A serendipitous discovery in the early 1990s set immunologist Gabriel Rabinovich, now at the Institute of Biology and Experimental Medicine of the National Scientific and Technical Research Council of Argentina, on a lifelong academic journey to study galectins, a family of proteins that binds to glycans and is key to immune cell processes.
Galectins may activate mechanisms that safeguard against autoimmune diseases, yet tumors can hijack such programs to evade immune detection. Their role in shaping immune responses makes these proteins great candidates for drug development. Rabinovich and his team seek to translate their work in the lab into therapies to fight cancer and autoimmune diseases. To achieve this, in August this year, they launched the biotechnology company Galtec.
Rabinovich's greatest wish is for galectins to function as the next glycocheckpoints, acting as regulatory signals that control the nature and magnitude of immune responses. Since these signals depend on the interactions between glycans and lectins, the team plans to modulate this interplay to target tumors that are resistant to classical immunotherapies.
How did you become interested in immunology?
My parents had a pharmacy in a neighborhood of Córdoba, Argentina. From a very young age, this inspired me. I felt that I had to do something for people who had diseases. At that point, I was uncertain whether my path would lead to medicine, pharmacy, or biochemistry, but during my high school years, chemistry captivated me. I ultimately decided to pursue a degree in biochemistry with the idea of eventually joining my parents’ pharmacy business.
However, my encounter with immunology during my undergraduate years reshaped those aspirations. The idea of an immune system that defends us from everything blew my mind. I thought that there was so little known and so much to find out. Upon completing my biochemistry degree in 1993, I decided that I wanted to do something related to immunology.
How did you begin studying galectins?
It all began in 1992 during the final year of my biochemistry degree. I worked as an assistant in a laboratory investigating intercellular communication in the retina. My mentor, Carlos Landa, a biochemist at the National University of Córdoba, proposed that I make polyclonal antibodies that react against different lectins in the chicken retina. I saved some of these antibody samples in the refrigerator at my parents’ house after the project ended. Little did I know that those tubes would set the course for three decades of work.
A few years later while working on my PhD project in neuroimmunology, I was looking for a receptor for a hormone in different immune cell populations, but I encountered challenges in obtaining results. During a moment of crisis, I remembered the antibodies that I had made with Landa. I thought that I could test some of them in the immune cell populations. I discussed the idea with him and my thesis advisor, Clelia Riera, an immunologist at the National University of Córdoba. With their support, I tested the antibodies.
One of the antibodies reacted with a 16-kilodalton protein (1). We didn't know what it was, but we purified and sequenced it. It ended up being a betagalactoside-binding protein in macrophages and monocytes that we now call galectin-1 (Gal-1). The findings opened up a new avenue of research.
At what point did you realize that galectins had clinical relevance?
At that time, we knew that lectins boosted lymphocyte proliferation, but we wondered what purpose they served for monocytes. To delve into this mystery, we exposed lymphocyte cultures to different doses of Gal-1. The next day there was nothing; the lymphocytes died in the presence of this macrophage lectin (2). Other publications also reported that Gal-1 induced lymphocyte cell death (3).
We next started looking for a link between galectins and various pathologies. We first focused on autoimmune diseases, which are characterized by a large number of pathogenic lymphocytes that hyperactivate and harm different tissues. In collaboration with the Kennedy Institute of Rheumatology, we showed that Gal-1 suppresses chronic inflammation through apoptosis of pathogenic T lymphocytes in a mouse model of arthritis. We injected mice with either recombinant Gal-1 or fibroblast cells transfected with a vector to produce high levels of Gal-1. Mice that could not walk walked again (4). It fully demonstrated that Gal-1 eliminated the immune response. I learned a lot from that project.
How did you begin studying galectins in cancer?
Various research teams had reported that some tumor cells express high levels of Gal-1 (5,6). I wondered whether this was an evasion mechanism to eliminate antitumor T lymphocytes. After moving to the University of Buenos Aires for a postdoctoral fellowship, our team tested that hypothesis by looking at patient samples and animal models.
In 2004, we reported the link between Gal-1 and tumor escape in a melanoma model (7). Since then, many researchers worldwide have investigated this phenomenon across various tumor types. Today, it represents an almost universal mechanism in breast, lung, pancreatic, and colorectal cancer.
