News U1

Protein-only Materials offer a new hope in colorectal cancer treatment

Breakthrough colorectal cancer treatment unveiled by NANBIOSIS Units promises enhanced precision & efficacy in targeted cancer therapies.

March 2024, UAB/Institut de Recerca Sant Pau/CIBER-BBN (Barcelona)

As we leave World Colorectal Cancer Day 2024 behind, marked on March 31st, there have been significant highlights in cancer treatment, a field in which targeted therapies are playing a crucial role.

In this context, researchers from the Nanobiotechnology team, at the Institut de Biotecnologia i de Biomedicina from Universitat Autònoma de Barcelona, led by Prof. Antonio Villaverde, in collaboration with the Oncogenesis and Antitumor Drugs team led by Prof. Ramón Mangues at Institut de Recerca Sant Pau, have made a significant breakthrough in the treatment of colorectal cancer. Their innovative approach, facilitated by their respective Unit 1 and Unit 18 of NANBIOSIS, promises to revolutionize current treatment methodologies and improve patient outcomes.

“In a clinical context, the use of these materials in the treatment of colorectal cancer should greatly improve the drug’s efficacy and patient comfort while minimizing unwanted side effects.”
Prof. Antonio Villaverde, Strategy Director of Unit 1

“It is important to highlight that such accumulation is more effective than when the protein is administered into the bloodstream. This fact offers a new and unexpected way to ensure high local levels of the drug and better clinical efficacy, avoiding repeated intravenous administration regimens,” explains Prof. Villaverde. “In a clinical context, the use of these materials in the treatment of colorectal cancer should greatly improve the drug’s efficacy and patient comfort while minimizing unwanted side effects.”

The team’s groundbreaking research centers around the development of self-contained protein-only materials at the microscale, capable of delivering therapeutic polypeptides in a time-prolonged manner. These materials, resembling the organization of secretory granules within the human endocrine system, are engineered to release functional polypeptide nanoparticles. These nanoparticles can selectively target tumors and destroy specific types of cancer cells, offering a promising avenue for more effective and precise cancer treatment.

The publication:

Notably, the researchers thorougly explored the molecular structure and dynamics of the secretion process of these materials, both in vitro and in vivo. In preclinical trials using an animal model of colorectal cancer, the system demonstrated remarkable efficacy upon subcutaneous administration. This was thanks to the released protein nanoparticles accumulating efficiently in tumor tissues. Importantly, this accumulation was found to be more effective than traditional intravenous administration methods, offering a novel strategy to ensure high local drug levels while minimizing systemic side effects.

A) Diagram illustrating theprotein administration protocol in a colorectal cancer mouse model. B) Accumulation of fluorescence in the tumour at days 1 and 10 after the administration, in two alternative formats (“IN” and “MPs”). Research product of a collaboration between NANBIOSIS **Unit 1** and **Unit 18**. For more information, check the full publication at Adv. Sci. 2024, 2309427.

Furthermore, several competitive research and technology transfer projects supported this research, as well as intramural CIBER-BBN projects. This further highlights the importance of interdisciplinary collaboration and funding initiatives in driving scientific progress.

The team’s work underscores the importance of continued investment in research and collaboration to tackle the challenges posed by colorectal cancer and other malignancies. As World Colorectal Cancer Day is observed globally, this breakthrough offers hope for a future where innovative treatments pave the way for improved outcomes and enhanced quality of life for cancer patients worldwide.

The successful development of this innovative treatment approach was possible through the collaborative efforts of two NANBIOSIS Units: the Protein Production Platform (Unit 1) and the Nanotoxicology Unit (Unit 18).

References:

[1] J. M. Sánchez, H. López-Laguna, E. Parladé, A. D. Somma, A. L. Livieri, P. Álamo, R. Mangues, U. Unzueta, A. Villaverde, E. Vázquez, Structural Stabilization of Clinically Oriented Oligomeric Proteins During their Transit through Synthetic Secretory Amyloids. Adv. Sci. 2024, 2309427. https://doi.org/10.1002/advs.202309427

About NANBIOSIS:

The goal of NANBIOSIS is to provide comprehensive and integrated advanced solutions for companies and research institutions in biomedical applications. All of this is done through a single-entry point, involving the design and production of biomaterials, nanomaterials, and their nanoconjugates. This includes their characterization from physical-chemical, functional, toxicological, and biological perspectives (preclinical validation).

In order to access our Cutting-Edge Biomedical Solutions, place your request here.

