMAC is to create an antigen specific antibody with a highly potent target specific drug conjugate that is able to produce greater clinical efficacy by synergistic effects of biologics and a small molecular drug.
Methods: DB-2306 is a TNFα targeted DIMAC molecule that has a novel payload with high potency, selectivity and long duration of action for glucocorticoid receptor (GR). In order to assess its in vivo efficacy, a mouse surrogate anti-TNF antibody conjugated with the DIMAC payload was generated. DB-2306 was further characterized in both fluorescein isothiocyanate (FITC) challenged acute contact hypersensitivity mouse model (mDTH) and a collagen induced arthritis mouse model (mCIA). .
Results: DB-2306 showed greater in vivo efficacy than that of the naked antibody in ameliorating ear swelling in a dose-dependent manner in mDTH. Furthermore, DB2306 displayed significant in vivo efficacy than that of the naked antibody in preventing both joint inflammation and bone erosion in a dose-dependent manner in mCIA. DB-2306 was well tolerated in animal models. The novel payload also exhibited a good safety profile and fast clearance in preclinical studies in rat.
Conclusion: DB-2306, the first successful molecule generating from the DIMAC platform, has clearly demonstrated greater synergistic in vivo efficacy than that of anti-TNFα mAb alone with limited systemic side effects of GC agonist in animal models. These data provide a strong rationale for the clinical development of DIMAC as a treatment for various autoimmune and inflammatory diseases.
Disclosures: X. Li, Duailty Biologics; Y. Zhang, None; B. Li, None; H. Hua, Hansoh Pharma.
