http://rdf.ncbi.nlm.nih.gov/pubchem/patent/US-2022333130-A1
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_5f43d9cf0c27d37341944f372f55f83b |
| classificationCPCAdditional | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K48-005 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N2840-206 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N2740-15043 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N2740-16043 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N2830-48 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N2840-203 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N2830-50 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K2317-35 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K2317-52 |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K16-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N15-86 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C12N15-67 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K16-18 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K48-005 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07K16-18 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C12N15-86 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K48-00 |
| filingDate | 2021-04-11-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_7b4835ebc4c4190bcd75a4d94b225786 |
| publicationDate | 2022-10-20-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | US-2022333130-A1 |
| titleOfInvention | Episomal expression, genomic integrated lentiviral vector expression and mRNA expression of Potent Immunoglobulins Including Dimeric Immunoglobulin A1 and A2 via a furin cleavage site and 2A self-processing peptide to Enable Mucosal and Hematological Based Immunity or Protection via Gene Therapy for Allergens, viruses, HIV, bacteria, infections, pathology associated proteins, systemic pathologies, cancer, toxins and unnatural viruses. |
| abstract | The present invention contemplates mRNA, episomal and retroviral genomic gene therapy based short-term, intermediate or long-term vaccine, immunization, protection or therapy—that can also be administered as a retroviral genomic gene therapy—method to provide mucosal and hematological protection to humans to protect against pandemic and non-pandemic viruses, bacterial infections, fungi, allergens or the cause of allergic reactions, systemic pathological conditions, cancer and anti-biowarfare agents (e.g. natural and unnatural viruses and toxins) where mucosal immunity and potentially hematological immunity is achieved through mRNA, episomal or genomic expression of dimeric immunoglobulin A1 (dIgA1) and dimeric immunoglobulin A2 (dIgA2). The present invention provides methods, immunoglobulin compositions and vector constructs to express potent immunoglobulins that are derived from human blood of a human currently infected with, affected by, exposed to or recovered from any of a wide range of allergens or the cause of allergic reactions, pathogens (including, viruses, virus mutants, bacterial infections and fungi) and systemic pathological ailments (including cancer and other disorders), developed from phage display technology or mice or other animals with a humanized immune systems, transgenic mice or chimeric antibodies a fusion of non-human vetebrates (e.g. mouse or rabbit) and human. The immunoglobulin compositions include the heavy chain variable, diversity and joining (VDJ or Variable Heavy Region genes) segment immunoglobulin DNA and/or polypeptide sequence from humans identified to have developed high affinity immunoglobulins against the antigen, protein or proteins of interest and either to use the exact immunoglobulin heavy chain and light chain polypeptide sequences identified from the memory B-cell that produced them or to modify or engineer some of the immunoglobulin heavy chain and light chain constant domains to reduce, change or modulate effector functions. Although, ideally there are no changes made to the immunoglobulins light and heavy chains as identified from the memory B-cell that produced them. Modification may occur at the Hinge region, Constant Heavy 2 (CH2) domain and Constant Heavy 3 (CH3) domain for the immunoglobulin heavy chain polypeptide with optional modification or change of Constant Heavy 1 (CH1), optional modification or change constant light (CL) chain domain. The resulting antibodies can either be used as a monoclonal or antibody cocktail of (Immunoglobulin Class G subclass1) IgG1, IgG2, IgG3 and other subclasses, IgA1 monomer and IgA2 monomer and dimeric IgA1 (dIgA1) and dimeric IgA2 (dIgA2) immunoglobulins (as identified by the binding affinity of B-cells that expressed immunoglobulins are coded for as necessary to represent the binding affinity (e.g. such as based on complementarity determining Regions (CDRs) or V-regions) in the monoclonal or antibody cocktail). Alternatively, combinatorial libraries of single chain variable fragments (scFv) may be generated from human B-cells or other animal B-cells that may or may not have been exposed to the allergen, pathogen, cancer, or pathological ailment, or suspected or identified biowarfare agent or protein where phage display technology and mutagenesis can be used to identify potent