Compositions and methods for targeted therapeutic delivery to bone
Inventors
Alvarez, Luis • Stewart, David • Park, Hyeon • HEIL, Todd
Assignees
Publication Number
US-12264187-B2
Publication Date
2025-04-01
Expiration Date
2041-04-14
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Abstract
Provided herein are polypeptides comprising a therapeutic targeted for delivery to an organ or tissue, and uses thereof.
Core Innovation
The invention is based on the creation of polypeptide compositions comprising a targeting polypeptide connected to a therapeutic polypeptide for targeted delivery to specific tissues, such as bone. The targeting polypeptide is designed to bind to materials like calcium phosphate on implantable devices, enabling local retention of therapeutic agents at sites where tissue regeneration is needed. The therapeutic polypeptide typically comprises sequences with osteogenic activity, such as bone morphogenetic proteins (BMPs) or related growth factors.
This invention addresses the problem of poor healing in critical-sized bone defects and insufficient tissue regeneration on orthopedic substrates. Current treatments like bone grafting carry limitations such as donor site pain, risk of rejection, limited supply, and infection risk, while implanted substrates often fail due to loss or scarcity of progenitor cells and poor facilitation of regeneration. The compositions described aim to overcome these limitations by sustaining progenitor cells at the injury site via targeted therapeutic delivery.
Examples of the invention include polypeptide compositions in which a targeting polypeptide comprising a sequence at least 95% identical to SEQ ID NO: 22 is connected to a therapeutic polypeptide comprising sequences with high identity to known osteogenic proteins (e.g., SEQ ID NOs: 32, 55, 58, 59, 60, 61, 62, 64, 65 or 71), with the targeting polypeptide providing binding to calcium phosphate. These modular constructs allow improved and localized delivery of osteoinductive agents, facilitating applications in bone and cartilage repair and regeneration.
Claims Coverage
The patent contains three independent claims, each defining a distinct inventive feature regarding the structure and function of polypeptide compositions for targeted delivery to bone.
Targeting polypeptide with therapeutic polypeptide for binding calcium phosphate
A polypeptide composition comprising: - A targeting polypeptide with a sequence at least 95% identical to SEQ ID NO: 22 (LLADTTHHRPWT VIGESTHHRPWS IIGESSHHKPFT GLGDTTHHRPWG ILAESTHHKPWT), - Connected to a therapeutic polypeptide with a sequence at least 95% identical to selected osteogenic sequences (SEQ ID NOs: 32, 55, 58, 59, 60, 61, 62, 64, 65, or 71), - Where the targeting polypeptide binds to calcium phosphate. This composition enables targeted delivery of therapeutic agents to bone or other calcium phosphate-containing substrates.
Targeting polypeptide with therapeutic polypeptide SEQ ID NOs: 46, 47, 48, 49, 50, 53, 54 or 75 for binding calcium phosphate
A polypeptide composition comprising: - A targeting polypeptide comprising a sequence at least 95% identical to SEQ ID NO: 22, - Connected to a therapeutic polypeptide comprising a sequence at least 95% identical to SEQ ID NOs: 46, 47, 48, 49, 50, 53, 54, or 75, - Where the targeting polypeptide binds to calcium phosphate. This broadens the therapeutic polypeptides to additional growth factors while preserving targeted delivery.
Targeting polypeptide with therapeutic polypeptide SEQ ID NOs: 82-100 for binding calcium phosphate
A polypeptide composition comprising: - A targeting polypeptide comprising a sequence at least 95% identical to SEQ ID NO: 22, - Connected to a therapeutic polypeptide comprising a sequence at least 95% identical to any of SEQ ID NOs: 82-100, - Where the targeting polypeptide binds to calcium phosphate. This feature allows the application of the targeting/therapeutic paradigm to a wider array of therapeutic proteins.
The claims provide broad and specific coverage for compositions in which a targeting polypeptide directs a therapeutic agent to calcium phosphate substrates, enabling tissue-specific delivery of various osteogenic and regenerative growth factors.
Stated Advantages
The polypeptide compositions can vastly improve bone healing and accelerate tissue regrowth.
The compositions increase and sustain the number of progenitor cells at bone and cartilage injury sites through stem cell capture.
The targeting allows for controlled, localized delivery of therapeutics with potential reduction of off-target effects.
The technology may enable longer persistence of therapeutic agents at the implant site, allowing for lower doses and potentially superior clinical outcomes.
By binding growth factors to resorbable substrates, local concentrations can be maintained over time to induce complete osteoinduction.
Improved bone healing, stronger bone formation, and enhanced angiogenesis were demonstrated in preclinical models compared to current standard treatments.
Documented Applications
Treatment of bone defects, including critical-sized bone defects, via targeted delivery of therapeutic agents to bone using the polypeptide compositions.
Promotion of bone or cartilage formation and regeneration by administering the compositions to a subject in need thereof.
Replacement and/or repair of bone or cartilage, including treatment of bone fracture or bone loss.
Delivery to soft tissue or for localized delivery of a therapeutic, as mentioned for soft tissue repair.
Use in spinal fusion procedures, including posterior lumbar fusion and interbody fusion.
Applications in trauma repair of bone, dental repair, craniomaxillofacial repair, ankle fusion, kyphoplasty, balloon osteoplasty, and scaphoid fracture repair.
Tendeno-osseous repair, treatment of osteoporosis, avascular necrosis, congenital skeletal malformations, and costal reconstruction.
Subchondral bone repair, cartilage repair, and treatment of osteochondral defects.
Application for hair follicle development, due to BMP-2 involvement.
Veterinary applications for mammals including human and non-human animals.
Use as bone void fillers and in orthopedic reconstructions.
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