Background/Purpose: IL-12, via its p35 subunit, drives Th1-mediated pathology in autoimmune diseases. Genome-wide association studies (GWAS) suggested that IL12A encoding IL12p35 is associated with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary biliary cholangitis (PBC), and Sjögren’s syndrome (SS), but IL12B and IL23R are not. Antibodies targeting IL12B and IL23A have been developed in the clinic but no proven effects were shown for the above-mentioned immune diseases. DM618, a monoclonal antibody selectively targeting IL12p35, was designed to inhibit IL-12 signaling without affecting IL-23. Preclinical efficacy was evaluated using a surrogate anti-mouse IL12p35 antibody.

Methods: Colocalization analyses of gene expression/protein quantitative trait loci (eQTLs/pQTLs) with autoimmune disease GWAS data were performed. Anti-IL12p35 antibody was generated in RenMab mice. Affinity was measured using Biacore, and IL-12 neutralization was assessed in reporter and primary cells. In vivo evaluation employed murine models: DNFB-induced skin inflammation, streptozotocin-induced SS, and IMQ-NZBWF1 lupus nephritis. Pharmacokinetics were evaluated in human FcRn transgenic mice.

Results: The eQTLs/pQTLs of IL-12 pathway genes IL12A and IL12RB2 colocalized with SLE, SSc, PBC, and SS, but not with other autoimmune diseases such as psoriasis (Pso), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), or inflammatory bowel disease (IBD). In contrast, IL12B and IL23R eQTLs colocalized with Pso, AS, CD, UC, and IBD, but not SLE, SSc, PBC, or SS. DM618, the lead candidate, exhibited high Biacore affinity (KD = 6.49 × 10⁻¹¹ M) and superior IL-12 neutralization (EC₅₀: 0.0059 µg/mL) compared to ustekinumab (anti-IL12p40; EC₅₀: 1.3 µg/mL) in IL-12 reporter cells. DM618 suppressed both exogenous and endogenous IL-12-induced IFN-γ secretion in primary cell-based assays, outperforming ustekinumab. Critically, DM618 did not inhibit IL-23 signaling. Due to its lack of cross-reactivity with mouse IL-12, preclinical validation was conducted using a surrogate anti-mouse IL12p35 antibody in murine models. The surrogate antibody significantly reduced ear thickness (P = 0.0026) in a subchronic DNFB-induced skin inflammation model, alleviated salivary gland inflammation in an SS model, and decreased albuminuria in a lupus nephritis model (10-fold reduction vs. controls). Importantly, the human genetic association data have informed the clinical development pathway for DM618.

Conclusion: DM618, a first-in-class anti-IL12p35 antibody, selectively inhibits IL-12 and demonstrates potential to address Th1-driven autoimmune pathology. Supported by human genetic evidence and preclinical validation using a surrogate antibody, DM618’s specificity preserves IL-23-mediated immunity, aligning with the distinct roles of IL-12 and IL-23 in their respective disease pathways. The preclinical efficacy of surrogate anti-mouse IL12p35 in lupus nephritis, SSc, and SS models provides proof of concept for selective IL-12 targeting and supports clinical development for these high-unmet-need diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dm618-a-novel-anti-il12p35-antibody-specifically-inhibiting-il-12-with-therapeutic-potential-in-a-set-of-autoimmune-diseases/