Dr. Novalia Pishesha, Boston Children Hospital and Harvard Medical School lectures on Engineered Nanobodies

UIPS International Seminar Programme

Dr. Novalia Pishesha, Division of Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, USA
Title: Engineered Nanobodies to Direct and Visualize Immune Tolerance

Wednesday October 7^th 10.00-12.00, David de Wied Building M1.01

Hosted by Robine Janssen, r.janssen4@uu.nl

Short Bio:

Novalia (Nova) Pishesha grew up in Indonesia as the daughter of toy shop owners with no formal high school education. Recognized early for her academic talents, she emigrated to the United States alone to pursue higher education. Nova attended the University of California, Berkeley, on a full-ride scholarship and later earned her PhD in Biological Engineering at MIT under the mentorship of Drs. Harvey Lodish and Hidde Ploegh. After PhD, Nova was elected as a Junior Fellow at the Harvard Society of Fellows, where she continued her research with Dr. Ploegh and received additional mentorship from Dr. Aviv Regev and Dr. Sangeeta Bhatia at the Broad Institute and the Koch Institute, respectively. Her work has laid the foundation for three biotech companies, including Cerberus and Orthrus Therapeutics, which she co-founded in 2022 and 2025, respectively. Nova has been honored with several awards, including the MIT Technology Review’s Innovators Under 35 (Asia Pacific) and the STAT+ Wunderkind by The Boston Globe. She is the recipient of the National Multiple Sclerosis Foundation Career Transition Award, the Rheumatology Research Foundation Innovative Award, and Breakthrough T1D Career Development Award. In January 2024, she launched her own lab as an Assistant Professor in the Division of Immunology at Boston Children’s Hospital and Harvard Medical School, focusing on advancing immune engineering to combat pathogenic immunity and infectious diseases.

Abstract: 

Current treatments for autoimmunity and allergy primarily manage symptoms rather than cure disease. We propose a curative nanobody-based approach that selectively silences pathogenic responses to specific antigens or allergens while preserving protective immunity, achieving durable antigen-specific immune tolerance. We also developed nanobody-based tools to map antigen processing and T cell responses in vivo, enabling precise visualization and quantification of tolerance induction and immune regulation at the molecular and cellular levels. We developed an engineering-based solution using alpaca-derived nanobodies (VHHs) that recognize all MHC class II molecules (VHH_MHCII). We covalently conjugated disease- or allergen-specific peptides-derived from myelin, insulin, and citrullinated collagen, as well as the model antigen ovalbumin (OVA) and house dust mite allergen to VHH_MHCII together with the anti-inflammatory drug dexamethasone (VHH_MHCII-antigen-DEX). A single dose of these trimodal conjugates induced durable, antigen-specific tolerance by promoting deletion, anergy, and regulatory differentiation of antigen-specific T cells. VHH_MHCII-Myelin-DEX reversed experimental autoimmune encephalomyelitis, VHH_MHCII-collagen peptides-DEX halted arthritis progression, and intranasal delivery of VHH_MHCII-OVA-DEX reduced OVA-specific IgG/IgE, mast cell activation, and airway inflammation. This approach imposed long-lasting tolerance in prophylactic and therapeutic settings while maintaining systemic heterotypic immunity. Complemented by newly developed nanobodies for tracking antigen-specific T cells, functionalized for fluorescence and positron emission tomography (PET) imaging, we achieved real-time visualization of antigen processing and tolerance induction. Together, these tools reveal how APC networks orchestrate tolerance and establish a modular, low-cost platform for antigen- and allergen-specific immunotherapy. The available human-specific version of VHH_MHCII broadly cross-reacts with human and non-human primate MHC class II alleles, which enables translation of the proposed approach to a clinical setting.