A scientific race towards patients

In 1993, when he was working on his doctoral thesis at the ‘National University of Córdoba’ (UNC), Gabriel Rabinovich, CONICET researcher and director of the ‘Glycomedicine Laboratory of the Institute of Biology and Experimental Medicine’ (IBYME, CONICET-F-IBYME) identified and purified for the first time a sugar-binding protein that was able to eliminate activated T lymphocytes, cells of the immune system responsible for attacking both pathogens and tumor cells. The molecular and functional characterization of this new protein, which would be known as Galectin -1 (Gal-1), was the subject of his doctoral thesis, directed by Claudia Riera. The antibodies that allowed researchers to identify the previously unknown protein had been developed in the laboratory of Carlos Landa , with whom Rabinovich did his thesis.

Thirty years after that discovery in the province of Córdoba, and after multiple investigations that allowed him to deepen the knowledge about the key role of Gal-1 in the regulation of the immune system in different physiological and pathological scenarios, Rabinovich, who is also full professor of Immunology at the ‘Faculty of Exact and Natural Sciences of the University of Buenos Aires’ (FCEN, UBA), created GALTEC with colleagues from CONICET and professionals from different disciplines. GALTEC is a technology-based company that aims to develop therapeutic products that can modulate Gal-1 activity, increase or block its expression (“turn it on” or “turn it off”) so as to manipulate the functioning of the immune system against different diseases.

Increasing the expression of Gal 1 could be necessary against the development of autoimmune diseases -such as multiple sclerosis, rheumatoid arthritis or diabetes- in which, according to different investigations, a deficiency in this protein could cause deregulation of tolerogenic circuits making the immune system attack functional tissues of the organism itself, with significant damage to the health and quality of life of the patient. Blocking Gal-1, on the other hand, could be necessary against certain cancers, in which it has been proven that the high expression of Gal-1 helps tumors to escape the response of the immune system’s T lymphocytes , as well as to create blood vessels that allow them to supply themselves with nutrients and oxygen to grow and spread.

Rabinovich, who entered the CONICET Scientific and Technological Researcher Career at the beginning of 2022, after a period as a postdoctoral fellow, associates Gal-1 with Dr Jekyll and Mr Hyde, the character in Robert Louis Stevenson’s novel, because according to what the scientist states, “sometimes it plays the role of a villain by helping tumors to evade the immune system’s response, whereas other times that of a heroine, by preventing the appearance of autoimmune diseases”.

Like many researchers, Rabinovich has always wished that his scientific work could help improve the lives of patients. In this sense, the creation of GALTEC is an important step towards that long-held aspiration. However, he always considered that the only way to achieve this goal was to first perform rigorous fundamental research, which would serve as a basis for the development of new therapeutic strategies. On this path, Rabinovich, together with his work teams, has made a long journey that has involved important achievements and numerous scientific publications, many of them in highly recognized journals.

Some achievements in basic research

One of the first important findings regarding the role of Gal-1 in autoimmune diseases was the discovery that the administration of this protein to mice with arthritis could reverse symptoms of the disease by eliminating activated T lymphocytes. This study was published in Experimental Medicine and highlighted in an article in Nature. Rabinovich recalls with emotion how they managed to get mice that could not walk to walk again.

Rabinovich’s hypothesis that if Gal-1 played a beneficial role against the development of autoimmune diseases, by suppressing T lymphocytes that attacked functional tissues, then it should play a detrimental role in cancer, by protecting the tumor from the immune system response, was verified in a job that was the cover of Cancer Cell. “The sweet kiss of death: Galectin-1 and tumor immune escape,” said that cover, referring to the fact that Gal-1 is a sugar-binding protein that helps tumors escape the immune response.

This study, in which Rabinovich was the director, showed that the inhibition of the gene that codes for Gal-1 led to a greater rejection of the immune system towards the tumor by means of T cells. “When Gal-1 was inhibited, a large number of T lymphocytes that attacked and eliminated the tumor appeared”, Rabinovich indicates. Thus, the hypothesis that, by negatively regulating the expression and survival of activated T lymphocytes, Gal-1 could play diverse and opposing roles against different diseases was confirmed. For this work, the researchers performed in vitro and in vivo experiments and used patient samples.

Over the following years, different studies directed by Rabinovich increased the knowledge about the impact that the interaction between Gal-1 and its receptors have on key components of the immune response, such as pathogenic T lymphocytes (Th1 and Th17), dendritic cells and regulatory cells. In turn, this paradigm managed to be demonstrated at the maternal-fetal interface (during pregnancy) and published in Nature Medicine.

