Production and characterization of rNGFSP: a recombinant fusion immunogen eliciting dual anti-NGF and anti-Substance P therapeutic antibodies for Degenerative Joint Disease.
Abstract: Anti-NGF monoclonal antibodies have recently been approved for treating degenerative joint disease, including osteoarthritis pain, in dogs and cats. However, their widespread use is limited by high cost and the requirement for repeated injections. Nerve Growth Factor and Substance P play central roles in the initiation and maintenance of inflammation and chronic pain in OA. There is a pressing need for new, safe, cost-effective therapies that target the underlying mechanisms of OA chronic pain. Here, we designed and produced a novel recombinant fusion protein, termed rNGFSP, which functions as an immunogen due to its unique molecular structure combining amino acid sequences from NGF and SP in a non-native conformation. When formulated and administered as a vaccine, rNGFSP elicits dual anti-NGF and anti-SP therapeutic antibodies in the host. rNGFSP was produced in and purified from inclusion bodies using metal affinity chromatography under denaturing conditions. Mass spectrometry confirmed the expected molecular weight (17.5 kDa) and preserved amino acid sequence. Structural prediction using Alphafold2 revealed rNGFSP presented a non-natural folding, but a preserved NGF core and a flexible SP tail, supporting antigenic presentation. Vaccination of mice, rabbits, horses, and dogs, showed that rNGFSP elicited cross-reactive IgG antibodies against the native conformations of NGF and SP. Furthermore, immunoglobulins elicited in vaccinated dogs neutralized the biological activity of NGF and SP in cell cultures, suggesting a therapeutic potential. These findings support rNGFSP as a promising vaccine candidate simultaneously targeting endogenous NGF and SP species, providing a cost-effective alternative to monoclonal antibodies.
© 2026 The Authors. Published by Elsevier B.V.
Publication Date: 2026-01-12 PubMed ID: 41608074PubMed Central: PMC12834844DOI: 10.1016/j.btre.2026.e00946Google Scholar: Lookup
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- Journal Article
- Analytical Methods
- Animal Health
- Animal Models
- Antibodies
- Antigen
- Biochemistry
- Biotechnology
- Chronic Obstructive Pulmonary Disease
- Degenerative Joint Disease
- Disease Treatment
- Immunization
- Immunology
- Inflammation
- Laboratory Methods
- Molecular biology
- Monoclonal Antibodies
- Pain Management
- Protein
- Vaccine
- Vaccine development
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
Overview
- This study developed and characterized a novel recombinant fusion protein (rNGFSP) designed as a vaccine to simultaneously induce therapeutic antibodies against Nerve Growth Factor (NGF) and Substance P (SP), two key molecules involved in chronic pain and inflammation in degenerative joint disease (such as osteoarthritis).
- The research demonstrated that rNGFSP elicits dual protective antibody responses and has the potential to serve as a cost-effective and safe alternative to monoclonal antibody therapies currently used to treat osteoarthritis pain in animals.
Background and Motivation
- Degenerative joint disease (DJD), including osteoarthritis (OA), causes chronic pain and inflammation that negatively affect quality of life in both humans and animals.
- Two molecules, Nerve Growth Factor (NGF) and Substance P (SP), are crucial mediators that initiate and maintain the inflammatory processes and chronic pain in OA.
- Monoclonal antibodies targeting NGF have been approved for managing OA pain but are limited by their high cost and need for frequent injections.
- There is a significant need for therapies that are both cost-effective and can target the underlying mechanisms of OA pain, including both NGF and SP pathways.
Design and Production of rNGFSP
- A novel recombinant fusion protein, rNGFSP, was engineered to contain amino acid sequences from both NGF and Substance P linked in a single molecule with a non-native structural conformation.
- This fusion protein was designed to function as an immunogen, meaning it can stimulate the immune system to produce antibodies against both NGF and SP simultaneously.
- rNGFSP was expressed in an unspecified host system and purified from inclusion bodies via metal affinity chromatography under denaturing conditions.
- Mass spectrometry confirmed the molecular weight to be approximately 17.5 kDa and verified the correct amino acid sequence as designed.
Structural Characterization
- Structural predictions were performed using Alphafold2, an advanced AI tool for protein folding prediction.
- The predicted structure revealed that rNGFSP does not fold into a natural conformation but retains:
- A preserved NGF core, which is important to maintain the antigenicity and mimic NGF.
- A flexible SP tail, which likely facilitates immune system recognition of the SP component.
