A multimechanistic antibody targeting the receptor binding site potently cross-protects against influenza B viruses

Shen, Chenguang; Chen, Junyu; Li, Rui; Zhang, Mengya; Wang, Guosong; Stegalkina, Svetlana; Zhang, Limin; Chen, Jing; Cao, Jianli; Bi, Xingjian; Anderson, Stephen F.; Alefantis, Timothy; Zhang, Minwei; Cai, Xiaoyang; Yang, Kunyu; Zheng, Qingbing; Fang, Mujing; Yu, Hai; Luo, Wenxin; Zheng, Zizheng; Yuan, Quan; Zhang, Jun; Shih, J. Wai-Kuo; Kleanthous, Harry; Chen, Hong‐Lin; Chen, Yixin; Xia, Ningshao

doi:10.1126/scitranslmed.aam5752

Cited by 71 publications

(81 citation statements)

References 32 publications

(47 reference statements)

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“…While a majority of these MAbs have neutralizing activity in vitro, broad protection conferred in vivo by nonneutralizing antibodies via Fc-Fc receptor interactions has been described as well (9)(10)(11). Data for broadly protective influenza B virus antibodies are sparse and limited to only a few studies reporting a small number of MAbs capable of displaying broad influenza B virus neutralization capacity in vitro (12)(13)(14)(15).…”

Section: Adcc Ha Influenza B Mabmentioning

confidence: 99%

Broadly Cross-Reactive, Nonneutralizing Antibodies against Influenza B Virus Hemagglutinin Demonstrate Effector Function-Dependent Protection against Lethal Viral Challenge in Mice

Arunkumar

Ioannou

Wohlbold

et al. 2019

J Virol

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Protection from influenza virus infection is canonically associated with antibodies that neutralize the virus by blocking the interaction between the viral hemagglutinin and host cell receptors. However, protection can also be conferred by other mechanisms, including antibody-mediated effector functions. Here, we report the characterization of 22 broadly cross-reactive, nonneutralizing antibodies specific for influenza B virus hemagglutinin. The majority of these antibodies recognized influenza B viruses isolated over the period of 73 years and bind the conserved stalk domain of the hemagglutinin. A proportion of the characterized antibodies protected mice from both morbidity and mortality after challenge with a lethal dose of influenza B virus. Activity in an antibody-dependent cell-mediated cytotoxicity reporter assay correlated strongly with protection, suggesting that Fc-dependent effector function determines protective efficacy. The information regarding mechanism of action and epitope location stemming from our characterization of these antibodies will inform the design of urgently needed vaccines that could induce broad protection against influenza B viruses.

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Section: Adcc Ha Influenza B Mabmentioning

confidence: 99%

Broadly Cross-Reactive, Nonneutralizing Antibodies against Influenza B Virus Hemagglutinin Demonstrate Effector Function-Dependent Protection against Lethal Viral Challenge in Mice

Arunkumar

Ioannou

Wohlbold

et al. 2019

J Virol

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“…Although detection of viruses that exhibit reduced susceptibility to NA inhibitors or baloxavir marboxil in immunocompetent patients has frequently been reported 1,[4][5][6][7][8][9] , such viruses usually do not dominate susceptible viruses with the exception of the worldwide spread of oseltamivir-resistant H1N1 virus in the 2007-2008 season. Recently, broadly protective human monoclonal antibodies (mAbs) against conserved regions of HA, including the receptorbinding site (RBS) and stem region, have been evaluated [10][11][12][13][14][15][16] and studies for their clinical application are being conducted [17][18][19][20] . However, no human mAbs are currently available for clinical use.…”

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confidence: 99%

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

2020

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Prolonged treatment of immunocompromised influenza patients with viral neuraminidase (NA) inhibitors is required, because the immune system of such patients fails to eradicate the viruses. Here, we attempted to eradicate influenza virus from the respiratory organs of nude mice, which is a model of immunocompromised hosts, by using combination therapy of the viral polymerase inhibitor favipiravir and monoclonal antibodies (mAbs) against the receptorbinding site (RBS) and stem of viral hemagglutinin (HA). Although monotherapy or combination therapy of two antivirals (two mAbs or favipiravir plus a mAb) suppressed virus replication, they failed to eradicate viruses from nude mice. In contrast, the triple combination therapy of favipiravir plus anti-Stem and anti-RBS mAbs completely stopped virus replication in nude mice, resulting in virus clearance. Triple combination approaches should be considered for the treatment of human immunocompromised patients with severe influenza.

