SEATTLE, WA – (BUSINESS WIRE) – Cyrus Biotechnology, Inc., a Seattle-based biotechnology firm with a proprietary platform for biologics discovery that combines software, AI and large-scale parallel protein screening, today announced that its pre-clinical stage COVID therapeutic lead molecule, ACE2.v2.4 strongly binds the spike protein of SARS-CoV-2 variant of concern (VOC) omicron. ACE2.v2.4 was engineered to bind to future variants of the virus, providing a therapeutic for COVID for years to come, and these data demonstrate that molecule is capable of providing superior protection against novel variants.

ACE2.v2.4, a soluble derivative of the natural receptor for the virus, was specifically designed in collaboration with researchers at the University of Illinois to tolerate mutations in the spike protein of the virus, and also has high affinity for the alpha and delta VOCs as well as for SARS-CoV-1 and for a set of unrelated bat coronaviruses (reported in Science Advances).

Testing from multiple laboratories, including at Cyrus, has shown that antibodies currently on the market – a cocktail from Regeneron and antibodies from Vir/GSK and from Eli Lilly – have lost some or all of their efficacy against omicron and other variants. In contrast, new work, performed at Cyrus and the University of Illinois, now shows that ACE2.v2.4 retains nearly all of its efficacy against omicron. These data are shown in the figure included alongside this press release, and confirm antibody results seen by others such as the Diamond group. ACE2.v2.4 has already been shown to tightly bind every VOC in cell-based assays and to neutralize the original virus in mouse studies. Recently released pseudovirus neutralization studies from the Hoshino laboratory in Kyoto confirms that Cyrus’s ACE2.v2.4 (and other Cyrus variants) successfully neutralize omicron.

“These are early data in a developing program, and we still need to see clinical performance, but Cyrus Biotechnology’s ‘ACE.v2’ SARS-CoV-2 decoy receptor — which was developed against the original Dec 2019 Spike — remains smashingly effective at neutralizing Omicron and other variants”, said Dr. Jeremy Kamil, associate professor of microbiology and immunology at Louisiana State University Health Shreveport.

“New COVID-19 variants continue to emerge and surprise us by escaping monoclonal antibody cocktails and vaccines. So called ‘decoys’ like ACEv2.4 represent exciting therapeutic candidates. Because ACE2.v2.4 mimics yet greatly improves upon how the human ACE2 receptor binds the viral spike protein, these candidate therapeutics work quite differently from monoclonal antibodies. So, the real promise here is that such interventions may be much harder for the virus to escape.”

Cyrus is pursuing confirmatory studies in animal models of COVID-19 and is continuing to improve pharmacokinetic performance of the lead molecule. Other related molecules with even higher potency against omicron and earlier SARS-COV-2 variants are also under evaluation. Initial development of ACE2.v2.4 has been published and newer data showing efficacy against VOCs has been accepted in a peer-reviewed journal. Cyrus will continue to expeditiously publish data on omicron and beyond.

ACE2.v2.4 is a dual-mode-of-action COVID-19 therapeutic lead molecule with virus neutralizing and anti-inflammatory/lung-protective enzymatic activity. “Many groups have created therapeutics that bind to the virus spike protein and prevent binding and entry of the virus into human cells”, said Dr. Erik Procko, Director of Discovery at Cyrus and Associate Professor of Biophysics at the University of Illinois. “The antibody therapies create new proteins to bind the spike, mimicking natural ACE2 binding. Cyrus took a different approach, starting from the natural ACE2 and improving it to have potency like antibody. By engineering ACE2.v2.4 to be as similar to natural ACE2 as possible, the ACE2.v2.4 is engineered to bind to any SARS-CoV-2 variant. New CoV-2 variants that do not bind ACE2.v2.4 will also not bind human cells and these variants will not be infective. Based on this engineering method, and results with delta and omicron and other variants, we believe that ACE2.v2.4 has a much better chance of neutralizing future VOCs than any antibody or cocktail of antibodies,” Dr. Procko added.

Therapeutic was designed and engineered to provide broad variant coverage, with the potential to offer COVID treatment for years to come. Current approved biologic drugs and clinical candidates show reduced or drastically reduced potency.