NANBIOSIS has worked with pharmaceutical companies of all sizes in the areas of drug delivery, biomaterials and regenerative medicine. Here are a few of them:

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New immunization research for SARS-CoV-2 with the collaboration of NANBIOSIS

This novel immunization platform, recently published in ACS, triggers potent antivirus response, promising efficient and cost-effective vaccination.

March 2024, UAB/Vall d’Hebron Research Institute/CIBER-BBN (Barcelona)

The battle against infectious diseases demands innovative solutions. The world is especially aware of this fact after facing threats such as the SARS-CoV-2 pandemic. In a very recent publication in ACS Materials Letters, researchers from the Universitat Autònoma de Barcelona (UAB) and Hospital de Sant Pau, both within the CIBER-BBN, have achieved a significant milestone in vaccine development. Their study, conducted in partnership with international teams as well as NANBIOSIS, has introduced a novel immunization approach utilizing synthetic protein secretory granules.

These protein materials, developed by the team and highlighted in the study, exhibit endocrine-like functionalities tailored for the sustained release of protein drugs in oncology. At the microscale, these self-organized, self-contained protein granules undergo a spontaneous disintegration process associated with secretion, releasing their protein building blocks under physiological conditions. This technology, developed in collaboration with NANBIOSIS units, particularly the Protein Production Platform (Unit 1) and Nanotoxicology (Unit 18), holds promise beyond oncology, extending to various biomedical applications.

A promising solution to address not only existing infectious diseases but also future emerging threats.

The ACS publication:

In their work published last February 2024 [1], the researchers explored the potential of these synthetic protein secretory granules as an antigen delivery system for SARS-CoV-2. Thus, by utilizing a recombinant form of the virus’s receptor-binding domain, they investigated its efficacy in inducing neutralizing antibody responses in mice. Notably, the granules were administered without adjuvants, demonstrating their ability to trigger potent antivirus neutralizing responses.

Graphical abstract of the ACS Materials Letters paper, product of a collaboration with NANBIOSIS **Unit 1** and **Unit 18**. ACS Materials Lett. 2024, 6, 3, 954-962.

The implications of this study are profound. Beyond the immediate context of COVID-19, this innovative immunization platform opens doors to more efficient vaccine delivery methods. By reducing dosage, costs, and the complexity of vaccination regimens, it presents a promising solution to address not only existing infectious diseases but also future emerging threats.

The collaborative nature of this research underscores the importance of synergistic partnerships. Alongside local institutions such as CIBER-BBN, ICREA, Institut de Recerca from Hospital Vall d’Hebró, and Hospital de Sant Pau, international collaboration with the University of São Paulo in Brazil has enriched the study’s scope and insights.

Funding for this groundbreaking research was provided by AGAUR through project 2020PANDE00003, and by CIBER-BBN through Intramural Projects NANOSARS and NANOREMOTE. Such support highlights the societal and scientific significance of this endeavor, emphasizing its potential to shape the future of vaccination strategies.

This publication marks a significant step forward in the fight against infectious diseases, showcasing the power of interdisciplinary collaboration and driving us towards a safer, healthier future. One in which NANBIOSIS will certainly contribute with the undisputable expertise of its researchers.

References:

[1] Zinc-Assisted Microscale Granules Made of the SARS-CoV-2 Spike Protein Trigger Neutralizing, Antivirus Antibody Responses. Marianna T. P. Favaro, Patricia Alamo, Nerea Roher, Miguel Chillon, Jara Lascorz, Merce Márquez, José Luis Corchero, Rosa Mendoza, Carlos Martínez-Torró, Neus Ferrer-Miralles, Luis C. S. Ferreira, Ramón Mangues, Esther Vázquez, Eloi Parladé, and Antonio Villaverde. ACS Materials Lett. 2024, 6, 3, 954–962. February 14, 2024 https://doi.org/10.1021/acsmaterialslett.3c01643

About NANBIOSIS:

In order to access our Cutting-Edge Biomedical Solutions, place your request here.

NANBIOSIS has worked with pharmaceutical companies of all sizes in the areas of drug delivery, biomaterials and regenerative medicine. Here are a few of them:

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NANBIOSIS U1_Protein Production Platform expands its facilities at the Autonomous University of Barcelona, strengthening its capabilities.

NANBIOSIS Unit 1 Protein Production Platform (PPP) of CIBER-BBN and UAB, has taken a significant step towards enhancing its service capabilities in the field of recombinant protein production and purification.

Until now, due to space constraints at the Institute of Biotechnology and Biomedicine (IBB), U1’s activities were confined to half of a small laboratory. However, thanks to the ongoing commitment of the center to bolster the PPP’s activities, this unit has gained access to a laboratory, along with an office, exclusively designated for the platform within the IBB premises, creating an optimal environment for the process of protein production and purification.

