From The Editor | February 11, 2021

Beating The AAV Vector Immunogenicity Challenge

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By Matthew Pillar, Editor, BioProcess Online

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In many gene therapy applications, an immune response barrier stands in the way of leveraging adeno-associated virus vectors. Here’s how Dr. Carsten Brunn’s clinical-stage firm Selecta Biosciences is addressing the challenge with its nanoparticle technology-based platform.

The Problem With Adeno Associated Virus

It’s one of those paradoxical quandaries of science, where the very immunogenicity a therapeutic seeks to induce creates an unwanted immune response in the patient. Administered in vivo, highly immunogenic AAV vectors produce very high antibody titers. That’s good, at least in theory. The challenge lies in the dilution of AAV vectors over time. They don’t self-replicate, so their therapeutic benefit is short-lived. However, because the initial dose creates such high antibody titers, a second dose could result in unwanted and dangerous adaptive responses to the transgene product. In biologic therapies, the formation of anti-drug antibodies can neutralize activity, alter the pharmacokinetics and biodistribution of biologic therapeutics, or cause hypersensitivity reactions and potentially life-threatening events. In self-antigens, unwanted immune responses can lead to autoimmune disease.

Why Meeting The Challenge Matters

AAV vectors are showing promise in trials for in vivo gene transfer to a wide array of tissues and cell types. Dozens of trials are underway involving serious and fatal diseases of the central nervous system, the eyes, the heart, the liver, the lungs, and the skeletal system. But the durability and repeat dosing safety issue has been exposed, most recently in the FDA’s Complete Response Letter rejecting BioMarin’s hemophilia A gene therapy candidate. The FDA’s newest guidance on gene therapy underscores that the durability issue is on the Agency’s radar. Still, according to MarketsandMarkets, the global viral vector manufacturing market is projected to reach $815.8 million by 2023 from $327.8 million in 2018, at a 20% CAGR.

Selecta Biosciences Responds To The Challenge

Dr. Carsten Brunn, President & CEO, Selecta Biosciences
Dr. Carsten Brunn, President & CEO, Selecta Biosciences

Dr. Carsten Brunn, President & CEO, Selecta Biosciences

Since joining the company in 2018, Selecta Biosciences President and CEO Carsten Brunn, Ph.D. has been building a business solely-focused on meeting the AAV vector challenge. He describes his company as an “immune tolerance platform company.” His company’s ImmTOR platform has already driven SEL-212, the company’s clinical candidate in chronic refractory gout licensed to Sobi last year, through Phase 3 clinical trials. On the back of clinical safety profile data proven out by this advanced candidate, Selecta has launched preclinical work in gene therapy.

The company’s ImmTOR platform is designed to induce antigen-specific immune tolerance by targeting rapamycin to immune cells using nanoparticle technology. When administered to a patient, ImmTOR nanoparticles are filtered out by lymph nodes, the spleen, and the liver, where they’re taken up by dendritic cells, a type of antigen-presenting cell that triggers immunogenic and tolerogenic responses from T cells. The platform promotes the induction of tolerogenic dendritic cells, which go on to activate antigen-specific regulatory T cells to suppress the immune response to the antigen.

During a recent interview on the Business of Biotech Podcast, Dr. Brunn shared that Selecta has “produced fairly compelling data in rodents and non-human primates demonstrating that combining our platform technology with an AAV vector prevents the formation of those antibodies that make it impossible to administer a second dose and express the transgene.”

Next Steps For ImmTOR’s Foray Into Gene Therapy

This year, Selecta Biosciences plans to file an IND and does its first gene therapy patient suffering a rare inborn metabolic disease called methylmalonic acidemia (MMA). The disorder inhibits the proper processing of certain proteins and lipids, disallowing the metabolization of methymalonyl-coenzyme A. The resulting buildup of methylmalonic acid appears in from infancy through the first year of life, and its symptoms include lethargy, vomiting, dehydration, weak muscle tone, acid-base imbalance and high levels of ammonia. Left untreated, MMA can lead to coma and death.

In the meantime, Dr. Brunn and company are eager to add to the collection of gene therapy developers they’re working with to overcome AAV vector challenges. The company is already executing licensing deals with established players including AskBio, Sarepta Therapeutics, and Sobi, and it’s working with preclinical companies in research and development phases.

Learn more about Selecta and Dr. Carsten Brunn’s work there on episode 27 of The Business of Biotech.