IgG3 enhances neutralization potency and Fc effector function of an HIV V2-specific broadly neutralizing antibody.
Simone I. Richardson,Bronwen E. Lambson,Andrew R. Crowley,Arman Bashirova,Cathrine Scheepers,Nigel Garrett,Nigel Garrett,Salim S. Abdool Karim,Salim S. Abdool Karim,Salim S. Abdool Karim,Nonhlanhla N. Mkhize,Mary Carrington,Margaret E. Ackerman,Penny L. Moore,Penny L. Moore,Lynn Morris,Lynn Morris +16 more
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TLDR
This study showed that co-operation between the variable and natural IgG3 constant regions enhanced the polyfunctionality of antibodies, indicating the value of leveraging genetic variation which could be exploited for passive immunity.Abstract:
Broadly neutralizing antibodies (bNAbs) protect against HIV infection in non-human primates and their efficacy may be enhanced through interaction with Fc receptors on immune cells. Antibody isotype is a modulator of this binding with the IgG3 subclass mediating potent Fc effector function and is associated with HIV vaccine efficacy and HIV control. BNAb functions are typically assessed independently of the constant region with which they are naturally expressed. To examine the role of natural isotype in the context of a bNAb lineage we studied CAP256, an HIV-infected individual that mounted a potent V2-specific bNAb response. CAP256 expressed persistently high levels of plasma IgG3 which we found mediated both broad neutralizing activity and potent Fc function. Sequencing of germline DNA and the constant regions of V2-directed bNAbs from this donor revealed the expression of a novel IGHG3 allele as well as IGHG3*17, an allele that produces IgG3 antibodies with increased plasma half-life. Both allelic variants were used to generate CAP256-VRC26.25 and CAP256-VRC26.29 IgG3 bNAbs and these were compared to IgG1 versions. IgG3 variants were shown to have significantly higher phagocytosis and trogocytosis compared to IgG1 versions, which corresponded to increased affinity for FcγRIIa. Neutralization potency was also significantly higher for IgG3 bNAbs, particularly against viruses lacking the N160 glycan. By exchanging hinge regions between subclass variants, we showed that hinge length modulated both neutralization potency and Fc function. This study showed that co-operation between the variable and natural IgG3 constant regions enhanced the polyfunctionality of antibodies, indicating the value of leveraging genetic variation which could be exploited for passive immunity.read more
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Journal ArticleDOI
FcγR Binding and ADCC Activity of Human IgG Allotypes.
Steven W. de Taeye,Arthur E. H. Bentlage,Mirjam M. Mebius,Joyce I. Meesters,Suzanne N. Lissenberg-Thunnissen,David Falck,Thomas Sénard,Nima Salehi,Manfred Wuhrer,Janine Schuurman,Aran F. Labrijn,Theo Rispens,Gestur Vidarsson +12 more
TL;DR: While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3.
Journal ArticleDOI
Hinge length contributes to the phagocytic activity of HIV-specific IgG1 and IgG3 antibodies
Thach H. Chu,Andrew R. Crowley,Iara M. Backes,Cheryl H. Chang,Matthew Zirui Tay,Thomas Broge,Marina Tuyishime,Guido Ferrari,Michael S. Seaman,Simone I. Richardson,Georgia D. Tomaras,Galit Alter,David A. Leib,Margaret E. Ackerman +13 more
TL;DR: Results suggest that when high phagocytic activity is desirable, therapeutic antibodies may benefit from being formatted as human IgG3 or engineered IgG1 forms with elongated hinges.
Journal ArticleDOI
Sensitive detection of total anti-Spike antibodies and isotype switching in asymptomatic and symptomatic individuals with COVID-19.
Yun Shan Goh,Jean-Marc Chavatte,Alicia Lim Jieling,Bernett Lee,Pei Xiang Hor,Siti Naqiah Amrun,Cheryl Yi-Pin Lee,Rhonda Sin-Ling Chee,Bei Wang,Chia Yin Lee,Eve Zhi Xian Ngoh,Cheng-I Wang,Barnaby Edward Young,Barnaby Edward Young,Paul A. Tambyah,Shirin Kalimuddin,Shirin Kalimuddin,Surinder Pada,Seow-Yen Tan,Louisa Jin Sun,Mark I-Cheng Chen,Yee Sin Leo,David C. Lye,Lisa F. P. Ng,Raymond T. P. Lin,Laurent Rénia,Laurent Rénia +26 more
TL;DR: In this paper, a flow cytometry-based method was developed to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein antibodies in individuals with COVID-19.
Journal ArticleDOI
A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site.
Taishi Onodera,Shunsuke Kita,Yu Adachi,Saya Moriyama,Akihiko Sato,Takao Nomura,Shuhei Sakakibara,Takeshi Inoue,Takashi Tadokoro,Yuki Anraku,Kohei Yumoto,Cong Tian,Hideo Fukuhara,Michihito Sasaki,Yasuko Orba,Nozomi Shiwa,Naoko Iwata,Noriyo Nagata,Tateki Suzuki,Jiei Sasaki,Tsuyoshi Sekizuka,Keisuke Tonouchi,Keisuke Tonouchi,Lin Sun,Shuetsu Fukushi,Hiroyuki Satofuka,Yasuhiro Kazuki,Mitsuo Oshimura,Tomohiro Kurosaki,Makoto Kuroda,Yoshiharu Matsuura,Tadaki Suzuki,Hirofumi Sawa,Takao Hashiguchi,Takao Hashiguchi,Katsumi Maenaka,Yoshimasa Takahashi +36 more
TL;DR: In this paper, a spike protein receptor-binding site (RBS) antibody with a germline VH gene was used to neutralize SARS-related coronaviruses.
Journal ArticleDOI
Coming together at the hinges: Therapeutic prospects of IgG3
TL;DR: The human IgG3 subclass is conspicuously absent among the formats for approved monoclonal antibody therapies and Fc fusion protein biologics as mentioned in this paper, which may be due to concerns about the potential for rapid degradation, reduced plasma half-life, and increased immunogenicity due to marked variation in allotypes.
References
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