Optimization of Fc-mediated effector functions of monoclonal antibodies

2009 ◽  
Vol 20 (6) ◽  
pp. 685-691 ◽  
Author(s):  
William R Strohl
2018 ◽  
Vol 2018 ◽  
pp. 1-23 ◽  
Author(s):  
Urai Chaisri ◽  
Wanpen Chaicumpa

This narrative review article summarizes past and current technologies for generating antibodies for passive immunization/immunotherapy. Contemporary DNA and protein technologies have facilitated the development of engineered therapeutic monoclonal antibodies in a variety of formats according to the required effector functions. Chimeric, humanized, and human monoclonal antibodies to antigenic/epitopic myriads with less immunogenicity than animal-derived antibodies in human recipients can be producedin vitro. Immunotherapy with ready-to-use antibodies has gained wide acceptance as a powerful treatment against both infectious and noninfectious diseases. Influenza, a highly contagious disease, precipitates annual epidemics and occasional pandemics, resulting in high health and economic burden worldwide. Currently available drugs are becoming less and less effective against this rapidly mutating virus. Alternative treatment strategies are needed, particularly for individuals at high risk for severe morbidity. In a setting where vaccines are not yet protective or available, human antibodies that are broadly effective against various influenza subtypes could be highly efficacious in lowering morbidity and mortality and controlling unprecedented epidemic/pandemic. Prototypes of human single-chain antibodies to several conserved proteins of influenza virus with no Fc portion (hence, no ADE effect in recipients) are available. These antibodies have high potential as a novel, safe, and effective anti-influenza agent.


1992 ◽  
Vol 33 (2) ◽  
pp. 135-138 ◽  
Author(s):  
B.J. Appelmelk ◽  
A.M.J.J. Verweij-Van Vught ◽  
J.J. Maaskant ◽  
L.G. Thijs ◽  
D.M. MacLaren

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Christopher T. Turner ◽  
Steven J. P. McInnes ◽  
Nicolas H. Voelcker ◽  
Allison J. Cowin

Monoclonal antibodies (mAbs), available for a range of diseases, including tumours, leukemia, and multiple sclerosis, are emerging as the fastest growing area of therapeutic drug development. The greatest advantage of therapeutic mAbs is their ability to bind with a high degree of specificity to target proteins involved in disease pathophysiology. In response, effector functions are triggered and these ameliorate the disease cascade. As an alternative to this reliance on effector functions, drugs can be conjugated to mAbs. The ability to target compounds to the site of pathology minimises the nonspecific side effects associated with systemic administration. In both instances, optimising the delivery, absorption, and distribution of the mAbs, whilst minimising potential side effects, remain the key hurdles to improved clinical outcomes. Novel delivery strategies are being investigated with more vigour in recent years, and nanoparticles are being identified as suitable vehicles. In conjunction with permitting a controlled release profile, nanoparticles protect the drug from degradation, reducing both the dose and frequency of administration. Moreover, these particles shield the patient from the immune complications associated with high dose mAb infusions or drug cytotoxicity. This review outlines recent advances in nanoparticle technology and how they may be of benefit as therapeutic mAb delivery/targeting vehicles.


2019 ◽  
Vol 17 (7) ◽  
pp. 2005-2012 ◽  
Author(s):  
Shuang Sun ◽  
Padma Akkapeddi ◽  
Marta C. Marques ◽  
Nuria Martínez-Sáez ◽  
Vukosava M. Torres ◽  
...  

Stable monoclonal antibodies are generated by the mild and efficient re-bridging of interchain disulfides using an isobutylene motif. Effector functions and pharmacokinetics of the stapled antibodies are maintained at a similar level as their native forms.


2019 ◽  
Vol 4 (32) ◽  
pp. eaav5062 ◽  
Author(s):  
Julie M. Fox ◽  
Vicky Roy ◽  
Bronwyn M. Gunn ◽  
Ling Huang ◽  
Melissa A. Edeling ◽  
...  

