Fab Biopharma is revolutionizing autoimmune disease treatment with its groundbreaking soluble bispecific receptor therapies. Tailored specifically to address complex and often life-threatening diseases like Sjögren’s disease and lupus, this patented technology leverages advanced high-throughput techniques to streamline the discovery phase. Poised to transform the treatment landscape, Fab Biopharma is on track to file two investigational new drug applications within the next 36 months, aiming to tackle diseases through innovative approaches to multi-pathway management.
Targeting Under-Resourced Women's Diseases with Novel Therapies
Fab Biopharma was founded specifically to tackle diseases that disproportionately affect women, a domain traditionally lacking in dedicated resources and approaches. Lupus and Sjögren’s disease were chosen as initial targets to leverage the team's extensive background in lupus research and development, which also provides a strong foundation for addressing Sjögren’s, a related but distinct autoimmune disorder characterized by extensive organ and exocrine gland involvement. More than lupus, Sjögren’s involves T cell–mediated as well as B cell–mediated processes, highlighting its unique pathology.
Historically, therapeutic strategies for Sjögren’s disease have been narrowly focused, targeting either T cells or B cells but not both, and have seen limited success. In contrast, treatments that concurrently address multiple immune pathways and cytokines have shown promise in diseases like atopic dermatitis, rheumatoid arthritis, and Crohn’s disease. Effective management of Sjögren’s, therefore, may require a nuanced strategy that moderates both B cell and T cell activity without entirely suppressing immune function. This balance ensures a favorable benefit-to-risk ratio, crucial for a disease as complex and varied as Sjögren’s disease.
Bispecific antibodies present one possible approach. Around a dozen have received marketing authorization, with many more in development, and their effectiveness is these applications has been demonstrated. Expectations are very high for future candidates as well, with several multi-billion-dollar cash exits occurring in recent months for companies with bispecific antibodies for the treatment of autoimmune diseases at relatively early development stages.
Given the limitations of conventional monoclonal therapies and bispecific antibodies, Fab Biopharma is pioneering the development of a new biologic drug modality: soluble bispecific receptors. This innovative approach not only circumvents some of the challenges associated with bispecific antibodies — such as the complex manufacturing processes and safety concerns related to cross-linking of cell types — but also offers significant advantages in safety and efficacy. Soluble receptors, exemplified by blockbusters like Enbrel® and Eylea®, target extracellular cytokines directly, reducing the likelihood of adverse immune reactions. Moreover, Fab's receptors are designed to engage initially only with previously validated targets, streamlining development by leveraging existing data from monotherapy studies to guide the comparative analysis and optimization of new bispecific constructs. Receptors have evolved to bind with affinity ranges that modulate but do not shut down relevant biological pathways.
By focusing on well-established targets that have previously been investigated using mono-targeting drugs, Fab Biopharma enhances the potential for clinical success and accelerates the path to regulatory approval and market entry, setting a new standard in the treatment of autoimmune diseases affecting women. Our novelty lies in addressing two validated autoimmune targets at the same time with one drug molecule, with receptor binding regions that are tuned to modulate B and T cells at the right levels.
Expert Insights Driving Innovative Therapeutics
Fab Biopharma’s technology team is distinguished by its profound expertise in the design, development, and manufacturing of protein drug structures, capitalizing on the unique attributes of the fragment crystallizable (Fc) region of antibodies and a variety of soluble receptor binding regions, such as Enbrel. The team's pioneering work includes the cloning and detailed characterization of tumor necrosis factor (TNF) and interferon-γ receptors. They have successfully elucidated the binding behaviors of these receptors, their subtypes, and their ligand variants, highlighting their enhanced specificity and stability and longer half-life compared with other molecular configurations.
Moreover, the team's capabilities extend to the intricate processes involved in antibody and receptor drug development. They have developed a deep proficiency in the rapid benchtop- and larger-scale production of proteins that are not only highly pure but also exceptionally stable, ensuring that therapeutic products meet the highest standards of quality and efficacy. Fab's founders drove the making and clinical testing of Benlysta from design through clinical trials, regulatory approval, and commercial-scale manufacture. Benlysta is the first approved biologic drug for treatment of lupus. It is an antibody to BAFF, the critical cytokine survival factor for B cells.
Through strategic innovations, Fab Biopharma has also leveraged its extensive experience to optimize the Fc region of soluble receptors. This optimization has led to significant improvements in half-life and reduced complement activity, as well as antibody-dependent cell-mediated cytotoxicity (ADCC) activity, critical for minimizing potential side effects in autoimmune treatments. The seamless integration of this expertise into their platform underscores Fab Biopharma's commitment to advancing autoimmune therapy, setting new benchmarks for safety and effectiveness in the industry.
Leveraging the Potency of Soluble Receptors
Soluble receptors present a compelling alternative to traditional antibodies, primarily because they have biologically evolved to function optimally within the body’s complex systems. Soluble receptors do not inherently possess a mechanism to destroy cells, which proves advantageous in treatments where cell preservation is essential. This attribute is particularly important in therapeutic contexts beyond oncology, where unnecessary cell destruction can be detrimental. Furthermore, leveraging the Fc region in soluble receptors minimizes their potential for cellular toxicity, a safety consideration that aligns with guidelines from regulatory bodies like the U.S. Food and Drug Administration (FDA).