“While new therapeutic antibodies can be generated over a period of months as new VOCs arise, a broadly active protein built as a decoy for the normal ACE2 receptor should provide an intervention that remains effective and clinically useful for years and perhaps indefinitely for endemic COVID-19,” said Cyrus CEO Lucas Nivon.

About Cyrus Biotechnology

Cyrus Biotechnology is a pre-clinical-stage biotech company combining computational and experimental protein design and screening to create novel biologics for serious unmet medical needs. Using this approach, Cyrus is developing an early pipeline of innovative programs in multiple indications. The Cyrus platform improves both the efficacy (binding affinity, aggregation propensity, solubility, and stability) and safety (binding specificity and immunogenicity) of natural proteins. Cyrus is also partnering with leading biotech and pharma companies and research institutes to bring collaborative programs forward from discovery to the clinic. Cyrus is based on core software from the lab of David Baker at the University of Washington. Cyrus has worked with over 90 industry partners. We are based in Seattle, WA and financed by leading US and Asian Biotech and Tech investors including Orbimed, Trinity Ventures, Springrock, Agent Capital, iSelect, Yard Ventures, WRF, and Alexandria.

https://www.businesswire.com/news/home/20211227005034/en/

Contacts

Lucas Nivon
lucas@cyrusbio.com
206-258-6561

– First collaboration program, leveraging Cyrus’ de novo computational approach to create proprietary IL-2 protein agonist targeting autoimmune and other deleterious immune conditions-

-Preclinical data demonstrate synergistic activity of ImmTOR in combination with IL-2 mutein to increase the level and durability of T_reg expansion-

– Unlocking a new generation of innovative biologic therapeutics with the potential to improve the lives of patients-

WATERTOWN, Mass. and SEATTLE, Sept. 08, 2021 (GLOBE NEWSWIRE) — Selecta Biosciences, Inc. (NASDAQ: SELB), a biotechnology company leveraging its clinically validated ImmTOR™ platform to develop tolerogenic therapies that selectively mitigate unwanted immune responses, and Cyrus Biotechnology, Inc. a leading protein design company, today announced a protein engineering collaboration combining Selecta’s ImmTOR platform with Cyrus’ ability to radically redesign protein therapeutics. The lead program in the collaboration is a proprietary interleukin-2 (IL-2) protein agonist designed to selectively promote expansion of regulatory T cells (T_reg) for the treatment of patients with autoimmune diseases and other deleterious immune conditions.

Novel IL-2 approaches and technologies are driving innovation in the therapeutic development space. The IL-2 pathway influences critical aspects of both immune stimulation and immune regulation, through the development and expansion of regulatory T cells (T_reg). These T_reg cells are a specialized subpopulation of T cells involved in suppressing certain immune responses and maintaining the body’s self-tolerance. Reductions in the number of T_reg cells have been shown to drive a spectrum of autoimmune diseases and conversely, increasing T_reg expansion may have clinical utility in reducing inflammation and improving disease outcomes. Early preclinical data investigating the effects of ImmTOR in combination with a T_reg-selective IL-2 mutant protein (IL-2 “mutein”) demonstrate substantial synergistic activity in increasing the percentage and durability of T_reg expansion in the spleen (Figure below). This supports the potential of ImmTOR in combination with IL-2 proteins to restore immunotolerance to autoantigens and forms the basis for this partnership. Although IL-2 has been an attractive target for autoimmune indications, overcoming its immunostimulatory activities, short half-life and anti-IL-2 antibody formation has been challenging. Building on recent advancements in the field, our strong preliminary data suggest that ImmTOR in combination with Cyrus’ novel IL-2 protein agonist has the potential to unlock the value of this target and drive the development of a next generation, best-in-class asset.

A figure accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/eb50b792-d824-4b4b-8e60-c2135fe26e2e

“We are excited to collaborate with Cyrus, and we see this strategic protein engineering partnership as an important step in advancing our ImmTOR platform for the treatment of autoimmune diseases,” said Carsten Brunn, Ph.D., President and Chief Executive Officer of Selecta. “We are encouraged by the preclinical data generated to date and the growing literature that supports the potential of IL-2 therapeutics in treating immunological diseases.”