This initiative has not only solidified the space that PPP occupies within the IBB and the UAB but also signifies a boost for UAB’s internal services, reinforcing its position as an integral part of ICTS NANBIOSIS, thereby strengthening its commitment to research and scientific excellence.

The center, in its steadfast support for PPP’s activities, has prioritized the allocation of this new space over other needs, recognizing the potential and strategic importance of this service for advancing molecular research, not only within the institution but also within the scientific community at large.

The immediate impact of this facility expansion has resulted in the provision of an optimal space to accommodate all FPLC-AKTA purification equipment, essential for providing quality service. Additionally, new equipment has been acquired, notably including the incorporation of a large-sized refrigerator capable of housing a FPLC-AKTA unit. This development represents a qualitative leap, enabling the PPP to optimize processes for purifying thermosensitive proteins.

The new spaces of the PPP are now adjacent to the spaces of the Nanobiotechnology Group (NBT), enhancing the exchange of information and knowledge between both, and facilitating direct access to shared resources, thereby stimulating interaction. The combination of expertise in protein design and purification with specialization in nanobiotechnology opens up a broad horizon for innovation and the development of disruptive solutions in various fields.

In the words of the responsible team, “this expansion represents a significant step forward, allowing NANBIOSIS U1 not only to advance in its current service provision but also to open doors to new improvement opportunities”.

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Good News! Protein Nanoparticles with a New Ligand Select and Destroy Tumor-associated Fibroblasts”

With the participation of two units of NANBIOSIS ICTS and the expertise of the scientists managing these units

The study, fruit of the collaboration between the Nanotechnology group of the Institute of Biotechnology and Biomedicine (IBB-UAB), led by Prof. Antonio Villaverde, and the Oncogenesis and Antitumor Drugs group of the Sant Pau Research Institute, led by Dr. Ramon Mangues, both members of CIBER-BBN, has made significant progress by identifying the natural ligand PDGFD as an effective tool to target protein nanoparticles to tumor-associated fibroblasts that overexpress the PDGFR-β receptor. Given the relevance of the discovery, this technology has been intellectually protected by a patent that is currently being processed (PCT/EP2023/081937).

The research, the details of which have recently been published in the journal Acta Biomaterialia, presents an innovative strategy focused on the development of protein nanoparticles that assemble autonomously and are capable of selectively recognizing and destroying tumor-associated fibroblasts with high levels of PDGFR-β. This cell type plays a fundamental role in the tumor microenvironment, providing mechanical and biological support for tumor growth and progression in various types of cancers.

Taking advantage of their solid experience in the development of tumor-targeting protein nanoparticles and their functional characterization in in vitro and in vivo models of different types of cancer, both groups set out on this occasion to design new nanoparticles targeting tumor-associated fibroblasts with PDGFR-β overexpression. Among the different ligands tested, PDGFD has been selected for its ability to induce selective penetration into target cells both in vitro and in vivo, using a murine model with a subcutaneous tumor. In these experiments, the PDGFD-GFP-H6 fusion protein, formed by the chosen ligand, the green fluorescent protein and a histidine tail with an important role in obtaining nanoparticles, accumulates precisely in tumor tissues, demonstrating its ability from being delivered in tumor.

By replacing GFP with a microbial toxin present in antitumor treatments approved for clinical use, a significant reduction in tumor volume growth is observed, without showing toxic collateral effects in mice. In this way, the PDGFR-β/PDGFD couple has been validated as a versatile tool for the targeted delivery of drugs to the tumor microenvironment. These promising results pave the way for future developments in nanomedicine and offer new hope in the search for more effective and less invasive treatments for cancer patients.

The research has been performed with the collaborative participation of two units of the ICTS “NANBIOSIS”, more specifically the units U1 of Protein Production Platform, PPP and U18, Nanotoxicology Unit, and is framed in the context of the intramural collaboration of the CIBER-BBN “FIBOLISM”, coordinated by Dr Lorena Alba Castellon.

Referenced article

Eric Voltà-Durán•, Lorena Alba-Castellón• , Naroa Serna, Isolda Casanova, Hèctor López-Laguna, Alberto Gallardo, Alejandro Sánchez-Chardi, Antonio Villaverde, Ugutz Unzueta, Esther Vázquez, Ramón Mangues*. High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles. Acta Biomaterialia 170 543-555 (2023) https://doi.org/10.1016/j.actbio.2023.09.001

• Equal contribution

*Corresponding authors

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NANBIOSIS U1 PPP invited to PEGS, the Protein & Antibody Engineering Summit

*Image explained by Merce Márquez Martínez, Coordinator of NANBIOSIS U1

The NBT group and Unit 1 of NANBIOSIS (Protein Production Platform, PPP), from CIBER-BBN and IBB-UAB, participated in the 15^th PEGS Europe conference held in Lisbon from November 14^th to 16^th. PEGS, or the Protein & Antibody Engineering Summit, is a prestigious conference, organized by the Cambridge Healthtech Institute (CHI), focusing on protein engineering and its applications in drug discovery, development, and delivery. This conference serves as a valuable platform for knowledge exchange among researchers, scientists, industry experts, and professionals in the field of protein science.

