Boosting half-life and effector functions of therapeutic antibodies by Fc-engineering: An interaction-function review

Fonseca, Marcela Helena Gambim; Furtado, Gilvan Pessoa; Bezerra, Marcus Rafael Lobo; Pontes, Larissa Queiroz; Fernandes, Carla Freire Celedônio

doi:10.1016/j.ijbiomac.2018.07.141

Cited by 19 publications

(18 citation statements)

References 63 publications

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“…In 2015 there were 44 antibodies approved for human use in the United States and Europe (2). Consistent with an expected annual approval rate of six to nine additional antibodies (3), the number of approved antibodies and antibody-like biologics in the United States has climbed to more than 70 (1, 4). It is estimated that global sales of antibody-based products approach $60–75 billion in any given year (2–8).…”

Section: Introductionmentioning

confidence: 88%

“…Since the approval of the first monoclonal antibody by the FDA in 1986 (1), there has been a rapid increase in the number of available monoclonal antibodies or antibody derivatives. In 2015 there were 44 antibodies approved for human use in the United States and Europe (2).…”

Section: Introductionmentioning

confidence: 99%

“…The antibody can vary in isotype depending on whether the alpha, mu, gamma, epsilon, or delta constant region gene segment is recombined with the variable region (22). Among the human gamma gene segments there are 4 different subclasses designated as gamma 1, 2, 3, and 4, which are approximately 90% identical to each other (1). In a clinical context, each subclass is important since each subclass specializes in the elimination of different types of pathogens (23).…”

Section: Introductionmentioning

confidence: 99%

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Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life

2019

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Antibodies and Fc-fusion antibody-like proteins have become successful biologics developed for cancer treatment, passive immunity against infection, addiction, and autoimmune diseases. In general these biopharmaceuticals can be used for blocking protein:protein interactions, crosslinking host receptors to induce signaling, recruiting effector cells to targets, and fixing complement. With the vast capability of antibodies to affect infectious and genetic diseases much effort has been placed on improving and tailoring antibodies for specific functions. While antibody:antigen engagement is critical for an efficacious antibody biologic, equally as important are the hinge and constant domains of the heavy chain. It is the hinge and constant domains of the antibody that engage host receptors or complement protein to mediate a myriad of effector functions and regulate antibody circulation. Molecular and structural studies have provided insight into how the hinge and constant domains from antibodies across different species, isotypes, subclasses, and alleles are recognized by host cell receptors and complement protein C1q. The molecular details of these interactions have led to manipulation of the sequences and glycosylation of hinge and constant domains to enhance or reduce antibody effector functions and circulating half-life. This review will describe the concepts being applied to optimize the hinge and crystallizable fragment of antibodies, and it will detail how these interactions can be tuned up or down to mediate a biological function that confers a desired disease outcome.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life

2019

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“…This section of the review is focused on rational methods to engineer the antigen-binding function of the Fab arm of the antibody. The enormous progress that has been achieved in modifying the Fc-related effector function of the antibody has been reviewed recently [86][87][88] and will be discussed later in this review. The hinges of Human IgG subtypes vary significantly in the number of residues and the number of possible disulfide bridges between the two heavy chains.…”

Section: Structure-based Antibody Engineeringmentioning

confidence: 99%

Antibody Structure and Function: The Basis for Engineering Therapeutics

et al. 2019

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Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. We also review the design and selection of binding arms, and avidity modulation. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included.

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“…14 Oen, the effects of the solvent environment such as pH are key factors in biochemical reactions, including the Fc-FcRn binding mechanism. 5,11,15,19 Although conventional molecular dynamics (MD) simulation has prompted molecular discovery in biological studies, system settings with a xed protonation state for solute titratable residues throughout the simulation may hinder the visualization of complex conformational changes in different pH environments. Thus, an auxiliary for MD simulation, constant pH molecular dynamics (CpHMD) simulation, which allows dynamic changes in the protonation states of titratable residues based on changes in the environmental pH was applied in this study.…”

Section: Introductionmentioning

confidence: 99%

Human IgG1 Fc pH-dependent optimization from a constant pH molecular dynamics simulation analysis

Lim

Choong

2020

RSC Adv.

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Boosting half-life and effector functions of therapeutic antibodies by Fc-engineering: An interaction-function review

Cited by 19 publications

References 63 publications

Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life

Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life

Antibody Structure and Function: The Basis for Engineering Therapeutics

Human IgG1 Fc pH-dependent optimization from a constant pH molecular dynamics simulation analysis

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