In early 2014, Rabinovich and his team published a paper that was nothing less than the cover of Cell, one of the most prestigious international scientific journals. The study, which was made in experimental models, proved that Gal-1, in addition to helping different types of cancers escape the immune response, creates blood vessels (known as angiogenesis) that allow tumors to obtain oxygen and nutrients to grow and metastasize. The work highlighted that this role of Gal-1 could be the reason why certain anti-angiogenic cancer treatments targeting the blockade of the Vascular Endothelial Growth Factor (VEGF) were ineffective. Tests in experimental models also showed that the administration of an anti-Gal-1 monoclonal antibody was able to counteract resistance to VEGF blockade and reduce tumor growth. “This study was very important for us because we managed to reveal a new role for Gal-1 in cancer, in addition to the immunosuppressive role that we already knew about”, indicates the researcher. Marta Toscano, Juan Ilarregui, Diego Croci, Mariana Salatino, Tomás Dalotto Moreno, Natalia Rubinstein and Santiago Méndez Huergo were the protagonists of these works.

Recently, in 2023, the team published a study in Proceedings of the National Academy of Sciences (PNAS) in which they demonstrated the clinical relevance of the work published in Cell. The new research, led by Nadia Bannoud, Juan Stupirski and Alejandro Cagnoni, showed, based on samples from melanoma patients, that Gal-1 can indeed promote angiogenesis upon VEGF blockade. In addition, the team presented a fully human anti-Gal-1 monoclonal antibody that was able to inhibit, in cell models in vitro, Angiogenesis driven by Gal-1-rich plasma from cancer patients treated with a VEGF inhibitor.

At the beginning of 2020, shortly before the start of the pandemic, in a paper published in PNAS, Rabinovich and his team concluded that Gal-1 is a hierarchical regulator of the immune system and functions as an inhibitory check-point that prevents the spontaneous onset of age-related autoimmune diseases. For this study, the researchers allowed Gal-1-deficient mice to age and observed that as these animals aged, they spontaneously developed a phenotype similar to Sjögren’s syndrome, an autoimmune disease characterized by inflammation of the salivary glands. “That mice without Gal-1 developed an autoimmune disease with age allowed us to conclude that Gal-1 has a hierarchical homeostatic role,” says Rabinovich. This research was co-directed by Marta Toscano and Verónica Martínez Allo was its first author. In addition to this work, other laboratory projects, led by Sebastián Maller, Luciano Morosi and Nicolás Pinto, had demonstrated the role of galectins in the regulation of the immune response in different tissues, such as intestinal tissue, adipose tissue and skin.

GALTEC: getting closer to patients

After three decades of basic research that allowed them to determine the importance of Gal-1 in different pathologies, as well as the therapeutic efficacy of blocking or stimulating its expression in models of different diseases, Rabinovich with colleagues and collaborators, decided that it was time to focus on the development of therapeutic strategies. With these goals in mind, among others, GALTEC was formally founded today. In this sense, they have already developed and presented candidates for the inhibition of Gal-1. Although the first anti-Gal-1 monoclonal antibodies used in various investigations were of a murine nature, in the study published in PNAS this year they already used, tested and characterized a human antibody.

“This monoclonal antibody can block Gal-1 and inhibit its angiogenic and immunosuppressive activity, and it has a high degree of specificity that allows it to recognize Gal-1 but not other members of the same family of proteins”, indicates Rabinovich. Two of GALTEC’s co-founders, Juan Manuel Pérez Saez and Pablo Hockl, CONICET researcher and support staff at IBYME respectively, were involved in this development. Alejandro Cagnoni, a CONICET researcher at IBYME and the company’s scientific advisor, was responsible for the functional and biophysical characterization of the neutralizing monoclonal antibody.

The development of a variant of Gal-1 that, when administered, compensates for its deficiency, has been complex -according to the words of specialists-. Nevertheless, the researcher indicates that, thanks to the contribution of experts in chemistry, modeling, and clinical research, such as Cagnoni himself, Santiago Méndez Huergo, Santiago Di Lellay and Karina Mariño, a CONICET researcher and GALTEC advisor, we are on the way to overcoming these problems. These studies have been carried out in collaboration with Argentine renowned scientists Darío Estrin and Julio Caramelo.
“Over three decades, after identifying the presence of Gal-1 in the immune system, we managed to determine many of the functions of this protein in different pathological and physiological scenarios. GALTEC’s main mission is to transform all these discoveries into technologies and products that can impact society and improve people’s lives”, concludes Rabinovich.