Engineering ACE2 Fc Fusion Proteins For COVID-19 Prophylaxis

Paradigm Immunotherapeutics, a California-based biotechnology company focused on disruptive technology for infectious and autoimmune diseases, has developed ACE2 Fc fusion proteins with extremely high affinity against SARS-CoV-2, the virus that causes COVID-19. The proteins are designed to be effective against any coronavirus variant, and they are currently being explored for use as COVID-19 prophylactics for immunocompromised and other high-risk individuals.

Absolute Antibody engineered and manufactured several versions of the ACE2 Fc fusion proteins, helping Paradigm design a protein with Fc silencing and extended half-life to improve its efficacy and safety in humans.

Targeting Coronavirus through the ACE2 Receptor

Paradigm is led by CEO Dr. Neil Bodie, a biotech veteran with more than a dozen issued or pending patents related to the immunopathology of infectious diseases and autoimmunity. He had previously studied antibody-dependent enhancement (ADE) in Ebola, an area which became highly relevant at the onset of the COVID-19 outbreak. Like much of research community in 2020, Dr. Bodie soon turned his attention toward addressing the global pandemic.

Dr. Bodie decided to target ACE2 (angiotensin-converting enzyme 2), the host cell receptor to which SARS-CoV-2 binds to initiate COVID-19 infection. ACE2 is found throughout the human body, meaning it has a low likelihood of inducing anti-drug antibodies. In addition, using the receptor rather than coronavirus itself helps ensure any therapeutic or prophylactic agents remain active against new coronavirus variants, as these continue to rely on interaction with their receptor ACE2.

The Paradigm team first explored the potential of using a hexameric IgM ACE2 protein, due to its large size and high avidity for the SARS-CoV-2 receptor. They asked two companies to synthesize an IgM Fc fusion protein and only Absolute Antibody was successful. However, further studies showed that the benefits of the IgM proteins were outweighed by a shorter half-life and less efficient manufacturability. The team decided to develop an IgG ACE2 Fc fusion protein, which they found was just as effective at neutralizing live SARS-CoV-2.

Engineering Fc Fusion Proteins

The Paradigm researchers modified full-length ACE2 with three mutations that significantly increased its binding affinity for SARS-CoV-2. Absolute Antibody then manufactured several Fc-engineered versions of an ACE2 Fc fusion protein, in which the mutated ACE2 was genetically linked to the Fc domain of human IgG.

The Fc domains were engineered with the YTE mutation in order to extend the protein’s half-life. They were also engineered with mAbsolve’s STR Fc silencing technology, the only truly silent Fc mutations described to date (PMID: 34932587). Absolute Antibody clients have easy license-free access to the STR silencing platform, which delivers an Fc region with no detectable binding to all Fc gamma receptors (FcγRs) and C1q.

The resulting proteins achieved low picomolar to low femtomolar binding affinity for Omicron BA.1/BA.2 respectively, the highest binding affinity reported for any ACE2 Fc fusion protein and one of the highest binding affinities for any anti-SARS-CoV-2 monoclonal antibodies. In addition, the Fc silencing helps to prevent the release of inflammatory cytokines, making the protein safer for patients.

Moving the Technology Forward

Paradigm’s goal is to offer the engineered ACE2 Fc fusion protein as an intranasal prophylactic for the three percent of the global population that is immunocompromised, as well as other high-risk individuals such as the elderly and healthcare workers. They hope to secure enough funding to enter human clinical trials soon.

Paradigm is also developing a version of the ACE2 Fc fusion protein without the Fc silencing mutations for therapeutic use. Finally, the company plans to offer different versions of the ACE2 Fc fusion proteins for research-use only in the Absolute Antibody catalog. This will include the Fc fusion proteins with a wild-type Fc region, as well as Fc fusion proteins with the half-life extending mutation and/or the Fc silencing mutation.

“Absolute Antibody and its CSO Mike Fiebig have an excellent understanding of Paradigm’s goals,” said Dr. Bodie. “They have an uncanny ability to take my in silico optimized amino acid sequences and turn them into world-class Fc fusion proteins. I couldn’t be more impressed with Mike and Absolute Antibody. I look forward to many years of successful collaboration.”

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