Interview with Gabriele Ugolini

Technologist at Bio@SNS Biology Laboratory of the Scuola Normale Superiore, and member of the PISA Biotech team

• Who makes up the working group?

The core working group, from which our initiative and spinoff project originated, is composed of Simonetta Lisi (technician at Bio@SNS), Antonino Cattaneo, professor of Physiology at the Scuola Normale—retired since 2024 and former director of Bio@SNS—and myself. Recently, Ajesh Jacob joined us: after completing his PhD at the Scuola Normale, he is now a research fellow at Bio@SNS.

Other people from the Scuola Normale may soon join the team, such as Francesco Raimondi, a professor of molecular biology with solid expertise in bioinformatics and computational methods. For now, the team has a technical-scientific background that, with a startup perspective, will be integrated with other members with cross-disciplinary backgrounds—especially managerial—bringing financial and legal skills to complement the scientific-technical expertise.

• What technical problem or specific need led you to develop this invention? Are there any limitations? If so, what are they?

To answer that question, a premise is necessary: the technology we are discussing (PISA – Post-translational Intracellular Silencing Antibodies) is just the tip of the iceberg of a body of know-how and technologies developed by the team over the years. In particular, I want to highlight the pioneering role of Antonino Cattaneo, one of the scientists who, at the end of the last century, developed the idea of using antibodies not as proteins but as genes (what are now called DNA or mRNA antibodies) to study or functionally block intracellular targets, and to create cellular and animal models of human diseases.

At the time, this was a small revolution that may have gone somewhat unnoticed because this idea only became part of the dominant paradigm in later decades. The field was not yet mature, and the clinical use of viral vectors in gene therapy either didn’t exist or was still in its infancy.

The original and highly innovative idea was to use antibodies—naturally extracellular proteins that target extracellular targets—as genes, expressing them inside a cell to attack an intracellular target, which is not their natural destination. From this idea arose the field of DNA or mRNA antibodies.

From a therapeutic standpoint, the limitation is that there are still no DNA or mRNA antibodies available on the pharmaceutical market. However, significant progress has been made—accelerated by the COVID-19 pandemic—when work on vaccine development showed that viral vectors (as DNA carriers) and messenger RNAs offer a real possibility for delivering proteins, expressed directly by the recipient cells.

With that premise, the development of the PISA technology addresses a crucial technical challenge in the pharmaceutical field: the existence of a wide array of molecular targets that cannot be tackled with pre-existing technologies—the world of proteins with Post-Translational Modifications (PTMs). PTMs are small molecules (like phosphate or acetyl groups) added to a protein after translation.

These modifications change the conformation of the modified protein, often conferring a new function—either physiological or pathological. In fact, certain PTM variants of a protein are responsible for specific diseases. The scientific problem our technology addresses is the ability to selectively recognize/target a specific conformational variant (PTM variant) of a protein.

• What is the main goal you want to achieve with this technology?

First and foremost, we aim to establish a method to validate a class of post-translationally modified pharmacological targets (currently undruggable) for research or pharmaceutical use. The goal of the spinoff project is to valorize the competitive know-how and the antibody technology platform developed over the years by the Intrabodies group at Bio@SNS. The target sector is the biotechnology and pharmaceutical industry.

The main product of the spinoff will be libraries of recombinant antibodies (the so-called SPLINT-PISA libraries), from which antibodies targeting post-translationally modified proteins (PTMs; Chirichella–Cattaneo patent) can be selected. SPLINT-PISA libraries act as a discovery engine, enabling the targeting of a wealth of new, as yet hard-to-validate targets. This technology spans a wide range of diagnostic and therapeutic areas. For example, in therapeutic terms, anti-PTM antibodies discovered and selected from the SPLINT-PISA libraries can serve as the basis for the development of new treatments in the field of precision medicine (at the molecular and subcellular levels), selectively targeting specific functional variants of proteins (PTMs or conformations) that play a pathological role inside cells—hitting the target where it is produced.

• In your view, what are the limitations of the technologies currently available in your field?

The powerful technologies currently used to validate targets—based on DNA (such as Gene Knockout or Gene Editing) or RNA (such as RNA interference)—are inherently unable to discriminate between protein conformations (or chemical modifications) that arise post-translation. They are therefore not selective for PTM variants. The technical alternative is to generate recombinant antibodies against chemically modified PTM peptides, but these antibodies typically do not recognize the native conformation of the target protein. As a result, when they bind the natural PTM target, they rarely block its function. These are significant limitations of pre-existing technologies. This is evidenced by the absence of marketed drugs (including biologics) targeting specific PTM variants of proteins.

