Xi Li, Yu Zhang, Bing Li and Haiqing Hua, Duality Biologics, Shanghai, China
Background/Purpose: BDCA2 (Blood Dendritic Cell Antigen 2) is specifically expressed on plasmacytoid dendritic cells (pDCs), a type I interferon-producing cells, which have been implicated in many autoimmune diseases such as systemic lupus erythematosus (SLE). BIIB059, an anti-BDCA2 monoclonal antibody developed by Biogen, has demonstrated clinical efficacy in CLE and SLE patients. Nevertheless, the results of its phase II clinical trials suggest an improved clinical efficacy of BIIB059 is needed even though its Phase III SLE studies are still on-going. On the other hand, small molecule immune modulators, such as glucocorticoids (GCs), are highly effective in treatment for various autoimmune diseases, including SLE. However, the adverse effects of GCs limited its prolonged clinical usage. Thus, generation of anti-BDCA2 based glucocorticoids drug conjugate may provide greater clinical efficacy by their synergistic effects and minimized systematic side effects. Based on our proprietary Duality Immune Modulating Antibody Conjugate (DIMAC) technology, DB-2304 was generated.
Methods: DB-2304 was synthesized by utilizing an anti-BDCA2 monoclonal antibody and a DIMAC payload that has high potency, selectivity and long duration of action on glucocorticoid receptor (GR). The inhibitory potency of DB-2304 was evaluated in purified human peripheral blood mononuclear cells (PBMCs) and/or pDCs. The mechanism of action (MOA) of DB-2304 was further investigated by RNA-seq in purified pDCs.
Results: DB-2304, inducing the internalization of BDCA2, displayed greater inhibitory potency than that of its naked antibody in a ligand stimulated cytokine and chemokine production in human PBMCs. Furthermore, comparing with naked antibody, DB-2304 completely suppressed IFN-a production and a broader spectrum of pro-inflammatory cytokine and chemokine productions in human pDCs (under TLR agonist stimulation). The mechanism of action (MOA) of DB-2304 was finally revealed by RNA-seq, which demonstrated greater impact on global gene expression by DB-2304 vs. its naked antibody in purified pDCs.
Conclusion: DB-2304, the second successful molecule generating from the DIMAC platform, has clearly demonstrated greater in vitro potency than that of its naked antibody in human PBMCs and pDCs. The MOA study further confirmed its synergistic effects on regulation of both type I interferon signature genes and GR-responsive genes in pDCs. Taken together, these data support clinical investigation of DB-2304 in the future.
Disclosures: X. Li, Duailty Biologics; Y. Zhang, None; B. Li, None; H. Hua, Hansoh Pharma.