- This non-natural folding supports the fusion protein’s ability to present antigenic sites effectively and elicit an immune response.
Immunogenicity and Functional Testing
- Vaccination with rNGFSP was conducted in multiple species: mice, rabbits, horses, and dogs, demonstrating broad immunogenicity.
- Vaccinated animals produced IgG antibodies that were cross-reactive, meaning these antibodies could recognize and bind to the native (natural) forms of both NGF and Substance P molecules.
- Specific focus was given to dogs as a target species for osteoarthritis therapy: IgG antibodies from vaccinated dogs were shown to neutralize the biological activity of NGF and SP in cell culture assays, indicating functional therapeutic potential.
Implications and Significance
- The study presents rNGFSP as a promising vaccine candidate able to generate dual therapeutic antibody responses targeting two key pain mediators.
- If effective in clinical settings, this vaccine approach could reduce the need for expensive and frequent monoclonal antibody treatments for OA pain.
- This strategy could offer a safer, more accessible, and cost-effective alternative, potentially improving management of chronic joint pain in veterinary medicine and possibly human medicine in the future.
- Future studies would be required to assess long-term safety, efficacy, and optimal vaccination protocols in target species.
Cite This Article
APA
Varela V, Costa M, Maciel C, Barbeito J, Barrera EE, Gutierre E, Correa A, Elgue M, Carrasco S, Larrosa MD, Pereira M, Correa J, Crosignani N, Beckman JS, Barbeito L, Trias E.
(2026).
Production and characterization of rNGFSP: a recombinant fusion immunogen eliciting dual anti-NGF and anti-Substance P therapeutic antibodies for Degenerative Joint Disease.
Biotechnol Rep (Amst), 49, e00946.
https://doi.org/10.1016/j.btre.2026.e00946 Publication
Researcher Affiliations
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Neurodegeneration Lab, Institut Pasteur de Montevideo, Montevideo 11.400, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Neurodegeneration Lab, Institut Pasteur de Montevideo, Montevideo 11.400, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Instituto de Histología y Embriología de Mendoza (IHEM), Universidad Nacional de Cuyo, CONICET, Mendoza, Argentina.
- Unidad de Farmacología, Departamento de Clínicas y Hospital Veterinario, Facultad de Veterinaria, UdelaR, Montevideo 13.000, Uruguay.
- Protein Engineering Unit, Institut Pasteur de Montevideo, Montevideo 11.400, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Unidad de Farmacología, Departamento de Clínicas y Hospital Veterinario, Facultad de Veterinaria, UdelaR, Montevideo 13.000, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Unidad de Clínica y Cirugía de Pequeños Animales, Facultad de Veterinaria, UdelaR, Montevideo 13000, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Unidad de Farmacología, Departamento de Clínicas y Hospital Veterinario, Facultad de Veterinaria, UdelaR, Montevideo 13.000, Uruguay.
- e-MSion Inc., 2121 NE Jack London Street, Corvallis, OR 97330, United States.
- Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, 97331, United States.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Neurodegeneration Lab, Institut Pasteur de Montevideo, Montevideo 11.400, Uruguay.
- Xeptiva Therapeutics, Montevideo 11.300, Uruguay.
- Neurodegeneration Lab, Institut Pasteur de Montevideo, Montevideo 11.400, Uruguay.
Conflict of Interest Statement
Valentina Varela, Josefina Correa, Luis Barbeito, and Emiliano Trias are co-founders and shareholders of Xeptiva Therapeutics. Valentina Varela, Luis Barbeito, and Emiliano Trias are inventors of one patent related to the technology described herein. International Patent Application No. PCT/IB2023/050517. Valentina Varela, Monique Costa, Cecilia Maciel, Melania Elgue, Magdalena Domínguez, María Pereira, and Luis Barbeito are or have been employees of, or have received compensation from, Xeptiva Therapeutics at some point during the conduct of the studies presented in this work. Agustín Correa was employed by the Institut Pasteur de Montevideo during the course of this study. He is currently a co-founder of the biotechnology startup Scaffold Biotech. Nadia Crosignani, Erica Gutierre, and Sebastián Carrasco are employees of the Facultad de Veterinaria, Universidad de la República. Joseph Beckman is a shareholder of Xeptiva Therapeutics. The work presented here was funded by Xeptiva Therapeutics, which also received grants from the National Agency for Research and Innovation (ANII) of Uruguay.
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