From left to right, Julieta María Sanchez, Merce Márquez, José Luis Corchero and Eloi Parlade

The conference typically includes workshops, seminars, keynote presentations, panel discussions, poster sessions, and exhibitions. These elements allow participants to delve into various aspects of protein engineering, covering topics such as novel technologies, therapeutic targets, biologics development, and innovative strategies for protein design and optimization. PEGS fosters networking, collaboration, and learning in the dynamic field of protein engineering.

The meeting featured parallel sessions covering various thematic areas like engineering, targets, bispecifics, immunotherapy, analytical methods, expression, machine learning, and training seminars. Notably, this year’s focus was on the application of antibodies as treatment platforms, particularly in oncology. Artificial intelligence topic, however, had a significant presence at the conference as a tool for the prediction of protein structures, understanding their functions, and accelerating drug discovery processes. Algorithms were discussed for analyzing extensive biological data to model protein behavior, predict protein folding patterns, identify potential drug targets, and design novel proteins with specific functions. Additionally, tools aiding in protein engineering, optimizing production methods, and facilitating the development of personalized medicine by analyzing individual variations in protein interactions were highlighted.

The NBT group, and PPP from NANBIOSIS, was the only Spanish research group invited to have an active participation in the meeting. Specifically, the group contributed invited oral presentations in the tracks of “cell line and systems engineering”, “Optimizing expression platforms” and “Protein process development”. These oral presentations, along with a poster, focused on presenting the latest results of the group in the field of microparticles as protein-only based platforms for drug delivery and optimizing the production of recombinant proteins in mammalian cells.

In addition, the Technical Coordinator of the NANBIOSIS’s Unit 1 (PPP) was invited as a chairperson to moderate and lead the session titled: “Overcoming expression and production challenges for unique proteins”.

In this setting, connections were established with researchers who share an interest in our work, and there is an anticipation of forging new collaborations.

The upcoming PEGS conference scheduled for 2024 will be held in Barcelona, and the group looks forward to showcasing their latest findings once more.

*Image: Representation by AI of Artificial Microparticles: Robot generating microparticles with embedded DNA fragments. These particles on micro scale are mainly composed by proteins that self-assemble into these larger structures when cations are added. These particles are able to slowly disintegrate into the constitutive proteins, functioning as an effective platform for drug delivery in several medical applications. Specifically designed as carriers, they provide a sustained and continuous release of protein-based drugs over several days, ensuring controlled and gradual administration for therapeutic purposes.

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Impactful research with NANBIOSIS participation in the Poster Tour of CIBER-BBN & CIBEREHD Annual Conference.

2023 CIBER-BBN Annual meeting has taken place at Santemar Hotel, in Santander during November 6-7. This year the format of our annual conferences has been changed towards a collective event scheme between the CIBER-BBN and CIBEREHD thematic areas.

On Monday 6 the scientific sessions werecommon for EHD and BBN, with appealing contents for the mixed audience.

On Tuesday 7 EHD and BBN sessions will specific for each area in separate rooms (with common coffee break).

Posters of both areas were on display in the exhibit hall throughout the entirety of the Annual Meeting.

Moreover, at the “Posters & beers” session (Monday 6th: 6:00 p.m. – 7:00 p.m.) poster tours were organized where attendees could cast their vote for the best poster and use this one-on-one time with presenters to learn more, ask juicy questions and discuss their work. At 8:00 p.m., the awards ceremony took place for the best oral communication and best poster by young authors – for each area.

It was an impactful information sessions on research carried out by the groups of CIBER-BBN and CIBEREHD thematic areas.

