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F - Immunological Aspects of Gene Therapy and Vaccines -> Immunological Aspects of Gene Therapy and Vaccines (Includes host responses, therapy/prevention of infectious diseases; excludes cancer immunotherapy and cancer vaccines)

A Novel Therapeutic Safely Suppresses Pre-Existing Neutralizing Antibodies and Enables Re-Administration of Hemophilia A Gene Therapy in Large Animals

Type: Oral Abstract Session

Presentation Details
Session Title: Late-breaking Abstracts 2
Location: Concourse Hall 152 & 153
Start Time: 5/19/2023 11:45
End Time: 5/19/2023 12:00

Despite clinical success, the major barrier to adeno-associated virus(AAV) vector mediated gene delivery is the high prevalence of neutralizingantibodies (NAbs), which block vector transduction of target tissues. Patientsthat would otherwise qualify for life-saving treatments are screened for NAbsand many are excluded from receiving the therapy. For patients that receivetreatment, it is approved only for one-time use due to the generation of hightiter NAbs that preclude vector re-administration. Thus, it is a top priorityto identify a method that can suppress NAbs so more patients qualify fortreatment, as most existing methods cannot reduce NAbs completely. Previously,we engineered a novel therapeutic based on mycoplasma Protein M (PM) thatsuppresses NAb titers by over 1,000-fold, which is two orders of magnitudegreater than any other current method. PM binds mammalian light-chains of allantibody classes (IgG, IgA, IgM, etc.) obscuring antigen recognition, which weuse to create a transient window of total antibody suppression for successfulgene transfer. Dose ranging studies in vitro and in vivo determined that asaturating dose threshold, at a ratio of 2 PM molecules to 1 IgG, is requiredfor total antibody suppression and AAV gene expression in NAb positive mice atlevels equal to naive mice. We performed a biodistribution study usingradiolabeled PM demonstrating broad biodistribution of PM in mice. Greatestsignal localized with high concentrations of serum antibodies, including inlarge vessels and organs such as the heart, lung, liver, and kidney. Pharmacodynamic measurements of AAV NAb titers pre/post PM dosing show peakreduction of titers from over 1:1,000 to undetectable levels in the first 4hrsthat slowly recover by 4-7 days. Previous studies show most humans havepre-existing NAb titers in the range of 1:5-1:100 for AAV8 or AAV9. We screenedserum from 12 NHPs for the presence of AAV8 NAbs and observed that 8 hadpre-existing neutralizing titers over 1:5 (range 1:20-1:640, mean 1:160) whichpreclude AAV based therapy. Incubation of the NAb positive NHP serums with PMreduced pre-existing titers to undetectable levels. We then performed doseranging, PK/PD, and toxicology studies in NHPs. As predicted, IV dosing of PM belowthe 2:1 antibody saturating ratio had no effect on serum NAb titers, while 180and 360 mg/kg reduced titers by approximately 10-fold and over 1,000-foldrespectively. All doses were safe and well tolerated. Based on successful AAVre-administration in mice and PM dose ranging in NHPs, we tested the safety andefficacy of PM pre-treatment to re-administer AAV gene therapy in Hemophilia Adogs with high titer AAV8 and AAV9 NAbs. Our results demonstrate PM dosing wassafe, resulting in a 24 hour window of complete AAV9 NAb suppression, andphenotypic correction using AAV9-FVIII (1.5-3 e13 vg/kg) in animals with AAV9NAb titers of 1:320 and 1:1,280 respectively. Whole blood andthromboelastography clotting times showed peak correction slightly above normal(17 and 4 min respectively) after 7 days, and maintained for over 6 monthswithout bleeding events or recombinant FVIII administration. Lastly, wedeveloped an ELISA based immunogenicity assay to detect anti-PM antibodies andconfirmed PM pre-immunization does not preclude re-administration efficacy inmice with both PM and AAV NAbs. This groundbreaking report is one of the firstto reduce high titer NAbs from a previous AAV gene therapy treatment to a levelthat permits re-administration.

Charles Askew1, David Thieker2, Amelia McCue2, Junjiang Sun2, Koen Van Rompay3, Brian Kuhlman1, Timothy C. Nichols4, Chengwen Li5

1Gene Therapy Center, University of North Carolina, Chapel Hill, NC,2University of North Carolina, Chapel Hill, NC,3California National Primate Research Center, University of California, Davis, CA,4Francis Owen Blood Research Lab, University of North Carolina, Chapel Hill, NC,5Pediatrics, Gene Therapy Center, University of North Carolina, Chapel Hill, NC
  C. Askew: 1; Commercial Interest i.e. Company X; NabGen, Inc.. 1; What was received? i.e. Honorarium; Equity. 1; For what role? i.e. Speaker; Founder.

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