R01AI163011

Development of Multivalent, Ultrapotent Nanobody Cocktails for SARS-CoV-2 Neutralization - Project Summary/Abstract

The outbreak of COVID-19 has severely impacted global health and the economy. Cost-effective, highly efficacious therapeutics are urgently needed. Camelid VHH antibodies or nanobodies (Nbs) are small, highly stable, easily bioengineered, and can be rapidly and economically manufactured from microbes. They are highly robust and are flexible for administration, including possible delivery by nebulization. Together, these unique properties of Nbs make their uses against respiratory viruses such as SARS-CoV-2 especially appealing.

We recently developed a disruptive proteomic technology for large-scale identification of multi-epitope, drug-quality Nbs (Xiang et al., Cell Systems. 2021). Using this technology, we identified > 8,000 high-affinity Nbs for the SARS-CoV-2 spike (S) receptor-binding domain (RBD), including Nbs that target highly neutralizing epitopes with sub-PM affinities and can neutralize SARS-CoV-2 at sub-ng/mL concentrations, which are unprecedented for antiviral antibody fragments. Structural proteomics revealed multiple distinct epitopes and potential neutralization mechanisms. Bioengineering of multi-epitope and multivalent constructs improved the potency to below 0.1 ng/mL (Xiang et al., Science. 2020).

Most recently, we have demonstrated the high preclinical efficacy of an ultrasotent and stable trimeric Nb construct (PIN-21) for inhalation treatment of SARS-CoV-2 infection in a sensitive COVID-19 model (Nambulli et al., Science Advances. 2021). Intranasal delivery of PIN-21 at 0.6 mg/kg substantially reduces viral burdens in both airways. Critically, aerosol delivery of PIN-21 at 0.2 mg/kg decreases lung viral titers by 6-logs, minimizing lung pathology post-infection and preventing viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the evolving pandemic and future events.

In the revision, we aim to identify and characterize highly potent Nbs that are highly resistant to the variants of concern (VoCs) of SARS-CoV-2, investigate the neutralization mechanisms by structural approaches, and develop ultrasotent Nb constructs into safe and effective therapeutics. Our central hypothesis is that Nbs can be bioengineered into multivalent and ultrasotent forms to resist the mutational escape and the variants of concerns (VoCs) of SARS-CoV-2. Completion of our proposed studies will lead to cost-effective and convenient COVID-19 therapeutic candidates for translation into clinical trials.

High-resolution structural studies will provide critical insights into how Nbs uniquely target the virus for high-affinity binding and neutralization. Critically, this project will serve as the testbed of our multidisciplinary platform to develop potent therapeutic and diagnostic reagents for future pandemics caused by coronaviruses or other pathogens.

Icahn School Of Medicine At Mount Sinai

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 297% from $769,010 to $3,051,157.