New research spotlights promise of isotype-specific monoclonal antibodies against Rift Valley Fever

Recent advances in the development of monoclonal antibodies have shown promise in the treatment of infectious diseases. 

Experiments with a mouse model treated with a specific type of monoclonal antibody now hint at its effectiveness against Rift Valley Fever virus in humans, a sometimes deadly mosquito-borne illness endemic to most of Africa and parts of the Middle East. 

A report on the experimental work by three researchers from the University of Pittsburgh School of Medicine was published Sept. 8 in mSphere, the online journal of the American Society for Microbiology. 

The study is titled “Isotype-Specific Fc Effector Functions Enhance Antibody-Mediated Rift Valley Fever Virus Protection In Vivo.”

Antibodies, Isotypes and Fc Effectors

An antibody is a large protein in the shape of a “Y” that can bind to a specific part of an invading bacterium or virus and neutralize or destroy it. Antibodies are produced by specialized white blood cells known as B cells.

Part of the two arms of the “Y” structure are known as Fab (fragment, antigen-binding) regions. The binding to the antigen (foreign substance) occurs at the tips of the “Y” called the antigen-binding site. There are many varieties of antigen-binding sites to deal with the millions of different antigens that may challenge the immune system. 

The trunk of the “Y” is known as the Fc (fragment, crystallizable) region. This is where effector cells, such as the natural killer cells and the helper T cells of the immune system, bind to the antibody. 

The Fc region of the antibody structure occurs in just five variants in mammals: IgA, IgD, IgE, IgG and IgM (where Ig stands for immunoglobulin, another name for antibody). These variants are known as the isotype or class. There are also subclasses of these isotypes, such as IgG1 and IgG2a. 

The isotype determines how the antibody interacts with T cells, B cells, and various other components of the immune system. The interaction of the Fc region with immune cells is known as Fc effector function.

Role of the Fc region in fighting viral infection

The authors note that in addition to neutralizing invaders, “antibodies provide protection through a variety of mechanisms via their ability to interact with Fc gamma receptors on innate immune cells.” These interactions have been found to play an essential role in protection against viral disease in Ebola virus, HIV/AIDS, and influenza A, they point out. 

“This suggests the potential for Fc effector functions to be an essential component” in the protection against Rift Valley fever virus using monoclonal antibodies, they write.

By switching the isotype subclass of three different partially protective monoclonal antibodies, the researchers were able to demonstrate a significant increase in the survival of laboratory mice receiving the antibodies of the IgG2a isotype subclass over the control mice which received the IgG1 isotype. 

In addition to increasing survival, the IgG2 monoclonal antibodies “also seemed to control viral infection more efficiently,” the authors report. Among the surviving mice in the control group (receiving the IgG1 isotype) viral RNA was detected at low levels 28 days after exposure to the virus. In contrast the viral RNA levels were below the level of detection for the mice treated with the IgG2 isotype. 

There was also some indication that the monoclonal antibodies can reduce viral load in the brains of the mice receiving the IgG2a variant. 

This accelerated viral clearance “may mitigate the development potential of late-onset encephalitis,” the authors write, noting that individuals seeking treatment for Rift Valley fever are often well into the disease course with serious brain inflammation.

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Haley Cartwright, et al. "Isotype-Specific Fc Effector Functions Enhance Antibody-Mediated Rift Valley Fever Virus Protection In Vivo mSphere," 2021. DOI: https://doi.org/10.1128/mSphere.00556-21