The poster session is always a popular feature at CIBER-BBN Annual Meeting for acknowledgment NANBIOSIS units’ participation in the research carried out during the year. These are the works presented in 2023:

Targeted nanotoxin for the selective depletion of CXCR4+ cancer cells and immune cell recruitment in a colorectal cancer mouse model. Luis Miguel Carrasco-Díaz, Naroa Serna, Eric Voltà-Durán, Ugutz Unzueta, Esther Vázquez, Antonio Villaverde, Patricia Álamo, Lorena Alba-Castellón, Ramón Mangues. With participation of NANBIOSIS Units U1 Protein Production Platform (PPP) and U18 Nanotoxicology Unit . (Contact:
luismiguelcarrascodiaz@gmail.com)

Improvement of the biodistribution of GLA enzyme by RGD-functionalized nanoGLA in a Fabry mouse model.
Zamira Vanessa Diaz Riascos, Marc Moltó Abad, Daniel Marijuan, Belen García Prats, Judit Tomsen Melero, Elisabet González Mira, Jose Luis Corchero, Andreu Soldevila, Miriam Royo, Alba Córdoba, Nora Ventosa, Guillem Pintos Morell, Simo Schwartz , Ibane Abasolo. With participation of the NANBIOSIS units U20 FVPR-In Vivo Experimental Platform, U3 Synthesis of Peptides Unit and U6 Biomaterial Processing and Nanostructuring Unit. (Contact:
vanessa.diaz@vhir.org)

An auristatin-based nanoconjugate induces apoptosis and inhibits the bone marrow leukemia burden in an acute myeloid leukemia mouse model. Annabel Garcia-León, Julián I. Mendoza, Ariana Rueda, Luis Carlos Navas, Vanessa Huaca, Ugutz Unzueta, Jorge Sierra, Esther Vázquez, Antonio Villaverde, Ramon Mangues, Isolda Casanova. With participation of NANBIOSIS Units U1 Protein Production Platform (PPP) and U18 Nanotoxicology Unit. (Contact: agarciale@santpau.cat)

FVPR/U20-NANBIOSIS Service Platform: from the Synthesis and Characterization of Nanotechnology-based Therapies, to the in vitro and in vivo Preclinical Validation. Diana Rafael, Zamira V. Diaz Riascos, Belén García, Alejandra Palacios, Sandra Mancilla, Laura Garcia, Ibane Abasolo. Description of NANBIOSIS Unit 20 FVPR-In Vivo Experimental Platform. (Contact: diana.fernandes_de_so@vhir.org)

Non-Viral Vector Development for Gene Therapy in the Treatment of Congenital Liver Metabolic Diseases Lucía Enríquez Rodríguez, Isabel Carbonell Simón, Idoia Gallego Garrido, Virginia Nieto Romero, Iván Maldonado Pérez, Aida Garcia Torralba, Gustavo Puras Ochoa, Miruna Giurgiu, Jose Carlos Segovia Sanz, María García Bravo, Oscar Quintana Bustamante, José Luis Pedraz Muñoz. With participation of NANBIOSIS U10 Drug Formulation unit. (Contact: lucia.enriquez@ehu.eus)

X-ray Photoelectron Spectroscopy (XPS) Analysis of Nitrogen Environment in Small Extracellular Vesicle Membranes: A Potential Novel Technique with Application for Cancer Screening.
Ana Martín-Pardillos, María Sancho-Albero , Silvia Irusta , Víctor Sebastián , Vicente Luis Cebolla , Roberto Pazo-Cid , Pilar Martín-Duque , Jesús Santamaría. With participation of NANBIOSIS U9 Synthesis of Nanoparticles Unit. (Contact: a.martin_pardillos@unizar.es)

Nanoparticle-based approach for blood-brain-barrier crossing and glioblastoma treatment. Júlia German-Cortés, Raquel Herrero, Diana Rafael, Ibane Abasolo, Fernanda Andrade. With participation of NANBIOSIS Unit 20 FVPR-In Vivo Experimental Platform. (Contact: fernanda.silva@vhir.org)

Exploiting mammalian cells for recombinant protein production: an improved protocol for transient gene expression. Aida Carreño Fibla, Roger Fernández Palomeras, José Luis Barra, Rosa Mendoza Moreno, Mercedes Márquez Martínez, Neus Ferrer-Miralles, Antonio Villaverde Corrales, José Luis Corchero Nieto. With participation of NANBIOSIS Units U1 Protein Production Platform (PPP). (Contact:jlcorchero@ciber-bbn.es)

Surface characterization of a PLA/Qr/Mg biocomposite after in vitro degradation in m-SBF. Juan Manuel Casares-López, Margarita Hierro-Oliva, Verónica Luque-Agudo, Amparo M. Gallardo-Moreno, María Luisa González-Martín. With participation of Unit 16 Surface Characterization and Calorimetry Unit (Contact: mlglez@unex.es)

The poster session was an effective forum for the exchange of information and a means to communicate ideas

NANBIOSIS U1 at UAB Innovation Fair

On October 17, 2023, the NANBIOSIS U1 of Protein Production Platform PPP, took part in the UAB Innovation Fair, where various research groups, spin-offs, service providers, research centers, and companies gathered to foster networking opportunities.

