Benjamí Oller‐Salvia

Institut Químic de Sarrià

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Meritxell Teixidò

Institute for Research in Biomedicine

Ernest Giralt

Universitat de Barcelona

Jason W. Chin

MRC Laboratory of Molecular Biology

Macarena Sánchez‐Navarro

Institute for Research in Biomedicine

Cristina Díaz‐Perlas

École Polytechnique Fédérale de Lausanne

Maria C. Lucana

Universitat Ramon Llull

Roberta Lucchi

Universitat Ramon Llull

Pol Arranz‐Gibert

Yale University

Roger Prades

Barcelona Biomedical Research Park

Roméo Cecchelli

Université d'Artois

Cooperative Institutions

Universitat de Barcelona

Institute for Research in Biomedicine

Hospital Clínic de Barcelona

Institut Químic de Sarrià

Universitat Ramon Llull

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Institute for Research in Biomedicine

FC Barcelona

MRC Laboratory of Molecular Biology

Medical Research Council

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Frontispiz: Efficient Phage Display with Multiple Distinct Non‐Canonical Amino Acids Using Orthogonal Ribosome‐Mediated Genetic Code Expansion

Angewandte Chemie (2019)

Benjamí Oller‐Salvia Jason W. Chin

Phagen-Display Die effiziente Einführung nichtkanonischer Aminosäuren in Phagen-Display-Proteine wird von J. W. Chin und B. Oller-Salvia in der Zuschrift auf S. 10960 beschrieben.

Genetic Code

Non canonical

10.1002/ange.201983261

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Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

Pharmaceutics (2021)

Maria C. Lucana Yolanda Arruga Emilia Petrachi Albert Roig Roberta Lucchi

Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency.

Proteolysis

Nanocarriers

Cyclic peptide

Peptidomimetic

10.3390/pharmaceutics13122065

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Citations (45)

Site-specific antibody masking enables conditional activation with different stimuli

New Biotechnology (2023)

Roberta Lucchi Maria C. Lucana Montserrat Escobar-Rosales Cristina Díaz‐Perlas Benjamí Oller‐Salvia

Antibody therapeutics show great potential to treat a variety of diseases. Often, the dose that can be safely administered is limited by side effects that arise from the interaction with the target outside the diseased tissue. Conditionally-active antibodies provide an additional layer of selectivity to improve safety. Distinct external stimuli or internal cues enable different control strategies and applications. However, current antibody masking strategies have low transferability across stimuli. Here we propose a versatile approach to conditionally mask antibody derivatives and its application to a single chain variable fragment (scFv) against a receptor expressed on cancer stem cells in several tumours. Our strategy relies on the site-specific conjugation of a polymer to an engineered cysteine residue through a chemically-synthesised linker that can be cleaved in response to the target stimulus. We show that the masking efficiency depends on the conjugation site and the size of the mask. An optimised mask decreases antigen binding by up to 20-fold and affinity can be fully recovered upon activation by exposure to light at 365 nm or by incubation with matrix metalloproteinases overexpressed in solid tumours. This approach opens up the possibility to rapidly engineer antibodies activatable with any internal or external stimulus.

Transferability

Linker

Stimulus (psychology)

10.1016/j.nbt.2023.10.004

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Citations (1)

Rapid and Efficient Generation of Stable Antibody–Drug Conjugates via an Encoded Cyclopropene and an Inverse‐Electron‐Demand Diels–Alder Reaction

Angewandte Chemie International Edition (2018)

Benjamí Oller‐Salvia Gene Kym Jason W. Chin

Abstract Homogeneous antibody–drug conjugates (ADCs), generated by site‐specific toxin linkage, show improved therapeutic indices with respect to traditional ADCs. However, current methods to produce site‐specific conjugates suffer from low protein expression, slow reaction kinetics, and low yields, or are limited to particular conjugation sites. Here we describe high yielding expression systems that efficiently incorporate a cyclopropene derivative of lysine (CypK) into antibodies through genetic‐code expansion. We express trastuzumab bearing CypK and conjugate tetrazine derivatives to the antibody. We show that the dihydropyridazine linkage resulting from the conjugation reaction is stable in serum, and generate an ADC bearing monomethyl auristatin E that selectively kills cells expressing a high level of HER2. Our results demonstrate that CypK is a minimal bioorthogonal handle for the rapid production of stable therapeutic protein conjugates.

Bioorthogonal Chemistry

Conjugate

Cyclopropene

Antibody-drug conjugate

Tetrazine

10.1002/anie.201712370

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Citations (96)

Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction

Journal of Visualized Experiments (2018)

Benjamí Oller‐Salvia

Antibody-drug conjugates (ADCs) used nowadays in clinical practice are mixtures of antibody molecules linked to a varying number of toxins at different positions. Preclinical studies have shown that the therapeutic index of these traditional ADCs can be improved by the site-specific linkage of toxins. However, current approaches to produce homogeneous ADCs have several limitations, such as low protein expression and slow reaction kinetics. In this protocol we describe how to set up an expression system to incorporate a cyclopropene derivative of lysine (CypK) into antibodies using genetic code expansion. This minimal bioorthogonal handle allows rapid conjugation of tetrazine derivatives through an inverse-demand Diels-Alder cycloaddition. The expression system here reported enables the facile production and purification of trastuzumab bearing CypK in each of the heavy chains. We explain how to link the antibody to the toxin monomethyl auristatin E and characterize the immunoconjugate by hydrophobic interaction chromatography and mass spectrometry. Finally, we describe assays to assess the stability in human serum of the dihydropyridazine linkage resulting from the conjugation and to test the selective cytotoxicity of the ADC for breast cancer cells with high levels of HER2 receptor.

