NucleoSpace | Dual Breakthroughs in Lipid- and Blood Pressure-Lowering Oligonucleotide Collaborations

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2023-12-21, Pfizer and BioNTech registered a Phase III clinical trial for their COVID-19/flu combination mRNA vaccine on the Clinicaltrials.gov website. The Phase III clinical trial plans to enroll 7,500 participants to explore two combinations, using an already marketed flu vaccine as a control, with an expected completion date of August 2024.

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Recently, RiboBio announced that it has signed a technology licensing agreement with Qilu Pharmaceutical, granting Qilu Pharmaceutical the rights to develop, manufacture, and commercialize the anti-PCSK9 small nucleic acid drug RBD7022 in Greater China (Mainland China, Hong Kong, and Macao).

According to the technology licensing agreement, Qilu Pharmaceutical will obtain the rights for clinical development, manufacturing, and commercialization of RBD7022 within the Greater China region. Ribo Biotech will receive an upfront payment and milestone payments totaling over 700 million RMB, as well as royalty rates in the high double digits.

Among them, RBD7022 is a GalNAc-conjugated siRNA drug independently developed by Ribio Biotech. By inhibiting the expression of PCSK9 protein, it reduces lysosomal degradation of low-density lipoprotein receptors (LDL-R) and lowers LDL-C levels in the blood. It is intended for patients with familial hypercholesterolemia and ASCVD patients whose LDL-C levels remain poorly controlled after statin treatment. Currently, it is undergoing Phase I clinical trials.

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On December 27, 2023, Innovent Bio and SANEGENEBIO announced a strategic collaboration agreement to jointly develop the small nucleic acid (siRNA) candidate drug SGB-3908 targeting Angiotensinogen (AGT) for the treatment of hypertension. Innovent Bio has also obtained the exclusive option for the future development, manufacturing, and commercialization of this drug.

According to the cooperation agreement, the two parties will jointly advance the development of SGB-3908 to a certain stage. Meanwhile, Innovent Bio will obtain an exclusive option and can pay an exercise fee in the future to acquire the exclusive rights for the development, production, and commercialization of SGB-3908 within different global scopes. After Innovent Bio exercises the option, SANEGENEBIO will also be entitled to subsequent R&D milestone payments, sales milestone payments, as well as tiered royalties based on net sales post-commercialization.

Among them, SGB-3908 is currently in the IND application preparation stage. It is an siRNA drug with independent intellectual property rights developed by SANEGENEBIO, based on the company's proprietary small nucleic acid drug development platform LEAD™ (Ligand and Enhancer Assisted Delivery).

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Recently, Catug Biotechnology and PersonGen BioTherapeutics announced the official signing of a strategic cooperation agreement. The two parties will carry out cutting-edge technology cooperation on mRNA-LNP delivery for In vivo CAR-T therapy on a global scale, aiming to significantly reduce the production costs of traditional CAR-T therapies, improve the accessibility of CAR-T therapies, and benefit more patients.

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Recently, a research paper titled "Biomimetic noncationic lipid nanoparticles for mRNA delivery" was published in the Proceedings of the National Academy of Sciences (PNAS) by a team led by Professor Deng Hongzhang from Xidian University.

The article points out that a safe and efficient mRNA delivery system is the key to the success of mRNA drugs. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers in clinical practice. LNPs offer many benefits for mRNA delivery, including simple formulation, modularity, good biocompatibility, and a large mRNA payload capacity. Despite significant progress in LNPs constructed with ionizable cationic lipids, the excessive positive charge of these LNPs often leads to unavoidable adverse events, including high inflammation and cytotoxic effects. Therefore, how to develop disruptive technologies to overcome the cationic nature of conventional LNPs remains a major challenge for achieving safe and effective mRNA delivery.

In the article, Professor Deng Hongzhang's team first demonstrated that strong hydrogen bonds can also form stable complexes with mRNA. Based on this principle, the research team developed non-cationic thiourea lipid nanoparticles (NC-TNP), which compress and package mRNA through strong hydrogen bonding interactions between the thiourea groups of NC-TNP and the phosphate groups of mRNA, abandoning traditional fixation and electrostatic forces. As a novel mRNA delivery system, the preparation technology of NC-TNP is simple, convenient, and reproducible, without the need to consider pH balance, and the inflammatory and cytotoxic side effects it induces are minimal, almost negligible. Additionally, the research team found that NC-TNP can escape the exocytic pathway, thereby inhibiting internalized nanoparticles from re-entering the extracellular environment, a common phenomenon in traditional LNPs. Therefore, the gene transfection efficiency of NC-TNP-encapsulated mRNA is higher than that of traditional LNPs in both in vitro and in vivo experiments. More importantly, compared with traditional LNPs, NC-TNP exhibits spleen-targeting delivery capability with a higher accumulation ratio (spleen/liver). Spleen-targeting NC-TNP carrying mRNA highly expresses mRNA-encoded antigen proteins in the spleen and induces a robust immune response.

In general, the study developed non-cationic thiourea lipid nanoparticles (NC-TNP), which encapsulate mRNA through strong hydrogen bonding interactions between the thiourea groups of NC-TNP and the phosphate groups of mRNA, abandoning the traditional electrostatic interactions of cationic and anionic ions, constructing a non-ionized mRNA delivery system. The preparation technology of NC-TNP is simple, convenient, and reproducible, with negligible inflammatory and cytotoxic side effects, high gene transfection efficiency, and the ability to target spleen delivery to induce immunity for disease treatment.

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