Pathotropic targeted gene delivery system for cancer and other disorders
Inventors
Hall, Frederick L. • Gordon, Erlinda M.
Assignees
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Publication Number
US-9017659-B2
Publication Date
2015-04-28
Expiration Date
Abstract
Systems for pathotropic (disease-seeking) targeted gene delivery are provided, including viral particles with extremely high titers. In particular, the viral particles are engineered to specifically deliver therapeutic or diagnostic agents to a disease site, such as cancer metastic sites. Personalized dosing regimens are also provided to treat diseases such as cancer efficaciously with reduced adverse side effects.
Core Innovation
The invention relates to inhibiting tumor metastasis in a human patient having a tumor that has metastasized by intravenously administering therapeutically effective amounts of retroviral particles. Each retroviral particle includes a modified retroviral envelope protein whose receptor binding region is modified to contain a collagen binding domain comprising the amino acid sequence Gly-His-Val-Gly-Trp-Arg-Glu-Pro-Ser-Phe-Met-Ala-Leu-Ser-Ala (SEQ ID NO:1). The retroviral particles further encode a heterologous therapeutic polypeptide that acts as a suicide protein chosen from a defined group.
The collagen-binding modification is positioned within the receptor binding region of the retroviral envelope protein to achieve a pathotropic, disease-seeking, targeted gene delivery system associated with collagen exposure. In particular implementations, a modified 4070A amphotropic envelope is used and a collagen-binding peptide is inserted into the native gp70 portion. The system is described as using high-titer retroviral vectors suitable for systemic administration to target metastasis-associated tissue changes.
The document also describes a manufacturing and collection approach for producing retroviral vectors at high titer, including transient transfection in producer cells, vector production/manufacturing with closed-loop manifold collection, and reported characteristics such as viral particle size and safety attributes. It further describes treatment paradigms that include systemic dosing with dose-escalation and a personalized, dose-dense induction concept based on tumor burden and imaging-derived measures, with evaluation endpoints such as necrosis/cystic changes, HU/PET SUV, and apoptosis and tumor infiltrating lymphocytes. It additionally describes combined cytocidal and cytokine transgene strategies for metastasis inhibition.
Claims Coverage
The independent claim recites a single overall method for inhibiting tumor metastasis, grounded in two main inventive aspects: (1) intravenously administered retroviral particles at a specified cumulative colony-forming-unit dose and (2) particle design combining a modified envelope collagen-binding domain with a heterologous suicide therapeutic polypeptide chosen from a defined set.
Intravenous administration of high-dose modified retroviral particles for metastasis inhibition
Intravenously administering a therapeutically effective amount of retroviral particles to a human patient with a metastasized tumor, at a cumulative dose of at least 1.8×10^11 colony forming units (cfu).
Collagen-binding modified envelope receptor-binding region containing SEQ ID NO:1
Each retroviral particle comprises a modified retroviral envelope protein in which the receptor binding region is modified to contain a collagen binding domain comprising the amino acid sequence Gly-His-Val-Gly-Trp-Arg-Glu-Pro-Ser-Phe-Met-Ala-Leu-Ser-Ala (SEQ ID NO:1).
Suicide therapeutic polypeptide encoded by the retroviral particle chosen from a defined group
Each retroviral particle encodes a heterologous therapeutic polypeptide that is a suicide protein chosen from thymidine kinase, cytosine deaminase, p450 oxidoreductase, carboxypeptidase G2, beta-glucoronidase, penicillin-V-amidase, penicillin-G-amidase, beta-lactamase, nitroreductase, carboxypeptidase A, linarmarase, E. coli gpt gene product, and E. coli Deo gene product.
Across the independent claim, metastasis inhibition is tied to the combination of systemic intravenous delivery at a cumulative cfu dose threshold and retroviral particles whose envelope receptor-binding region includes the specified collagen-binding domain sequence (SEQ ID NO:1) together with an encoded suicide therapeutic polypeptide selected from the defined group.
Stated Advantages
Objective anti-tumor effects, including tumor regression/partial responses and necrosis/apoptosis.
Progression-free survival reported in subsets.
Limited safety/tolerability issues, including no dose-limiting toxicity reported up to high cumulative vector doses.
Low immunogenicity, with no neutralizing anti-vector antibodies.
No recombination-competent retroviral generation is described.
No detected vector integration in non-target organs is described.
Documented Applications
Clinical examples in pancreatic cancer and other solid tumors are described, including metastatic lymphadenopathy, metastatic liver foci, and metastatic portal node.
Progression-free survival and objective anti-tumor responses are described in the context of clinical trial Phase I/II and expanded access in the described tumor types.
Treatment of a human patient with a metastasized tumor by intravenously administering modified retroviral particles to inhibit tumor metastasis.
Targeted delivery associated with collagen exposure in areas where collagen is exposed, including lesion categories such as neoplastic lesions, active angiogenesis, metastatic tumor invasion, cancerous lesions, vascular injury, surgical sites, inflammatory sites, and tissue destruction areas.
Personalized systemic dosing paradigms based on tumor burden and imaging-derived measures to evaluate metastasis-related outcomes using endpoints such as necrosis/cystic changes, HU/PET SUV, apoptosis and tumor infiltrating lymphocytes.
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