ViewPoints Interview: Neoleukin’s Daniel-Adriano Silva Shares Insight on Novel Protein Designed to Treat or Block SARS-COV-2

In a recent interview with PharmaShots Daniel-Adriano Silva, PhD, Co-founder and Vice President Head of Research at Neoleukin shared the significance and promise of the findings published in Science and discuss the details of its De Novo Protein Design

Shots:

• NL-CVX1 (CTC-445.2d) demonstrated the ability to prevent infection of multiple human cell lines in vitro and to protect hamsters from serious consequences of SARS-CoV-2 infection
• NL-CVX1 is designed to mimic the natural human ACE2 receptor. By doing so, it is designed to be resistant to viral mutation
• De novo protein design begins computationally, where we identify the structure of the molecule we are trying to build and its interaction with the biological target

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Tuba: Can we have an insight into Neoleukin’s research published in “Science”?

Daniel: The publication describes the potential of Neoleukin’s de novo protein design platform. In less than three months, our team was able to create novel molecules designed to treat or prevent infection by the virus that causes COVID-19, SARS-CoV-2. Specifically, it details the creation of de novo protein decoys that were designed to bind the SARS-CoV-2 spike protein with high affinity and prevent its association with the viral receptor hACE2, which is required for infection.

Our lead molecule, NL-CVX1 (CTC-445.2d), demonstrated the ability to prevent infection of multiple human cell lines in vitro and to protect hamsters from serious consequences of SARS-CoV-2 infection. Additionally, prophylactic intranasal administration of NL-CVX1 led to survival of all hamsters challenged with a lethal dose of SARS-CoV-2.

The full article “De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2”  can be accessed from the publications page of our website here.

Tuba: Tell us more about De Novo Protein Design?

Daniel: De novo protein design is a fundamentally different way to think about drug discovery.  Most traditional biologics are created by taking natural proteins and modifying them. De novo protein design begins computationally, where we identify the structure of the molecule we are trying to build and its interaction with the biological target.  These computational designs are then further refined and taken into the lab to be tested to evaluate whether the molecule demonstrates the desired properties.

This new way of protein engineering, called protein design, allows us to design proteins to have specific biologic activities and properties that provide potentially superior benefit over native proteins. Neoleukin Therapeutics is pioneering the application of de novo protein design to the development of therapeutic molecules.

Tuba: Discuss the potential of NL-CVX1 in protecting against SARS-CoV-2 infection?

Daniel: NL-CVX1 is designed to mimic the natural human ACE2 receptor.  By doing so, it is designed to be resistant to viral mutation.

In addition, NL-CVX1 is designed to be stable and could potentially be administered by intranasal spray or inhalation to prevent and treat infection in the lungs and upper airways by SARS-CoV-2.

Tuba: What can we learn about the potential of de novo protein design based on your experience in the development of NL-CVX1?

Daniel: NL-CVX1 was developed in less than three months from concept to preclinical validation. As such, we believe it represents the fastest development of a therapeutic de novo protein.  This rapid timeline demonstrates the potential of our de novo protein design platform to address a wide array of important biological problems.

Tuba: When can we expect NL-CVX1 (CTC-445.2d) to enter into clinical studies?

Daniel: We are currently evaluating the possibility of advancing this molecule to clinical trials in humans, as well as potential strategic partnership opportunities.

Tuba: Can we have a review on NeoLeukin’s lead program, NL-201 which is the world’s first computationally-designed de novo protein therapeutic?

Daniel: Our first program, NL-201, is a de novo receptor agonist of the IL-2 and IL-15 receptors, designed to expand cancer-fighting CD8 T cells and natural killer (NK) cells without any bias toward cells expressing the alpha receptor subunit (CD25). Previously presented preclinical data has demonstrated the ability of NL-201 to stimulate and expand CD8+ and NK cells at very low doses with minimal impact on immunosuppressive regulatory T cells. Treatment with NL-201 in animal models was well-tolerated and induced durable, anti-tumor immunity.  Additionally, minimal immunogenicity was reported following five weekly doses of NL-201 in non-human primates.

Our corporate update released on November 9, 2020 announced that we remain focused on our efforts to submit an Investigational New Drug (IND) application for NL-201 during the fourth quarter of 2020 and that we do not expect a delay in the submission of our IND due to COVID-19 but acknowledge the potential exists for this timing to be impacted. In addition, we have submitted a Clinical Trial Notification (CTN) application for NL-201 in Australia. The planned first-in-human clinical trials for NL-201 will test intravenous, monotherapy in patients with advanced solid tumors to determine the safety and tolerability of various dosing regimens.

Tuba: . Are you planning to collaborate with academia and industry to explore new applications of Neoleukins’ technology in other therapy areas or indications?

Daniel: De novo protein design is in its infancy, and we would welcome the opportunity to collaborate with academia and industry partners to move this technology forward.  We are focused on developing drugs in the oncology and autoimmune space.  However, given the potentially broad application of the technology, we would be open to exploring collaborations and other research efforts to design other molecules in areas outside oncology and autoimmune disease as well. 

While we are initially focused on establishing single agent activity for NL-201 in cancer, we recognize there may be an opportunity to combine NL-201 with other therapies such as checkpoint inhibitors, cell therapy, antibodies and other agents. 

About Daniel-Adriano Silva:

Daniel-Adriano Silva is aCo-founder and Vice President Head of Research at Neoleukin and is a leader in the fields of protein folding, structure, dynamics, and function and is the primary architect of the Neoleukin Platform.

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