Antibody-oligonucleotide conjugates (AOCs) are a novel class of therapeutics composed of an antibody, a linker, and an oligonucleotide. AOCs combine the antigen-specific binding capability of an antibody and the gene-regulatory function of an oligonucleotide to achieve targeted and efficient therapeutic intervention across a range of diseases. Although AOCs are in the early stages of development, progress has been steady over the last few decades. The structural complexity and mechanistic diversity of AOCs contribute to manufacturing and quality control challenges, requiring strategies to ensure therapeutic efficacy and minimize off-target toxicity. The design, manufacturing, and quality control of AOCs are essential to ensuring their safety and efficacy. This review summarizes the history and current clinical development of AOCs, focusing on mechanisms of action, molecular design with various linkers, and recent advances in manufacturing processes and quality control. Additionally, the current challenges and future prospects for the development of AOC therapeutics are highlighted.

Antibody–drug conjugates (ADCs) represent a novel approach to cancer treatment. Enfortumab vedotin (PADCEV), as a prominent example, has demonstrated remarkable clinical efficacy. However, its ocular toxicity has raised concerns. This study aimed to explore the molecular mechanisms underlying PADCEV—induced ocular toxicity. SD rats, whose ocular structures are similar to those of humans, were selected to establish an ocular toxicity model to mimic the human response. In vitro experiments were conducted using human primary corneal epithelial cells, HCE-T. The results confirmed that nectin-4 plays a crucial role in the cellular uptake of PADCEV, and non-specific pinocytosis is also involved. Additionally, a variant was obtained by introducing point mutations in the Fc region of PADCEV, which was found to reduce corneal epithelial toxicity. The findings of this study not only deepen our understanding of ADC-induced ocular toxicity but also provide new insights into optimizing ADC design and enhancing treatment safety.

The applications of CE-SDS in analyzing the purity and fragments of mAbs, characterizing positional isomers of ADCs, and identifying mismatch impurities in bsAbs and details key regulatory considerations for CE-SDS in biopharmaceutical development.

Background/Objectives: Virus-like particles (VLPs) are effective vaccine platforms but are susceptible to degradation, which compromises stability and immunogenicity. A key challenge is the lack of sensitive early indicators of instability. This study aimed to systematically evaluate the stability of an aluminum-free recombinant hepatitis E virus VLP vaccine under various stresses and identify predictive markers of instability. Methods: The VLP vaccine was subjected to thermal stress (4 °C, 25 °C, 37 °C, 56 °C for up to 28 d), repeated freeze–thaw cycles (up to 30 cycles), and mechanical agitation (orbital shaking at 100 and 300 rpm for up to 12 d). Stability was assessed using a multi-parameter panel monitoring critical quality attributes: conformational and colloidal stability, formation of high-molecular-weight species, mean particle size, polydispersity index, charge heterogeneity, and antigen content. Results: Changes in charge heterogeneity were the earliest indicator of instability, detectable within 3 days at 25 °C, 8 h at 37 °C, and 4 h at 56 °C, preceding losses in structural integrity or antigen-binding function. The VLPs remained stable at 25 °C for 28 d. Freeze–thaw cycles induced a basic shift in charge variants without compromising structure or function, while high-intensity shaking (300 rpm) caused aggregation after 3–6 d. The effects of common excipients were also characterized. Conclusions: Charge-variant analysis serves as a sensitive and predictive marker for VLP vaccine instability. The study delineates the distinct impacts of different stress factors and provides critical data for optimizing formulation design and storage strategies to enhance VLP vaccine stability.