scholarly journals Fc-engineered antibody therapeutics with improved efficacy against COVID-19

2021 ◽  
Author(s):  
Jeffrey Ravetch ◽  
Rachel Yamin ◽  
Andrew Jones ◽  
Hans-Heinrich Hoffmann ◽  
Kevin Kao ◽  
...  
Keyword(s):  
Weight Loss ◽  
Monoclonal Antibodies ◽  
Animal Models ◽  
Clinical Efficacy ◽  
Clinical Benefit ◽  
Effector Function ◽  
Antibody Therapeutics ◽  
Limited Efficacy ◽  
High Doses ◽  
Full Protection

Abstract Monoclonal antibodies (mAbs) with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefit in cases of mild to moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these mAbs with limited efficacy in preventing disease complications or mortality among hospitalized COVID-19 patients5. Here we report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease. In several animal models of COVID-19 disease6,7, we demonstrate that selective engagement of activating FcγRs results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection upon SARS-CoV-2 challenge and treatment of pre-infected animals. Our results highlight the importance of FcγR pathways in driving antibody-mediated antiviral immunity, while excluding any pathogenic or disease-enhancing effects of FcγR engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered mAbs with optimal Fc effector function and improved clinical efficacy against COVID-19 disease.

scholarly journals An anti-SARS-CoV-2 non-neutralizing antibody with Fc-effector function defines a new NTD epitope and delays neuroinvasion and death in K18-hACE2 mice

2021 ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Yaozong Chen ◽  
Irfan Ullah ◽  
Jérémie Prévost ◽  
William D. Tolbert ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Animal Models ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Transgenic Mouse Model ◽  
Effector Function ◽  
Effector Functions

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.

109-LB: Potent Weight Loss Mechanism by a Novel Long-Acting Glucagon Analog, HM15136, in Animal Models

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 109-LB
Author(s):  
JONG SUK LEE ◽  
JUNG KUK KIM ◽  
JINYOUNG KIM ◽  
EUNJIN PARK ◽  
SANG HYUN LEE ◽  
...  
Keyword(s):  
Weight Loss ◽  
Animal Models ◽  
Loss Mechanism ◽  
Long Acting

scholarly journals Pervasive Resistance to Pyrethroids in German Cockroaches (Blattodea: Ectobiidae) Related to Lack of Efficacy of Total Release Foggers

2019 ◽  
Vol 112 (5) ◽  
pp. 2295-2301 ◽  
Author(s):  
Zachary C DeVries ◽  
Richard G Santangelo ◽  
Jonathan Crissman ◽  
Alonso Suazo ◽  
Madhavi L Kakumanu ◽  
...  
Keyword(s):  
Active Ingredient ◽  
Pyrethroid Resistance ◽  
Low Cost ◽  
Population Based ◽  
Susceptible Population ◽  
Limited Efficacy ◽  
Metabolic Detoxification ◽  
Do It Yourself ◽  
High Doses ◽  
Cockroach Blattella Germanica

Abstract Despite limited efficacy data, do-it-yourself (DIY) insecticide products often promise low-cost alternatives to professional pest control. Total release foggers (TRFs, ‘bug bombs’), which are prominent DIY products, were recently shown to be ineffective at reducing German cockroach (Blattella germanica L.) infestations, in contrast to highly effective baits. However, the reason(s) for TRF failure remain unknown. Therefore, we investigated insecticide resistance of apartment-collected cockroaches from homes where TRFs failed. In topical (direct) application assays, resistance to cypermethrin (a common active ingredient in TRFs) was 202 ± 33 times that of a laboratory insecticide-susceptible population (based on LD50 ratios), while resistance to fipronil, a common bait active ingredient, was considerably lower at 14 ± 2 times that of the laboratory insecticide-susceptible population. The addition of PBO, a P450 inhibitor that synergizes pyrethroids, enhanced the efficacy of cypermethrin, but only at high doses of cypermethrin. Additionally, >96% of screened cockroaches possessed at least one copy of the L993F mutation in the voltage-gated sodium channel, known to confer resistance to pyrethroids (knockdown resistance, kdr). Because TRF treatments killed insecticide-susceptible sentinel cockroaches but failed to kill apartment-collected cockroaches, these results suggest that pyrethroid resistance is a major factor contributing to the failure of TRFs. Multiple mechanisms of resistance, including metabolic detoxification of the pyrethroids and kdr mutations that confer target-site insensitivity, suggest that TRFs would lack efficacy against German cockroaches in residential settings, where high levels of pyrethroid resistance have been documented globally.

