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Development and Validation of a Small Single-domain Antibody That Effectively Inhibits Matrix Metalloproteinase 8
Delphine Demeestere1,2, Eline Dejonckheere1,2, Sophie Steeland1,2
1Inflammation Research Center, VIB, Ghent, Belgium.
Abstract:
A detrimental role for matrix metalloproteinase 8 (MMP8) has been identified in several pathological conditions, e.g., lethal hepatitis and the systemic inflammatory response syndrome. Since matrix MMP8-deficient mice are protected in the above-mentioned diseases, specific MMP8 inhibitors could be of clinical value. However, targeting a specific matrix metalloproteinase remains challenging due to the strong structural homology of matrix metalloproteinases, which form a family of 25 members in mammals. Single-domain antibodies, called nanobodies, offer a range of possibilities toward therapy since they are easy to generate, express, produce, and modify, e.g., by linkage to nanobodies directed against other target molecules. Hence, we generated small MMP8-binding nanobodies, and established a proof-of-principle for developing nanobodies that inhibit matrix metalloproteinase activity. Also, we demonstrated for the first time the possibility of expressing nanobodies systemically by in vivo electroporation of the muscle and its relevance as a potential therapy in inflammatory diseases.
Insights
Matrix metalloproteinase 8 (MMP8) contributes to diseases like hepatitis. MMP8 inhibitors, developed using nanobodies, show promise for treating inflammatory conditions by blocking MMP8 activity.
Area of Science:
- Biochemistry
- Immunology
- Therapeutics
Background:
- Matrix metalloproteinase 8 (MMP8) plays a detrimental role in pathological conditions such as lethal hepatitis and systemic inflammatory response syndrome.
- MMP8-deficient mice exhibit protection against these diseases, highlighting the potential clinical value of specific MMP8 inhibitors.
- The structural homology across the 25-member matrix metalloproteinase family presents a challenge for developing targeted inhibitors.
Purpose of the Study:
- To generate and characterize MMP8-binding nanobodies as potential inhibitors of MMP8 activity.
- To establish a proof-of-principle for nanobody-based inhibition of matrix metalloproteinase activity.
- To demonstrate the feasibility of systemic nanobody expression via in vivo muscle electroporation for therapeutic applications in inflammatory diseases.
Main Methods:
- Generation of single-domain antibodies (nanobodies) specifically binding to MMP8.
- Assessment of nanobody-mediated inhibition of MMP8 enzymatic activity.
- In vivo electroporation of muscle to achieve systemic expression of generated nanobodies.
Main Results:
- Successfully generated small MMP8-binding nanobodies.
- Established proof-of-principle for nanobodies inhibiting matrix metalloproteinase activity.
- Demonstrated systemic expression of nanobodies through in vivo muscle electroporation, showing relevance for inflammatory disease therapy.
Conclusions:
- Nanobodies are a viable platform for developing specific inhibitors of matrix metalloproteinase 8 (MMP8).
- In vivo muscle electroporation enables systemic nanobody expression, offering a novel therapeutic strategy.
- This approach holds potential for treating inflammatory diseases where MMP8 plays a detrimental role.
