Non-specificity as the sticky problem in therapeutic antibody development

Ausserwöger, Hannes; Schneider, Matthias M.; Herling, Therese W.; Arosio, Paolo; Invernizzi, Gaetano; Knowles, Tuomas P. J.; Lorenzen, Nikolai

doi:10.1038/s41570-022-00438-x

Cited by 42 publications

(46 citation statements)

References 236 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation indicates that the charge distribution in the antibody structure can play a key role in mAb developability. 9…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Non-specificity fingerprints for clinical stage antibodies in solution

Herling

Invernizzi

Ausserwoeger

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) have successfully been developed for the treatment of a wide range of diseases. The clinical success of mAbs, does not solely rely on optimal potency and safety, but also require good biophysical properties to ensure high developability potential. In particular, non-specific interactions are a key developability measure to monitor during discovery. Despite an increased focus on the detection of non-specific interactions, their physicochemical origins remain poorly understood. Here, we employ solution-based microfluidic technologies to characterise a set of clinical stage mAbs and their interactions with commonly used non-specificity ligands to generate non-specificity fingerprints, providing quantitative data on the underlying physical chemistry. Furthermore, the solution-based analysis enables us to evaluate the contribution of avidity in non-specific binding by mAbs. Based on our findings, we propose a quantitative solution-based non-specificity score, which can be exploited in the development of biological therapeutics and more widely in protein engineering.

show abstract

“…This observation indicates that the charge distribution in the antibody structure can play a key role in mAb developability. 9…”

Section: Resultsmentioning

confidence: 99%

“…the suitability of antibody drug candidates to succeed as medicines, Figure 1. 5,8,9 Consequently, screens for non-specificity are rapidly becoming industry standard and are implemented in parallel with functionality measures during the discovery and optimisation phases. 5,8–12,23…”

Section: Figurementioning

confidence: 99%

Non-specificity fingerprints for clinical stage antibodies in solution

Herling

Invernizzi

Ausserwoeger

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“… 37 Readers interested in the non-specific binding of antibodies can read a recent review focusing on the molecular origins of this phenomenon. 38 …”

Section: Drug-like Properties Of Antibodiesmentioning

confidence: 99%

Approaches to expand the conventional toolbox for discovery and selection of antibodies with drug-like physicochemical properties

Svilenov

Arosio

Menzen³

et al. 2023

mAbs

Self Cite

View full text Add to dashboard Cite

Antibody drugs should exhibit not only high-binding affinity for their target antigens but also favorable physicochemical drug-like properties. Such drug-like biophysical properties are essential for the successful development of antibody drug products. The traditional approaches used in antibody drug development require significant experimentation to produce, optimize, and characterize many candidates. Therefore, it is attractive to integrate new methods that can optimize the process of selecting antibodies with both desired target-binding and drug-like biophysical properties. Here, we summarize a selection of techniques that can complement the conventional toolbox used to de-risk antibody drug development. These techniques can be integrated at different stages of the antibody development process to reduce the frequency of physicochemical liabilities in antibody libraries during initial discovery and to co-optimize multiple antibody features during early-stage antibody engineering and affinity maturation. Moreover, we highlight biophysical and computational approaches that can be used to predict physical degradation pathways relevant for long-term storage and in-use stability to reduce the need for extensive experimentation.

show abstract

“…Antibodies are proteins that can target a broad range of molecular species, and mediate the adaptive immune response of vertebrates by isolating, binding, and sequestering antigens. [ 121 ] Nucleic acid nanotechnology empowers the incorporation of multiple antibody ligands with unprecedented control over the spatial organization.…”

Section: Immunomodulation With Nucleic Acid Nanodevicementioning

confidence: 99%

Immunomodulation with Nucleic Acid Nanodevices

Ding

Zhang

Chen

et al. 2023

Small

View full text Add to dashboard Cite

The precise regulation of interactions of specific immunological components is crucial for controllable immunomodulation, yet it remains a great challenge. With the assistance of advanced computer design, programmable nucleic acid nanotechnology enables the customization of synthetic nucleic acid nanodevices with unprecedented geometrical and functional precision, which have shown promising potential for precise immunoengineering. Notably, the inherently immunologic functions of nucleic acids endow these nucleic acid‐based assemblies with innate advantages in immunomodulatory engagement. In this review, the roles of nucleic acids in innate immunity are discussed, focusing on the definition, immunologic modularity, and enhanced bioavailability of structural nucleic acid nanodevices. In light of this, molecular programming and precise organization of functional modules with nucleic acid nanodevices for immunomodulation are emphatically reviewed. At last, the present challenges and future perspectives of nucleic acid nanodevices for immunomodulation are discussed.

show abstract

Non-specificity as the sticky problem in therapeutic antibody development

Cited by 42 publications

References 236 publications

Non-specificity fingerprints for clinical stage antibodies in solution

Non-specificity fingerprints for clinical stage antibodies in solution

Approaches to expand the conventional toolbox for discovery and selection of antibodies with drug-like physicochemical properties

Immunomodulation with Nucleic Acid Nanodevices

Contact Info

Product

Resources

About