This event proved highly advantageous for the PPP, as it not only facilitated the identification of potential new clients but also paved the way for collaborative efforts aimed at enhancing and refining the final product offered by the PPP.

In the picture PPP NANBIOSIS U1 Scientists at PPP stand at the Fair: Neus Ferrer, Scientific Director; Rosa Mendoza, Laboratory Manager, and Mercedes Marquez, Scientific Coordinator. — PPP NANBIOSIS U1 Scientists at PPP stand at the Fair: **Neus Ferrer, Scientific Director; Rosa Mendoza, Laboratory Manager, and Mercedes Marquez, Scientific Coordinator**.

The UAB Innovation Fair is a day for relations between the world of research and the business environment that aims to recognize the transfer of knowledge from research groups and show the wide range of technologies, services, innovative ideas and entrepreneurial projects generated on the UAB campus.

Its inauguration was in charge of Montserrat López Merlos, president of the Social Counsel Academic Commision, Lluis Juncà, director general director of Innovation of the Generalitat de Catalunya, Javier Lafuente, rector of the UAB.

The inauguration was followed by an inspirational talk on Innovation, trends and challenges by Jordi Puigneró, mayor deputy of Institutional Relations, Good Government and Digital City of Sant Cugat del Vallès City Council.

Ater a fruitful matchmaking session between research groups and startups and companies, a round table took place with biopharmaceutical companies “Company-University Collaboration, model for excellence” was organiced with the participation of:

Ignasi Belda, CEO of MiWEndo Solutions
Ferran Briansó, Innovation Projects Manager at Roche Diagnostics
Fabiana d’Aniello, R&D Director at Ferrer
Joaquim Mallorquí, Bioterapeutics R&D Director at Hipra
Montse Monsalvatje, Processes Deevelopment Director at Esteve
Moderador: Dani Cordero, Economy Manager of El País Catalunya

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Nanoligent raised €2.8 M and completed Seed round financing with support of i&i Biotech Fund

September 27th 2022 – Nanoligent SL, a Spanish biotech company specialized in the development of cancer treatments based on unique protein conjugates, today announces the completion of a Seed financing round of total € 2.8 M. The final closing of the Seed round consists of € 1 M investment by i&i Biotech Fund I (i&i Bio), an early-stage Life Science fund with teams in Luxemburg and Prague which is backed by the European Investment Fund. i&i Bio joined previous Nanoligent investors, Italian Angels for Growth, the largest network of business angels in Italy, and AVANTECA Partners, a Swiss privately held asset management firm.
Jaromir Zahrádka, Managing partner of i&i Bio, said: “Nanoligent is the fifth investment of our fund and it belongs to a group of targeted oncology therapies in our portfolio. We are excited by deep scientific background and uniqueness of the technology. The platform is developed by highly motivated, experienced, and fully engaged team of scientists and managers. Based on obtained scientific data, the project has a great potential to become an effective treatment for multiple metastatic-cancer types.”
Nanoligent is focused on the development of new drugs for the treatment of more than 20 different metastatic cancer types. The lead molecule is based on the targeted elimination of cancer cells overexpressing the CXCR4 receptor, a recognized biomarker for poor prognosis and therapy resistance. Nanoligent is developing a new proprietary nano-technological platform, with the potential to overcome current limitations of Antibody-Drug-Conjugates.
“Less than a third of newly diagnosed metastatic patients respond to current therapies, making metastasis one of the most pressing unsolved challenges in cancer. With the support of i&i Bio together with our existing investors, we secure our current milestone to provide the first drug candidate of our portfolio of metastasis-targeted therapies” said Montserrat Cano, CEO of Nanoligent.
The seed round financing will allow Nanoligent to foster the development of multiple drug candidates and advance the pre-clinical development of its lead candidate in a variety of tumor types.
“We are happy to welcome the i&i Biotech Fund I in Nanoligent. As in previous cases, we have been impressed by the depth of their scientific due diligence and the professionality of their management. They are going to be an important partner for Nanoligent and we are delighted to continue to co-invest with i&i Bio,” said Michele Marzola who, together with Alessandro Toniolo, are co-champions from IAG in this investment.
Two of the investors already joined the Nanoligent’s Board which includes: Michele Marzola (IAG), Michael Milos (Avanteca Partners), Manuel Rodríguez (Chairman) and Montserrat Cano (CEO).
“The i&i Biotech Fund I is the right partner for the further development of Nanoligent. They have shown in depth scientific knowledge as well as being well connected within the pharmaceutical network. We all together are looking forward to bringing Nanoligent’s development plan effectively to the next stages,” said Michael Milos from AVANTECA Partners.

