COVID-19 Treatment (LAVO-77)
Lavoisier’s current portfolio consists of three programs, which span multiple disease areas including immunology/inflammation/cytokine storm, viral pneumonia, SARS-Cov-2 infection, vaccine, and gout, and represent disease areas with significant urgent and unmet need for patients and large potential market opportunities.
Excessive production of reactive oxygen species (ROS) is strongly corelated with inflammation, oxidative injury, as well as viral infection and replication. Abnormally elevated ROS level is also associated with overexpression of cytokine resulting in cytokine storm and hyperinflammation. One of the most well-known diseases causing cytokine storm/hyperinflammation is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cytokine storm and hyperinflammation prove to be damaging to body tissues and organs and in many severe cases, they are the leading cause of death among COVID-19 patients.
Currently, there is no effective treatment such as broad-spectrum antiviral against COVID-19, and current management is primarily supportive and without specific antivirus drugs. Treatment of hyperinflammation and immunosuppression have been extensively used to address the immediate need to reduce the mortality of COVID-19. Options of immunosuppression treatments include steroids (e.g., dexamethasone), intravenous immunoglobulin, and selective cytokine blockade. Dexamethasone is the only treatment demonstrated to be effective to certain extent in reducing the mortality rate among the severe to mortally ill COVID-19 patients. However, alleviating cytokine storm/hyperinflammation in COVID-19 patients requires very high dosing regimen of dexamethasone, which may cause a broad spectrum of side effects: glaucoma, cataract, fluid retention, hypertension, psychological effects (e.g., mood swings, memory issues, confusion or irritation), weight gain, or increased risk of infections and osteoporosis.
Under a pathological condition, where ROS are excessively produced but antioxidant enzyme is suppressed, ROS may be accumulated locally or systematically, which oxidizes proteins and damages tissues of COVID-19 patients. Based on our understanding of interactions among overexpression of ROS, tissues damages, and death of COVID-19 patients, we proposed that eliminating the excessive ROS in COVID-19 patients may provide a safe treatment to minimize the formation of downstream ROS and prevent the oxidative injury and avoid immunopathogenesis as a result.
We have designed a new formulation containing a carefully selected recombinant protein produced by a genetically modified expression system, which is subsequently nanoencapsulated with the Lavoisier polymer platform. The combination of eukaryote expressed catalase and nanoencapsulation with the Lavoisier platform (nanoencapsulated protein ) vastly improves the chemical, thermal, and biological stability, rendering Lavoisier’s proprietary formulation suitable for both injectable administration and inhalable administration. Furthermore, experimental results demonstrate that nanoencapsulation increases the activity by 10-20% in comparison to uncoated protein.
COVID19 Vaccine (LAVO-99)
Betacoronavirus (BetaCoV or Beta-CoV) is one of four genera (Alpha-, Beta-, Gamma-, and Delta-) of the coronavirus family. Betacoronaviruses are notorious for infecting mammals and sometimes cause serve respiratory diseases in humans. Bats and rodents are believed to be the natural reservoir for beta coronaviruses. Beta-CoV is enveloped, positive-sense, single-stranded RNA viruses of zoonotic origin. Beta-CoV genus contains four such lineages, among which three lineages are of greatest clinical importance concerning humans. For example, OC43 and HKU1 of the A lineage are responsible for the common cold inhuman. Among B lineage, MERS-CoV is the first Beta-CoV known to infect humans causing Middle East respiratory syndrome with an average fatality rate of around 33%. Lineage B has caught most attention in the past two decades. SARS-CoV of lineage B caused the SARS (severe acute respiratory syndrome) outbreak in 2002-2003. Fortunately, SARS-CoV is not highly contagious and did not become a global pandemic even though it has a rather high fatality rate of around 10%. SARS-CoV-2 of the B lineage was first identified in Wuhan, Italy, and Iran at the end of 2019 and early 2020 and has caused a global pandemic of COVID-19 since then.
As a major countermeasure of the COVID-19 pandemic, vaccines were quickly developed and rushed for large-scale clinical trials globally. Notably, most of the vaccines, either being developed or already obtained Emergency Use Authorization by drug/medicine regulatory agencies around the world, only focus on generating antibodies to neutralize the spike protein (S protein) of SARS-CoV-2 in order to prevent or lower the chance of the infection by the virus. However, S protein of SARS-CoV-2 mutates rapidly and at least four major variants of SARS-CoV-2 have emerged in different countries, e.g., UK B.1.1.7 variant, Brazil P.1 variant, South African B.1.351 variant, and Indian B.1.617 variant. It is believed that these variants, in particular B.1.617, may be able to partially or completely escape the current vaccines, due to extensive mutations in the genetic sequence encoding S protein. Therefore, there is an urgent need to develop a new generation of vaccines, which is not sensitive to rapid mutation of SARS-CoV-2, to contain the pandemic caused by the virus and its variants.
In contrast, nucleocapsid protein (N protein) of betacoronavirus, e.g., SARS-CoV, SARS-CoV-2, and MERS-CoV, are genetically conservative. N protein of SARS-CoV-2 is responsible for genome packaging after viral RNA is replicated within the infected cells. Based on the slow mutation of N protein and its function in viral replication, we hypothesized that a vaccine against N protein of SARS-CoV-2 may generate a sufficient amount of antibody to disrupt the function of N-protein and therefore inhibiting the assembling/packaging of viral RNA with the newly produced viral protein shell from the infected cells to form mature SARS-CoV-2 virus. Notably, we do not expect the N protein vaccine to prevent SARS-CoV-2 infection because N protein is not involved in the process of initial infection. Instead, we hypothesized that the N protein vaccine may be able to alleviate the severity of SARS-CoV-2 infection, reduce the need for hospitalization, and eventually lower the fatality rate or even completely eliminate the death of COVID-19 patients. The N-protein vaccine currently being developed by Lavoisier may be the first vaccine-resistant to the mutation of SARS-CoV-2.
Based on our hypothesis, we developed an N-protein formulation containing both uncoated nucleocapsid protein of wild type of Wuhan, Italy, Iran strain of SARS-CoV-2 virus and nanoencapsulated N protein with Lavoisier polymer (LAVO-99). Both components will be administered to a human in one transdermal injection dose. Nanoencapsulation of the antigen (N-protein) in combination with other commonly used immunogenic excipients for vaccines are aimed to deliver the antigen to dendritic cells, extend the antigen half-life and assist the antigen-presentation to T-cell, induce cross-presentation in the dendritic cell, and influence geminal center reaction to produce an antibody with high affinity. Nanoencapsulation therefore may enhance antibody titer and avidity, and induce strong T-cell response and production of memory T-cells.
Preclinical Data and Preliminary Conclusions
The immunogenicity of LAVO-99 is being evaluated using a male BLAB/c mice model. Preliminary experimental results demonstrate that IgG and IgM have been successfully generated in the testing animals and the Lavoisier polymer platform has a significant effect on the immunogenicity of the LAVO-99 vaccine. More preclinical animal tests are being arranged and LAVO-99 formulation may be further adjusted based on the experimental results.