Longitudinal changes of Anti-AAV9 and Anti-AAVrh74 antibodies in treated and untreated patients

Topic:

Clinical Trials

Poster Number: M185

Author(s):

Stephanie Salabarria, BHSc, University of Florida, Kirsten Coleman, MBA, University of Florida, Megan Wichman, BSc, University of Florida, Julie Berthy, DNP, University of Florida, Carmen Leon, MD, U of Florida, Manuela Corti, PT, PhD, University of Florida, Barry Byrne, MD, PhD, University of Florida

Background: Candidacy to receive systemic AAV-related gene therapy depends on the evidence of low or absent Anti-AAV antibodies. Literature regarding longitudinal changes in antibody titers and seroconversion is scarce, including in those that have received an AAV-related product. The aim of this study is to assess immunoglobulin (IgG) levels over time.

Methods: Prospective observational study of Anti-AAV9 and Anti-AAVrh74 IgG in healthy subjects, patients with neuromuscular diseases (untreated), and subjects that received an AAV-related product (treated). Circulating IgG to the AAV9 and AAVrh74 capsid were analyzed in plasma or serum using an enzyme linked immunosorbent assay. A level 50 U/mL was considered positive.

Results: 169 untreated subjects (115 male) with 1 plasma/serum sample for analysis were included. Median age was 13 (3-37). Of these, 92 (54%) were seropositive for Anti-AAV9 IgG at initial collection. Forty-seven of the 169 subjects (28%) were also screened for Anti-AAVrh74 IgG resulting in 37 subjects (79%) being seropositive. Sixty-two subjects were followed  1 year. Thirteen (21%) subjects seronegative for Anti-AAV9 IgG seroconverted following initial collection.

Twenty treated subjects (17 male) had samples 1 year after treatment. Median age (range) at treatment was 4y (0-14). Subjects received SGT-001 (N=7), Zolgensma (N=7), PF-06939926 (N=2), AT132 (N=1), LYS-SAF302 (N=1), PGTC PD-AAV004 (N=2), all AAV9 products. Median (range) Anti-AAV9 IgG 1, 2, 3, 4, 5 years after dosing were 204,300 U/mL (70,160-1,221,996) (N=7), 215,379 U/mL (9,750-901,056) (N=9); 279,621 U/mL (591-790,121) (N=11); 307,723 U/mL (54,084-1,038,724) (N=6); 102,972 U/mL (351-638,985) (N=4), respectively.

Discussion: Anti-AAV IgG levels in seropositive patients do not significantly change over time. Treated patients have a rapid increase in IgG after treatment with some variation over time maintaining levels significantly above clinically established thresholds. Elevated titers hinder the possibility of redosing. Immunomodulatory regimens are being actively pursued to overcome the challenges of humoral response to AAV therapy. Immunomodulation may allow access to AAV-related therapies for patients with elevated anti-AAV antibodies.