• How does your invention overcome these limitations? What makes it truly innovative compared to existing solutions?

Our invention overcomes these limitations because it enables the selective targeting of conformational variants (particularly PTMs) of specific proteins, making previously undruggable targets accessible. Moreover, the recombinant antibodies we produce are engineered as intrabodies—intracellular antibodies whose functionality is ensured inside the cell (including towards intracellular targets).

It is undoubtedly an innovative solution, especially considering that, at least initially, the antibody is used as a gene and not as a protein. This is tied to the mode of selection of our antibodies, which occurs intracellularly.

• What tangible advantages does this technology offer for the industry, the scientific community or end users?

There are many advantages. Beyond significantly expanding the universe of diagnostic and therapeutic targets in the pharmaceutical space, our SPLINT/PISA libraries allow for the isolation of antibodies directly from gene sequences (from cDNA to antibodies), without the need to express the antigen protein; this in itself is a major benefit. One can certainly say that selecting antibodies directly within yeast cells removes a well-known obstacle to antibody production: the need to produce and purify both the target protein (antigen) and the antibody.

• How do you think this technology could have a social, economic or environmental impact?

In recent years, antibodies—especially monoclonal ones—have become the fastest-growing segment of the pharmaceutical and biotech market. To put it in perspective: in 2024, the therapeutic antibody market was worth over $245 billion, with projections to exceed $685 billion by 2034. In this market space, offering a competitive and unique antibody discovery platform positions us to potentially play a leading role in at least three key areas:

1. The technological platform of libraries and selection procedures can be a valuable economic asset in itself through licensing agreements and industrial collaborations;
2. The availability of an enabling technology for PTM target validation: these pharmacological targets (PTM proteins), which our platform can validate, are currently untapped due to the lack of adequate PTM-targeting validation technologies;
3. Our technology enables new therapeutic approaches, with significant impacts on health, society and the productive system.

• What are the next steps planned to advance the development of this technology?

At present, the technology is functional, robust and attractive to the pharmaceutical industry. However, for the past few years, we have been actively working on upgrading it—to PISA 2.0—to further enhance our ability to select antibodies faster and more effectively, against targets still considered undruggable. The PISA 2.0 selection pipeline, and its corresponding service offering, will also include computational and AI modules for structural antibody and antigen-antibody complex prediction, affinity maturation, further improvements in specificity and selectivity, and the design of libraries enriched in antibodies of interest.

A key element of novelty, innovation and competitiveness in the spinoff lies in the fusion of wet biotech (i.e., hands-on experimental work)—unique at the international level and the result of pioneering efforts that anticipated current market trends by decades—with consolidated know-how in machine learning algorithms and language models applied to structural bioinformatics. For this reason, we plan to position ourselves in the market as a company producing “Intelligent antibodies,” supported by a dual-purpose platform: one wet and one computational, working in synergy to select/design/optimize next-generation antibodies, including therapeutic ones.

• Are there any ongoing collaborations or planned industrial applications?

Since 2021, the team has been engaged in an initial exploratory phase of the spinoff project, engaging in in-depth and repeated discussions with various stakeholders. At least five venture capital investment firms have expressed appreciation for the project and its innovative potential. These exploratory talks—and the feedback we received—helped us refine and better characterize the uniqueness of the technology, integrate the pipeline and finalize the business plan. The current goal is to raise the capital needed to launch operations and automate the pipeline.

• What kind of support or contribution have you received from the Scuola Normale Superiore for this project?

The academic research underlying the invention—namely, the patented PISA technology—was conducted within the Bio@SNS laboratory. The Scuola Normale has therefore primarily supported the academic research through its institutional backing. The Scuola Normale is also the owner of the PISA patent family, so its support has been crucial from the outset, particularly in managing the patents and providing related financial support.

The SNS Research and Technology Transfer Office has always been at the forefront in promoting the valorization of the invention, helping us draft an initial business proposal and supporting our first steps outside the sphere of academic research. As a result, our proposal, in its first version, won first prize in the Start Cup Toscana 2021 and performed very well in the subsequent National Innovation Award. We were also national finalists at Expo Dubai in early 2022, in the Life Sciences sector of the Intellectual Property Award (2021 edition) and in MIT4LS (2022). These events marked the beginning of our interactions with VC investors.