A fundamental component of preventing new infections and treating established infections is our ability to engineer effective immune responses and therapies. This encompasses our four priority pillars:
- P1. Next-Generation LNP Delivery, Vaccines, and Therapeutics
- P2. Antibody Engineering Technologies
- P3. Cell-Based Therapies to Combat Infectious Diseases
- P4. Biological Resilience, Antimicrobial Resistance, and Health Threats
P1. Next-Generation LNP Delivery, Vaccines, and Therapeutics
Lipid nanoparticle (LNP) systems have broad applications in most human tissues, including immune cells, tumor tissue, and neurons, with the potential to treat virtually any genetic disease, as well as use with therapeutic vaccines.
Objectives under this priority include:
- Enhancing LNP delivery technology for developing formulations that will be maintained in circulation for prolonged time periods for more efficient delivery of RNA/DNA-based drugs and vaccines and other pharmacological agents to extrahepatic tissues.
- Optimizing/targeting mRNA LNP vaccines to achieve an enhanced immune response.
- Optimizing the adjuvant effect of the ionizable cationic lipid component.
- Developing technologies that restrict therapies to particular tissues and cells, for example:
- direct targeting of LNP systems employing targeting ligands such as mAb;
- nucleic acid payloads engineered for specific expression in target tissue;
- LNPs activatable by external stimuli such as laser light or radiofrequency radiation to “turn on” molecular vaccines and therapies in target regions.
- Developing innovative approaches to vaccine technology, including self-amplifying RNA (saRNA) vaccines.
In collaboration with other national hubs, our program of research will also focus on developing a variety of delivery systems beyond LNPs, including:
- Lipid, polymeric, or proteinaceous nanoparticles;
- Viral vectors, including both bacteriophage and mammalian viruses;
- Electronic or mechanical devices; and
- Targeting complexes, such as antibody-drug conjugates.
This approach will overcome a multitude of challenges related to delivering therapeutic cargo, such as: protecting the payload from the patient immune system, increasing half-life, targeting specific tissues, or limiting off-target toxicities.
Other approaches that will be considered include:
- Developing protein and peptide-based vaccines and vector-based approaches,
- Developing novel adjuvants
The focus of our development will be identifying outstanding programs of scientific research and the creation of appropriate mechanisms for such work to progress through to biomanufacturing either as academic projects or in partnership with industry.
P2. Antibody Engineering Technologies
Convalescent plasma and therapeutic antibodies were a critical early-stage component of the pandemic response to COVID-19. These approaches to mAb technologies can also accelerate the development of novel cellular therapies by providing the ability to rapidly generate novel cancer or autoimmune targeting moieties (such as chimeric antigen receptors [CARs] or engineered T-cell receptors). CIEBH will fortify research in this area to ensure that Canada’s capabilities for rapid development of therapeutic antibodies remain at the leading-edge.
Objectives for this priority include:
- Using antibody engineering approaches to address key challenges facing mAb technologies, such as susceptibility to pathogen evasion from evolutionary drift, limited treatment windows, and high costs, which have historically limited the potential impact of this modality. For example, antibodies engineered to have significantly increased half-life and/or higher potency could enable prophylactic use and reduce the doses required.
- Generating more specific knowledge regarding 3D structures of target molecules to enable more effective antibody design.
- Engineering of new antibody-based modalities, such as bispecific antibodies and antibody fusions, to expand functional potency, defending against evolutionary divergence, and engaging novel mechanisms of action.
- Leveraging RNA technology to provide opportunities for next-generation antibody therapies, including self-amplifying RNAs (saRNA) for rapidly deployable antibodies.
P3. Cell-Based Therapies to Combat Infectious Diseases
Engineered cells have demonstrable capabilities in a range of conditions in ways that are not possible with traditional pharmaceuticals. Although cell-based therapies were not necessary to manage COVID-19 in most people, in severely ill and/or immunocompromised people—an important health equity consideration—SARS-CoV-specific T-cells could have been an effective “rescue” therapy, especially in the early days of the pandemic, before widespread vaccination.
The overarching objective for this priority area is to have a well-established, clinically experienced cell therapy program that could rapidly generate T cell and/or NK cell products against a future deadly infectious agent at the scale and quality required for testing in early-stage clinical trials.
Specific research objectives include:
- Developing cell-based therapies to address major health threats, including chronic and acute viral infections, as well as other high-priority pathogens, using engineered human CAR-T cells that have been developed with T regulatory function, producing CAR-T cells with varying functions, potentially mitigating tissue damage.
- Developing LNP mRNA systems that enable in vivo CAR-T cell therapy to avoid many of the complexities associated with ex vivo approaches.
P4. Biological Resilience, Antimicrobial Resistance, and Health Threats
Within the context of human health threats, antimicrobial resistance (AMR), whereby pathogens develop strategies to protect themselves against current drugs, constitutes one of the major public health threats at a global level, driven in part by widespread use of antibiotics. The transition of zoonotic infections from animals to humans represents another important way resilience mechanisms can emerge, with significant consequences for human health. No new classes of antibiotics have been discovered in the last 40 years, and the pipeline for new antibiotics is severely limited and focused on relatively few high priority pathogens. Hence, projects under this priority area will focus on applying immuno-engineering to address AMR in new ways beyond current approaches, with the following objectives:
- Using multidisciplinary structural biology approaches involving X-ray crystallography NMR and cryo-EM to refine the structures of macromolecular assemblies that facilitate broad-spectrum resistance, for example, to beta-lactam antibiotics, and develop further the design of inhibitors that either block existing antibiotic-resistance mechanisms or address virulence factors such as the type 3 secretion system (T3SS) used by several WHO pathogens as essential virulence mechanisms for invoking disease in humans.
- Developing host-directed therapies based on natural antimicrobial compounds, such as host defense peptides, that have both antimicrobial and immunomodulatory functions in vivo, including preclinical studies to bring candidates forward to commercialization.
- Developing understanding on how the human microbiome has a direct effect on immunity and antimicrobial genes and their contribution to disease protection or pathogenesis.
- Developing collaborations from laboratory to clinical trial to commercialization to develop innovative solutions for addressing AMR.
- Developing the LNP-mRNA platform to develop new vaccines against select pathogens exhibiting AMR with focus on clinically relevant Gram-negative bacteria, including enteropathogenic Escherichia coli, Salmonella enterica and Pseudomonas aeruginosa, using genomic, proteomic, and reverse vaccinology approaches.
- Developing and assessing candidate LNP mRNA vaccines in animal models.
- Moving successful vaccine candidates forward to commercialization.
- View the four cross-cutting themes