The first is a Phase I trial in the US, a multi-centre, randomised, double-blinded, placebo-controlled single and multiple ascending dose study to assess the safety, tolerability and pharmacokinetics of IGM-6268 administered intranasally in healthy volunteers. The second is a Phase Ia/IIb clinical trial in South Africa and is a multi-centre, randomised, double-blinded, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of IGM-6268 administered intranasally – first in healthy volunteers and once an appropriate dose cohort has been cleared, in outpatients with mild to moderate COVID-19.
Neutralising mAb therapies offer a key advantage in the fight against COVID-19”
Having shown significantly increased potency against wild-type SARS-CoV-2 relative to an immunoglobulin G (IgG) antibody with the same binding domains, IGM-6268 has also exhibited potent neutralisation against the Alpha (B.1.1.7), Gamma (P.1) and Beta (B.1.351) variants of SARS-CoV-2, as well as other receptor binding domain (RBD) mutants that conferred resistance to several IgG antibodies authorised for emergency use.
Following this, IGM Biosciences has also announced that results from in vitro pseudovirus testing indicate that IGM-6268 exhibits neutralisation of the Omicron (B.1.1.529) variant at an IC50 of 230 ng/mL, as well as potent in vitro neutralisation activity against other SARS-CoV-2 variants of concern and variants of interest.
Here, Dr Chris Takimoto from IGM Biosciences provides further detail about how IGM-6268 works to tackle SARS-CoV-2 and delves into the most promising results seen during pre-clinical studies of the antibody.
Why are mAbs particularly of interest in the fight against SARS-CoV-2?
Neutralising mAb therapies offer a key advantage in the fight against COVID-19 – high specificity and potency against targeted viral antigens and therefore, minimal off-target effects. However, traditional monoclonal IgG neutralising antibodies also have a key vulnerability which is high susceptibility to the emergence of resistance in mutant viral variants. At IGM Biosciences, we design and manufacture engineered monoclonal IgM antibodies, which our pre-clinical data suggest offer improved resilience against the emergence of viral resistance, as well as superior potency, all while exhibiting the hallmark high specificity of traditional mAbs.
How did you discover and develop IGM-6268?
IGM Biosciences has worked to overcome the manufacturing and protein engineering hurdles that have traditionally limited the therapeutic use of IgM antibodies and has created a proprietary IgM technology platform for the development of this class of antibodies for those clinical indications where their inherent properties may provide advantages as compared to IgG antibodies. As IgM antibodies are the first antibodies produced by the immune system when a virus attacks, we took a keen interest in applying our technology platform to the fight against COVID-19 and through a collaboration with the University of Texas System, US developed IGM-6268.
Can you explain the mechanism of action for IGM-6268?
The primary mechanism of action of IGM-6268 is to block the binding of the SARS-CoV-2 RBD on the virus spike (S) protein to human angiotensin converting enzyme 2 (hACE2), the cellular receptor for SARS-CoV-2. By blocking this binding, IGM-6268 neutralises the infectivity of the virus. As IGM-6268 is an IgM antibody, it has 10 antigen binding domains, versus the two in an IgG antibody. This translates into much higher avidity, or overall binding strength, to SARS-CoV-2 for IGM-6268 than for an IgG antibody with the same antigen binding domains to the virus.
What have your most promising pre-clinical results for IGM-6268 shown and how have you shown the antibody is effective against SARS-CoV-2 variants of concern?
In pre-clinical animal studies, IGM-6268 has been shown to be highly effective in preventing and treating experimental SARS-CoV-2 infection after intranasal administration. Due to its ability to bind to SARS-CoV-2 with high avidity, or overall binding strength, IGM-6268 has demonstrated much greater neutralising potency against wild-type SARS‑CoV-2 in in vitro neutralisation assays than an IgG antibody with the same antigen binding domains to the virus. IGM-6268 has also demonstrated potent in vitro neutralisation activity against all SARS-CoV-2 variants of concern and variants of interest tested to date, including the Omicron (BA.1) and Delta variants.
IGM-6268 is currently in Phase I trials – has it shown success here and what are the next steps for its development?
We anticipate that preliminary data from our global Phase I trials will be available in mid-2022. At the same time, we are working to understand how the therapeutic landscape for COVID-19 is evolving and to identify key existing or emerging areas of unmet medical need for patients.
About the author
Dr Chris Takimoto has served as IGM Biosciences’ Chief Medical Officer since 2021. He joins IGM with 30 years of experience in cancer research and development, most recently as Senior Vice President, Oncology, Gilead Sciences. Prior to Gilead, Chris was Chief Medical Officer of Forty Seven and he has also served as Vice President of Experimental Medicine Early Development, Oncology Therapeutic Area for Janssen Research and Development. Chris received a BS in chemistry from Stanford University, a PhD in pharmacology from Yale University and an MD from Yale University School of Medicine.