COVID-19 research efforts

Division Of Basic Sciences - Nci

Investigators

Abstract

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.