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Enlisting Monoclonal Antibodies in the Fight Against COVID-19

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B38 Antibody and SARS-CoV-2 wtih ACE2 Receptor
Caption: Antibody Binding to SARS-CoV-2. Structural illustration of B38 antibody (cyan, green) attached to receptor-binding domain of the coronavirus SARS-CoV-2 (magenta). B38 blocks SARS-CoV-2 from binding to the ACE2 receptor (light pink) of a human cell, ACE2 is what the virus uses to infect cells. Credit: Y. Wu et a. Science, 2020

We now know that the immune system of nearly everyone who recovers from COVID-19 produces antibodies against SARS-CoV-2, the novel coronavirus that causes this easily transmitted respiratory disease [1]. The presence of such antibodies has spurred hope that people exposed to SARS-CoV-2 may be protected, at least for a time, from getting COVID-19 again. But, in this post, I want to examine another potential use of antibodies: their promise for being developed as therapeutics for people who are sick with COVID-19.

In a recent paper in the journal Science, researchers used blood drawn from a COVID-19 survivor to identify a pair of previously unknown antibodies that specifically block SARS-CoV-2 from attaching to human cells [2]. Because each antibody locks onto a slightly different place on SARS-CoV-2, the vision is to use these antibodies in combination to block the virus from entering cells, thereby curbing COVID-19’s destructive spread throughout the lungs and other parts of the body.

The research team, led by Yan Wu, Capital Medical University, Beijing, first isolated the pair of antibodies in the laboratory, starting with white blood cells from the patient. They were then able to produce many identical copies of each antibody, referred to as monoclonal antibodies. Next, these monoclonal antibodies were simultaneously infused into a mouse model that had been infected with SARS-CoV-2. Just one infusion of this combination antibody therapy lowered the amount of viral genetic material in the animals’ lungs by as much as 30 percent compared to the amount in untreated animals.

Monoclonal antibodies are currently used to treat a variety of conditions, including asthma, cancer, Crohn’s disease, and rheumatoid arthritis. One advantage of this class of therapeutics is that the timelines for their development, testing, and approval are typically shorter than those for drugs made of chemical compounds, called small molecules. Because of these and other factors, many experts think antibody-based therapies may offer one of the best near-term options for developing safe, effective treatments for COVID-19.

So, what exactly led up to this latest scientific achievement? The researchers started out with a snippet of SARS-CoV-2’s receptor binding domain (RBD), a vital part of the spike protein that protrudes from the virus’s surface and serves to dock the virus onto an ACE2 receptor on a human cell. In laboratory experiments, the researchers used the RBD snippet as “bait” to attract antibody-producing B cells in a blood sample obtained from the COVID-19 survivor. Altogether, the researchers identified four unique antibodies, but two, which they called B38 and H4, displayed a synergistic action in binding to the RBD that made them stand out for purposes of therapeutic development and further testing.

To complement their lab and animal experiments, the researchers used a particle accelerator called a synchrotron to map, at near-atomic resolution, the way in which the B38 antibody locks onto its viral target. This structural information helps to clarify the precise biochemistry of the complex interaction between SARS-CoV-2 and the antibody, providing a much-needed guide for the rational design of targeted drugs and vaccines. While more research is needed before this or other monoclonal antibody therapies can be used in humans suffering from COVID-19, the new work represents yet another example of how basic science is expanding fundamental knowledge to advance therapeutic discovery for a wide range of health concerns.

Meanwhile, there’s been other impressive recent progress towards the development of monoclonal antibody therapies for COVID-19. In work described in the journal Nature, an international research team started with a set of neutralizing antibodies previously identified in a blood sample from a person who’d recovered from a different coronavirus-caused disease, called severe acute respiratory syndrome (SARS), in 2003 [3]. Through laboratory and structural imaging studies, the researchers found that one of these antibodies, called S309, proved particularly effective at neutralizing the coronavirus that causes COVID-19, SARS-CoV-2, because of its potent ability to target the spike protein that enables the virus to enter cells. The team, which includes NIH grantees David Veesler, University of Washington, Seattle, and Davide Corti, Humabs Biomed, a subsidiary of Vir Biotechnology, has indicated that S309 is already on an accelerated development path toward clinical trials.

In the U.S. and Europe, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership, which has brought together public and private sector COVID-19 therapeutic and vaccine efforts, is intensely pursuing the development and testing of therapeutic monoclonal antibodies for COVID-19 [4]. Stay tuned for more information about these potentially significant advances in the next few months.

References:

[1] Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region. Wajnberg A , Mansour M, Leven E, Bouvier NM, Patel G, Firpo A, Mendu R, Jhang J, Arinsburg S, Gitman M, Houldsworth J, Baine I, Simon V, Aberg J, Krammer F, Reich D, Cordon-Cardo C. medRxiv. Preprint Posted May 5, 2020.

[2] A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Wu Y. et al., Science. 13 May 2020 [Epub ahead of publication]

[3] Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature. 18 May 2020 [Epub ahead of print]

[4] Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV): An unprecedented partnership for unprecedented times. Collins FS, Stoffels P. JAMA. 2020 May 18.

