Document text
Principal Investigator: Thomas Waldmann
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2021
Award: $450,222
Funding agency: National Cancer Institute
Dr. Liyanage P. Perera, a member of our group, is an expert in the introduction of IL-15 into vaccines to augment their function. He is working on 2 candidate vaccines for COVID-19, a full-length spike S protein, as well as a truncated subdomain of it that carries the receptor-binding domain of a NaMVA platform which is molecularly adjuvanted with IL-15 (genome CSF and Flt3L) which we hope will both turbo-charge both humoral and CTL responses against the spike protein. The construct we are developing will be assayed in human ACE2 transgenic mice. A second project involves the development of long-acting IL-15 to augment the action of antibodies to COVID-19. An approach to the treatment of COVID-19 involves the development of antibodies to this virus, in parallel with the effective antibody treatment of Ebola. Our laboratory co-discovered the cytokine IL-15, demonstrated its dramatic efficacy in increasing the number and state of activation of NK cells and antibody-dependent cellular cytotoxicity (ADCC) and antibody efficacy. IL-15 administered by continuous intravenous infusion (CIV) at 2 mcg/kg for 5 or 10 days increased the number of NK cells 38-fold and CD56bright NK cells 358-fold. Furthermore, in a series of clinical trials in mice and in humans it increased ADCC and antitumor efficacy. However, CIV IL-15 would not receive patient or physician acceptance. To address this issue, we have established a collaboration with Dr. Daniel Santi, UCSF, ProLynx LLC to develop IL-15 as a long-acting cytokine. In this process, IL-15 is covalently tethered to a long-acting carrier by a linker that slowly cleaves by beta elimination. Here a macromolecular carrier is attached to a linker that is connected to IL-15 via a carbamate group. The alpha carbon has an acidic carbon-hydrogen bond (C-H) with a PK that is controlled by electron withdrawing PK MeSO2. Upon hydroxide ion catalyzed protein removal, a rapid beta elimination occurs to cleave the linker carbamate bond and release the IL-15 with an aminopropyl remnant. The carrier used is a large bore tetra-PEG hydrogel with a uniform 50 micro molar microsphere. The PK of the long-acting IL-15 in mice SC injection was approximately 125 hours for 5 days. A dramatic dose expansion of NK cells and CD44hi CD8 T-cells was observed in PBMCs following a single injection in mice of laIL-15 conjugate. The NK expansion yielded an elevated NK level for 14 days. The expansion of CD44hi CD8 T-cells remained elevated for more than 3 weeks. The efficacy of long-acting IL-15 will be initially evaluated in SCID/NOD mice bearing MET-1 ATL leukemia model receiving mogamulizumab to define its efficacy in ADCC and antitumor effectiveness. Ultimately it will be tested against COVID-19.
Terms: <2019-nCoV vaccine><ACE2><Ab-dependent cellular cytotoxicity><Abscission><Address><Adjuvant><Antibodies><Antibody Therapy><Assay><Bioassay><Biologic Assays><Biological><Biological Assay><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID-19 antibody><COVID-19 therapy><COVID-19 treatment><COVID-19 vaccine><COVID19><COVID19 therapy><COVID19 treatment><COVID19 vaccine><CV-19><CV19><Carbamates><Carbon><Charge><Cleaved cell><Clinical Trials><Collaborations><Continuous Intravenous Infusion><Cytotoxic cell><Development><Dose><Ebola><Effectiveness><Electrons><Excision><Extirpation><FLT 3 Ligand><FLT3 ligand><FLT3L><FLT3LG><FLT3LG gene><FMS-Related Tyrosine Kinase 3 Ligand Gene><FMS-Related Tyrosine Kinase-3 Ligand><Genome><Goals><H-bond><Hour><Human><Hydrogels><Hydrogen Bonding><Hydroxide Ion><IL-15><IL15><IL15 Protein><Injections><Interleukin-15><Interleukin-15 Precursor><K lymphocyte><Laboratories><Length><MGC9721><Mice><Mice Mammals><Microbeads><Microspheres><Modeling><Modern Man><Molecular><Murine><Mus><NK Cell Activation><NK Cells><NOD/SCID mouse><Natural Killer Cell Activation><Natural Killer Cells><Negative Beta Particle><Negatrons><PBMC><Patients><Peripheral Blood Mononuclear Cell><Physicians><Process><Proteins><Removal><Research><SARS-CoV-2 antibody><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vaccine><SARS-CoV2 antibody><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><STK1-ligand><Series><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Surgical Removal><T8 Cells><T8 Lymphocytes><Testing><Transgenic Mice><Vaccines><Virus><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody based therapies><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody to COVID-19><antibody to SARS-CoV-2><antibody to SARS-CoV2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><antibody treatment><antibody-based therapeutics><antibody-based treatment><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><cleaved><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 antibody><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 vaccine><cytokine><developmental><flk2 ligand><flk2-flt3 ligand><flt3 ligand protein><hydroxyl ion><leukemia><member><novel><receptor binding><receptor bound><resection><response><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><stem cell tyrosine kinase 1 ligand><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><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 candidate><vaccine for novel coronavirus>