Background/Purpose: BDCA2 (blood dendritic cell antigen 2) is specifically expressed on plasmacytoid dendritic cells (pDCs), whose over-production of type I interferon (IFN-I) is crucial in the pathogenesis of systemic lupus erythematosus (SLE) and other autoimmune diseases. The combination of anti-BDCA2 monoclonal antibody and small molecule immune modulators, such as glucocorticoids (GCs), has demonstrated clinical efficacy in CLE and SLE patients. The improvement in efficacy and reduction in adverse effects associated with GC usage may further benefit patients. Our previous studies showed that anti-BDCA2-based antibody‒drug conjugates (ADCs) showed anti-inflammatory effects with superior IFN-I inhibition with broader inflammatory cytokine suppression in pDCs. Thus, we developed an anti-BDCA2-based ADC, DB-2304, using a novel glucocorticoid receptor (GR) agonist (P2025) as a payload conjugate with an anti-BDCA2 antibody. The preclinical efficacy and safety of DB-2304 was evaluated in vitro and in vivo.

Methods: A novel monoclonal BDCA2 antibody was developed and conjugated with P2025 to generate DB-2304. Antigen-dependent payload delivery was measured by a reporter assay. The inhibitory potency of DB-2304 was evaluated in purified human peripheral blood mononuclear cells (PBMCs) in vitro. The pharmacokinetics，pharmacodynamic and safety profile were characterized in cynomolgus monkeys. The in vivo therapeutic efficacy was also evaluated in psoriasis model in monkeys.

Results: The novel BDCA2 antibody Hu033-03 showed high affinity for both human and cyno BDCA2 with quick induction of BDCA2 internalization upon binding. Conjugation with P2025 did not affect its binding affinity. DB-2304 showed good suppression of IFN-a production and a broader spectrum of proinflammatory cytokine and chemokine production in human PBMCs (under TLR agonist stimulation) without cytotoxicity. It also reduced pDC cell surface BDCA2 level in an ADC serum concentration-dependent manner and inhibited pathogenesis in Imiquimod induced psoriasis in cynomolgus monkey. DB-2304 also showed a good safety profile with the no-observed-adverse-effect-level (NOAEL) of 85 mg/kg.

Conclusion: DB-2304 has clearly demonstrated greater in vitro and in vivo potency with synergistic effects on the regulation of both type I interferon genes and proinflammatory cytokines in pDCs. Taken together, these data support the clinical investigation of DB-2304 in the future.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/db-2304-an-immunomodulatory-antibody%e2%80%92drug-conjugate-adc-targeting-bdca2-displays-strong-in-vivo-efficacy-in-pharmacodynamic-and-psoriasis-models/