A general Fc engineering platform for the next generation of antibody therapeutics

Chen, Da; Zhao, Yingjie; Li, Mingyu; Shang, Han Lin; Li, Na; Li, Fan; Wang, Wei; Wang, Yuan; Jin, Ruina; Liu, Shiyu; Li, Xun; Gao, Shan; Tian, Yujie; Li, Ruonan; Li, Huanhuan; Zhang, Yongyan; Du, Mingjuan; Cao, Youjia; Zhang, Yan; Li, Xin; Huang, Yi; Hu, Liaoyuan A.; Li, Fubin; Zhang, Hongkai

doi:10.7150/thno.51299

Cited by 18 publications

(16 citation statements)

References 50 publications

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“…S10). The activity of CD40 agonist antibodies independent of Fc receptor-mediated cross-linking might be disconcerting due to the potential for adverse events (29,30). Therefore, the cross-linking-dependent C04 antibody was chosen for further characterization.…”

Section: Screening Cd40 Agonist Antibody Using the Function-based Scr...mentioning

confidence: 99%

High-throughput functional screening for next-generation cancer immunotherapy using droplet-based microfluidics

Wang

Jin

Shen³

et al. 2021

Sci. Adv.

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Currently, high-throughput approaches are lacking in the isolation of antibodies with functional readouts beyond simple binding. This situation has impeded the next generation of cancer immunotherapeutics, such as bispecific T cell engager (BiTE) antibodies or agonist antibodies against costimulatory receptors, from reaching their full potential. Here, we developed a highly efficient droplet-based microfluidic platform combining a lentivirus transduction system that enables functional screening of millions of antibodies to identify potential hits with desired functionalities. To showcase the capacity of this system, functional antibodies for CD40 agonism with low frequency (<0.02%) were identified with two rounds of screening. Furthermore, the versatility of the system was demonstrated by combining an anti-Her2 × anti-CD3 BiTE antibody library with functional screening, which enabled efficient identification of active anti-Her2 × anti-CD3 BiTE antibodies. The platform could revolutionize next-generation cancer immunotherapy drug development and advance medical research.

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Section: Screening Cd40 Agonist Antibody Using the Function-based Scr...mentioning

confidence: 99%

High-throughput functional screening for next-generation cancer immunotherapy using droplet-based microfluidics

Wang

Jin

Shen³

et al. 2021

Sci. Adv.

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“…Mammalian display systems for antibody Fc engineering have been previously reported. A lentiviral-based mammalian display platform was recently reported by Chen et al ( 52 ), who screened >10 4 Fc variants in HEK293T cells to identify Fc variants with enhanced FcγRIIIa (∼10-fold improved K d ) and FcγRIIb binding (∼2.6-fold improved K d ) as well as enhanced cellular activities. In our study, we were able to screen 7 × 10 6 individual Fc-displaying CHO cells expressing ∼6 × 10 6 unique sequences using an episomal system.…”

Section: Discussionmentioning

confidence: 99%

An antibody Fc engineered for conditional antibody-dependent cellular cytotoxicity at the low tumor microenvironment pH

Liu

Lee

Nguyen

et al. 2022

Journal of Biological Chemistry

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“…Furthermore, newly identified Fc-variants can be substituted in nearly any antibody, which has been shown in the study for trastuzumab and rituximab, as well as for CD40 agonists. The selected antibodies with new identified Fc part showed a higher antitumor efficacy in in vitro and in vivo models in comparison to the original mAbs [192].…”

Section: Further Strategies To Modify Fc:fcγr Interactionmentioning

confidence: 92%

“…Engineering and investigating therapeutic antibody variants with individually designed effector functions bearing a favorable safety and efficacy profile, requires many recourses in terms of time and costs [191,192]. Implementing new technologies and platforms will help in the future to further optimize this process.…”

Section: Further Strategies To Modify Fc:fcγr Interactionmentioning

confidence: 99%

“…Implementing new technologies and platforms will help in the future to further optimize this process. Recently, Chen et al developed a mammalian cell display-based Fc-engineering platform [192]. A large number of Fc-variants was screened with mammalian cell display and next generation sequencing and thereby candidates with selectively enhanced affinities for FcγRIIIa or FcγRIIb were identified.…”

Section: Further Strategies To Modify Fc:fcγr Interactionmentioning

confidence: 99%

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The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

Gogesch

Dudek

Zandbergen

et al. 2021

IJMS

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Since the approval of the first monoclonal antibody (mAb) in 1986, a huge effort has been made to guarantee safety and efficacy of therapeutic mAbs. As of July 2021, 118 mAbs are approved for the European market for a broad range of clinical indications. In order to ensure clinical efficacy and safety aspects, (pre-)clinical experimental approaches evaluate the respective modes of action (MoA). In addition to antigen-specificity including binding affinity and -avidity, MoA comprise Fc-mediated effector functions such as antibody dependent cellular cytotoxicity (ADCC) and the closely related antibody dependent cellular phagocytosis (ADCP). For this reason, a variety of cell-based assays have been established investigating effector functions of therapeutic mAbs with different effector/target-cell combinations and several readouts including Fcγ receptor (FcγR)-mediated lysis, fluorescence, or luminescence. Optimized FcγR-mediated effector functions regarding clinical safety and efficacy are addressed with modification strategies such as point mutations, altered glycosylation patterns, combination of different Fc subclasses (cross isotypes), and Fc-truncation of the mAb. These strategies opened the field for a next generation of therapeutic mAbs. In conclusion, it is of major importance to consider FcγR-mediated effector functions for the efficacy of therapeutic mAbs.

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A general Fc engineering platform for the next generation of antibody therapeutics

Cited by 18 publications

References 50 publications

High-throughput functional screening for next-generation cancer immunotherapy using droplet-based microfluidics

High-throughput functional screening for next-generation cancer immunotherapy using droplet-based microfluidics

An antibody Fc engineered for conditional antibody-dependent cellular cytotoxicity at the low tumor microenvironment pH

The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

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