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“…It is worth noting that neutralization and ADCC are not mutually exclusive. Antibodies with both anti-viral mechanisms have also been identified and characterized in recent studies, which demonstrated that ADCC activity could occur concurrently with a neutralization response [23,106]. Shen et al reported that one HA head-targeted antibody, C12G6, can not only neutralize Yamagata, Victoria and earlier lineages of influenza B viruses, but also inhibits the membrane fusion, virus egress, and induces an ADCC response [106].…”

Section: Hi-positive Head-targeting Mabs Cannot Mediate Robust Adcc Amentioning

confidence: 99%

“…Antibodies with both anti-viral mechanisms have also been identified and characterized in recent studies, which demonstrated that ADCC activity could occur concurrently with a neutralization response [23,106]. Shen et al reported that one HA head-targeted antibody, C12G6, can not only neutralize Yamagata, Victoria and earlier lineages of influenza B viruses, but also inhibits the membrane fusion, virus egress, and induces an ADCC response [106]. Notably, they also demonstrated that the potency of C12G6-mediated ADCC activity against different viruses followed an opposite trend to its HI activity, in which higher HI titer was found to be associated with relatively lower ADCC activity, and vice versa.…”

Section: Hi-positive Head-targeting Mabs Cannot Mediate Robust Adcc Amentioning

confidence: 99%

Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

Gao

Sheng

Sreenivasan

et al. 2020

Viruses

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Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) titers exhibited by vaccine-induced neutralizing antibodies, which correlate fairly well with vaccine-conferred protection. Contrarily, non-neutralizing antibodies and their therapeutic potential are less well defined, yet, recent advances in anti-influenza antibody research indicate that non-neutralizing Fc-effector activities, especially antibody-dependent cellular cytotoxicity (ADCC), also serve as a critical mechanism in antibody-mediated anti-influenza host response. Monoclonal antibodies (mAbs) with Fc-effector activities have the potential for prophylactic and therapeutic treatment of influenza infection. Inducing mAbs mediated Fc-effector functions could be a complementary or alternative approach to the existing neutralizing antibody-based prevention and therapy. This review mainly discusses recent advances in Fc-effector functions, especially ADCC and their potential role in influenza countermeasures. Considering the complexity of anti-influenza approaches, future vaccines may need a cocktail of immunogens in order to elicit antibodies with broad-spectrum protection via multiple protective mechanisms.Viruses 2020, 12, 276 2 of 20 the infected cell, HA on the virion still interacts with the SA receptors on the host cell membrane. The tetrameric NA spike functions to release the viral progeny through cleaving α-ketosidic linkage between the SA and an adjacent sugar residue [5].α-ketosidic linkage between the SA and an adjacent sugar residue [5].The HA and NA proteins are also highly immunogenic and antibodies targeting both glycoproteins can be isolated after natural infection or vaccination. Through binding to viral surface proteins HA and NA, antibodies can block the essential steps in the virus replication cycle, thereby limiting the spread of infection. Due to the host immune pressure and error-prone RNA polymerase, HA and NA are very plastic and display difference in antigenic properties. According to the antigenic difference, influenza A virus can divide into 18 HA (H1-H18) and 11 NA (N1-N11) subtypes [6]. According to the Weekly U.S. Influenza Surveillance Report released by CDC, H1N1(pdm09) and B/Victoria lineage viruses are equally dominant and responsible for the majority of death cases during the 2019-2020 influenza season [7].

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A multimechanistic antibody targeting the receptor binding site potently cross-protects against influenza B viruses

Cited by 71 publications

References 32 publications

Broadly Cross-Reactive, Nonneutralizing Antibodies against Influenza B Virus Hemagglutinin Demonstrate Effector Function-Dependent Protection against Lethal Viral Challenge in Mice

Broadly Cross-Reactive, Nonneutralizing Antibodies against Influenza B Virus Hemagglutinin Demonstrate Effector Function-Dependent Protection against Lethal Viral Challenge in Mice

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

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