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Insider Highlights from Bioinsider’s Friday Roundtable, “How COVID-19 has Changed the Immunogenicity Risk of Immune Modulatory Biologics”

Insider Highlights from Bioinsider’s Friday Roundtable, “How COVID-19 has Changed the Immunogenicity Risk of Immune Modulatory Biologics”

Scientists are making rapid and significant strides to develop anti-COVID-19 therapeutics. However, it is vital to understand the nature of the immune response in COVID-19 infected people and, whether, the infection has an influence on the ability of the immune system to cause a differential immune response is an important consideration that needs to be evaluated during therapeutic clinical trial evaluations.

Bioinsider hosted its virtual Friday Roundtable, How COVID-19 has Changed the Immunogenicity Risk of Immune Modulatory Biologics, to discuss the impact of COVID-19-mediated immune modulation and the impact on response to investigational biotherapeutics. This discussion was moderated by Drs. Vibha Jawa, Director and Lead, Predictive and Clinical Immunogenicity, PPDM, Merck & Co Inc, and Narendra Chirmule, CEO, SymphonyTech Biologics; CSO, AcuImmune.

Critical questions posed in the discussion:

  1. Does COVID-19-mediated hyper activation of the immune system result in dysregulation of immune responses?
    • We now understand that COVID-19 evades a critical early type-1 IFN response early allowing it to spread and cause a tremendous hyperinflammatory syndrome.
      • Studies have shown that COVID-19 viral proteins bind to Toll-like receptors 3 and 8, and downstream proteins of the innate phase. This results in the inhibition of interferon (IFNα and β) production and subsequent IFN receptor-mediated signaling.
      • IL-1 and IL-6 are hallmarks of this massive systemic inflammatory response.
    • Patients treated with IFN-α, cleared the virus more quickly compared to untreated patients.
    • CD4 T-helper cells (Th1) produce cytokines the produce proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses.
      • COVID-19-induced Th1-type cytokines have been shown to damage normal tissues.
    • NK cells, macrophages, and ϒδ T-cells have also shown to be activated by COVID-19. Panel members believe that T-cell networks are being highly impacted.
    • COVID-19-induced inflammatory response is thought to increase the activation of pre-existing autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, which is why these patients are even higher risk of mortality.
    • The microbiome is also involved, but it is unknown to what degree it is impacted by COVID-19.

Investigative initiatives

    • An FDA task force has been created for collecting IFN response information from patients being treated with various biotherapeutics in current clinical trials in order to modify or prevent the disease from becoming severe.
    • Pharmaceutical companies are now ramping-up IFN-based clinical trials, where a Th1-type IFN is given prior to therapeutic administration.
    • The National Institutes for Health is conducting a detailed analysis of cytokine responses in patients infected with COVID-19.
  1. How does a hyperinflammatory immune response affect biotherapeutics?
    • It is really a black box. Scientists don’t understand the effect of the hyperinflammatory state on immunogenicity on biotherapeutics.
    • Experts who have experience treating patients with familial hemophagocytic lymphohistiocytosis and macrophage activating syndrome, which have a similar a similar hyperinflammatory disorder similar to that observed in patients infected with COVID-19, are unsure if whether there would be an enhancement or diminished response to protein therapeutics in this context.
    • There is also strong evidence of diminished response to protein therapeutics in preclinical models of hyperinflammation, this may suggest that patients with a hyperinflammatory response may have limited benefit.

