Prophylaxis CTLA4-ig reduces anti-AAV neutralizing antibodies in AAV gene therapy for hemophilia
Year: 2025
Type: conference-abstract
Abstract: Objective: This study aimed to investigate the inhibitory effect of CTLA4-Ig on anti-AAV neutralizing antibody (Nab) development after AAV gene therapy in hemophilia patients, providing an immunomodulatory strategy for potential re-treatment. Methods: Key immune targets were identified through analysis of single-cell RNA sequencing (scRNA) data from a hemophilia B gene therapy clinical trial (NCT04135300; n=7) and flow cytometry data from a hemophilia A gene therapy trial (NCT05454774; n=8). To recapitulate human immune responses to AAV in murine models, an AAV immune-adopted murine model was established. Wild-type (WT) and immune-adopted mice received intravenous infusion of AAV843-Gaussia luciferase (Gluc; 5×10¹² vg/kg). Abatacept (CTLA4-Ig, 5 mg/kg) or an equivalent PBS was administered intraperitoneally 3 days prior to vector infusion, followed by twice-weekly maintenance dosing for 6 weeks. Gluc expression and anti-AAV Nab titers were monitored. Concurrently, an Investigational New Drug (IND) clinical trial (CTR20233400) was initiated. Adult male hemophilia A patients with baseline FVIII:C <2 IU/dL, no history of FVIII inhibitors, and pre-existing anti-AAV Nab titers ≤1:4 were enrolled. Prophylaxis CTLA4-Ig (5 mg/kg) was administered 3 days prior to AAV vector (BBM-H803) infusion. Patients were followed for six months to observe anti-AAV Nab titers dynamics. Results: The scRNA and flow cytometry analysis revealed significant activation of monocyte pathways post-AAV infusion. The proportion of CD86⁺CD16⁺ monocytes showed characteristic fluctuations (D0: 25% → D3: 15% [p<0.05] → W2: 30% [p<0.05]). In the mouse model, anti-AAV Nab titers were significantly lower in the CTLA4-Ig group versus the control group: WT mice at Week 6 (1:16 vs. 1:2,048, p<0.05) and pre-immune mice (1:16 vs. 1:4,096, p<0.05). In the clinical trial, among 5 evaluable patients with a median follow-up of 26 weeks, anti-AAV Nab titers induction during the CTLA4-Ig treatment period (≤Week 12) was significantly attenuated (median log₂[W12/baseline]: 8 vs. 11, p<0.05). Conclusion: Prophylaxis administration of CTLA4-Ig effectively suppresses anti-AAV Nab formation following AAV gene therapy in hemophilia A patients, creating a potential immunological tolerance window for re-treatment.
Source: Blood
Authors: Dandan Yu, Bingqi Xu, Wei Liu, Feng Xue, Chen Yunfei, Xiaofan Liu, Mankai Ju, Sun Ting, Xinyue Dai, Huan Dong, Wenjing Gu, Yang Renchi, Xiao Xiao, Xia Wu, Xiaolei Pei, Lei Zhang
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4417019508