Why We Partnered with Nxera Pharma
This month, on November 5th, we signed a multi-target partnership and licensing agreement with Nxera Pharma (formerly known as Sosei Heptares) to design antibodies against several G-protein coupled receptor (GPCR) targets.
We are thrilled to be working with Nxera – with over 15 years of experience in GPCR target identification and structural determination, they bring a wealth of experience and expertise in GPCR drug discovery. Their platform, NxWave?,? synergises incredibly well with our AI antibody design capabilities, by feeding our platform with structural data necessary to create novel antibody therapeutics. Together, we aim to design antibodies for some of the most challenging GPCR targets.
GPCRs are critically relevant targets in medicine. Because they are linked to hundreds of diseases, drugs targeting GPCRs can transform the lives of hundreds of thousands of patients globally. Around a third of all new drugs target GPCRs, generating aggregate sales of almost $1 trillion. Yet, these drugs only cover around 20% of this diverse receptor family. An estimated 220 GPCRs with known disease links remain undrugged, highlighting a fantastic opportunity for us to create life-changing therapies for patients.
Why do GPCRs remain neglected in drug discovery??
For the last two decades, empirical design has consumed most drug discovery efforts for these targets. This 'brute-force' approach to drug discovery has been fruitful for many targets, allowing researchers to create hundreds of transformative therapies. However, GPCRs are particularly challenging targets, and drugs that bind them are especially rare. Since empirical design relies on serendipity, many discovery campaigns using this method have failed.?
However, if one knows the crystal structure of the GPCR, it becomes possible to design drugs rationally. Unfortunately, determining the crystal structure of GPCRs is challenging because they are membrane-bound receptors. Pulling them from the hydrophobic membrane environment causes them to become disfigured and deformed. Without the native structure, rational drug design is impossible, and thus, most drug discovery for GPCRs has remained empirical.?
Nxera's platform determines GPCR structures
However, this changed when Heptares Therapeutics (acquired by Sosei in 2015 to become Sosei Heptares, now known as Nxera Pharma) began working on GPCR structural determination in 2007. When Heptares was founded, the only resolved crystal structure of a GPCR was rhodopsin. Since then, the team have revealed the structures of several GPCRs crucial to the pathology of many diseases. These include the glucagon receptor, which is important in diabetes; CCR9, involved in viral entry, cancer spread, and inflammatory diseases; C5a, important in rheumatoid arthritis; and GLP-1, the target behind the wave of therapies treating diabetes and obesity (We recently published an article on this).?
Nxera's technology places mutations in the GPCR structure to help stabilise them for crystallisation, without sacrificing the structural integrity. This breakthrough has allowed the team to determine the crystal structures of GPCRs where it was not previously possible. With these crystal structures, researchers can design drugs for GPCRs rationally, opening many opportunities to develop new therapies, and gradually phasing empirical design for GPCRs into redundancy. Today, Nxera's pioneering work has enabled them to support a pipeline of around 30 R&D programmes, mostly focused on GPCR targets.?
GPCRs are challenging targets
Regardless of whether one knows the target's crystal structure, GPCRs are still notoriously challenging to drug. Most of a GPCR is buried deep within the cell membrane. This leaves very little area exposed to the outside of the cell for binding, thus, drugs must be designed very, very precisely. Exacerbating the problem, GPCRs have high homology with other subtypes of GPCRs. This makes off-target binding events likely, meaning GPCR-targeting drugs commonly suffer from severe side effects, many of which are deemed too toxic for practical therapeutic use.
Fortunately, antibodies are generally more specific than small molecules, offering an exciting modality to target GPCRs. Frustratingly, because antibodies are large, other, more prominent receptors on the cell surface can block antibodies from reaching their target during screening. Typically, antibody screening must be performed on cells since you cannot isolate GPCRs from the cell membrane. Thus, even with the structural models available for rational design, it remains challenging to target GPCRs.
However, Nxera can stabilise GPCRs for soluble environments by placing mutations in the sequence. Therefore, we can screen our antibodies against the soluble protein, removing the steric hindrance by larger receptors on cells and making discovery much easier.
Antiverse can design antibodies for challenging GPCR targets?
To solve these issues, we use generative AI to design epitope-specific libraries, a more targeted approach to traditional antibody libraries. Where traditional libraries host billions of random, empirically designed antibodies, we use machine learning to design antibodies rationally against the epitope of interest, creating libraries with much higher specificity. Then, we screen our antibodies against cell lines that express the target of interest in extremely high densities, reducing interference from other receptors and ensuring rare GPCR binders are captured for further functional testing.?However, when available, we aim to use Nxera’s soluble proteins to screen our libraries.
Learn more about our technology: https://www.antiverse.io/
Nxera and Antiverse's Platform Synergy
In 2024, we transitioned from a sequence-based antibody design approach to a structure-based approach. This shift in our methodology reflects a desire to design antibodies with greater specificity. A structure-centred approach enables us to design with conformational specificity, unlocking the ability to tailor our antibodies with specific bioactivity relevant to various therapeutic requirements. We do this by computationally generating a repertoire of target structures that reflect the dynamic state of the receptor in vivo. This compares to our previous method, which would rely on the target sequence?to design antibodies. When the structure of the GPCR isn’t available, which is often the case, our sequence-based method is ideal.
Naturally, Nxera's ability to reveal the structures of many disease-relevant GPCRs provides valuable data that can support us in the design of GPCR-targeted antibodies. Nxera has previously shown that its NxStaR platform can create structures for successful antibody discovery in a recent partnership with Kymab targeting CXCR4, which now undergoing pre-clinical trials. In addition, Nxera’s physical samples of soluble GPCR proteins allow us to screen our antibodies without background interference from cell receptors. Working together, our platforms will create many GPCR-targeted antibodies that could transform patients' lives worldwide.?
Achieve your biologics discovery goals for challenging drug targets. Contact us today.
This Month In Antibody Discovery
Oct 30th: Roche's Anti-Amyloid Antibody Shows Promise Despite Safety Concerns in Alzheimer’s Trial
Oct 31st: Absci and Twist Bioscience Collaborate on AI-Driven Antibody Design
Nov 4th: Lonza’s Synaffix and BigHat Collaborate on AI-Designed Next-Gen ADC
Nov 5th: Nxera and Antiverse Partner to Design Antibodies for GPCR Targets
Nov 13th: BioNTech Acquires Biotheus for $800M to Advance PD-L1 x VEGF Bispecific Antibody
Nov 14th: Merck Secures $3.3B Deal for LaNova's PD-1xVEGF Bispecific Antibody
Nov 21st: Novartis Cuts Pipeline by 40%, Focuses on High-Value Biologics
About Antiverse
Antiverse is an artificial intelligence-driven techbio company that specialises in antibody design against challenging targets, including G-protein coupled receptors (GPCRs) and ion channels. Headquartered in Cardiff, UK and with offices in Boston, MA, Antiverse combines state-of-the-art machine learning techniques and advanced cell line engineering to develop de novo antibody therapeutics. With a main focus on establishing long-term partnerships, Antiverse has collaborated with three top global pharmaceutical companies. In addition, they are developing a strong internal pipeline of antibodies against several challenging drug targets across various indications. For more information, please visit: