R01AI173059

A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents - Abstract

In previous NIH sponsored research, we successfully tested the hypothesis that integrating structural and mechanistic information into heteromultimeric VHH-based neutralizing agent (VNA) design facilitated development of antitoxins with even greater efficacy and versatility.

In this renewal proposal, we will apply these findings to test the hypothesis that our designer VNA platform, which is rapidly responsive to new threats, will permit development of highly practical, next-generation antitoxin and antiviral products that possess excellent potencies in treating intoxications or viral infections and are effective against a broad range of natural pathogen variants.

Our research will focus on two pathogens that are major current threats which could benefit from next-generation therapeutics: botulinum neurotoxin (BONT) and SARS-CoV-2.

We propose two specific aims which will be underway simultaneously throughout the five years of research.

In Aim 1, we will develop a small pool of antitoxin VNAs that protect against all subtypes of the three prevalent BONT serotypes (A, B, and E). BONTs are CDC Tier 1 select agents. However, the few available antitoxin treatments against BONTs primarily derive from large animal polyclonal antisera, such as the equine botulism antitoxin HBAT, which suffer from multiple manufacturing and storage challenges. Our goal is to test the platform's ability to produce highly practical VNAs as a next-generation BONT antitoxin product, likely delivered as RNA nanoparticles, which improves on the potencies and natural variant specificities of the current HBAT antitoxin product and is rapidly responsive to potential new BONT threats.

In Aim 2, we will develop a single VNA antiviral agent that protects against known variants of SARS-CoV-1 and SARS-CoV-2. SARS-CoV-2 is the viral cause of the ongoing COVID-19 pandemic. A promising strategy for rapid development of a therapy is development of SARS-CoV-2 neutralizing antibodies, especially antibodies targeting the spike protein, for prophylactic or passive immunotherapies. However, novel variants of SARS-CoV-2, which cause enhanced infection and transmission, have emerged, and more dangerous variants are expected to evolve. Of immediate concern are variants that partially escape neutralization by current Ab-based therapies and in vaccinated or previously-infected COVID-19 patients, leading to reduced vaccine efficacy in certain areas with a high prevalence of these variants.

We propose an mRNA-based antiviral product that, once administered, elicits expression of a VNA with extremely high virus neutralizing potency. The VNA will contain multiple covalently linked VHHs binding to conserved epitopes of the spike protein. This approach will test the platform's ability to develop a product that minimizes the risks of immune escape through evolution and selection of clinical strains of SARS-CoV-2 and SARS-CoV-1.

If successful, this technology platform could have broad applications in creating practical therapeutics for a wide variety of emerging and potential pandemic viral infections, bioterror threat agents, and other infectious diseases.

Trustees Of Tufts College

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]

North Grafton, Massachusetts 015361828 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 272% from $865,682 to $3,217,894.