Homology Medicines Presents Proof-of-Concept Data for New Antibody Gene Transfer Platform

Homology Medicines is a clinical-stage company that aims to cure rare diseases using gene therapy and nuclease-free gene editing approaches. It is notable for HMI-102, an investigational phenylketonuria therapy delivered via AAVHSC15 vector. The liver targeting vector is produced using its proprietary adeno-associated virus vector derived from the hematopoietic stem cells (AAVHSCs) platform.

At the 2021 virtual ASGCT meeting, Homology Medicines presented encouraging results validating its recently unveiled GTx-mAb platform. The Bedford, Massachusetts—based company shared preclinical data demonstrating proof of principle for its new approach. By doing so, it showcased the potential for AAV-mediated gene transfer in transforming the liver into an antibody-producing factory.

Engineering AAVHSCs to Produce Functional Antibodies

The introduction of recombinant monoclonal antibodies is an effective treatment for several diseases, but redosing can lead to several complications in patients. AAV-mediated gene therapy overcomes this issue with a one-time treatment that prevents redosing.

By taking advantage of the natural tropism of AAVHSCs, Homology Medicines engineered vectors to produce functional antibodies in vivo using liver-specific promoters.

Talking to GeneOnline, Albert Seymour, Ph.D., Chief Scientific Officer, said, “Hepatocytes are cells that naturally secrete antibodies. Since we target the liver very well, we tested whether we could engineer AAVHSC to deliver sequences to make a fully functional monoclonal antibody. We engineered the vector genome to attain the full heavy and light chain sequences of an IgG molecule under the expression of a liver-specific promoter.”

Encouraging Data

For proof of concept, they chose the anti-complement protein 5 antibody. In both in vitro and in vivo studies, the fully assembled antibodies were highly expressed and were functional. Data showed proof of concept that single i.v. dose of AAVHSCs efficiently delivered vectors to the liver and secreted antibodies throughout the body.

This resulted in sustained expression levels consistent with C5 antibody therapeutics in a humanized mouse model. They were able to go above the required antibody levels in both NOD-SCID mice and humanized liver models. Besides, a stable and robust in vivo IgG expression was successfully demonstrated in NOD-SCID mice for the duration of the study.

The data suggest that AAVHSCs are a possible one-time treatment leveraging the liver to produce fully functional antibodies. This could enable Homology to expand its pipeline to treat diseases with larger patient populations. Seymour said that there hadn’t been any safety concerns in any of the studies conducted so far.

When asked about the timeline and future plans for the program, Seymour said, “Our goal this year is to nominate a development candidate and eventually move into formal IND-enabling studies and GMP toxicology studies. On average, it takes around 18-24 months to transition from the stage of nominating a development candidate to move into the clinic.”

Homology Medicines was featured as one of GeneOnline’s 10 top gene therapy companies to look out for in 2021.

Author

Rajaneesh K. Gopinath

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