The behavior of therapeutic antibodies in immunotherapy

Date:
August 13, 2020
Source:
CNRS
Summary:
Since the late 1990s, immunotherapy has been the frontline treatment
against lymphomas where synthetic antibodies are used to stop the
proliferation of cancerous white blood cells. However, in the more
than 20 years since their use began, the molecular mechanisms that
underlie this therapy are still little understood. For the first
time, scientists have observed the interaction between therapeutic
antibodies and their target protein.



FULL STORY ========================================================================== Since the late 1990s, immunotherapy has been the frontline treatment
against lymphomas where synthetic antibodies are used to stop the
proliferation of cancerous white blood cells. However, in the more
than 20 years since their use began, the molecular mechanisms that
underlie this therapy are still little understood. For the first time, scientists from the CNRS, Institut Pasteur and Universite' de Bordeaux
have observed the interaction between therapeutic antibodies and their
target protein. The research, published in Science on 14 August 2020,
describes these molecular mechanisms and opens the way to the development
of new treatments.


========================================================================== Non-Hodgkin lymphomas are among the most common cancers affecting almost
1.5 million people globally. They cause uncontrolled proliferation of
B lymphocytes, a type of white blood cell, to the detriment of healthy
cells.

Since the end of the 1990s, immunotherapy had been a frontline treatment
using synthetic antibodies to target a protein on the surface of B
lymphocytes called CD20. The body's defences then identify these cells
covered in antibodies as pathogens and destroy them.

Presently, the types of therapeutic antibodies used are classified into
two groups according to how many CD20 molecules they bind to and the
immunity response they trigger. Antibodies from the first group have the ability to interact with twice as many CD20 molecules than antibodies
from the second group and can set off a cascading immune response called
a "complement pathway." Until now, the molecular mechanisms at the root
of underlying the differences between these two groups were unknown.

By using cryogenic electron microscopy, scientists from the CNRS, Institut Pasteur, and Universite' de Bordeaux1 were able, for the first time, to
observe on an atomic level the interaction between the representatives of
both groups of antibodies and their target molecules. They have shown that because of the availability of space, CD20 proteins can bind to two type
1 antibodies but to only one type 2 antibody. Due to their larger numbers
on the surface of B lymphocytes, type 1 antibodies can form clusters. The
team demonstrates that these clusters trigger the complement pathway which leads to the destruction of the target B lymphocytes. Type 2 antibodies,
on the other hand, are thinly dispersed on the cell surface and therefore
do not trigger a cascading response. Other independent immune responses
are still able to destroy the cells.

Never before has the mechanism of action of therapeutic antibodies been described with such precision. This research could lead to new synthetic antibodies able to control a patient's immune response. In addition,
this description of the mechanism activating the complement pathway opens
the way to new research possibilities aiming at an understanding of how
immune defences work.

Notes:1- With scientists from the Laboratoire de Microbiologie
Fondamentale et Pathoge'nicite' (CNRS/Universite' de Bordeaux), the
"Humoral Immunity" laboratory (Inserm/Institut Pasteur/Sorbonne
Universite'), the "Me'canismes des prote'ines membranaires" unit
(Institut Pasteur) and the European Institute of Chemistry and Biology (IECB/Universite' de Bordeaux).


========================================================================== Story Source: Materials provided by CNRS. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Anand Kumar, Cyril Planchais, Re'mi Fronzes, Hugo Mouquet and
Nicolas
Reyes. Binding mechanisms of therapeutic antibodies to human CD20.

Science, 14 August 2020 DOI: 10.1126/science.abb8008 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200813142347.htm

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