Dr. Brunn added, “We look forward to leveraging Cyrus’ ability to both reengineer immune epitopes and rationally design novel proteins using non-traditional starting sequences, including non-human, non-natural and ancestral versions. For our first program, this combination will allow us to potentially mitigate unwanted immune responses by reducing the inherent immunogenicity of the protein while also promoting immune tolerance. We are fortunate to have this opportunity to optimize and advance our portfolio through the design and generation of innovative protein therapeutics. Beyond leading a paradigm shift in the way biologics are made, ultimately this collaboration has the potential to unlock new treatment options and improve the lives of patients who suffer from serious and debilitating diseases.”

Lucas Nivon, Ph.D., Chief Executive Officer of Cyrus, commented, “We welcome Selecta as a deeply experienced partner. This collaboration is in perfect alignment with our protein design expertise and represents an important endorsement of our platform, which has the potential to further enhance the potency of ImmTOR’s tolerizing power. With our current partners, we have demonstrated our ability to redesign existing protein biologics or build them from the ground-up — expanding the potential for therapeutics and intellectual property. We look forward to executing on our shared vision.”

Under the terms of the collaboration, Selecta has provided an upfront payment, and Cyrus is eligible to earn discovery, development and sales based milestones. Novel engineered protein therapeutic candidates from the partnership will be used to expand Selecta’s proprietary pipeline and further bolster Selecta’s clinically validated ImmTOR platform.

https://www.globenewswire.com/news-release/2021/09/08/2293345/0/en/Selecta-Biosciences-and-Cyrus-Biotechnology-Enter-Collaboration-to-Create-Novel-Engineered-Therapeutic-Proteins.html

About Selecta Biosciences, Inc.
Selecta Biosciences Inc. (NASDAQ: SELB) is a clinical stage biotechnology company leveraging its ImmTOR™ platform to develop tolerogenic therapies that selectively mitigate unwanted immune responses. With a proven ability to induce tolerance to highly immunogenic proteins, ImmTOR has the potential to amplify the efficacy of biologic therapies, including redosing of life-saving gene therapies, as well as restore the body’s natural self-tolerance in autoimmune diseases. Selecta has several proprietary and partnered programs in its pipeline focused on enzyme therapies, gene therapies, and autoimmune diseases. Selecta Biosciences is headquartered in the Greater Boston area. For more information, please visit www.selectabio.com.

About Cyrus Biotechnology
Cyrus Biotechnology is a pre-clinical-stage biotechnology company applying leading computational protein design capabilities coupled with massively parallel in vitro screening to engineer novel biologics drugs. Cyrus is advancing a novel pre-clinical infectious disease therapeutic and developing a pipeline of internal and partnered discovery programs over a range of indications, including next-generation CRISPR therapeutics in collaboration with the Broad Institute. Cyrus founders include Dr. David Baker of the University of Washington and the company’s platform is based on core software from the Baker lab. The company has worked with over 100 industry partners, including 13 of the top 20 global Pharma firms. Cyrus is based in Seattle, WA and financed by leading Biotech and Tech investors including Orbimed, Trinity, Springrock, WRF and Alexandria. For more information please visit cyrusbio.com.

Contacts
Cyrus Biotechnology, Inc.
Lucas Nivon, 206-258-6561
lucas@cyrusbio.com

Summary

Cyrus has developed a “NextGen” antibody structure prediction tool (NextGen) based on the RosettaCM “hybridize” algorithm (1). Cyrus customized and modified RosettaCM for antibody structures with an antibody-specific database, sequence parsing, and by taking antibody-specific heavy-light chain orientation into account. 

NextGen was developed and benchmarked on the test set of antibody structures from the AMA-II (2). In those tests, the NextGen tool produced more accurate models (measured by RMSD metrics) for the AMA-II antibodies, compared with all other entrants in AMA-II, including Schrödinger, CCG and older Rosetta algorithms. 

