http://rdf.ncbi.nlm.nih.gov/pubchem/patent/US-2022033851-A1
Outgoing Links
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| filingDate | 2021-07-07^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_7b4835ebc4c4190bcd75a4d94b225786 |
| publicationDate | 2022-02-03^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | US-2022033851-A1 |
| titleOfInvention | mRNA, episomal and genomic integrated lentiviral and gammaretroviral vector expression of dimeric immunoglobulin A and polymeric immunoglobulin A to Enable Mucosal and Hematological Based Immunity/Protection via Gene Therapy for Allergens, viruses, HIV, bacteria, pneumonia, infections, pathology associated proteins, systemic pathologies, cancer, toxins and unnatural viruses. CAR engineered and non-CAR engineered immune cell expression of dimeric immunoglobulin A and polymeric immunoglobulin A. |
| abstract | The present invention contemplates mRNA, episomal and retroviral genomic gene therapy based short-term, intermediate or long-term vaccine, immunization, immune protection or cancer—that can also be administered as a retroviral genomic gene therapy both in vivo and ex vivo—method to provide epithelial and hematological protection to humans to protect against cancer especially carcinomas, pandemic and non-pandemic viruses, bacterial infections, 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 for some diseases hematological immunity is achieved through mRNA, episomal or genomic integrated lentiviral and gammaretroviral vector expression of dimeric immunoglobulin A1 (dIgA1), dimeric immunoglobulin A2 (dIgA2) and engineered variants. Additionally, in some embodiments a method to agglutinate cancers including carcinomas and hematological cancers to prevent metastasis with polymeric immunoglobulin A and dimeric immunoglobulin A and engineered variants. 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 non-human vertebrates with engineered immune systems or humanized immune systems, transgenic mice or chimeric antibodies a fusion of non-human vertebrates (e.g. mouse or rabbit), mouse antibody V-regions, human antibodies. 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 therapeutically relevant 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 B-cell that produced them or to modify or engineer some of the immunoglobulin heavy chain and light chain constant domains to modulate effector functions. Although, ideally there are no changes made to the immunoglobulins light and heavy chains as identified from the B-cell that produced them. Modifications may occur at the Hinge region, Constant Heavy 2 (C H 2) domain and Constant Heavy 3 (C H 3) domain for the immunoglobulin heavy chain polypeptide with possible modification or change of Constant Heavy 1 (C H 1), possible modification or change constant light (C L ) 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. 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 (scF V ) will 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 V L immunoglobulin fragments that can be incorporated into full-length immunoglobulin heavy and light chains and even reduced length immunoglobulin heavy 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 thymus, liver and bone marrow into mice. 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 vertebrates (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 will optionally 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 or even the lung, via ingestion or administration proximal to lymph nodes or as an ex vivo administration into any of B-cells, T-cells, Natural Killer (NK) Cells and other immune cell types. 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 (also referred to as a long-lived plasma cell), naïve B-cells, NK cells, T-cells, including chimeric antigen receptor T-cells (CAR T-cells) as well as any CAR engineered immune cell. Additionally, the vector may encode for both the CAR and the polymeric and dimeric immunoglobulin in a single vector construct. In cases where the CAR engineered immune cell is selected to receive the polymeric immunogloublin A and dIgA encoding vector the retrovirus may optionally be pseudotyped with a protein that is anti to the CAR single chain variable fragment (scFv) such that conditional transduction occurs only on CAR engineered 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, gammaretroviral delivery system, lentiviral mRNA delivery via mutated reverse transcriptase protein, gammaretroviral mRNA delivery via mutated reverse transcriptase protein, lentiviral retroviral vector, gammaretroviral vector or episomal 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 deficient lentivirus retroviral vector or gammaretroviral vector, integration deficient lentivirus retroviral vector or gammaretroviral vector, encoding for dIgA1, dIgA2 or polymeric immunoglobulin A 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 between each gene of any number of consecutive transgenes as a single open reading frame. 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, germinal center B-cells, and even potentially memory plasma B-cells (also referred to as a long-lived plasma cell) 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 therapeutically relevant binding affinity to the virus, bacteria, antigen, allergens, self-antigen, pathogenic protein, or other foreign and non-foreign bodies and proteins of interest. |
| isCitedBy | http://rdf.ncbi.nlm.nih.gov/pubchem/patent/WO-2023279121-A3 |
| priorityDate | 2020-08-03^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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