Additionally, pathologists told us that blocking Gal-1 significantly reduced the number of blood vessels in tumors. So, we came up with the idea that Gal-1 might modulate angiogenesis, that is, it might promote vascularization as well as immunosuppression. Ultimately, we showed that Gal-1’s interaction with sugars plays a critical role in the resistance against antiangiogenic therapy (8).
Our findings led us to the paradigm that we often refer to as the case of Dr. Jekyll and Mr. Hyde. Gal-1 is an immune response suppressor, and this is good for autoimmune diseases, but it’s bad for cancer.
What prompted your transition from basic research to translational clinical applications?
At a certain point, I realized that my goal in life was not just to publish papers. While I took pride in identifying a new paradigm, I felt compelled to design therapeutic strategies. Ten years ago, my colleagues and I sketched out a plan to achieve these goals.
For treating cancer, we resolved to make a neutralizing monoclonal antibody that specifically targets Gal-1 and effectively blocks its function without cross reacting with other family members. That took us a long time because many of the antibodies we designed were limited in efficacy or specificity. After multiple efforts, we came up with a high-quality antibody. Ultimately, we transformed it into a human antibody for potential therapeutic applications.
We also sought to design a Gal-1-based tool for treating autoimmune diseases. The main challenge is Gal-1’s instability, which requires us to use large doses. As a result, we engineered a Gal-1 variant tailored for autoimmune disease therapy.
We then contemplated various routes to transform these into drug products. Among these potential avenues was the prospect of licensing them to a pharmaceutical company. Taking the advice of various colleagues, we created a startup company, which allowed us to provide comprehensive support for our products, enhancing their value and facilitating their maturation. We navigated a long, tedious, and somewhat bureaucratic process, but we finally established Galtec in August of this year.
What are your next challenges?
Our journey has just begun. Our ultimate aspiration is to see these discoveries translated into practical applications for patients.
Our goal at Galtec is to manufacture our products to the highest standards and present them to the most rigorous regulatory authorities in Argentina and globally. This will allow us to ultimately initiate Phase 1 clinical trials for some of our products. We also have other technologies in earlier stages of development that we are committed to nurturing.
Meanwhile, we continue to engage in basic scientific research to delineate the roles of other galectins in different physiological processes. Our overarching approach is always oriented towards a medical perspective. From the inception of any project, our goal is to identify a therapeutic target, while rigorously elucidating the underlying mechanisms of action.
My greatest dream is that when I reach the age of 110, I will be able to say that I contributed to understanding the functions of these mysterious proteins.
This interview was conducted in Spanish. It has been translated, condensed, and edited for clarity.
- Rabinovich, G. et al. Regulated expression of a 16-kd galectin-like protein in activated rat macrophages. J Leukoc Biol 59, 363-70 (1996).
- Rabinovich, G. et al. Activated Rat Macrophages Produce a Galectin-1-Like Protein That Induces Apoptosis of T Cells: Biochemical and Functional Characterization. J Immunol 160, 4831-40 (1998).
- Perillo, N.L. et al. Apoptosis of T cells mediated by galectin-1. Nature 378, 736-9 (1995).
- Rabinovich, G. et al. Recombinant Galectin-1 and Its Genetic Delivery Suppress Collagen-Induced Arthritis via T Cell Apoptosis. J Exp Med 190, 385-98 (1999).
- van den Brûle, F.A. et al. Increased expression of galectin-1 in carcinoma-associated stroma predicts poor outcome in prostate carcinoma patients. J Pathol 193, 80-7 (2001).
- Cindolo, L. et al. Galectin-1 and galectin-3 expression in human bladder transitional-cell carcinomas. Int J Cancer 19, 39-43 (1999).
- Rubinstein, N. et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: A potential mechanism of tumor-immune privilege. Cancer Cell 5, 241-51 (2004).
- Croci, D.O. et al. Glycosylation-Dependent Lectin-Receptor Interactions Preserve Angiogenesis in Anti-VEGF Refractory Tumors. Cell 156, 744-58 (2014).