Human monoclonal antibodies for SARS-CoV-2
Antibodies are the principal mediators of protection against viral infection and severe disease after vaccination or natural infection. Increasingly, we are gaining the capacity to harness this natural form of protection as a drug strategy for prevention or treatment.
Our research team at Vanderbilt is fully focused on isolating and validating the effectiveness of human monoclonal antibodies (mAbs) for infectious diseases, especially those agents with the potential to cause major epidemics or pandemics. We live and breathe this stuff. We are pursuing a program we have termed AHEAD100, to generate best-in-class neutralizing human antibodies for the 100 most likely causes of epidemics. We are well into this ~ 10 years of work, with the discovery of potent human mAbs for poxviruses, filoviruses, flaviviruses, alphaviruses, paramyxoviruses, influenzas, bunyaviruses and many others. [We are seeking philanthropic support of ~ $1-2 B total to move each of the leads into Phase I trials].
The philosophy is to develop the solution ahead of time so we are ready when outbreaks occur and don't have to scramble as we have done for so many recent events (avian influenzas, SARS, chikungunya, Ebola, Zika, etc). This seems like such an obvious pattern, why do we not have the will as a people to address these problems proactively? or finish the job when we start in on the work? There is the casual proverb "Fool me once . . . fool me twice, shame on me", suggesting that after being surprised once, one should be wary to avoid being surprised again. If you look at the Wikipedia list of epidemics we have been fooled not twice but hundreds of times. I spoke about this recurring nature of epidemics in a TedX talk in 2017. Things haven't changed, except maybe these are now bigger, faster, more frequent.
However . . . . we know we don't yet have mAbs for everything possible, so we also have been developing platform technologies for moving as fast as possible in the case that a pandemic occurs. We are participants in the DARPA Pandemic Prevention Platform (P3).
And got amazing support from Merck KGaA through the Future Insight Prize for Pandemic Protection
. . and other encouragements. The idea of these programs is to develop ultra-fast techniques for developing and testing antibody therapeutics.
In reflection, developing rapid response platforms even at the turn of the year in 2020 felt like a fun, challenging exercise. Last year we did a simulated all-out "sprint" in which we did a timed exercise for rapid mAb discovery while tweeting out the progress live to the world.
That public sharing felt risky at the time, to show people the actual real-time progress of the work, with the inevitable obstacles, instrument failures, and logistical difficulties. The process was a little like improv, with the game "Yes, And", which is very simple. Actors are required to accept their fellow actors' ideas (or in our case unexpected glitches) and build on them. We went from a blood sample to complete protection of nonhuman primates in 78 days. The challenge and success was exhilarating (our paper on this 'sprint' effort will be out shortly). But no one was actually dying. Little did we know we were going to do this work for real very shortly, in a much more sobering and stressful environment.
By the third week of January, we activated our team on the fly to make human mAbs for SARS-CoV-2, working with colleagues to study the B cells of the first cases in North America (including case 1).
This work was exceptionally challenging in so many ways. Launching a full-on 24/7 discovery effort without any real personal planning of our own lives was very disruptive. Our Vanderbilt COVID team members worked every day since January, sometimes 20 hours a day, and back to work after a nap. We had to buy sleeper couches for the breakroom. No one had planned for this. I personally was attempting to do a brief strategic planning sabbatical in Italy, which immediately became an epicenter around me for the epidemic, and essentially I had to evacuate in March on one of the last flights out of Rome to the US. (Now it isn't possible to fly to Italy from the US, as national fortunes have reversed). Lacking reagents and assays, we launched without a clear path forward. But the improv impulse kicked in rapidly.
We figured out in real-time how to sort on our Sony cytometer, stimulate, and interrogate single spike protein-specific B cells, and even perform single B cell neutralization assays on a Beacon microfluidic device.
We also took advantage of recent developments in single-cell RNAseq and synthetic genomics with rapid synthesis at Twist Biosciences to run simultaneously a parallel discovery platform (redundancy mitigates the risk of failure).
Both pipelines delivered amazingly potent antibodies.
The teams at Vanderbilt and Wash U developed real-time 384-well plate neutralization assays on an xCelligence cell impedance device, on the fly, in BSL3 conditions.
The world research community committed to unprecedented rapid sharing of sequences, structures, and other essential information. Our many gifted collaborators at Wash U, UNC, Beth Israel, AstraZeneca, Emory, Univ Washington, and Univ of Toronto did all that was possible, as fast as is possible. Technology companies like Berkeley Lights, 10X Genomics, and Twist Biosciences went to extraordinary lengths to support the work, including sending instruments and applications specialists to us in Nashville.
We tried to communicate constantly with the public along the way about what we were doing, including participating in some better-produced segments with talented communicators, for ex. this Seeker episode that saw over 100k views, and this animated communication about our COVID-19 work, podcasts (Epidemics with Celine Gounder) etc. We did the best we could to communicate while keeping the trains running.
A lot of craziness occurred, with too many stories to tell.
A cat sitting on a delivery box containing $250,000 of synthesized human mAb cDNAs.
A lost shipment of blood cells in an international airport tracked down by Fedex Critical.
Deliveries at home every Sunday!
Drive-by touchless pickups in Walgreens parking lots. The remarkable generosity of the amazing businesswoman and philanthropist (not to mention legend) Dolly Parton. Studies of an exceptionally motivated survivor who flew to Nashville to donate samples, including 3 blood draws in 18 hours with realtime results for each and adjustment of experimental parameters in the moment, the last draw a stopover en route to the Nashville airport for a flight minutes later.
In the end, we made nearly 2,000 antibodies from a sample we received March 14, downselected with in vitro studies, two mouse challenge models, and nonhuman primate studies, and out the back end of this pipeline there are now dozens of promising mAbs. We achieved 100% protection of monkeys with monotherapy. We describe the work in detail in an article in Nature out today. Many of the technical innovations in pipeline development were described last week in a paper in Nature Medicine. Several of these mAbs will be in the clinic in Q3 2020 with two different commercial partners, IDBiologics and AstraZeneca. As academics at Vanderbilt, we don't do GMP manufacturing or clinical trials. I am grateful to the talented scientists and business teams at these companies who are racing forward to finish the job.
We are all hopeful to make a positive impact on public health with this work.
Proud of our many, many dedicated collaborators and our team at Vanderbilt.
Good science is team science.