Multiplexing Phenotype and Function for More Biologically Relevant Insights - 31

Related Article from
lenges. These challenges were discussed at the Eighth Annual Immunogenicity
BioAssay Summit, which took place recently in Baltimore. The event provided a
forum for discussing bioassay development issues. For example, it highlighted
strategies for detecting NAbs and facilitating lot release.
Regulatory agencies generally prefer cell-based assays. When these assays are
designed appropriately, they mimic the drug's mechanism of action in vitro.
However, contention around the use of cell-based functional assays versus noncell-based competitive ligand binding assays for NAb detection exists within the
field.
"The tides are turning a little bit," said Rusnak, referring to the use of ligand binding
assays. "When cell-based assays are a challenge to develop, ligand binding assays
can sometimes come in and take their place if ligand binding is a first and critical
step for drug impact."
Ligand Binding Shown to Advantage
One presentation at the summit that illustrated this "turning of tides" directly
compared a ligand binding assay against a cell-based platform for the detection
of in vitro NAb against benralizumab. Benralizumab, a monoclonal antibody used
to treat severe, uncontrolled asthma, depletes eosinophils through a mechanism
of action called antibody-dependent cell-mediated cytotoxicity (ADCC), where
drug binding to interleukin 5 receptor alpha (IL-5Rα) instructs effector cells of the
immune system to remove eosinophils through apoptosis.
Yuling Wu, Ph.D., a principal scientist at MedImmune, validated both a ligand
binding assay and a cell-based assay used to determine if ADAs collected from the
serum of patients on benralizumab neutralized drug activity in vitro. The ligand
binding assay evaluated the ability of the ADAs to prevent the labeled drug from
binding to soluble recombinant IL-5Rα, while the cell-based assay used a cell line
stably transfected with IL-5Rα as target cells and a reporter cell line as effector cells.
Dr. Wu concluded that the "data demonstrated that the ligand binding assay
was more sensitive, drug tolerant, and robust than the cell-based assay," and
MedImmune decided to move forward with the ligand binding NAb assay for their
Phase III trials of benralizumab.

31

| January, 2019

This protocol comparison highlights how bioassays from DiscoverX can obtain rapid results.
(A) The PathHunter Bevacizumab Bioassay uses cryopreserved ready-to-use cells that do not
require any cell culture. The entire assay can be completed in less than 24 hours with a simple
add-and-read protocol. (B) The HUVEC proliferation assay requires that cells be cultured one
to two weeks before they can be used in a proliferation assay that takes an additional three to
four days.


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Multiplexing Phenotype and Function for More Biologically Relevant Insights

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