<p>Antibody-drug conjugates (ADCs) combine
the cytotoxicity of traditional chemotherapy with the site-specificity of
antibodies by conjugating payloads to antibodies with immunoaffinity. However,
the conjugation alters the physicochemical properties of antibodies, increasing
the risks of various types of degradation. The effects of common risk factors
such as pH, temperature, and light on the stability of ADCs differ from their
effects on monoclonal antibodies (mAb) due to these altered physicochemical
properties. </p>
<p>To date, ADC researchers have
developed linkers with improved <i>in vivo</i> stability, and begun to
understand the deconjugation mechanisms <i>in vivo</i>. In contrast, the <i>in
vitro</i> stability of ADCs has not gained comparable attention. All nine of
the U.S. FDA approved ADCs are lyophilized to minimize the potential for
degradation. However, there are few studies on the solid-state stability of
ADCs. To evaluate lyophilized solids, pharmaceutical development relies heavily
on accelerated stability studies, which take months to determine the best formulation.
Characterization methods that are often used orthogonally with accelerated
studies include Fourier-transform infrared spectroscopy (FT-IR), Raman
spectroscopy, near-infrared spectroscopy (NIR), differential scanning
calorimetry (DSC), and x-ray powder diffraction (XRPD). Results from these methods are often poorly
correlated with stability, however. Thus, stability evaluation of solid-state ADC
products, and other recombinant protein drugs, is often a bottleneck in their
development.</p>
<p>To provide knowledge on how to
improve the <i>in vitro</i> stability of lyophilized ADC formulations, the solid-state
stability of ADC formulations with varying risk factors was studied in this
dissertation project. The first study investigated interactions between an ADC
and excipients in terms of solid-state stability enhancement. The second study
investigated the process-driven instability of ADCs during lyophilization using
various concentrations of ADCs. The first two studies incorporate a new method
called solid-state hydrogen/deuterium exchange coupled with mass spectrometry
(ssHDX-MS) as an analytical predictor of solid-state stability. The last study
investigated the effects of pH on the stability of labile hydrazones, as a
model for common linker chemistry used in ADCs. </p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/15062859 |
| Date | 28 July 2021 |
| Creators | Eunbi Cho (11192397) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | In Copyright |
| Relation | https://figshare.com/articles/thesis/Solid-state_Stability_of_Antibody-drug_Conjugates/15062859 |
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