Virus-like particle conjugates for diagnosis and treatment of tumors
Inventors
de los Pinos, Elisabet • Schiller, John Todd • Kines, Rhonda C. • MacDougall, John
Assignees
Aura Biosciences Inc • US Department of Health and Human Services
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Publication Number
US-10117947-B2
Publication Date
2018-11-06
Expiration Date
2034-09-18
Abstract
The present disclosure is directed to methods and compositions for the diagnosis and/or treatment of tumors, such as ocular tumors, using virus-like particles conjugated to photosensitive molecules.
Core Innovation
The invention provides methods and compositions for the diagnosis and/or treatment of tumors, such as ocular tumors, using virus-like particles conjugated to photosensitive molecules. These virus-like particles (VLPs), assembled from capsid proteins (L1 or L1 and L2), are conjugated to photosensitive molecules that can be photoactivated by exposure to light. Upon photoactivation, these molecules absorb photons and produce molecular changes causing cellular toxicity, enabling the selective killing of cancerous tumor cells without damaging healthy cells.
The problem solved involves the limitations of current cancer treatments, especially for ocular cancers such as ocular melanoma and retinoblastoma, which have few effective and non-invasive treatments. Standard therapies like invasive surgery and plaque brachytherapy have significant complications and side effects, including vision loss and radiation-related damage. Moreover, existing photodynamic therapies are limited by poor delivery of photosensitive molecules exclusively to tumor cells and insufficient targeting mechanisms.
This disclosure is based on the unexpected discovery that virus-like particles can be chemically modified to carry high numbers of photosensitive molecules (ranging from about 50 to 1000 or more) without interfering with their specificity for tumor tissue. Conjugation to surface-exposed amino acids via covalent amide bonds allows preservation of binding to heparan sulphate proteoglycans on tumor cells, maintaining targeted delivery. The approach enables multivalent targeting with high payload delivery, enhancing selective tumor cell killing upon light activation and minimizing off-target effects common in antibody-based or conventional photodynamic therapies.
Claims Coverage
The claims include several independent claims focusing on tumor-targeting papilloma virus-like particles conjugated to photosensitive molecules and methods of administering such particles to treat tumors.
Tumor-targeting papilloma virus-like particles with conjugated near infrared phthalocyanine dyes
The particles comprise about 50 to about 500 near infrared phthalocyanine dye molecules conjugated to papilloma virus capsid proteins, where the dyes become toxic or produce a toxic molecule upon light activation.
Use of non-human or modified human papilloma virus capsid proteins with reduced immunogenicity
The papilloma virus capsid proteins can be non-human or modified human papilloma virus L1 capsid proteins that do not cross-react with neutralizing antibodies to HPV 16 or HPV 18, optionally combined with wild-type HPV L2 capsid proteins, resulting in reduced immunogenicity and/or antigenicity relative to wild-type virus-like particles.
Covalent conjugation of photosensitive molecules to capsid proteins via amide bonds
Near infrared phthalocyanine dye molecules are covalently conjugated to capsid proteins, specifically to lysine residues, through covalent amide bonds, preserving binding of the virus-like particles to tumor cell surfaces and to heparan sulphate proteoglycans.
Methods of administering tumor-targeting papilloma virus-like particles to subjects with tumors
Methods involve administering the tumor-targeting papilloma virus-like particles comprising photosensitive molecules that become toxic upon light activation to subjects with tumors, including ocular tumors, using routes such as topical, intraocular, intravitreal, or suprachoroidal administration.
Overall, the claims cover virus-like particles with high conjugation of photosensitive dyes enabling selective photodynamic therapy, using modified papilloma virus capsid proteins to reduce immunogenicity, and methods of administration for treating various tumors, notably ocular tumors, with selective light-activated cytotoxicity.
Stated Advantages
Virus-like particles can deliver a high payload of photosensitive molecules (from about 50 to more than 1000) without losing tumor-targeting specificity or structural stability.
Photosensitive molecule conjugation does not compromise virus-like particle binding to tumor cells or heparan sulphate proteoglycans.
This approach allows selective killing of tumor cells upon light activation while minimizing damage to healthy cells, overcoming limitations of antibody-based delivery.
The method enables targeting of tumors lacking identified tumor-specific receptors, including ocular melanoma and other difficult-to-treat cancers.
Photosensitive virus-like particles provide therapeutic, diagnostic, and prophylactic uses, including imaging and photodynamic therapy.
Documented Applications
Diagnosis and treatment of tumors including ocular tumors such as ocular melanoma, retinoblastoma, and tumors located in various tissues including lung, liver, pancreas, stomach, esophagus, colon, breast, ovary, prostate, brain, kidneys, bladder, head, neck, cervix, larynx, and skin.
Targeted photodynamic therapy employing virus-like particles conjugated with photosensitive molecules for selective tumor cell killing upon light activation.
Use in diagnosis via imaging by administering photosensitive virus-like particles that can be visualized by activating fluorescent or infrared dyes.
Treatment methods include intraocular, intravitreal, suprachoroidal, topical, intravenous, or implantation routes of administration for targeting tumors.
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