UH2AI171611

Targeting Glycoprotein (G) Domain-III for Pan-Lyssavirus Nanobody Therapeutics - Abstract

The lethal rabies encephalitis diseases are caused by members of the zoonotic Lyssavirus genus. The high genetic diversity separates Lyssavirus members into three phylogroups, while cross-phylogroup (especially to phylogroups 2 and 3) protection has not been established by current post-exposure prophylaxis (PEP) or antibody therapeutics.

To achieve more broadly effective countermeasures to rabies disease worldwide and to prepare for the emergence of new Lyssaviruses, effective therapeutic agents against all phylogroups are necessary.

Lyssavirus G glycoprotein is the sole antibody target on the virion surface, which adopt distinct conformations between pre- and post-fusion states as other class-III viral fusion machineries. Domain-III of Lyssavirus G glycoprotein encompasses a large neutralizing antibody-accessible surface in the native state.

Sequence analysis on Domain-III revealed several conserved patches across all phylogroups, which could potentially serve as target epitopes for pan-Lyssavirus neutralizers.

Antigen-specific nanobodies have been considered as promising therapeutic agents against various infectious diseases and non-infectious diseases, which have the advantage in binding compact and hidden epitopes that are out of reach for conventional antibodies.

We hypothesized that by focusing immune recognition on the Lyssavirus G Domain-III conserved epitopes, we can identify pan-Lyssavirus neutralizing nanobodies for immunotherapeutics.

In this study, we propose two specific aims: (1) to use a structure-based and antibody-guided approach to design and characterize the antigenicity of Lyssavirus glycoprotein Domain-III, a site of viral vulnerability targeted by several broadly neutralizing antibodies, for revelation of the antibody neutralization mechanism; (2) to identify and characterize pan-Lyssavirus neutralizing nanobodies for therapeutics by focusing immune recognition on Lyssavirus G Domain III conserved epitopes.

University Of Texas Health Science Center At Houston

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]

Texas United States

State-Wide

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-21-268)

Amendment Since initial award the End Date has been extended from 02/28/25 to 02/28/26 and the total obligations have decreased 12% from $456,428 to $403,175.