About Nanoligent
Nanoligent was founded in 2017 by co-founder and Chairman Manuel Rodriguez Mariscal, as a spin-off coming from more than 10 years of fruitful collaboration between the Nanobiotechnology group – NANBIOSIS U1 PPP at the Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, co-lead by full professor Antonio Villaverde and Principal Investigator Esther Vázquez, and the Oncogenesis and Antitumor Drug Group – NANBIOSIS U18 Nanotoxicology Unit at the Biomedical Research Institut Sant Pau of the Hospital de la Santa Creu i Sant Pau, headed by full professor Ramon Mangues, the three of them also co-founders of the company. Montserrat Cano joined the company in 2020, with more than 15 years of experience in pharma and biotech companies. The aim of the company is to develop a pioneering technological platform based on protein-drug nanoconjugates to target metastasis across several tumor types. www.nanoligent.com

About Italian Angels for Growth
IAG, founded in 2007, is a leader in the Italian seed venture capital: more than 270 protagonists of the entrepreneurial, financial and industrial world that invest time, skills and capital for the growth of innovative startups. Italian Angels for Growth, in more than ten years of activity, has analyzed more than 6,500 startups and its members have made over 100 investments, for a total of over 300 million euros invested by IAG members and co-investors. IAG business angels support innovative projects financially by investing their own capital, but at the same time, thanks to the mix of skills of the members, support the founders of the startups in the definition of the business model in all its aspects. www.italianangels.net

About AVANTECA Partners
AVANTECA Partners is a Swiss-based, privately held asset management company that invests in early-stage life science companies. www.avanteca.com

About i&i Bio
i&i Bio is a Luxembourg-based venture capital firm that invests in innovative European Life Sciences companies focused on drug discoveries, medical devices, diagnostics, and digital health. The Fund was created thanks to the cooperation of the biotech incubator i&i Prague and the European Investment Fund (see below). With over €45M under management, i&i Bio plans to invest in about 20 early-stage companies. i&i Bio is led by an experienced team of professionals with backgrounds in private equity, healthcare and venture capital supporting entrepreneurs on their journey to global success. Thanks to the close cooperation with the fund’s sponsor, the biotech academic incubator i&i Prague, i&i Bio is supporting and advancing transformative Central European technology companies. www.inibio.eu

About European Investment Fund
i&i Bio is supported by an investment from the EIF, with the support of:

lnnovFin Equity, with the financial backing of the European Union under Horizon 2020 Financial Instruments and the European Fund for Strategic Investments (EFSI) set up under the Investment Plan for Europe. The purpose of EFSI is to help support financing and implementing productive investments in the European Union and to ensure increased access to financing; and
the Pan-European Guarantee Fund (EGF), implemented by the EIF with the financial support of the Participating Member States. The objective of EGF is to respond to the economic impact of the COVID-19 pandemic by ensuring that companies in the Participating Member States have sufficient short-term liquidity available to weather the crisis and are able to continue their growth and development in the medium to long-term.Nanoligent SL – B66970088

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Two NANBIOSIS Units of CIBER-BBN at UAB, one of the 300 best universities in the world, according the Shanghai Ranking

The Academic Ranking of World Universities (ARWU), known as Shanghai Ranking, which was made public on August 15, places the Autonomous University of Barcelona among the elite of the 300 best universities in the world.

This indicator organizes up to 20,000 university centers worldwide,
based on transparent methodology and objective third-party data. ARWU is regarded as one of the three most influential and widely observed university rankings

Two of NANBIOSIS Units created by UAB and CIBER-BBN are part of this university:

U1 Protein Production Platform (PPP), led by Toni Villaverde, Neus Ferrer and Mercedes Marquez, offer an “tailored” service for the design, production and purification of recombinant proteins using both prokaryotic and eukaryotic expression systems

U25 NMR: Biomedical Applications I, led by Carles Arús and Ana Paula Candiota, with a recognized research track record in the use of NMR as a tool for biomedical applications, and more especifically to identify biomarkers of different pathologies, the main objective of this unit is the acquisition, processing and/or interpretation of Nuclear Magnetic Resonance data

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How engineered protein helps Nanomedicine againts Cancer

The use of protein nanoparticles as biomaterials have been rising in recent years due to their characteristics: high biocompatibility, structural versatility, biodegradability and plasticity of design. We can later incorporate peptide ligands for specific targeting as fusion proteins and use these nanoparticles for targeted nanomedicine.

