Tricalcium phosphate binding peptides and uses thereof
Inventors
Alvarez, Luis • Griffith, Linda G. • Guerrero, Yadir • Stockdale, Linda • Rivera, Jaime
Assignees
Massachusetts Institute of Technology • United States Department of the Army
Publication Number
US-10329327-B2
Publication Date
2019-06-25
Expiration Date
2031-12-06
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Abstract
The invention is directed to a composition comprising all or a portion of a beta-tricalcium phosphate (β-TCP) bound to all or a portion of a β-TCP binding peptide and methods of use thereof.
Core Innovation
The invention relates to compositions comprising beta-tricalcium phosphate (β-TCP) bound to β-TCP binding peptides, and methods of using these compositions. The β-TCP binding peptides specifically bind to β-TCP, enabling stable surface tethering of proteins or peptides such as epidermal growth factor (EGF) on β-TCP scaffolds. This surface modification extends the bio-functionality of β-TCP and improves clinical performance by allowing presentation of bioactive ligands that promote cellular responses.
The problem addressed is that β-TCP, although widely used clinically for bone repair, has material and physical properties that limit direct chemical surface modification and handling. This restricts the ability to design molecular surface treatments to improve its bio-functionality and clinical outcomes. Thus, there is a need for compositions and methods that permit modifying β-TCP surfaces to tether proteins or peptides to enhance cellular interactions and tissue regeneration.
The invention demonstrates that β-TCP binding peptides discovered via phage display can be engineered and concatenated to bind β-TCP with high affinity, and fused to bioactive proteins such as EGF. Compositions tethering EGF to β-TCP scaffolds promote increased proliferation and survival of mesenchymal stem cells (MSCs) without compromising differentiation. This approach offers a versatile platform to present various ligands on β-TCP surfaces for therapeutic benefit in bone repair and tissue engineering.
Claims Coverage
The patent includes sixteen independent and dependent claims covering compositions and methods related to β-TCP bound to β-TCP binding peptides and β-TCP binding peptides fused to additional proteins or peptides.
High-affinity binding of concatenated β-TCP binding peptides to β-TCP
A composition comprising β-TCP non-covalently bound to a concatenated multimer of two or more β-TCP binding peptides, wherein at least one has the sequence LLADTTHHRPWT (SEQ ID NO: 1) and binds with a Kd of 3.5 μM or lower.
Use of β-TCP scaffolds and composites
The β-TCP is present as a β-TCP scaffold, optionally comprising polylactide-co-glycolide (PLGA) and porogens such as sucrose, with scaffold shapes including cross-shaped implants approximately 5×5×3 mm.
Varied repeats of β-TCP binding peptides
Concatenated multimers comprising two to twenty repeats of β-TCP binding peptides bound to β-TCP.
Variety of β-TCP binding peptide sequences
At least one β-TCP binding peptide comprises one or more of specified sequences including LLADTTHHRPWT (SEQ ID NO: 1) and several others from SEQ ID NOs: 2-22.
Fusion of β-TCP binding peptides to additional peptides or proteins
One or more β-TCP binding peptides are fused to additional peptides or proteins, optionally via a linker, allowing tethering of bioactive molecules to β-TCP.
Fusion to growth factors or cytokines
Fusions include growth factors or cytokines such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), bone morphogenic proteins (BMPs), osteogenic proteins, and collagen binding proteins.
Coiled coil linkers for fusion protein constructs
The linker between β-TCP binding peptides and additional proteins or peptides can be a coiled coil linker, for example, a leucine zipper.
Pharmaceutical compositions including β-TCP binding peptide compositions
Pharmaceutical compositions comprising the β-TCP binding peptide compositions, optionally including mesenchymal stem cells.
The claims cover compositions of β-TCP bound to concatenated β-TCP binding peptides with specified sequences and binding affinities, including scaffolds and composites. They further cover fusion proteins tethering growth factors or peptides to β-TCP via linkers such as coiled coils, and pharmaceutical compositions including these materials for therapeutic applications such as bone repair.
Stated Advantages
Enables stable surface tethering of bioactive proteins such as EGF to β-TCP, extending its bio-functionality.
Promotes increased proliferation and survival of mesenchymal stem cells without compromising differentiation.
Provides an improved method of delivering growth factors in a spatially controlled manner on clinically important β-TCP substrates.
Allows expansion of progenitor cell populations at wound sites, improving bone wound healing outcomes.
Offers exceptionally tight binding and slow release of tethered proteins, enhancing stability and therapeutic efficacy.
Documented Applications
Use in bone repair by administering β-TCP scaffolds bound to β-TCP binding peptides fused to growth factors such as EGF to individuals in need thereof.
Delivery of proteins and peptides tethered to β-TCP scaffolds for therapeutic effect, including administration to wound sites such as bone injuries.
Culturing mesenchymal stem cells on β-TCP scaffolds tethered with β-TCP binding peptide fusion proteins to promote proliferation and differentiation.
Improving survival of MSCs in harsh wound environments by tethering growth factors to β-TCP substrates.
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