Development of Multispecific Antibodies for the Treatment of Acinetobacter baumannii Infection
Abstract
Acinetobacter baumannii is a gram-negative bacterium commonly found in soil and water. A. baumannii can cause severe community and hospital-acquired infections. A high proportion of A. baumannii infections are multidrug-resistant, with colisitin the only viable treatment option in many cases. Drug-resistant A. baumannii is listed as a serious threat by the Centers for Disease Control and Prevention (CDC) and a critical priority by the World Health Organization (WHO), emphasizing the importance of developing novel therapeutics for this important emerging pathogen. Thus, the proposed project addresses the topic area of Antimicrobial Resistance. A series of antimicrobial therapeutics based on combinations of single domain antibodies (sdAb) utilizing multiple mechanisms of action to circumvent development of resistance is currently in development. Using this platform, it is possible to develop a tetravalent, bispecific antibody capable of eliminating A. baumannii. This antibody will target the type 6 secretion system (T6SS) and opsonize bacteria via the type I pilus. Hypothesis: The work will be guided by the hypothesis that multi-specific antibodies that combine T6SS-blocking capabilities with opsonization and subsequent Fc effector functions will be able to effectively combat multidrug-resistant strains of A. baumannii. The hypothesis assumes that the antibodies created as a result of this project will be able to recreate the phenotype observed when mutations are introduced into the T6SS machinery. However, bacterial clearance will be enhanced because of the opsonization component. In this Discovery Award, antibodies that have been already identified as binding to their respective targets will be utilized to identify lead candidates and construct a tetravalent, bispecific antibody that blocks T6SS activity and opsonizes the bacterium. Future Steps: Following these studies, we will have at least one lead anti-Acinetobacter antibody identified, which we will then develop as a first-in-class therapeutic antibody for treating A. baumannii infections. Innovation: There are currently no antibody-based therapeutics against A. baumannii in clinical trials. All current antibiotic efforts against this pathogen are small molecule-based. Antibody-based therapeutics have the advantage over small molecule antibiotics of being pathogen-specific, not eradicating beneficial flora. In addition, multi-targeting antibodies reduce the possibility of the emergence of resistance, a significant problem with A. baumannii. Utilizing the flexibility of modular antibody formats enables incorporation of multiple single domain antibodies (sdAb) into a unified molecule. This innovative technology allows one to functionally optimize antibodies by increasing valency or adding multiple binding specificities into a single therapeutic. These unique formats are very simple in nature, highly stable, and have excellent developability profiles. Notably, tetravalent, bispecific therapeutics, such as those described above, are smaller and less complex than even a conventional antibody (100 kDa vs. 150 kDa, respectively). This enables the increase of the functionality of a therapeutic without prohibitively increasing molecular complexity. Impact: If this project is successful, the ability of multi-specific antibodies to eliminate drug-resistant A. baumannii will be proven. In this case, the platform that was used to develop the proposed therapeutic will be used to develop antibodies, with the same characteristics, for other bacterial infections that have shown drug resistance. This will be immensely important to military personnel deployed around the world, facing drug-resistant bacteria that are widespread today – while only having access to field medicine. Furthermore, the general public will benefit from this new and effective antimicrobial option, making hospitalization safer without the fear of drug-resistant bacterial inf
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810131
Entities
People
- Andrew Hollands
Organizations
- Inhibrx (United States)
- United States Army