Chikungunya virus (CHIKV) is an emerging mosquito-borne virus that has caused explosive outbreaks worldwide. Although neutralizing monoclonal antibodies (mAbs) against CHIKV inhibit infection in animals, the contribution of Fc effector functions to protection remains unknown. Here, we evaluated the activity of therapeutic mAbs that had or lacked the ability to engage complement and Fcγ receptors (FcγR). When administered as post-exposure therapy in mice, the Fc effector functions of mAbs promoted virus clearance from infected cells and reduced joint swelling—results that were corroborated in antibody-treated transgenic animals lacking activating FcγR. The control of CHIKV infection by antibody-FcγR engagement was associated with an accelerated influx of monocytes. A series of immune cell depletions revealed that therapeutic mAbs required monocytes for efficient clearance of CHIKV infection. Overall, our study suggests that in mice, FcγR expression on monocytes is required for optimal therapeutic activity of antibodies against CHIKV and likely other related viruses.


2001 ◽  
Vol 50 (5) ◽  
pp. 275-284 ◽  
Author(s):  
Kazuyasu Nakamura ◽  
Yuko Tanaka ◽  
Kenya Shitara ◽  
Nobuo Hanai

2010 ◽  
Vol 79 (2) ◽  
pp. 918-927 ◽  
Author(s):  
Allan Jefferson Guimarães ◽  
Susana Frases ◽  
Bruno Pontes ◽  
Mariana Duarte de Cerqueira ◽  
Marcio L. Rodrigues ◽  
...  

ABSTRACTHistoplasma capsulatumcan efficiently survive within macrophages, facilitatingH. capsulatumtranslocation from the lung into the lymphatics and bloodstream. We have recently generated monoclonal antibodies (MAbs) to anH. capsulatumsurface-expressed heat shock protein of 60 kDa (Hsp60) that modify disease in a murine histoplasmosis model. Interestingly, the MAbs induced different degrees of yeast cell agglutinationin vitro. In the present study, we characterized the agglutination effects of the antibodies to Hsp60 onH. capsulatumyeast cells by light microscopy, flow cytometry, dynamic light scattering, measuring zeta potential, and using optical tweezers. We found that immunoglobulin Gs (IgGs) to Hsp60 causeH. capsulatumaggregation dependent on the (i) concentration of MAbs, (ii) MAb binding constant, and (iii) IgG subclass. Furthermore, infection of macrophages using agglutinates of various sizes after incubation with different Hsp60-binding MAbs induced association to macrophages through distinct cellular receptors and differentially affected macrophage antifungal functions. Hence, the capacity of IgG MAbs to agglutinateH. capsulatumsignificantly impacted pathogenic mechanisms ofH. capsulatumduring macrophage infection, and the effect was dependent on the antibody subclass and antigen epitope.


2021 ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Yaozong Chen ◽  
Irfan Ullah ◽  
Jérémie Prévost ◽  
William D. Tolbert ◽  
...  

SummaryEmerging evidence in animal models indicate that both neutralizing activity and Fc- mediated effector functions of neutralizing antibodies contribute to protection against SARS-CoV-2. It is unclear if antibody effector functions alone could protect against SARS-CoV-2. Here we isolated CV3-13, a non-neutralizing antibody from a convalescent individual with potent Fc-mediated effector functions that targeted the N- terminal domain (NTD) of SARS-CoV-2 Spike. The cryo-EM structure of CV3-13 in complex with SAR-CoV-2 spike revealed that the antibody bound from a distinct angle of approach to a novel NTD epitope that partially overlapped with a frequently mutated NTD supersite in SARS-CoV-2 variants. While CV3-13 did not alter the replication dynamics of SARS-CoV-2 in a K18-hACE2 transgenic mouse model, an Fc-enhanced CV3-13 significantly delayed neuroinvasion and death in prophylactic settings. Thus, we demonstrate that efficient Fc-mediated effector functions can contribute to the in vivo efficacy of anti-SARS-CoV-2 monoclonal antibodies in the absence of neutralization.


Biomaterials ◽  
2018 ◽  
Vol 167 ◽  
pp. 58-68 ◽  
Author(s):  
Young Min Kim ◽  
Jin Se Park ◽  
Sang Kyung Kim ◽  
Kyung Min Jung ◽  
Young Sun Hwang ◽  
...  

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