From structure to sequence: Antibody discovery using cryoEM

Antanasijevic, Aleksandar; Bowman, Charles A.; Kirchdoerfer, Robert N.; Cottrell, Christopher A.; Ozorowski, Gabriel; Upadhyay, Amit A.; Cirelli, Kimberly M.; Carnathan, Diane G.; Enemuo, Chiamaka A.; Sewall, Leigh M.; Nogal, Bartek; Zhao, Fangzhu; Gröschel, Bettina; Schief, William R.; Sok, Devin; Silvestri, Guido; Crotty, Shane; Bosinger, Steven E.; Ward, Andrew B.

doi:10.1126/sciadv.abk2039

Cited by 31 publications

(20 citation statements)

References 58 publications

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“…Solving their high-resolution structures can provide useful footprints for HIV-1 vaccine design. A high-throughput antibody discovery technology has been developed by Ward et al 58 based on cryo-EM based EMPEM and high-resolution structural analysis for novel monoclonal antibody discovery that can further determine detailed structure- and sequence-based information from the pediatric and adult bnAbs of multiple-epitope specificities. Such advanced techniques have benefits over previously used high-throughput phage display technology-based HIV-1 bnAb isolation from random mutant libraries based on recombinant antibodies.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

An Overview of Human Anti-HIV-1 Neutralizing Antibodies against Diverse Epitopes of HIV-1

2023

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In this Review, we have addressed some recent developments in the discovery and applications of anti-human immunodeficiency virus type− 1 (HIV−1) broadly neutralizing antibodies (bnAbs) isolated from infected adults and children. The recent developments in human antibody isolation technologies have led to the discovery of several highly potent anti-HIV-1 bnAbs. Herein, we have discussed the characteristics of recently identified bnAbs directed at distinct epitopes of HIV-1, in addition to the existing antibodies, from adults and children and have shed light on the benefits of multispecific HIV-1 bnAbs and their role in the design of polyvalent vaccines.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

An Overview of Human Anti-HIV-1 Neutralizing Antibodies against Diverse Epitopes of HIV-1

2023

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“…Shortening the screening and structure optimization time of highly efficient antibodies is a long-term goal of antibody development strategies. A recent study reported that the combination of cryo-EM and next-generation sequencing can quickly obtain key epitope information without isolating monoclonal antibodies, greatly shortening the time for antibody development [ 98 ]. The main process is shown in Fig.…”

Section: Application Of Cryo-em In Antibody Drug Developmentmentioning

confidence: 99%

Applications and prospects of cryo-EM in drug discovery

Zhu

Yuan

et al. 2023

Military Med Res

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Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

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“…EM-based polyclonal epitope mapping (EMPEM) is a tool for rapid and comprehensive structural analysis of immune complexes featuring vaccine-elicited polyclonal antibodies (pAbs) purified from sera ( 9–12 ). Additionally, we have recently shown that structural information from the reconstructed high-resolution maps can be used to identify sequences of polyclonal antibody families ( 13 ). EMPEM has thus far been only applied to recombinantly produced minimal antigens.…”

Section: Introductionmentioning

confidence: 99%

High-resolution structural analysis of enterovirus-reactive polyclonal antibodies in complex with whole virions

et al. 2022

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Non-polio enteroviruses (NPEVs) cause serious illnesses in young children and neonates including aseptic meningitis, encephalitis, and inflammatory muscle disease, among others. While over 100 serotypes have been described to date, vaccine only exists for EV-A71. Efforts towards rationally designed pan-NPEV vaccines would greatly benefit from structural biology methods for rapid and comprehensive evaluation of vaccine candidates and elicited antibody responses. Towards this goal, we introduced a cryo-electron-microscopy-based approach for structural analysis of virus- or vaccine-elicited polyclonal antibodies (pAbs) in complex with whole NPEV virions. We demonstrated the feasibility using coxsackievirus A21 and reconstructed five structurally distinct pAbs bound to the virus. The pAbs targeted two immunodominant epitopes, one overlapping with the receptor binding site. These results demonstrate that our method can be applied to map broad-spectrum polyclonal immune responses against intact virions and define potentially cross-reactive epitopes.

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From structure to sequence: Antibody discovery using cryoEM

Cited by 31 publications

References 58 publications

An Overview of Human Anti-HIV-1 Neutralizing Antibodies against Diverse Epitopes of HIV-1

An Overview of Human Anti-HIV-1 Neutralizing Antibodies against Diverse Epitopes of HIV-1

Applications and prospects of cryo-EM in drug discovery

High-resolution structural analysis of enterovirus-reactive polyclonal antibodies in complex with whole virions

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