Investigative initiatives

    • None exist. A detailed risk assessment is imperative. For example, patients should be profiled for the potential to have anti-drug (i.e. antibody/biologic) antibodies and these patients should not be treated.
  1. What is the influence of COVID-19 on B-cell responses?
    • It is known that some patients induce robust neutralizing antibodies targeting the Spike protein, while other patients have poor antibody production.
    • Contrasting observations further complicate the therapeutic relevance of neutralizing antibodies. For example, a high level of neutralizing antibodies occurs in patients with severe viral disease. However, the absence of neutralizing antibodies has also occurred in infected patients who do not develop severe disease. Taken together, these observations suggest a strong antibody response may not be therapeutically relevant for COVID-19.
    • The proportion of antibody isotype (IgG1, IgA1, 2, …, IgM) is thought to be important. Patients with delirious cell counts contained preferential levels of certain antibody isotypes. Thus, the isotype ratios are important and need to be considered.
    • Currently, evidence points to that neutralizing antibodies do not induce an increased mutation rate for COVID-19.
  1. What about use of immune checkpoint inhibitor antibodies to treat COVID-19?
    • The data is conflicting but ultimately not encouraging.
    • PD-1 has been shown to overexpressed and decreased on the cell surface of immune cells in patients infected with COVID-19.
    • A recent study showed that patients with lung cancer who were also COVID-19+ had severe infection severity (>50% hospitalizations, ~25% deaths). PD-1 blockade was not associated with an increased risk of severity of COVID-19.
    • However, a combination of concurrent IFN therapy was discussed and potentially effective.

Conclusion and open questions

The conclusions from this discussion were several, however, the most pressing is that more research is rapidly needed to understand immunogenicity of COVID-19 in its natural pathogenesis in order to identify potential responders and nonresponders to biotherapeutic therapies.

Due to high demand, Bioinsider will provide a follow-up Friday Roundtable to discuss and find potential solutions to these open questions. If you missed the first one, make sure to sign up for the follow-up Friday Roundtable on this topic here.

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James E. Crowe, Jr., MD,

Director, Vanderbilt Vaccine Center; Professor, Pediatrics and Pathology, Microbiology and Immunology, Ann Scott Carell Chair; Founder, IDBiologics

Dr. Crowe’s laboratory has a broad portfolio of work in the area of viral immunology and antibody sciences, with the goal to discover mechanisms of immunity important to developing new therapeutics and vaccines.

Dr. Crowe received his MD degree from the University of North Carolina at Chapel Hill, where he also completed his pediatrics residency. Following his clinical training, Dr. Crowe received five years of post-doctoral training in the laboratory of Infectious Diseases at the NIH. He completed infectious diseases fellowship training in 1996 at Vanderbilt and has run an independent laboratory at Vanderbilt since that time. He is currently Professor of Pediatrics and of Pathology, Microbiology and Immunology, and the Ann Scott Carell Chair, Vanderbilt University Medical Center. The laboratory’s work has been published in over 300 publications in high-quality science journals including Cell, Science and Nature, and leading medical journals including the New England Journal of Medicine and JAMA. Dr. Crowe was elected to the National Academy of Medicine in 2014 and the National Academy of Inventors in 2017. He has been the recipient of investigator awards from the March of Dimes, American Society for Microbiology, Pediatric Infectious Diseases Society, and Society for Pediatric Research. He was awarded the Judson Infectious Daland Prize of the American Philosophical Society, the Oswald Avery Award of the IDSA, the E. Mead Johnson Award for Excellence in Pediatrics, the Outstanding Investigator Award of the American Federation for Medical Research, the Norman J. Siegel Award of the American Pediatric Society, the Samuel Rosenthal Prize for Excellence in Academic Pediatrics, the Stanley J. Korsmeyer Award of American Society for Clinical Investigation, the Distinguished Medical Alumnus Award from UNC School of Medicine, Chapel Hill, NC. He is an elected Fellow of AAM, AAAS, ASCI, and AAP, IDSA, APS, and others. His research team was selected as the Best Academic Research Team at the 11th Annual Vaccine Industry Excellence Awards. He was awarded the inaugural 2019 Merck Future Insight Prize, a 1M Euro prize shared with Pardis Sabeti. 

He is the Founder of IDBiologics, Inc., an early-stage biotech company developing human monoclonal antibodies for infectious diseases.