scholarly journals Anti-D monoclonal antibodies from 23 human and rodent cell lines display diverse IgG Fc-glycosylation profiles that determine their clinical efficacy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Belinda M. Kumpel ◽  
Radka Saldova ◽  
Carolien A. M. Koeleman ◽  
Jodie L. Abrahams ◽  
Agnes Hipgrave Ederveen ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Lines ◽  
Clinical Efficacy ◽  
Rodent Cell

scholarly journals Animal Models of Atrial Fibrillation

2020 ◽  
Vol 127 (1) ◽  
pp. 91-110 ◽  
Author(s):  
Dominik Schüttler ◽  
Aneesh Bapat ◽  
Stefan Kääb ◽  
Kichang Lee ◽  
Philipp Tomsits ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Models ◽  
Human Heart ◽  
Swot Analysis ◽  
Unmet Needs ◽  
Business Community ◽  
Therapeutic Options ◽  
Mouse Heart ◽  
Vast Array ◽  
Limited Efficacy

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although “natural” AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a “perfect” animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.

scholarly journals Effect of mushrooms on obesity in animal models: study protocol for a systematic review and meta-analysis

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Denise Grotto ◽  
Isabella Ferreira Camargo ◽  
Katia Kodaira ◽  
Lauren Giustti Mazzei ◽  
Juliana Castro ◽  
...  
Keyword(s):  
Systematic Review ◽  
Weight Loss ◽  
Body Weight ◽  
Animal Models ◽  
Meta Analysis ◽  
Experimental Studies ◽  
Body Weight Loss ◽  
Preclinical Research ◽  
Medicinal Mushrooms ◽  
Aquatic Mammal

Abstract Background Obesity and its consequences are worldwide epidemic problem; therefore, studies with strategies and mechanisms that favor weight loss to improve outcomes in health are necessary. Effects of mushrooms on body weight are uncertain. The aim of this systematic review is to determine the efficacy of mushrooms in weight loss in animal preclinical models. Method This is a systematic review of preclinical studies of animal models of obesity (any type of non-aquatic mammal), which were exposed to edible and medicinal mushrooms orally in comparison with the control. The following databases will be used: MEDLINE (PubMed), Web of Science, BIOSIS, SCOPUS, and gray literature. There will be no restriction of language, date, or publication status. The primary outcome will be body weight loss. And the secondary outcomes include the total amount of food consumed by the animals, analysis of metabolic parameters, inflammatory mediators, mortality for any causes, and any adverse effect reported. A team of reviewers will select, in pairs and independently, the titles and abstracts, extract data from qualifying studies, and assess bias risk (using SYstematic Review Centre for Laboratory animal Experimentation SYRCLE’s risk of bias tool and the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist). The standardized mean difference (SMD) will be calculated to measure treatment effect, with 95% confidence intervals (95% CI). The heterogeneity between-study will be calculated by I2 inconsistency values and Cochran’s Q statistical test, where I2 > 50% and/or p < 0.10 suggest high heterogeneity meta-analyses of random effects will be conducted as possible. Discussion Although many experimental studies about the effects of mushrooms on obesity have already been published, there is still no consensus in the literature. This study will provide evidences of preclinical research on mushrooms and their relation to body weight loss in animal models of obesity, being non-aquatic mammals. Also, this systematic review will show the limitations and strengths of the studies available in the literature, as well as it will to encourage the financing of new studies by public health managers and governmental entities. Systematic review registration PROSPERO (CRD42019125299).

scholarly journals Immunogenicity of Innovative and Biosimilar Monoclonal Antibodies

Antibodies ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 21 ◽  
Author(s):  
Erik Doevendans ◽  
Huub Schellekens
Keyword(s):  
Monoclonal Antibodies ◽  
Immune System ◽  
First Generation ◽  
Chimeric Antibodies ◽  
Human Antibodies ◽  
Limited Efficacy ◽  
Hybridoma Technology ◽  
Infusion Reactions ◽  
Opening Up ◽  
High Immunogenicity

The development of hybridoma technology for producing monoclonal antibodies (mAbs) by Kohler and Milstein (1975) counts as one of the major medical breakthroughs, opening up endless possibilities for research, diagnosis and for treatment of a whole variety of diseases. Therapeutic mAbs were introduced three decades ago. The first generation of therapeutic mAbs of murine origin showed high immunogenicity, which limited efficacy and was associated with severe infusion reactions. Subsequently chimeric, humanized, and fully human antibodies were introduced as therapeutics, these mAbs were considerably less immunogenic. Unexpectedly humanized mAbs generally show similar immunogenicity as chimeric antibodies; based on sequence homology chimeric mAbs are sometimes more “human” than humanized mAbs. With the introduction of the regulatory concept of similar biological medicines (biosimilars) a key concern is the similarity in terms of immunogenicity of these biosimilars with their originators. This review focuses briefly on the mechanisms of induction of immunogenicity by biopharmaceuticals, mAbs in particular, in relation to the target of the immune system.

scholarly journals Priming of Antiviral CD8 T Cells without Effector Function by a Persistently Replicating Hepatitis C-Like Virus

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Alex S. Hartlage ◽  
Christopher M. Walker ◽  
Amit Kapoor
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Animal Models ◽  
Cd8 T Cells ◽  
Persistent Infection ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Viral Escape

ABSTRACT Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV. IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

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