To independently validate these results we worked with BIOCAD (https://biocadglobal.com) on a 26-protein test set to compare Cyrus NextGen antibody structure prediction with Schrödinger and  another major vendor software. Tests were performed as follows:

• BIOCAD scientists ran predictions using all non-Cyrus software
• Cyrus scientists produced models by running NextGen
• BIOCAD scientists calculated the metrics described below on the models produced by Cyrus and other software

Cyrus NextGen was the most accurate antibody modeling tool across all of the tested methods in this independent test (Figure 1). 

A sample structure overlay of a crystal structure and a NextGen antibody model is shown in Figure 2. 

Cyrus is releasing these results here directly for rapid dissemination and will release a more detailed white paper describing the methods and results once that manuscript is ready.

Figure 1. Antibody model accuracy over the BIOCAD set of 26 antibody-Fv structures using the sum of metrics described here in “BIOCAD structure similarity metrics” — lower is more accurate. 

Figure 2. Example structure prediction using NextGen antibody, with Cyan = Crystal Structure. Light Brown = NextGen predicted structure (PDB 4M61)

BIOCAD Dataset

The BIOCAD antibody data set consists of 26 recently-released structures of bound and unbound antibody structures (Fv domains consisting of heavy (V_H) and light (V_L) chains), which Cyrus did not use as templates for NextGen structure prediction. 

BIOCAD structure similarity metrics

BIOCAD calculated the structural variation of predicted models for each V_H-V_L antibody complex in comparison to the crystal structures in order to compare model quality of the top-performing algorithms. Combined, there are 50 parameters for each structure which fall into 10 categories.

1. RMSD of all Ca per chain when aligned by chain

The first type of metric calculates the Root Mean Square Deviation (RMSD) between alpha Carbons (Ca) of the experimental and predicted structures when aligned by chain. (2 parameters per structure).

2. RMSD of CDR N-Ca-C when aligned by chain

The second metric calculates the RMSD between the backbone atoms (Nitrogen, Ca, and Carbonyl Carbon aka N-Ca-C) in the CDR residues of the experimental and predicted structures when aligned by chain. (6 parameters per structure).

3. RMSD of CDR Heavy Atoms when aligned by chain

The third metric calculates the RMSD between the Heavy Atoms CDR residues of the experimental and predicted structures when aligned by chain. (6 parameters per structure).

4. RMSD of CDR N-Ca-C when aligned by CDR

This metric calculates the RMSD between the Na-Ca-C in the CDR residues of the experimental and predicted structures when aligned by each CDR. (6 parameters per structure)

5. RMSD of CDR Heavy Atoms when aligned by CDR

The third metric calculates the RMSD between the Heavy Atoms in the CDR residues of the experimental and predicted structures when aligned by each CDR. (6 parameters per structure).

6. Difference between the Stem Length for each loop

For each loop, the distance is calculated between the Ca of the two Framework (Fr) residues before and after the loop. (6 parameters per structure).

7. Alpha and Tau Angles per CDR

For each loop, the Alpha Angle is calculated by measuring the flat angle created by the last 3 Ca in the CDR. The Tau Angle is calculated by measuring the dihedral angle created by the last 3 Ca in the CDR and the next Fr Ca. (12 parameters per structure).

8. Distance between the pivot for V_H and V_L

Four non-atomic positions are defined by Marze et al (3) which characterize the orientation between the Heavy and Light chains. Positions 2 and 3 are the pivot points for the Heavy and Light chains. This distance is calculated once for the structure (c in figure 3). (1 parameter per structure).

9. Two flat and one dihedral Angle for the Marze positions

For the four positions defined by Marze et al, there are two flat angles between positions 1, 2, and 3 and between positions 2, 3, and 4 and the dihedral for all 4 positions. These were calculated once per structure (a, d, and e in Figure 3). (3 parameters per structure).

Figure 3. From Marze et al (3), a) orientation between the heavy and light chain is calculated by establishing 4 positions at conserved spots with respect to 4 framework sheets. b) The Packing angle, c) Interdomain distance, d) light Opening Angle, and the heavy Opening Angle are calculated as shown based on these 4 points.

10.  Principal Component Analysis (PCA) Angles

Dunbar et al (4) described a PCA protocol for calculating the orientation between Heavy and Light chains. Two of those flat angles, Tilt and Twist, are calculated following that method. (2 parameters per structure). 