Daniel Chen, MD, PhD

CMO, IGM Bioscience

Daniel S. Chen, MD, PhD, is the Chief Medical Officer for IGM Biosciences, and former Vice President, Global Head of Cancer Immunotherapy Development at Genentech/Roche.  He received a BS degree in Biology from the Massachusetts Institute of Technology (1990), a PhD in Microbiology & Immunology (1996), and MD (1998) from the University of Southern California. His PhD work and publications focused on “Early Events in Coronavirus Infection.”

Daniel completed an Internal Medicine Residency and Medical Oncology Fellowship at Stanford University (2003). He went on to complete a Post-doctoral fellowship with Mark Davis in Immunology, where he was a Howard Hughes Medical Institute Associate. He also ran the metastatic melanoma clinic at the Stanford Cancer Center from 2003-2006. In that time, he studied human anti-cancer immune responses pre- and post-cancer vaccination and cytokine administration to determine why anti-tumor immune responses were not more clinically effective. He received a U19 grant to develop better immunologic tools to interrogate human immune responses and ultimately patented the MHC cellular microarray to detect and functionally characterize antigen-specific T cell states.

He continued as Adjunct Clinical Faculty at Stanford from 2006-2016, where he cared for melanoma patients. At Genentech from 2006-2018, Daniel focused on the clinical development of anti-angiogenic and immune-modulatory targeted therapies in both early and late development, as well as the diagnostic tools to aid their development. This included leading the clinical development for atezolizumab, a PD-L1 inhibitor, from the time the program was in research through IND, Phase I, Phase II, Phase III, to filing and approvals in multiple indications worldwide. At IGM, Daniel focuses on the development of novel engineered multivalent and multispecific therapeutics. He is a reviewer for Nature, Immunity, and Clinical Cancer Research, serves on the Board of Directors for SITC, co-chair of the CRI cancer Immunotherapy consortium, gave the keynote presentation at the AACR NCI EORTC Annual Meeting 2014 and presented at the US Congressional Briefing on Immuno Oncology in 2017. He has continued to publish with academic and industry collaborators in the field of cancer immunotherapy, including the often-referenced Chen and Mellman manuscripts, “Elements of cancer immunity and the cancer-immune set point” and “Oncology meets Immunology: The Cancer-Immunity Cycle.”

Imre Berger

Founding Director, Max Planck Bristol Centre; Chair in Biochemistry and Chemistry; University of Bristol UK

Imre Berger was trained as a biochemist and synthetic biologist at Leibniz University and Medical School (MHH) in Hannover (Germany), at MIT (Cambridge, USA), and at ETH Zurich (Switzerland). Imre’s team develops enabling methods for DNA delivery and genome engineering, engineers synthetic vaccines and nanosensors and researches the structure and mechanism of multiprotein complexes in human health and disease. After Group Leader posts at ETH (2005) and EMBL (2007), Berger joined Bristol as Full Professor of Biochemistry (2014) with a joint appointment in Chemistry (2019). He is Founding Director of the Max Planck Centre for Minimal Biology in Bristol, Director of the BBSRC/EPSRC research center for synthetic biology BrisSynBio and Co-director of the Bristol Biodesign Institute BBI.

Imre Berger holds international patents for DNA and protein technologies, co-founded three biotech companies, and received numerous distinctions, notably the Swiss Technology Award, the W.A. DeVigier Foundation Award, and a Wellcome Trust Senior Investigator Award for his innovative research. Since 2019, he is an Investigator of the European Research Council (ERC).

Prof. Berger has participated in leading roles in numerous European Commission (EC) projects, including the pan-European structural biology infrastructure INSTRUCT. He has been Coordinator of the EC FP7 HEALTH ComplexINC project enhancing production tools for complex biologics in academic and industrial R&D (2011-2016) and is partner in the EPSRC funded Innovative Future Vaccine Manufacturing Research Hub.

