Towards a Universal Immunotherapy
Harnessing the immune system with protein engineering.
This is Part 2 in our New Science research series, where our Fellows explain the visions behind their work. This post was written by Avadhoot Jadhav.
Pathogens constantly spread, infect, and evolve. Lower respiratory tract infections and diarrheal diseases remain amongst the world’s top five leading causes of death. More than 6 million people — a conservative estimate — have died from COVID alone and new variants continue to emerge. Despite the threats that pathogens pose, we have limited tools to design drugs to fight them. Indeed, drug discovery remains a lengthy, costly, difficult, and inefficient process. In the COVID19 pandemic, nature is (kind of) winning — vaccines and antibodies help, but it is hard to keep up with an evolving virus.
Mother Nature can serve as a source of inspiration for drug design. The human immune system has its own unique method to keep pace with evolving pathogens. And, no matter how virulent a pathogen is, the human species has so far managed to adapt and (largely) survive.
It is thanks to proteins in our blood, called antibodies, that we can swiftly shut down dangerous invaders. With protein ‘tips’ of a flexible design, antibodies can “see” different structural features in a pathogen’s proteins. Upon binding to a viral invader or other pathogen, the antibodies signal and recruit various immune components, such as effector cells (a type of white blood cell), to eliminate infected cells.
Although we have gained some knowledge of how the immune system operates, the sheer complexity involved in its adaptive behavior is not easy to understand. But imagine if we could replicate this process synthetically. I propose a therapeutic strategy to do so, using protein engineering.
Physicians and scientists have made many attempts to manipulate the immune system. Vaccination and passive immunization are two examples, and both have been wildly successful, with millions of lives saved.
By exposing your body to a weakened version of a pathogen, or just a piece of a pathogen, one can train the immune system to produce antibodies that help fight that pathogen when it is first encountered in the wild. Despite the success of vaccines in tempering the COVID19 pandemic, there is already evidence of enhanced transmissibility and reduced vaccine effectiveness against emerging variants of concern, including Delta and Omicron. Current vaccines also have a narrow target range.
Moreover, a slow vaccination drive tends to increase selection pressure on the pathogen, leading to the emergence of more infectious variants. Current vaccines cannot keep up with new variants, and revamped generations of vaccines are constantly required. There are also psychological and logistical limits to how often people can be vaccinated, and we are still collecting data about these vaccines and immune-related adverse events.
At Caltech, Pamela Bjorkman has developed a mosaic-nanoparticle based vaccine that covers a broad range of targets, including variants of concern. Still, it can only prevent new infections once vaccine-driven immunity has built up, which takes time; it cannot deal with established infections.
Passive immunization is one alternative to vaccines — people are given antibodies that recognize the pathogen in question. But monoclonal antibodies, while efficacious, are expensive. Regeneron’s two-drug cocktail for COVID19 costs around $1,250 per infusion, according to Kaiser Health News. Monoclonal antibodies also must be kept cold, so as not to lose their efficacy. Even minor changes in a target virus’ protein structures can reduce the antibody’s effectiveness. That is why we still need a sustainable, cost-effective therapy with broad target specificity.
Two years ago, I was studying drug resistance in malarial parasites (as a part of the iGEM IISER Pune Team). It was then that I realized how structural changes in a viral protein, caused by mutations from drug-driven selection pressure, can be a root cause of therapies losing their efficacy. Naturally, I wondered: If shifting proteins can evade antibodies and cause this problem, maybe they can also provide a solution. After all, if nature has managed to devise an adaptable approach for keeping up with new pathogens, why can’t medicine do the same?
Proteins are modular in nature and are composed of domains, which are independently folded regions within a protein. Such modularity enables functional protein domains to be joined together synthetically or genetically, with the goal of altering their function to modulate the immune system. The therapeutic efficacy of a protein of such a design can be enhanced by choosing fusion partners that selectively target particular cell types or receptors.
Nanobodies — the smallest immune recognition modules derived from a unique class of antibodies found only in camelids — serve as the perfect functional building blocks to create such fusion constructs. They can recognize antigens, they are easy to produce and — equally important — they are cheap to make. Nanobodies show exquisite specificity, they are structurally stable, and they are capable of modulating immune responses.
At New Science, I am using protein fusions to develop a pan-coronavirus therapy.
Antibodies have two functions: they recognize antigenic proteins, and they recruit immune components. Immune evasion occurs when small structural changes in the antigenic protein render the antibody unable to recognize it. To overcome this problem, I built a computational algorithm that uses crystallographic structures of various protein-binding partners, such as receptors and antibody complexes, to generate a library of peptides, or small proteins, that can bind at many distinct sites on the viral protein’s surface.
My summer plan, from here, is simple. I took my computationally designed peptides — each of which recognize a site on the coronavirus' spike protein — and attached each of them, individually, to nanobodies that recruit different immune components to selectively eliminate infected cells.
Unlike monoclonal antibodies, which “see” a single structural feature on a virus, my approach can theoretically address any emerging variants of a viral pathogen. Changes in the virus’ antigenic protein, acquired by mutation and selection, should not result in resistance or impact the peptide cocktail's function because the designed peptides target several distinct sites across the protein’s surface. While resistance can easily develop against a single peptide or antibody, a range of peptide-nanobody fusions, each recognizing a distinct epitope, would be far more challenging for a virus to evade.
After assembling the peptide-nanobody fusions, I will test them in mice to see if they are effective at preventing or treating SARS-CoV-2 infections.
Are there limitations to my approach? Side effects may occur, as is the case for any other new drug. But I don’t know. This project is in its early stages, and any fusion proteins would go through rigorous, years-long testing, much like other therapies.
If this project works as intended, we will have developed a tool that can harness the immune system in completely new ways. It should be possible to selectively target, label, or destroy any cells we desire (be it SARS-CoV-2-infected cells or cancer cells), based on the antigens that are expressed on the surface of those cells. Most importantly, this type of therapy is inherently modular — built by fusing bits of proteins together — and should thus enable us to deal with any new or emerging pathogens. Only time will tell, and I’ll update soon with my progress.
Edited by Niko McCarty
Thanks to Alexey Guzey, Sasha Targ, and Hidde Ploegh for reading this.
Cite this essay:
Jadhav, A. “Towards a Universal Immunotherapy.” newscience.org. 2022 September. https://doi.org/10.56416/591plq