The manufacturing process of bispecific soluble receptors offers advantages over that of bispecific antibodies. Bispecific soluble receptors require the introduction of only a single gene for expression, unlike the four genes typically necessary for bispecific antibodies (two heavy and two light chains). This simplification not only leads to faster initial expression and testing but also to faster process development times. Using a single expression cassette can also improve the stability of the recombinant cells during bioreactor runs.
Often, the crystal structures of these receptors and the receptor–ligand complexes are readily available, providing critical insights into their molecular interactions, which aids in the design of more potent binding molecules.
At Fab Biopharma, we utilize human genes for receptor expression — ensuring that our therapeutic proteins are fully human. This practice significantly reduces the risk of immunogenic reactions compared with humanized or chimeric proteins used in earlier therapies, making our products safer for patients.
Soluble receptors also excel in their biological and functional characteristics. They recognize and bind to the three-dimensional structures of cytokines, which mirrors the natural interaction dynamics of receptor–ligand binding. This level of specificity substantially reduces the likelihood of off-target effects — an issue that occurs occasionally with antibodies that may bind to multiple similar proteins.
By leveraging these inherent advantages, Fab Biopharma is poised to redefine treatment paradigms across a range of diseases, harnessing the natural efficacy and safety of soluble receptors to offer innovative, targeted therapies.
Strategically Targeting T and B Cells for Safer Treatment
Fab Biopharma is dedicated to advancing the treatment of autoimmune diseases with a primary focus on developing soluble bispecific receptor Fc fusion proteins. These proteins are designed to selectively inhibit both T cells and B cells, offering a targeted therapeutic approach to Sjögren’s disease and lupus as initial indications. By utilizing the endogenous extracellular binding domains of soluble receptors, Fab’s platform capitalizes on the natural interaction of these domains with their cytokine targets. This strategy ensures that the targets, previously validated through extensive clinical research on mono-targeting molecules in Sjögren's and related immune diseases like lupus, are engaged more effectively and safely.
For Sjögren’s disease, an intricate condition that can start as a mild T cell disease and progress to severe T and B cell pathology in up to half of the patients, Fab’s technology aims to fuse a receptor targeting T cells with another targeting B cells within the same molecule. This method offers a broader range of action and higher sensitivity compared with traditional bispecific antibodies. Crucially, unlike existing bispecific antibodies, such as monetuzumab, eporitamab, and golfitamab, which necessitate simultaneous binding of the target proteins to function, Fab’s soluble receptors are engineered to function without requiring concurrent target engagement. This design further minimizes the risk of inadvertently bringing T and B cells into close proximity — a known risk with bispecific antibodies like blinamotumab and teclistamab, where antigens may be membrane bound, which can lead to adverse immune reactions.
The Potential of Bispecific Soluble Receptors
Fab Biopharma is advancing a revolutionary approach in the treatment of autoimmune diseases with its development of bispecific soluble receptors that uniquely leverage only the binding regions of cytokines rather than their entire extracellular domains. This innovative design allows for shorter amino acid sequences, enhancing the molecular efficiency and enabling the introduction of specific point mutations to finely tune binding affinity. Such precision is crucial as inflammatory cytokine levels in many autoimmune diseases are elevated — often three to five times higher than normal — meaning that the receptors do not require excessively high activity to effectively regulate these levels.
A critical component of these receptors is the incorporation of the Fc region, which significantly extends the half-life compared with normal monomeric receptors. This extended activity reduces the need for overly stringent binding affinity, as the receptors remain active in the body for a longer duration. Remarkably, the inclusion of Fc regions, optimized through mutagenesis, can amplify the molecule's potency more than tenfold. This potency enhancement allows for lower dosing levels, thereby decreasing production demands and ultimately reducing the cost of goods.
The bispecific soluble receptors developed by Fab Biopharma feature a unique configuration that includes a short proprietary linker and a combination of mutations within the Fc region to optimize function and stability. Additionally, each receptor may contain point mutations that are strategically placed to adjust binding properties. This results in entirely novel molecular entities that have never been synthesized before, providing Fab Biopharma with significant opportunities to establish valuable intellectual property (IP).
Comparative Development Strategy
A cornerstone of our development strategy involves comparison of our innovative bispecific soluble receptor scaffolds with established mono-targeting receptors and other related molecular constructs. This comparative approach is grounded in our substantial expertise in not only soluble receptor drugs but also in the design, production, and evaluation of antibodies, including those with single binding domains and bispecific configurations. Our capability extends to crafting complex molecular structures such as receptor–receptor fusions, receptor–antibody fusions, and various forms of bispecific antibodies.
The objective behind these comparative studies is to compile a comprehensive data set that illustrates the efficacy of different constructs against specific target pairs. This data is crucial for affirming the expected advantages of our bispecific soluble receptors and informs the ongoing development of new platforms tailored to autoimmune diseases. By analyzing how these constructs perform relative to one another, we can fine-tune our molecules to ensure superior efficacy and safety.