Links:

Coronavirus (COVID-19) (NIH)

Monoclonal Antibodies (National Cancer Institute/NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences


Creative Minds: Exploring the Role of Immunity in Hypertension

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Meena Madhur

Meena Madhur / Credit: John Russell

If Meena Madhur is correct, people with hypertension will one day pay as much attention to their immune cell profiles as their blood pressure readings. A physician-researcher at Vanderbilt University School of Medicine, Nashville, Madhur is one of a growing number of scientists who thinks the immune system contributes to—or perhaps even triggers—hypertension, which increases the risk of stroke, heart disease, kidney disease, and other serious health problems.

About one of every three adult Americans currently have hypertension, yet a surprising number don’t know they have it and less than half have their high blood pressure under control—leading many health experts to refer to the condition as a “silent killer”[1,2]. For many folks, blood pressure control can be achieved through lifestyle changes, such as losing weight, exercising, limiting salt intake, and taking blood pressure medicines prescribed by their health-care provider. Unfortunately, such measures don’t work for everyone, and some people continue to suffer damage to their kidneys and blood vessels from poorly controlled hypertension.

Madhur wants to know whether the immune system might be playing a role, and whether this might hold some clues for developing new, more targeted ways of treating high blood pressure. To get such answers, this practicing cardiologist will use her 2016 NIH Director’s New Innovator Award to conduct sophisticated, single-cell analyses of the immune systems of people with and without hypertension. Her goal is to produce the most comprehensive catalog to date of which human immune cells might be involved in hypertension.


Regenerative Medicine: Making Blood Stem Cells in the Lab

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Endothelial cells becoming hematopoietic stem cells

Caption: Arrow in first panel points to an endothelial cell induced to become hematopoietic stem cell (HSC). Second and third panels show the expansion of HSCs over time.
Credit: Raphael Lis, Weill Cornell Medicine, New York, NY

Bone marrow transplants offer a way to cure leukemia, sickle cell disease, and a variety of other life-threatening blood disorders.There are two major problems, however: One is many patients don’t have a well-matched donor to provide the marrow needed to reconstitute their blood with healthy cells. Another is even with a well-matched donor, rejection or graft versus host disease can occur, and lifelong immunosuppression may be needed.

A much more powerful option would be to develop a means for every patient to serve as their own bone marrow donor. To address this challenge, researchers have been trying to develop reliable, lab-based methods for making the vital, blood-producing component of bone marrow: hematopoietic stem cells (HSCs).

Two new studies by NIH-funded research teams bring us closer to achieving this feat. In the first study, researchers developed a biochemical “recipe” to produce HSC-like cells from human induced pluripotent stem cells (iPSCs), which were derived from mature skin cells. In the second, researchers employed another approach to convert mature mouse endothelial cells, which line the inside of blood vessels, directly into self-renewing HSCs. When these HSCs were transplanted into mice, they fully reconstituted the animals’ blood systems with healthy red and white blood cells.


AIDS Vaccine Research: Better By Design?

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OD-GT8 60mer

Caption: eOD-GT8 60mer nanoparticle based on the engineered protein eOD-GT8. Yellow shows where eOD-GT8 binds antibodies; white is the protein surface outside the binding site; light blue indicates the sugars attached to the protein; dark blue is the nanoparticle core to which eOD-GT8 has been fused.
Credit: Sergey Menis and William Schief, The Scripps Research Institute

A while ago, I highlighted a promising new approach for designing a vaccine against the human immunodeficiency virus (HIV), the cause of AIDS. This strategy would “take the immune system to school” and teach it a series of lessons using several vaccine injections—each consisting of a different HIV proteins designed to push the immune system, step by step, toward the production of protective antibodies capable of fending off virtually all HIV strains. But a big unanswered question was whether most people actually possess the specific type of precursor immune cells that that can be taught to produce antibodies that kill HIV.

Now, we may have the answer [1]. In a study published in the journal Science, a research team, partly supported by NIH, found that the majority of people do indeed have these precursor cells. While the total number of these cells in each person may be low, this may be all that’s needed for the immune system to recognize a vaccine. Based in part on these findings, researchers plan to launch a Phase 1 clinical trial in human volunteers to see if their latest engineered protein can find these precursor cells and begin coaxing them through the complicated process of producing protective antibodies.


Molecular Answers Found for a Mysterious Rare Immune Disorder

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Harry Hill and Patient Images

Caption: Helping to solve a medical mystery. Top left, University of Utah’s Harry Hill; Bottom, CVID patient Roma Jean Ockler; Right, Ockler showing the medication that helps to control her CVID.
Credit: Jeffrey Allred, Deseret News

When most of us come down with a bacterial infection, we generally bounce back with appropriate treatment in a matter of days. But that’s often not the case for people who suffer from common variable immunodeficiency (CVID), a group of rare disorders that increase the risk of life-threatening bacterial infections of the lungs, sinuses, and intestines. CVID symptoms typically arise in adulthood and often take many years to diagnose and treat, in part because its exact molecular causes are unknown in most individuals.

Now, by combining the latest in genomic technology with some good, old-fashioned medical detective work, NIH-funded researchers have pinpointed the genetic mutation responsible for an inherited subtype of CVID characterized by the loss of immune cells essential to the normal production of antibodies [1]. This discovery, reported recently in The New England Journal of Medicine, makes it possible at long last to provide a definitive diagnosis for people with this CVID subtype, paving the way for them to receive more precise medical treatment and care. More broadly, the new study demonstrates the power of precision medicine approaches to help the estimated 25 to 30 million Americans who live with rare diseases [2].


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