Mehdi Arbabi, Ph.D.

Senior Research Officer

Department of Immunobiology and Cancer Immunology, Human Health Therapeutic Research Center (HHT), National Research Council Canada (NRC)

Speaker Bio:

As a former member of the camelid heavy chain-only discovery team in Belgium and a leading scientist in the field of Camelidae single-domain antibodies (sdAbs), Dr. Arbabi has significantly contributed to the development of Camelid single-domain antibody technology and the establishment of proof-of-principle for VHH/sdAbs/Nanobodies as novel antigen-binding reagents for the first time. These antibody domains are now a leading class of therapeutic molecules for treating cancer and infectious diseases. Dr. Arbabi has been involved in numerous research projects aimed at developing therapeutic molecules against cancer and infectious diseases, most notably the development of anti-Campylobacter nanobodies for the treatment of diarrheal illness, which is currently in phase II clinical trials with Lumen Bioscience. Dr. Arbabi has also co-led another research project to develop anti-CD22 CAR-T cells using nanobodies. This project has received more than $1.5 million CAD in funding, and its preclinical phase has now been approved by Health Canada. He has also been part of recently awarded Multiple Myeloma and OICR grants (over $1 million) to NRC, Ottawa U, and OHRI. His scientific investigations have resulted in 16 patents and 50 peer-reviewed scientific articles and book chapters. Dr. Arbabi was awarded an NRC-IBS Industrial Partnership Award in 2011 for his contributions to human sdAb technology development, which led to collaborative work with Novartis, an NRC Outstanding Achievement Award in 2016 for the IGF1R BBB-crossing antibody work, and an NRC Intellectual Property Award for the development of anti-CD22 CAR-T cells in 2020.

Talk title:

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22

Talk abstract:

Camelid single-domain antibodies (sdAbs) (also known as VHH or nanobodies) have been widely developed as unique reagents with high specificities for fighting against a wide range of diseases including cancer, inflammation, haematology and infectious diseases, as well as for diagnostic and imaging applications. With the approval of the first dimeric VHH-based therapeutic (Caplacizumab) by EMA and FDA and the first CAR-T based nanobody Ciltacabtagene autoleucel (Carvykti, Jannsen Biotech Inc.) by FDA, VHH-based therapies are gradually finding their niche in the biologics and cell therapy markets. As immunotherapeutic reagents for Chimeric antigen receptor (CAR) T cell therapies, nanobodies are particularly well positioned due to their small size and easier assembly than single-chain variable fragments (scFvs) which has been used in most CARs. In this study, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adultLlama glamawith CD22 recombinant protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansionin vitro,although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb.

Scott McComb, Ph.D.

Research Officer

Department of Immunobiology and Cancer Immunology, Human Health Therapeutics Research Center (HHT), National Research Council Canada (NRC)

Speaker Bio:

Dr. Scott McComb is a researcher with the National Research Council Canada's (NRC) Cancer Immunology team, working to develop the next generation of chimeric antigen receptor T-cell therapy (CAR-T) and other immunotherapies for cancer. Before joining the NRC in Ottawa, Dr. McComb earned his Ph.D. from the University of Ottawa, followed by postdoctoral studies on cell death pathways in pediatric acute lymphoblastic leukemia in Zurich, Switzerland. Dr. McComb works with a multidisciplinary team at the NRC to design new CAR molecules based on the unique properties of antibodies derived from llamas (known as nanobodies), testing the functionality of these nanobody-CARs for reprogramming human T cells or natural killer (NK) cells to kill cancer cells both in vitro and in mouse models. Dr. McComb led the Canadian team that developed a highly active CAR targeting human CD22 for the treatment of lymphoma and leukemia, which is planned to enter clinical trials in Canada in 2024. In the long term, Dr. McComb aims to create an open toolbox of CAR components that can be used by clinicians and researchers across Canada to build the next generation of safe, effective, affordable, and accessible cell therapies.

