Engineering New Therapeutic Solutions for COVID-19

As a pandemic respiratory virus, SARS-CoV-2 presents a number of challenges for emerging therapeutics. From active immune suppression, infection in different compartments and microenvironments within the host, to mutations and variants, an emerging understanding of the complexity of COVID-19 virus and host biology interactions is urgently needed.

These and critical characteristics of the viral infection will be discussed during the upcoming virtual event, Therapeutic Pipeline for COVID-19, produced by Bioinsider. Dr. Emily Le, producer of the event, got together with Dr. Chen of IGM Biosciences to learn more about his research and how it can be applied to addressing the complications associated with COVID-19.

EL: Tell us about your background and current role

DC: I am a trained medical oncologist, immunologist, and virologist. I am currently the chief medical officer at IGM Biosciences, and I was the former vice president, global head of cancer immunotherapy at Genentech/Roche. I received a Bachelor of Science 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.

My PhD work and publications focused on “Early Events in Coronavirus Infection.” I then completed an Internal Medicine Residency, Medical Oncology Fellowship at Stanford University (2003) and a post-doctoral fellowship with Mark Davis in Immunology. I also ran the metastatic melanoma clinic at the Stanford Cancer Center from 2003-2006. In that time, I 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.

I was also part of 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 in cancer and post-different influenza vaccination approaches. I’ve continued to be interested in the intersection between engineering and biology, and have 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.”

EL: Why did IGM Biosciences choose IgM or IgA antibodies as opposed to traditional IgG antibodies, specifically when moving to COVID-19?

DC: IGM Biosciences has focused on the development of engineered IgM and IgA antibodies for the treatment of viral diseases such as COVID-19 due to inherent differences and potential advantages of this therapeutic platform: high avidity, high specificity and high affinity for the target, active transport to tissue compartments such as the mucosa of the respiratory and GI tracts where viruses primarily infect, and the larger surface area of these molecules when binding and coating a pathogen. These features may enhance the benefit of neutralizing therapeutic antibodies in terms of potency, compartment effect, antibody-dependent enhancement, and viral variants.

EL: As a physician, are there any concerns or unique aspects to pay attention to when administering IgM or IgA antibodies over IgG antibodies? Could one concern be a PK-toxicity relationship?

DC: Engineered IgM and IgA antibodies, which are distinct from natural IgM and IgA antibodies, have different characteristics to be aware of, that are considerations for development. One relates to the relatively shorter expected circulating exposure—which may improve the safety profile and enhance biologic modulation in specific circumstances—due to more rapid clearance and distribution to different compartments, but may also affect dosing, dependent on the application and route of administration.

EL: Will you orchestrate any upcoming clinical trials for current IGMs antibody candidates?

DC: IGM-2323 and IGM-8444 are both clinical phase therapeutics currently in testing for lymphoma and solid tumors. Clinical studies for COVID19 therapeutics may be initiated in 2021, if supported by ongoing pre-clinical data.

EL: How does your training as both a physician and scientist prepare you for your new encounter with COVID-19?

DC: Development of new human therapeutics requires a clear understanding of both biology and human health and disease. By training in both areas, scientific and engineering advances can be properly focused and developed in terms of being clearly directed at specific clinical challenges and patient needs.

EL: I believe you are an oncologist/immunologist by training. How have your roles and skill sets had to adapt for a virology context with COVID-19?

DC: Per the above, I’ve trained in these three distinct disciplines. With an understanding of biology across these areas: the intersection of coronavirus biology and human immunity are clearly translating for COVID19. The medical oncology training, patient care and oncology drug development provide a clear appreciation and experience for drug development—what can we learn from pre-clinical studies, what do we need to establish in First in Human studies, and the challenges of accelerated approvals in high unmet need areas and Global Confirmatory studies.

EL: What is your message to the scientific community, who are working tirelessly to find a cure for COVID-19?

DC: Never before in our lifetimes have we faced a medical and scientific challenge like COVID-19 and SARS-CoV-2. This is our moment. It is our responsibility as a community to conquer this pathogen as rapidly and successfully as possible, with as many different approaches as we are capable of. It is a difficult challenge, but with appropriate collaboration and effort, it is doable. Failure is not acceptable.