Antibacterial resistance is a global public health crisis. Antibiotic-resistant Clostridium difficile is responsible for more than 29,000 deaths in the US each year and the infection represents an urgent threat to public health worldwide. Of most concern is that the incidence of C. difficile infection (CDI) and disease severity is rapidly increasing in recent years due to the emergence of hypervirulent and antibiotic-resistant strains. CDI is caused by two major toxins TcdA and TcdB, absent which the bacterium is avirulent. Current standard treatment with antibiotics is sub-optimal and accompanied by a high recurrence rate due to the disruption of gut microbiota. Approaches using antibodies to target the major virulence factors represent a new treatment option against CDI. However, the most advanced therapeutic antibody bezlotoxumab, an anti-TcdB monoclonal antibody from Merck, only showed a comparable effect as antibiotic fidaxomicin on reducing CDI recurrence in recent Phase III trials. This less-than-desirable efficacy is likely due to targeting a single epitope of the toxin and low potency of the antibody. We have developed a novel tetra-specific, humanized antibody FZ001 based on 4 VHHs targeting distinct epitopes, two on each of the toxins. FZ001 potently and broadly neutralizes both toxins from different clinical isolates and demonstrates a potent therapeutic efficacy against both primary and recurrent CDI in mice. cGMP-grade CHO lines have been constructed with a high expression level of FZ001. In response to RFA-AI-16-034, we propose to develop cell culture parameters and analytic assays and subsequent manufacturing process in order to generate FZ001 for GLP toxicology. This project will allow the generation of the critical data of chemical, manufacturing, and control (CMC) for future IND filing and Phase I clinical trials.

Public Health Relevance

Antibiotic-resistant super-bug Clostridium difficile kills more than 29,000 people in the US each year but no effective treatment available. We propose to develop a novel treatment based on our highly potent therapeutic protein and scale up its production under manufacturing setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI132207-04
Application #
9941044
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Ranallo, Ryan
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Fzata, Inc.
Department
Type
DUNS #
080062872
City
Halethorpe
State
MD
Country
United States
Zip Code
21227