VH and VL immunoglobulin fragments that can be incorporated into full-length immunoglobulin heavy and light chains incorporated into vectors for mRNA expression, episomal expression or retroviral gene delivery (retroviral insertion into genomic DNA) based gene-therapy. Further, mice or other animals can also achieve humanized immune system by implanting human hematopoietic progenitor cells into the animal or transplanting human fetal thymus, liver and bone marrow into mice or other animals where exposure to antigens, allergens or other foreign and non-foreign proteins can result in an adaptive immune response and potential affinity maturation. Additionally, transgenic mice where human immunoglobulin (Ig) genes are inserted into the genome to replacing the endogenous Ig genes making the mice or other non-human vertebrate such as rabbits or hamsters capable of producing fully human antibodies from exposure to antigen may be used to identify potent immunoglobulins. Non-human vetebrates (e.g. mouse or rabbit) may be used to identify potent immunoglobulin binding regions or potent immunoglobulin complementarity determining regions (CDRs) for fusion with human antibodies giving rise to chimeric antibodies. The identified immunoglobulins from these methods may be further optimized through mutagenesis techniques and will be expressed in the recipient via mRNA, via an episome or via retroviral insertion into their genomic DNA of the cells of interest to be expressed via intramuscular administration, intravenous administration, endoscopy based administration to the lamina propria of the stomach and/or small intestine, via ingestion or administration proximal to lymph nodes. Preferred cells to target to receive the vector include muscle cells, liver cells especially hepatocytes and B-cells including memory B-cells, Germinal Center B-cells, memory plasma B-cells, a plasma blast, and naïve B-cells. The vector will be ideally delivered as a naked vector, in a vesicle based delivery system such as a lipid nano-particle, in a recombinant Adeno Associated Virus (rAAV) with preference for AAV serotype 8 (AAV8) containing a single-stranded Deoxyribonucleic acid (ssDNA), an adenovirus delivery system, a lentivirus delivery system, lentiviral mRNA delivery via mutated reverse transcriptase protein, lentiviral retroviral vector or mRNA delivery via mutated integrase protein, or a vesicle-based delivery system using mRNA, single-stranded DNA or double-stranded DNA. When designing an mRNA, AAV viral vector, adenovirus vector, integration incompetent lentivirus vector or lentivirus retroviral vector, encoding for dIgA1 or dIgA2 a single vector will code for the entire immunoglobulin and J chain (Joining Chain) expression for dIgA1 or dIgA2 where expression may occur with a single start codon and stop codon for each transgene and in some embodiments a second start codon for J chain expression. The use of a single start and stop codon is enabled by placing in the 5′ to 3′ direction a furin cleavage site concomitantly followed by a 2A self-processing peptide or furin cleavage site only between each gene of any number of consecutive transgenes as a single open reading frame. Further, in some embodiments MZB1 will optionally be encoded in the mRNA, viral, retroviral or non-viral vectors (See FIGS. 13, 15, 16, 17, 18, 19, 20 as examples). The specific DNA of the human donor can be identified as follows: Cluster of Differentiation 27+(CD27+) IgG+ and CD27+ IgA+ memory B-cells, other memory B-cells, or plasmablast B-cells and even potentially memory plasma B-cells will be isolated from blood using established methods. Each resulting isotype of memory B-cell or together will be subjected to a competitive binding assay using magnetic pull down and Fluorescence Activated Cell Sorting (FACS) methods to identify the memory B-cells with the greatest binding affinity to the virus, bacteria, antigen, allergens, self-antigen, pathogenic protein, or other foreign and non-foreign bodies and proteins of interest. Isolated CD27+ or other Cluster of Differentiation memory B-cells will use well-established methods to identify the genetic sequence and in turn the polypeptide sequence of the immunoglobulin heavy and light chains of the cell surface IgG+ or IgA+ receptor. Immunoglobulin mRNA or DNA will be incorporated into vector construct coding for antibodies to be evaluated for binding affinity and safety in addition to modifying them in a variety of ways as described herein and then to be incorporated into an mRNA vector to enable mRNA based expression or viral or non-viral vector to enable episomal immunoglobulin expression. Alternatively, the lentivirus vectors may be used for episomal expression or as a retroviral vector intended for retroviral integration in the host genomic DNA. Additionally, a method to improve the potency of a vaccine is designed by targeted delivery of antigenic proteins or protein encoding mRNA to the lamina propria of the respiratory tract or gastrointestinal tract. |
| isCitedBy | http://rdf.ncbi.nlm.nih.gov/pubchem/patent/WO-2023279121-A3 |
| priorityDate | 2021-04-11-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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