Background: Deep B-cell depletion is a promising therapeutic strategy for AIDs. For patients with AIDs, therapy needs to be safe, lead to predictable, deep B cell depletion, and offer convenient patient accessibility. TCEs – proteins that link T-cells and cells expressing a target antigen – are emerging as promising “off-the-shelf” therapies for deep cell depletion. Current therapeutic strategies apply TCEs directly as proteins and typically require step-up dosing to minimize the risk of cytokine release syndrome (CRS) at efficacious concentrations. Delivering an mRNA encoding the TCE introduces a pharmacokinetic (PK) buffer due to the time required for translation. This leads to a slower accumulation of the protein, mimicking the exposure profile otherwise achieved through step-up dosing. ABO2203 is a novel lipid nanoparticle-encapsulated mRNA encoding a half-life extended CD3 × CD19 TCE.

Objectives: To evaluate the preclinical and clinical PK and pharmacodynamic (PD) profiles of ABO2203, as well as its safety and preliminary efficacy, in adult patients with refractory AIDs.

Methods: Safety was confirmed in rodents and non-human primates. Subsequently, the first-in-human trial (NCT06747156) comprising intra-patient dose-escalation, fixed-dose-escalation, and dose-expansion phases of subcutaneously administered ABO2203 was initiated. Primary endpoints were safety and tolerability; secondary endpoints included PK, PD, and efficacy. Patients with active, treatment-refractory AIDs received weekly, subcutaneous ABO2203 for one month. No premedication was applied. The intra-patient escalation phase employed dose cohorts of 1–10 μg, 10–30 μg, 30–240 μg, and 120–480 μg, utilizing an accelerated titration design for the first three cohorts. The fixed-dose-escalation phase was subsequently initiated at an efficacious dose.

Results: Upon subcutaneous administration in rodents and non-human primates, ABO2203 exhibits a smooth-rising PK profile of the TCE protein. This led to an efficient depletion of B-cells with marked reduction in cytokine release. As of December 16, 2025, 15 patients were enrolled in the clinical trial, including 13 in the intra-patient dose-escalation phase and two in the fixed-dose phase. Diagnoses included systemic lupus erythematosus (n=5), lupus nephritis (LN, n=4), rheumatoid arthritis (n=3), Sjögren’s syndrome (n=1), antiphospholipid syndrome (n=1), and systemic sclerosis (n=1). Patients were refractory to a median of 3 therapies. ABO2203 was well tolerated at all evaluated doses. No CRS, immune effector cell associated-neurotoxicity syndrome, or hepatotoxicity occurred. All 9 patients who received a starting dose of 120 µg demonstrated robust TCE expression, with a maximum serum concentration (C _max ) of 95.2 ng/mL, a delayed time to C _max of 4 days, and a terminal half-life of 7.3 days. Rapid peripheral B-cell depletion was observed in all patients after the first 120 μg dose. Bone marrow biopsies confirmed B-cell depletion via flow cytometry and single-cell RNA sequencing. B-cell reconstitution occurred in three patients by Week-16 or -20 following complete B-cell aplasia. Patients with LN in the 120–480 μg cohort achieved reductions in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores and 2/3 patients attained complete renal response.

Conclusions: In summary, these data demonstrate the successful preclinical to clinical translation and therapeutic potential of ABO2203, a first-in-class, subcutaneously administered, mRNA encoding a CD3 × CD19 TCE. ABO2203 showed a favorable PK profile, characterized by gradual in vivo expression of the TCE, correlated with minimal cytokine release that translated into a superior safety profile. Despite skipping steroid premedication, no CRS was observed. Patients exhibited fast B-cell depletion in blood and bone-marrow and promising clinical response. Hence, mRNAs encoding TCE might display a wider therapeutic window and represent a promising class of therapeutics that might be administered safely in the outpatient setting.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Mengyan Wang: None declared, Tingting Liu: None declared, qihua Dai: None declared, Jialin Teng: None declared, Yaping Wu: None declared, Jinchao Jia: None declared, Jianfen Meng: None declared, Yuning Ma: None declared, Hui Shi: None declared, Xiaobing Cheng: None declared, Honglei Liu: None declared, Yutong Su: None declared, Junna Ye: None declared, Huihui Chi: None declared, Zhuochao Zhou: None declared, Yue Sun: None declared, Yan Wu Suzhou Abogen Biosciences Co., Ltd., Shiping Ma Suzhou Abogen Biosciences Co., Ltd., Peng Gao Suzhou Abogen Biosciences Co., Ltd., Wenjie Song Suzhou Abogen Biosciences Co., Ltd., Rui Lin Suzhou Abogen Biosciences Co., Ltd., Wei Yin Suzhou Abogen Biosciences Co., Ltd., Bo Ying Suzhou Abogen Biosciences Co., Ltd., Chengde Yang: None declared, Qiongyi Hu: None declared.