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-11110181-B2
Publication Date
2021-09-07
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 present disclosure 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, particularly those assembled from papilloma virus capsid proteins L1 and/or L2, are conjugated with photosensitive molecules which, upon light activation, absorb photons leading to molecular changes that cause cellular toxicity. Importantly, conjugation of photosensitive molecules to the capsid proteins does not hinder the virus-like particles' tissue or tumor tropism, allowing selective targeting of tumor cells.
A key problem addressed is the difficulty in treating certain cancers, especially ocular cancers like ocular melanoma and retinoblastoma, which have limited and highly invasive treatment options that frequently cause adverse side effects. Existing cancer treatments often suffer from unsatisfactory selectivity towards tumor cells, leading to damage to healthy tissue, severe complications, and ineffective targeting, especially in tumors lacking identified tumor-specific receptors.
The innovation achieves high delivery capacity of photosensitive molecules to tumor cells by conjugating many photosensitive molecules (from about 10 to about 1000, and in some embodiments 1000) to each virus-like particle, markedly exceeding the capacities of antibody-based targeting methods. The virus-like particles maintain specific binding through interactions with heparan sulphate proteoglycans (HSPGs) on tumor cells, and the photosensitive molecules can be activated by infrared, near-infrared, or ultraviolet light to either visualize tumors or selectively induce tumor cell death without damaging healthy cells.
Claims Coverage
The patent includes two independent claims: one directed to a tumor-targeting virus-like particle composition and one directed to a method of delivering such virus-like particles to a subject. Main inventive features focus on the virus-like particle composition and its method of use.
Tumor-targeting virus-like particle comprising papilloma virus capsid proteins and photosensitive molecules
A virus-like particle comprising papilloma virus capsid proteins conjugated with about 50 to 1000 photosensitive molecules, wherein the photosensitive molecules include (a) a photosensitive molecule that becomes toxic or produces a toxic molecule upon light activation, and (b) a photosensitive molecule that does not become toxic or produce a toxic molecule upon light activation.
Use of non-human papilloma virus capsid proteins in virus-like particles
The papilloma virus capsid proteins may be non-human, specifically comprising or consisting of L1 capsid proteins from non-human papillomaviruses.
Covalent conjugation of photosensitive molecules to capsid proteins
The photosensitive molecules are covalently conjugated to the papilloma virus capsid proteins, enabling stable attachment of 50 to 1000 photosensitive molecules per virus-like particle.
Method of delivering tumor-targeting virus-like particles to a subject
Administering to a subject a tumor-tropic virus-like particle comprising papilloma virus capsid proteins and 50 to 1000 photosensitive molecules conjugated to the capsid proteins, where the photosensitive molecules include both types that become toxic or remain non-toxic upon light activation.
Activation of photosensitive molecules for imaging and therapy
Methods further include activating the photosensitive molecule that does not become toxic upon light exposure at a wavelength that permits visualization, and activating the photosensitive molecule that becomes toxic at a wavelength that kills tumor cells.
Virus-like particle administration route
The virus-like particle can be delivered to a subject by injection, supporting diverse clinical administration modes.
The claims cover tumor-targeting virus-like particles with a substantial number of photosensitive molecules conjugated covalently to papilloma virus capsid proteins, emphasizing non-human L1 proteins. The method claims cover delivery of these particles to subjects with options to activate the photosensitive molecules for diagnostic or therapeutic purposes, highlighting the particles' conjugation and activation features and modes of administration.
Stated Advantages
Photosensitive virus-like particles allow delivery of a high number of photosensitive molecules per particle, greatly exceeding the delivery capacity of antibodies.
Selective targeting of cancerous tumor cells is achieved without damaging healthy cells, reducing off-target effects common in other therapies.
Conjugation of photosensitive molecules does not compromise the virus-like particles' binding specificity to tumor cells via heparan sulphate proteoglycans (HSPGs).
The compositions can target tumors that lack identified tumor-specific receptors, overcoming limitations of antibody-based targeting methods.
The method enables both diagnostic imaging and selective photodynamic therapy using light activation wavelengths that respectively permit visualization or induce cytotoxicity.
The approach is effective for treatment of various tumors including ocular, metastatic, pre-cancerous, and rare orphan tumors and enables treatment of distant metastases.
Documented Applications
Diagnosis and treatment of ocular tumors, such as ocular melanoma and retinoblastoma, including tumors located in various parts of the eye such as vitreous, choroidal space, iris, and retina.
Targeting tumors located in diverse tissues including lung, pleura, liver, pancreas, stomach, esophagus, colon, breast, ovary, prostate, brain, meninges, testis, gastrointestinal tract, kidneys, bladder, head, neck, cervix, larynx and skin.
Use in selective photodynamic therapy to kill cancerous tumor cells upon activation of photosensitive molecules by infrared, near-infrared or ultraviolet light.
Use in imaging to detect tumors by administering the virus-like particles conjugated to fluorescent or infrared dyes and visualizing them with appropriate light sources.
Treatment of tumors accessible without surgical intervention through injection, topical administration, or implantation of virus-like particles conjugated with photosensitive molecules.
Anti-cancer therapy for tumors resistant or untreatable by standard approaches, including metastatic and pre-cancerous tumors, as well as orphan or rare diseases.
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