Scoring and Ranking

Starting from these 50 parameters, BIOCAD ran PCA to determine the correlation among parameters. They found that 99% of the variance can be retained without 34 of the 50 parameters. As a result, BIOCAD defined 16 parameters and calculated a linear combination of the original 50 parameters. The weights for the linear combinations are the first 16 eigenvectors of the covariance matrix. 

The resulting difference score is the euclidean norm of the final 16 components. If the compared structures are the same, the sum is equal to zero. The more the structures differ, the larger the sum becomes. A perfect prediction algorithm would score 0 in this sum metric, but of course even crystal structures of the same protein under different conditions differ slightly, so a 0 score is not possible.

Scores are then used to rank each antibody from each group/algorithm/method. The sum of the ranks provides an overall performance ranking per group of all 26 antibodies in the BIOCAD dataset. A lower overall summed score indicates better predictive performance for each group/algorithm.

References

1. High-Resolution Comparative Modeling with RosettaCM. Song Y, DiMaio F, Yu-Ruei Wang R, Kim D, Miles C, Brunette TJ, Thompson J, Baker D. Structure. 2013 Oct;21(10):1735-1742
   https://www.sciencedirect.com/science/article/pii/S0969212613002979

2. Second Antibody Modeling Assessment (AMA-II). Almagro JC, Teplyakov A, J Luo, RW Sweet, S Kodangattil, F Hernandez-Guzman, G. Gilliland. Proteins. 2014 Aug;82(8): 1552-1562. 
   https://onlinelibrary.wiley.com/doi/abs/10.1002/prot.24567

3. Improved prediction of antibody VL-VH orientation. Marze NA, Lyskov S, Gray JJ. Protein Eng Des Sel. 2016 Oct;29(10):409-418.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036862/
   
4. ABangle: characterising the VH-VL orientation in antibodies. Dunbar J, Fuchs A, Shi J, Deane CM. Protein Eng Des Sel. 2013 Oct;26(10):611-20.
   https://academic.oup.com/peds/article/26/10/611/1509255

Attachments

2020.07.16.-Cyrus-Antibody-Nextgen-BIOCAD.pdf

SEATTLE, WA March 20, 2020 — Software to predict the change in protein stability upon point mutation is a valuable tool for a number of biotechnological and scientific problems. To facilitate the development of such software and provide easy access to the available experimental data, the ProTherm database was created. Biases in the methods and types of information collected has led to disparity in the types of mutations for which experimental data is available. For example, mutations to alanine are hugely overrepresented whereas those involving charged residues, especially from one charged residue to another, are underrepresented. ProTherm subsets created as benchmark sets that do not account for this often underrepresented certain mutational types. This issue introduces systematic biases into previously published protocols’ ability to accurately predict the change in folding energy on these classes of mutations. To resolve this issue, we have generated a new benchmark set with these problems corrected. We have then used the benchmark set to test a number of improvements to the point mutation energetics tools in the Rosetta software suite.

https://www.biorxiv.org/content/10.1101/2020.03.18.989657v1

Authors:

Brandon Frenz, Steven Lewis, Indigo King, Hahnbeom Park, Frank DiMaio, Yifan Song

About Cyrus Biotechnology

Cyrus Biotechnology, Inc. is a privately-held Seattle-based biotechnology software company offering software and partnerships for protein engineering to accelerate discovery of biologics and small molecules for the Biotechnology, Pharmaceutical, Chemical, Consumer Products and Synthetic Biology industries. Cyrus methods are based on the Rosetta software from Prof. David Baker’s laboratory at the University of Washington and HHMI, the most powerful protein engineering software available. Cyrus customers include 13 of the top 20 Global Pharmaceutical firms and is financed by leading investors in both Technology and Biotechnology, including Trinity Ventures, Orbimed, Springrock Ventures, Alexandria Venture Investments, and W Fund.

https://www.cyrusbio.com

Contacts
Cyrus Biotechnology, Inc.
Lucas Nivon, 206-258-6561
lucas@cyrusbio.com