However, not all proteins can be used as scaffolds for targeted drug delivery, as they need to meet certain criteria. First, it is crucial that the proteins used as a scaffold allow site-specific drug conjugation. The stability and proteolysis resistance of these proteins is also important to remain assembled during the bloodstream circulation. In addition, the scaffolds must be biologically neutral, meaning that they should not interact with other human proteins that interfere with their capacity to reach and specifically deliver their cargo. The lack of immunogenicity of these proteins is also desired to avoid immune system recognition. And, ideally, the proteins used as a scaffold should not have post-translational modifications to ensure that they fold equally in both prokaryotic and eukaryotic cell factories for production.

The scaffolds that have all these properties have a better chance to both achieve a proper biodistribution and to successfully deliver their cargo molecules into the target cells. The Green Fluorescent Protein (GFP) satisfy most of the desired characteristics for a scaffold. Moreover, its intrinsic fluorescence allows the tracking of the protein distribution and intracellular localization both in vitro and in vivo.

The use of GFP as a protein scaffold for targeted drug delivery has been extensively studied in our group. We have been able to deliver cytotoxic drugs through our patented platform for targeted delivery. This platform consists of a cationic peptide ligand (T22) and a hexa-histidine peptide that act as self-assembling tags. T22 is a CXCR4 ligand that enables a targeted delivery to CXCR4⁺ cells, a receptor that is overexpressed in metastatic cancer cells. We have demonstrated previously in an in vivo model that more than the 85% of the administered product was accumulated in the tumor and that we could efficiently conjugate Floxuridine (a genotoxic antimetabolite) to our T22-GFP-H6 nanoparticles, resulting in a strong anti-metastatic activity.

Despite these very promising results, GFP is an exogenous protein from Aequorea victoria and, consequently, triggers an immune response, which limits its clinical use. Thus, we needed to find a human protein that matches the exceptional properties of GFP as a protein scaffold. Fortunately, a non-fluorescent GFP-like protein has been described in humans and it corresponds to one of the three globular domains of Nidogen, a structural protein that binds to collagen IV, laminin and perlecan with high affinity. The globular domain G2 has a beta-barrel structure with a central alpha-helix that folds very similarly to the GFP, despite that these proteins share very low sequence identity. Notably, this domain does not have post-translational modifications that could interfere with its production and folding in prokaryotic cells.

However, perlecan and collagen IV binding sites have been reported within this G2 domain. Therefore, we needed to selectively mutate these binding sites in order to assure the biological neutrality of the nanoparticles. After a thorough structural analysis, we incorporated four different mutations to engineer a biologically neutral product that was named HSNBT. There were no differences detected between the wild-type G2 domain and the engineered HSNBT protein regarding the predicted structural epitopes, which suggested that the introduced mutations would not generate immunogenicity.

In order to validate the new scaffold, we used the above-mentioned patented platform with T22 and the hexa-histidine tag, replacing GFP for the new HSNBT scaffold. First, we characterized the resulting nanoparticles and we determined, both by Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM), that they had a size of around 10 nanometers. Then, we observed that the T22-HSNBT-H6 nanoparticles were internalized effectively by CXCR4⁺ cells. This specificity was corroborated when we used a CXCR4 antagonist (AMD) and we saw a notable decrease of their internalization. Then, we successfully conjugated floxuridine to the nanoparticles (T22-HSNBT-H6-FdU) through the free lysine-amino groups of the protein and we demonstrated that the nanoconjugates had a potent cytotoxic effect in CXCR4⁺ cells.

Once we have validated these nanoconjugates in vitro, we tested them in a colorectal cancer mouse model. Notably, we saw an important tumor growth inhibition after several doses of these nanoconjugates. The inhibitory effect was slightly higher when using the new scaffold than with GFP. We also saw a significant increase in cell death bodies and caspase-3 activation in the tumor after the treatment with the nanoconjugates. Again, the effect was more potent with HSNBT as a scaffold than with GFP. Remarkably, the treatment did not result in any histological toxicity and there were no differences between the weight of the treated mice when compared to the untreated mice.

This technology is protected by 3 patents: The ligand to enter CXCR4+ cells (WO2012/095527), the nanoconjugates (EP17382461.6) and the human scaffold protein HSNBT, (EP19383201), all three licensed to Nanoligent SL.

All in all, these results confirm that the G2 domain of nidogen can be used as a protein scaffold for targeted drug delivery. Its performance both in vitro and in vivo not only matches the observed with GFP, but it is even more efficient than GFP when conjugated with floxuridine. Therefore, the engineered HSNBT protein shows a very exciting potential to be used in the development of protein-based nanomedicines.

By Carlos Martínez Torró (NANBIOSIS U1 PPP)

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