antibody – Lightsources.org

Antibody rigidity regulates immune activity

2022/07/132022/07/15

Scientists at the University of Southampton have gained unprecedented new insight into the key properties of an antibody needed to stimulate immune activity to fight off cancer, using the ESRF’s structural biology beamlines, among others.

The interdisciplinary study, published in Science Immunology, revealed how changing the flexibility of the antibody could stimulate a stronger immune response. The findings have enabled the team to design antibodies to activate important receptors on immune cells to “fire them up” and deliver more powerful anti-cancer effects. The researchers believe their findings could pave the way to improve antibody drugs that target cancer, as well as automimmune diseases.

In the study, the team investigated antibody drugs targeting the receptor CD40 for cancer treatment. Clinical development has been hampered by a lack of understanding of how to stimulate the receptors to the right level. The problem being that if antibodies are too active they can become toxic. Previous research by the same team had shown that a specific type of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, since it is more active than other antibody types. However, the reason why it is more active had not been determined. What was known, however, is that the structure between the antibody arms, the so called hinges, changes over time.

This latest research harnesses this property of the hinge and explains how it works: the researchers call this process “disulfide-switching”. In their study, the team analysed the effect of modifying the hinge and used a combination of biological activity assays, structural biology, and computational chemistry to study how disulfide switching alters antibody structure and activity.

Read more on the ESRF website

Image: Flexibility of the monoclonal antibody F(ab) arms is conferred by the hinge region disulphide structure

Credit: C. Orr

Understanding how a key antibody targets cancer cells

2021/10/122021/10/14

Immunotherapy can be used as a precise intervention in cancer treatments. Jean-Philippe Julien is a Canada Research Chair in Structural Immunology, a Senior Scientist in the Molecular Medicine Program at The Hospital for Sick Children (SickKids), and an Associate Professor in the Departments of Biochemistry and Immunology at the University of Toronto. Along with colleagues from the U.S., Spain and Canada, he used the Canadian Light Source at the University of Saskatchewan to study how a candidate antibody therapeutic interacts with a surface receptor on cancer cells, which provides important molecular insights for designing improved cancer therapies. He mentioned how the synchrotron is “incredibly important for researchers like myself” and how “we cannot do the research that we do without it.” The team used the CMCF beamline at the CLS and their findings were published in the Journal of Biological Chemistry.Immunotherapy can be used as a precise intervention in cancer treatments. Jean-Philippe Julien is a Canada Research Chair in Structural Immunology, a Senior Scientist in the Molecular Medicine Program at The Hospital for Sick Children (SickKids), and an Associate Professor in the Departments of Biochemistry and Immunology at the University of Toronto. Along with colleagues from the U.S., Spain and Canada, he used the Canadian Light Source at the University of Saskatchewan to study how a candidate antibody therapeutic interacts with a surface receptor on cancer cells, which provides important molecular insights for designing improved cancer therapies. He mentioned how the synchrotron is “incredibly important for researchers like myself” and how “we cannot do the research that we do without it.” The team used the CMCF beamline at the CLS and their findings were published in the Journal of Biological Chemistry.

Learn more on the CLS website

Image: Jean-Philippe Julien

Credit: Canadian Light Source

New possibilities against the HIV epidemic

2019/03/222019/03/22

Research identifies new antibodies with potent activity against virus and infected cells

The Human Immunodeficiency Virus type-1 (HIV-1) currently infects 37 million people worldwide, with an additional 2 million new infections each year. Following infection, the virus has a long period of latency, during which it multiplies without causing symptoms. HIV attacks the cells of the immune system, especially the cells called CD4+ T-lymphocytes, which are responsible for triggering the body’s response chain against infections. Thus, by suppressing the action of the immune system, the virus destroys the body’s ability to defend itself against other diseases, leading to the so-called Acquired Immunodeficiency Syndrome, or AIDS.
Even with the development of antiretroviral therapies that have improved quality of life and increased the life expectancy of patients with HIV/AIDS, it is widely accepted that the only way to effectively curb this devastating epidemic is through the development of an HIV-1 vaccine.

Image: Part of the structure of the CAP228-16H protein with the region of the V2 loop highlighted in yellow. (Full image here)

Targeting bacteria that cause meningitis and sepsis

2018/10/222018/10/25

The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Our central nervous systems (brain and spinal cord) are surrounded by three membranes called “meninges.” Meningitis is caused by the swelling of these membranes, resulting in headache, fever, and neck stiffness. Most cases of meningitis in the United States are the result of viral infections and are relatively mild. However, meningitis caused by bacterial infection, if left untreated, can be deadly or lead to serious complications, including hearing loss and neurologic damage.

The bacterium responsible for meningitis (Neisseria meningitidis) can also infect the bloodstream, causing another life-threatening condition known as sepsis. N. meningitidis is spread through close contact (coughing or kissing) or lengthy contact (e.g. in dorm rooms or military barracks). In this work, researchers were interested in understanding how humans develop immunity to bacterial meningitis and sepsis, collectively known as meningococcal disease, by vaccination with a new protein-based vaccine.

Image: The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Insights into an antibody directed against dengue virus

2018/10/162018/10/19

We are one step further to uncovering a new way to stave off dengue fever thanks to important work carried out at the I02 beamline at Diamond Light Source.

The study, recently published in Nature Immunology, describes how an antibody effectively targets the dengue virus.
Dengue virus affects hundreds of millions of people worldwide and is an untreatable infection. Secondary infections with dengue can lead to a life-threatening form of the disease due to a phenomenon called antibody-dependent enhancement (ADE). Additionally, efforts to develop a vaccine against the virus have been hindered by ADE.

A huge collaborative effort sought to investigate ADE in dengue, and two antibodies were characterised that bound to the envelope protein of the dengue virus. One of the antibodies was found to be a potent neutraliser of the virus, but importantly was unable to promote ADE.

Image: Fab binding in the context of the mature virion. e, Comparison of 2C8 Fab and 3H5 Fab docked onto a E dimer. 2C8 (green) and 3H5 (orange) Fabs were docked onto PDB ID 3J27 by aligning the EDIII potion of the structures. The Fabs are shown as surfaces and the E dimer is displayed in cartoon representation. A side view is of the E dimer on the viral surface is shown. The approximate location of the viral membrane is shown schematically.