Novalia Pishesha

The Pishesha Lab studies the biological complexities of antigen processing and presentation. We explore how these processes can be manipulated to modulate immunity. To that end we use engineered nanobodies and -for some applications- engineered red blood cells. Our research involves basic immunology, protein biochemistry, chemical immunology, and immune engineering.

Nanobodies: A Cornerstone of Our Research

The tools we use are nanobodies (also known as VHH, or variable heavy domains of heavy-chain-only antibodies, expressed recombinantly) derived from camelid species. These molecules combine antibody-like precision in the recognition of three-dimensional targets with simplicity in their manufacture and modification. We perform alpaca immunization campaigns, nanobody library construction and screening to identify nanobodies with the desired properties (specificity, affinity, inhibition of target function(s)). We collaborate with colleagues across the Greater Boston area and beyond. We use chemical and enzymatic conjugation methods to engineer nanobodies into therapeutic agents, immune modulators, and tools for biochemistry and non-invasive immune imaging (e.g. IVIS or PET).

Therapeutic Applications

For therapeutic applications we use modified nanobodies to suppress unwanted immune responses. This is achieved through control of timing and location of anti-inflammatory cues delivered to immune cells. The goal is to generate durable, antigen-specific immune tolerance and thus modify the course of autoimmune and allergic diseases. To evaluate these strategies, we study diverse preclinical mouse models of autoimmunity (multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus) and allergy (asthma). Where possible, we include patient-derived samples to bridge the gap between preclinical findings and clinical application.

As a counterpoint, we have developed nanobody-based approaches to enhance immune responses. These efforts address the less-than-optimal immune responses often seen in infections with flu, malaria and in cancer. Our goal is to use modified nanobodies to improve the effectiveness of immunotherapies for both cancer and infectious diseases.

Immune Imaging

To improve our understanding of how the above interventions work, we use nanobody-based positron emission tomography (immunoPET). This non-invasive imaging method enables visualization of antigen-specific immune responses in vivo and an assessment of the effects of the therapeutics we are developing. Immuno-PET can provide critical insights into the dynamics of immune responses and the therapeutic efficacy of nanobody-based interventions.