mRNA encoding of immune receptor-targeting antibodies for the augmentation of vaccine-elicited cellular immunity.

Document text

Principal Investigator: Ross M Kedl
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2023
Award: $194,375
Funding agency: National Institute of Allergy and Infectious Diseases

Project summary.
Clinically relevant cellular responses to either experimental or FDA approved vaccine adjuvant formulations
have been difficult to generate and/or detect. We have long been investigating a combined adjuvant
formulation (composed of a TLR agonist and an agonistic antiCD40 antibody) which generates cellular
immunity on par with that observed to infectious challenge. The complexity of this three-part vaccine (antigen
plus TLR/CD40) is limiting to its clinical application. However, the success of lipid nanoparticle (LNP)
encapsulated mRNA vaccines for Covid provides a possible avenue by which our combination adjuvant might
be successfully translated into clinical use against chronic infectious diseases and cancer. Our preliminary
results show that we can agonize the CD40 pathway, sufficient to augment CD8 T cell responses, by mRNA-
mediated delivery of the heavy and light chains of the agonistic anti-CD40 antibody FGK45. The success of
this method for targeting CD40 strongly favors the hypothesis that antibodies specific for other
immunotherapeutic molecular targets (eg. CTLA4, PD1) might also be successfully delivered via the mRNA
vaccination strategy. Completion of this project would not only identify a new and powerful means by which
the established potency of our combined adjuvant might be leveraged for clinical application, they open an
entirely new paradigm in the use of mRNA vaccination for targeting immunologically relevant molecules for the
purposes oncologic checkpoint therapy and beyond.

Terms: <2019-nCoV vaccine><Ab response><Adjuvant><Adjuvant Study><Adjuvant Trials><Admission><Admission activity><Agonist><Anti-CD40><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antigens><Area><Bp50><CD152><CD152 Antigen><CD152 Gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD40><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CDW40><COVID-19><COVID-19 immunity><COVID-19 vaccine><COVID19><COVID19 immunity><COVID19 vaccine><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><CV-19><CV19><Cancers><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Chronic><Clinical><Clinical Evaluation><Clinical Testing><Clinical Treatment Moab><Communicable Diseases><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Development><Encapsulated><Engineering><FDA approved><Formulation><Frequencies><Genes><Goals><Humoral Immunities><IV Infusion><Immune><Immune Targeting><Immune response><Immune system><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunologic><Immunologic Receptors><Immunological><Immunological Receptors><Immunological response><Immunologically><Immunologics><Immunotherapeutic agent><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Interferon Type I><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravenous infusion procedures><LYT3><Life><Light><Lipids><MGC9013><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Memory><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Molecular Target><Monoclonal Antibodies><Murine><Mus><Nature><Oncology><Oncology Cancer><PD 1><PD-1><PD1><Pathway interactions><Patients><Phenotype><Photoradiation><Progenitor Cells><Qualitative Evaluations><R-Series Research Projects><R01 Mechanism><R01 Program><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Research Grants><Research Project Grants><Research Projects><SARS-CoV-2 immunity><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 vaccine><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stimulus><T cell response><T memory cell><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TNFRSF5><TNFRSF5 gene><Technology><Testing><Therapeutic><Therapeutic Intervention><Translating><Treatment Efficacy><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Tumor Promotion><Vaccination><Vaccine Adjuvant><Vaccines><Validation><Variant><Variation><Work><aCTLA-4><aCTLA4><aPD-1><aPD1><adjuvant protocol><anti programmed cell death 1><anti-CTLA-4><anti-CTLA4><anti-PD-1><anti-PD1><anti-programmed cell death protein 1><antiPD-1><antiPD1><antibody biosynthesis><antibody-based immunity><biological signal transduction><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chronic infection><clinical applicability><clinical application><clinical implementation><clinical relevance><clinical test><clinically relevant><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 immunity><coronavirus disease 2019 vaccine><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus infectious disease-19><cost><cytotoxic T-lymphocyte antigen 4><deliver vaccines><developmental><experiment><experimental research><experimental study><experiments><host response><immune check point blockade><immune check point therapy><immune checkpoint blockade><immune checkpoint therapy><immune drugs><immune receptor><immune system response><immune-based therapeutics><immunity against COVID-19><immunity against COVID19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunization strategy><immunogen><immunoglobulin biosynthesis><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><in vivo><intervention efficacy><intervention therapy><interventional strategy><intravenous infusion><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><mRNA delivery><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><malignancy><manufacture><memory T lymphocyte><monoclonal Abs><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><non-human primate><nonhuman primate><p50><pandemic><pandemic disease><particle><pathway><persistent infection><programmed cell death 1><programmed cell death protein 1><programmed death 1><protein purification><research clinical testing><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><stem cells><success><systemic lupus erythematosus susceptibility 2><therapeutic efficacy><therapeutic target><therapy efficacy><thymus derived lymphocyte><tumor><vaccination strategy><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine delivery><vaccine for novel coronavirus><vaccine platform><vaccine-induced immunity><vaccine-induced protection><validations><viral transmission><virus transmission><α-CTLA-4><α-CTLA4><αCTLA-4><αCTLA4><αPD-1><αPD1>