Our platform and IP portfolio are specifically engineered to identify the most effective bispecific target combinations aimed at treating autoimmune disorders. We focus on developing multifunctional proteins that can be rapidly scaled and mass-produced. This involves rigorous optimization processes, including targeted mutagenesis, to refine the effectiveness of both our bispecific soluble receptors and antibodies. Each screening phase, from expression and purification to biophysical characterization and target ligand binding analysis, is meticulously managed to ensure that every bispecific soluble receptor fusion advancing towards clinical trials is benchmarked against corresponding bispecific antibodies targeting the same molecular interactions.
Encouraging Early Outcomes from Soluble Receptor Studies
Because we are leveraging the natural properties of soluble receptors, which are pre-evolved to bind specifically to their targets, our development process is significantly streamlined. Unlike traditional methods that require extensive efforts to generate, screen, and optimize large libraries of novel binding regions, our approach allows for the rapid accumulation of data. Within just 12 months, we have successfully created a small yet potent library of soluble receptors tailored to combat various inflammatory cytokines linked to autoimmune diseases.
Our team has designed numerous single receptor fusions, which are not only quickly expressed and purified through a streamlined one-step process but have also undergone initial binding studies using advanced techniques like the Octet® Binding Assay and Biacore systems. The binding efficiency of these receptors sometimes surpasses that of conventional monoclonal antibody controls, providing compelling evidence of their superior therapeutic potential.
As we continue to expand our library of single receptor fusions, we utilize these data to identify the most promising candidates for further development into bispecific receptor fusions. An initial series of these full-length bispecific soluble receptor fusion drugs, protected under Fab’s IP, is already in the pipeline, with gene synthesis underway. This growing proprietary library provides Fab with the ability to quickly make and test new target combinations in our bispecifics, for any given medical indication.
Moreover, we have initiated screening with cell-based assays to measure the binding efficacy of our receptors to intended target pairs. Concurrently, we are developing proprietary bioassays to ascertain the impact of our bispecific soluble receptors on the proliferation, and potentially the motility, of B and T cells, as well as their cytokine activity. This comprehensive evaluation will also explore how these receptors, both individually and in combination, affect primary B and T cells from patients with Sjögren's. As an initial step, we test our bispecific fusions along with controls in a number of single-target readout cell lines to confirm target activity.
The selection of candidates for progression to animal studies is based on stringent criteria: high levels of expression, precise target binding, effective modulation of T and B cell activity without complete suppression, outstanding stability in biological systems, and optimal tissue distribution.
Our preclinical investigations will employ multiple animal models to reflect the complex pathology of Sjögren's and lupus, which share several physiological disruptions. Leveraging our validated lupus model could provide invaluable insights into the crossover potential of our therapies. This dual-disease focus enhances our understanding of the safety and dosage requirements needed to advance into studies with nonhuman primates.
Ultimately, our aim is to develop first-in-class drugs that not only exhibit robust binding to modulate but not completely inhibit key molecular targets but also demonstrate extended half-life and minimal side effects. These bispecific soluble receptors are designed to neutralize critical cytokines involved in Sjögren’s and lupus, offering a reduction in complement activation and tailored delivery through subcutaneous administration. This innovative approach ensures that our therapies can be produced reliably at high concentrations, maintaining stability and efficacy to significantly alleviate the burden of autoimmune diseases.
Advancing Rapidly to the Clinic
Sjögren’s disease is a predominantly affects older adult women (45 and above) and is characterized by chronic arthritis and dryness of the eyes and mouth. Many patients also experience complications in their joints, skin, lungs, gastrointestinal tract, nervous system, and kidneys. The prevalence of Sjögren’s varies widely, with estimates suggesting that between 700,000 to 15.8 million people globally are affected, making it the second most common rheumatic disorder in the U.S., after osteoarthritis. Currently, no fully effective treatment exists for this complex condition. Up to 40% of Sjogren's patients will develop organ failure, and up to 15% will develop cancers. Sjogren's is a painful and life-threatening disease.
The Fab team has the opportunity to apply successful learnings from the clinical development of BENLYSTA (belimumab) for the treatment of lupus, as well as Sjogren's, including with respect to clinical trial design and biomarker disease activity correlations, clinical operations, biostatistical analyses and data management, and clinical endpoint determination.
Efforts at Fab Biopharma are currently concentrated on rapidly identifying promising drug leads. The organization aims to file two investigational new drug (IND) applications within the next 36 months, targeting autoimmune diseases with a focus on those affecting women and involving both T and B cell mechanisms.
On the patent front, Fab Biopharma has laid a robust foundation to protect its innovations. A provisional patent was filed in March 2022 in the United States, followed by the filing of a non-provisional international patent in March 2023. These patents encompass a wide range of modifications, including mutations and optimizations. Additional patent applications are in preparation, covering specific lead molecules as they are identified, with a comprehensive second international patent planned for early 2025 to secure final optimization changes, formulations, and dosage specifics.