Talk title:

Broadly Reactive Anti-VHH Antibodies: A Powerful New Tool for Characterizing, Blocking, or Activating Nanobody-Based Therapies

Talk abstract:

Production of chimeric antigen receptor T-cell (CAR-T) therapies depends on the use of antibody reagents to label, isolate, and/or expand T-cell products. We sought to create antibody-based tools that directly target the variable domain of heavy-chain-only antibodies (VHH or nanobodies) used in some CAR molecules. Two murine antibodies were identified that bind to distinct epitopes in the conserved framework regions of llama-derived VHHs, but not to human VH domains. We produced a high-quality dual-clonal anti-VHH antibody product that reacts with over 98% of VHH proteins, regardless of their antigenic specificity. Anti-VHH binding did not disrupt the VHH/antigen interaction and could thus be used for secondary labeling to assess the cellular or tissue reactivity of VHH molecules. This anti-VHH labeling reagent was widely deployed to generate important VHH and VHH-CAR characterization data, supporting the development of CD22sdCAR-T, which is currently entering a first-in-human clinical trial in Canada. We also found that anti-VHH antibodies were highly effective at blocking CAR-T activation and cytolytic killing of target cells, and thus could be applied as a titratable CAR inhibitor in preclinical or clinical CAR therapies. When immobilized, anti-VHH antibodies could also be applied to activate and expand VHH CAR-T cells, inducing a 730-fold mean expansion, >94% CAR purity, with retained CD8/CD4 heterogeneity. Functionally, anti-VHH antibody-expanded CAR-T cells maintained strong antigen-specific activity without functional exhaustion. Overall, these data identify a useful new tool for understanding and manipulating VHH-based CAR-T cells.

Risini Weeratna, Ph.D.

Director of the Disruptive Technology Solutions for Cell and Gene Therapy Program

Human Health Therapeutic Research Center (HHT), National Research Council Canada (NRC)

Speaker Bio:

Dr. Risini Weeratna is the Director of the Disruptive Technology Solutions for Cell and Gene Therapy Program at Human Health Therapeutics Research Center of the National Research Council Canada. In this role, she provides scientific leadership and strategic vision for the Program which is aimed at developing innovative technologies to help enable affordable engineered cell and gene therapies for chronic diseases and rare genetic disorders affecting Canadians, and coordinating a national effort to increase accessibility of these therapies. Prior to joining the NRC, Dr. Weeratna was a Senior Principal Scientist at Pfizer Vaccine Research and Associate Director, Pharmacology at Coley Pharmaceutical Group.

Dr. Weeratna is a Fulbright and a Killam scholar with 25+ years’ experience in the biopharmaceutical industry and holds a MSc in bacteriology from University of Wisconsin-Madison, USA and PhD in microbiology/immunology from Dalhousie University, Nova Scotia, Canada.

Talk title:

Advancing Innovations in Engineered Cell & Gene Therapy in Canada

Talk abstract:

With decades of fundamental research in cancer and genetic diseases, and recent advances in synthetic biology, microfluidics, immunotherapy, stem cell research, and gene editing technologies, many opportunities to develop safer and more effective engineered cell and gene therapies exist today. However, there are still significant limitations to the pace of innovation, and the prohibitive costs of commercial treatments limit the accessibility of these therapies in Canada.

The Cell and Gene Therapy (CGT) Program hosted by the Human Health Therapeutic Research Center of the NRC is aimed at developing disruptive technology solutions to help enable affordable engineered cell and gene therapies for chronic diseases and rare genetic disorders affecting Canadians and coordinating a national effort to increase accessibility. Through this Program, we have built a pipeline of novel therapeutics, some of which will advance to human clinical trials within the 7-year lifetime of the Program. We have also built a robust set of tools and technology platforms to advance the development of engineered cell and gene therapies and to facilitate cost effective biomanufacturer of these therapies. The talk will provide an overview of NRC’s CGT Program, opportunities to collaborate and the therapeutics, tools and technologies built to date that are available to advance innovation of CGT.