Bioorthogonal Chemistry

Conjugate

Immunoconjugate

Antibody-drug conjugate

10.3791/58066-v

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Citations (3)

Development of simplified, photo-active, and TfR1-targeted poly(β-aminoester)-zwitterion nanovehicles for gene delivery across brain endothelium

Maria C. Lucana Shambhavi Pandey Salvador Borrós Benjamí Oller‐Salvia

Although nucleotide-based therapeutics hold promise for a variety of diseases, their clinical application is limited because of low stability and poor bioavailability. Among non-viral gene delivery vectors, poly(β-aminoester)s (pBAEs) stand out because of their low cytotoxicity, high transfection capacity, and adequate biodegradation profile. Oligopeptide end-Modified pBAEs (OM-pBAEs) enable enhanced polynucleotide encapsulation, cellular internalization, and transfection. Despite the outstanding properties of OM-pBAEs as non-viral gene delivery vectors, traditional OM-pBAE formulations have low cell selectivity and require formulation with two or more polymers. In this study, we first develop a simplified OM-pBAE formulation with a single polymer (pBAE-CRHR) and then add a zwitterionic moiety as part of the end-capping process (pBAE-CRHR-Zw). Subsequently, we show that addition of a photo-cleavable moiety enabled selective recovery of transfection capacity. Finally, we functionalize pBAE-CRHR-Zw with BrainBike-4, a bicyclic peptidomimetic binding transferrin receptor 1, and show that the targeted polyplexes display improved capacity to transfect cells with high levels of TfR1 and to transmigrate in a human cell-based model of the BBB.

Zwitterion

10.26434/chemrxiv-2025-wcxb8

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MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

Angewandte Chemie International Edition (2015)

Benjamí Oller‐Salvia Macarena Sánchez‐Navarro Sonia Ciudad Marc Guiu Pol Arranz‐Gibert

Abstract Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.

Peptidomimetic

Neurotoxin

Apamin

10.1002/anie.201508445

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Citations (77)

Inside Cover: MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery (Angew. Chem. Int. Ed. 2/2016)

Angewandte Chemie International Edition (2015)

Benjamí Oller‐Salvia Macarena Sánchez‐Navarro Sonia Ciudad Marc Guiu Pol Arranz‐Gibert

Drug delivery to the brain can be enhanced by using peptides that cross the blood–brain barrier. However, the efficacy of peptides is often limited by their protease lability. In their Communication on page 572 ff., M. Teixidó, E. Giralt et al. develop a cyclic peptidomimetic (the key) derived from bee venom that efficiently transports cargoes into the brain parenchyma of mice and across human endothelial cells. This carrier is protease-resistant and has negligible toxicity and immunogenicity.

Peptidomimetic

Oligopeptide

Parenchyma

Protease inhibitor (pharmacology)

10.1002/anie.201511247

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Citations (2)

Branched BBB-shuttle peptides: chemoselective modification of proteins to enhance blood–brain barrier transport

Chemical Science (2018)

Cristina Díaz‐Perlas Benjamí Oller‐Salvia Macarena Sánchez‐Navarro Meritxell Teixidò Ernest Giralt

The blood-brain barrier (BBB) hampers the delivery of therapeutic proteins into the brain. BBB-shuttle peptides have been conjugated to therapeutic payloads to increase the permeability of these molecules. However, most BBB-shuttles have several limitations, such as a lack of resistance to proteases and low effectiveness in transporting large biomolecules. We have previously reported on the THRre peptide as a protease-resistant BBB-shuttle that is able to increase the transport of fluorophores and quantum dots

10.1039/c8sc02415d

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Citations (46)

Dual system for the central nervous system targeting and blood‐brain barrier transport of a selective prolyl oligopeptidase inhibitor

Biopolymers (2013)

Meritxell Teixidò Esther Zurita Laura Mendieta Benjamí Oller‐Salvia Roger Prades

Less than 2% of all potential neurotherapeutics cross the blood-brain barrier (BBB). Here, we sought to build a construct with the capacity to cross this barrier, to behave as a chemical delivery system, and, once inside the central nervous system, to be transformed and then act as an enzyme inhibitor. With all this in mind, here, we describe the entire process to obtain such a compound, from the initial candidate selection to preparation of the compound library and posterior evaluation and final selection of the most promising candidates in terms of selectivity, serum stability, and BBB-transport.

Oligopeptidase

10.1002/bip.22275

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Citations (9)