Mechanistic insights into the rational design of masked antibodies

Orozco, Carolina T.; Bersellini, Manuela; Irving, Lorraine; Howard, Wesley W.; Hargreaves, David; Devine, Paul W. A.; Siouve, Elise; Browne, Gareth J.; Bond, Nicholas J.; Phillips, Jonathan J.; Ravn, Peter; Jackson, Sophie

doi:10.1080/19420862.2022.2095701

Cited by 7 publications

(7 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The above results were contrary to the previous understandings 17,20 that the more copies of GCN4 the better efficiency. This phenomenon may be caused by the steric hindrance of neighboring peptide binding sites 17,21 .…”

Section: Resultsmentioning

confidence: 99%

SunTag-PE: a modular prime editing system enables versatile and efficient genome editing

Tian

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

Prime editing (PE) holds tremendous potential in the treatment of genetic diseases because it can install any desired base substitution or local insertion/deletion. However, the full length PE effector size (6.3kb) was beyond the packaging capacity of adeno-associated virus (AAV), hindering its clinical transformation. Various splitting strategies have been used to improve its delivery, but always accompanied by compromised PE efficiency. Here, we developed a modular and efficient SunTag PE system that splits PE effectors into GCN4 nCas9 and single chain variable fragment (scFv) tethered reverse transcriptase (RT). We observed that SunTag PEs with one GCN4 in the N terminus of nCas9 was the most efficient configuration rather than multiple copies of GCN4. This SunTag PE strategy achieved editing levels comparable to canonical fused PE and higher than other split PE strategies (including sPE and MS2 PE) in both PE2 and PE3 forms with no increase in insertion/deletion (indel) byproducts. Moreover, we successfully validated the modularity of SunTag PE system in the Cas9 orthologs of SauCas9 and FrCas9. Finally, we employed dual AAVs to deliver SunTag ePE3 and efficiently corrected the pathogenic mutation in HBB mutant cell line. Collectively, our SunTag PE system provides an efficient modular splitting strategy for prime editing and further facilitate its transformation in clinics.

show abstract

Section: Resultsmentioning

confidence: 99%

SunTag-PE: a modular prime editing system enables versatile and efficient genome editing

Tian

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…As mentioned above, a plethora of masking strategies have been applied to generate activatable antibodies responsive to a variety of environmental cues for diverse applications, and more details can be found in other recent reviews. ,, These masking groups either employ spatial hindrance-based fragments (e.g., via direct caging of the binding site) or affinity peptides (e.g., those derived from mutated antigens) to shield the antigen-binding site. ,, Spatial-hindrance-based fragments often show high masking efficiency together with high-affinity restoration after activation. More importantly, such a “lock” is generally applicable to a variety of antibodies.…”

Section: How Are Antibodies Used?mentioning

confidence: 99%

“…498,511,512 These masking groups either employ spatial hindrance-based fragments (e.g., via direct caging of the binding site) or affinity peptides (e.g., those derived from mutated antigens) to shield the antigen-binding site. 498,499,513 Spatial-hindrance-based fragments often show high masking efficiency together with high-affinity restoration after activation. More importantly, such a "lock" is generally applicable to a variety of antibodies.…”

Section: Modified Antibodiesmentioning

confidence: 99%

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

et al. 2023

View full text Add to dashboard Cite

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more “undruggable” targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

show abstract

“…100 Antibodies with masked binding domains have been engineered to have one or more of their antigen-binding sites temporarily inactivated or "masked". 101,102 These antibodies can be designed to change their binding properties under specific conditions. Their applications include conditional activation, for instance, an antibody may only become active when exposed to specific environmental factors or cellular cues; reduced off-target effects�in some cases, masking can be used to prevent antibody binding to nontarget tissues or cells until it reaches the desired site.…”

Section: Adc Basicsmentioning

confidence: 99%

The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress

Sasso,

Tenchov,

Bird

et al. 2023

Bioconjugate Chem.

View full text Add to dashboard Cite

Antibody–drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.

show abstract

Mechanistic insights into the rational design of masked antibodies

Cited by 7 publications

References 49 publications

SunTag-PE: a modular prime editing system enables versatile and efficient genome editing

SunTag-PE: a modular prime editing system enables versatile and efficient genome editing

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress

Contact Info

Product

Resources

About