Sina Bavari, PhD

CSO, Edge BioInnovation Consulting and Management; former CSO, Scientific Director US Army Medical Research Institute of Infectious Diseases (USAMRIID)

Dr. Sina Bavari is the co-founder of Healion Bio. He is one of the lead (non-gov) scientific adviser to the World Health Organization on SARSCoV-2. He has spent over 30 years developing rapid response diagnostics, prophylaxis, therapeutics, and vaccines for some of the world’s deadliest infectious diseases. Prior to co-founding Healion Bio, Dr. Bavari founded Edge BioInnovation Consulting and Mgt. and was the Chief Scientific Officer and Scientific Director at USAMRIID (US Army Research Institute of Infectious Diseases), where he spent over twenty years leading the discovery and development of vaccines, therapeutics, and diagnostics or diseases such as SARS and MERS CoVs, Ebola, Marburg, Zika, Smallpox, Sudan, Nipah, alpha viruses, Anthrax and many others. He has worked extensively with the FDA to successfully develop clinically proven countermeasures for many so-called envelope viruses like SARS-CoV-2. Dr. Bavari has contributed to ~20 drug development candidates such as Remdesivir, 30 patents, and many IND filings. He has trained over 70 scientists and managed over 500 scientists and supporting staff. His work has resulted in over 350 publications in many of the leading scientific journals including Nature, Nature Medicine, Cell, Cell Hosts, New England Journal of Medicine and many others. He has degrees from USC, and the University of Nebraska where he received his PhD in Immunotoxicology and Pharmaceutical Science.

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Ralph Rogers, MD

Assistant Professor of Medicine, Clinician Educator, Infectious Diseases, Warren Alpert Medical School of Brown University

Ralph Rogers, MD is an infectious disease specialist at the Lifespan Cancer Institute. He earned his medical degree from The Warren Alpert Medical School of Brown University where he also completed his residency and fellowship in infectious diseases. Dr. Rogers is Assistant Professor of Medicine, Clinician Educator Division of Infectious Diseases Warren Alpert Medical School of Brown University. He is a member of the Infectious Diseases Society of America (IDSA), the American Society for Microbiology (ASM) and the American Society of Transplantation (AST).

John Sninsky, PhD

Consultant, Translational Sciences

John J. Sninsky, PhD is a translational medicine consultant with deep understanding of diagnostics and diagnostics paired with medicine intervention. John has served in senior management positions in small and large CLIA service laboratories and in vitro diagnostic kit companies including Cetus, Roche Molecular Systems, Celera, Quest and CareDx. He was a member of the pioneering Cetus team that developed and optimized PCR technology for research and diagnostic use; specifically, the virology team developed the HIV, HTLV, HPV, HCV and HBV PCR assays. John put in place a surveillance initiative for viral variants and presented at the first FDA PMA advisory meeting for HIV PCR approval.

Timothy J. O’Leary, MD, PhD

Adjunct Professor, Pathology, University of Maryland School of Medicine; Former Chief Research and Development Officer, Veterans Affairs

Timothy O’Leary, MD, is Adjunct Professor of Pathology at the University of Maryland and served as Chief Research and Development Officer (CRADO) of the Department of Veterans Affairs from 2013-2015. He holds a doctorate in physical chemistry from Stanford University and a medical degree from the University of Michigan.

He is certified in anatomic pathology by the American Board of Pathology and in molecular genetic pathology by the American Board of Pathology and the American Board of Medical Genetics. Prior to his VA service, O’Leary chaired the Department of Cellular Pathology and Genetics at the Armed Forces Institute of Pathology for more than 15 years. He joined VA in 2004 and served as Director of Biomedical Laboratory Research and Development, Director of Clinical Sciences Research and Development, and Deputy CRADO prior to his appointment as CRADO. O’Leary also served as a reserve member of the Public Health Service Commissioned Corps from 1979 to 2010, serving two tours on active duty. His research interests include genomics, proteomics, and ultrasensitive detection of biological toxins. He has served on numerous federal panels and advisory committees, including the Health and Human Services Clinical Laboratory Improvement Advisory Committee and the Food and Drug Administration Hematology and Devices Panel. O’Leary, the holder of four patents, has authored or co-authored more than 190 journal articles and numerous book chapters and technical reports. He is a past president of the Association for Molecular Pathology and served as editor-in-chief for the Journal of Molecular Diagnostics.