Fc-fusion Proteins in Therapy: An Updated View

Jafari, Reza; Zolbanin, Naime Majidi; Rafatpanah, Houshang; Majidi, Jafar; Kazemi, Tohid

doi:10.2174/0929867324666170113112759

Cited by 69 publications

(52 citation statements)

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“…Biomolecules such as receptors, cytokines, enzymes, and peptides can be genetically fused to antibody Fc domains, and several such molecules are approved for clinical use or are in clinical development for indications such as cancer, autoimmunity, and blood disorders. 242 An important advantage of IgG-Fc fusion is the ability to bind FcRn and increase half-life, although Fc-fusion proteins generally have weaker FcRn binding and shorter half-lives (~2 weeks vs.~3 weeks) than IgG molecules. 242,243 Depending on the groups attached, Fc-fusion may retain FcgR-mediated effector functions but generally lose the ability to fix complement.…”

Section: Fusion Proteinsmentioning

confidence: 99%

“…242 An important advantage of IgG-Fc fusion is the ability to bind FcRn and increase half-life, although Fc-fusion proteins generally have weaker FcRn binding and shorter half-lives (~2 weeks vs.~3 weeks) than IgG molecules. 242,243 Depending on the groups attached, Fc-fusion may retain FcgR-mediated effector functions but generally lose the ability to fix complement. 243,244 Other potential benefits include increased stability and solubility, as well as facile purification using protein Aand G-based resins.…”

Section: Fusion Proteinsmentioning

confidence: 99%

“…243,244 Other potential benefits include increased stability and solubility, as well as facile purification using protein Aand G-based resins. 242 From a design standpoint, it is possible to fuse proteins to either end of the Fc. In practice, it is more common to attach functionality to the N-terminus of the Fc to more closely mimic the native IgG structure.…”

Section: Fusion Proteinsmentioning

confidence: 99%

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Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

184

154

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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Section: Fusion Proteinsmentioning

confidence: 99%

Section: Fusion Proteinsmentioning

confidence: 99%

Section: Fusion Proteinsmentioning

confidence: 99%

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Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

184

154

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“…It should be noted that the EDIII protein used in this study was fused with a C-terminal hFc tag. Fc-fusion proteins have been approved by the FDA for human therapy, and their safety and pharmacokinetic activity have been evaluated extensively [60][61][62][63]. Fusion of Fc tag to recombinant proteins may promote the proteins to form dimeric structures, significantly improving their solubility, stability, and avidity, as well as increasing their immunogenicity and/or efficacy [64][65][66].…”

Section: Discussionmentioning

confidence: 99%

Effects of Adjuvants on the Immunogenicity and Efficacy of a Zika Virus Envelope Domain III Subunit Vaccine

et al. 2019

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Zika virus (ZIKV), a mosquito-borne flavivirus, has attracted global attention due to its close association with congenital Zika syndrome and neurological diseases, and transmission through additional routes, such as sexual contact. Currently there are no vaccines approved for ZIKV, and thus, there is an urgent need to develop an effective and safe ZIKV vaccine. Domain III (DIII) of the ZIKV envelope (E) protein is an important vaccine target, and a vaccine developed using a mutant DIII of E (EDIII) protein protects adult and pregnant mice, and unborn offspring, against ZIKV infection. Here, we have used immunocompetent BALB/c mice treated with anti-interferon-α/β receptor 1 (Ifnar1) antibodies to investigate whether three adjuvants (aluminum (Alum), monophosphoryl lipid A (MPL), and MF59), either alone or in combination, could improve the efficacy of this EDIII subunit vaccine. Our data show that, although vaccine formulated with a single adjuvant induced a specific antibody and cellular immune response, and reduced viral load in mice challenged with ZIKV, the combination of Alum and MPL adjuvants led to a more robust and balanced immune response, stronger neutralizing activity against three recent ZIKV human strains, and greater protection against a high-dose ZIKV challenge. Particularly, the combination of Alum with MPL significantly reduced viral titers and viral RNA copy numbers in sera and tissues, including the male reproductive organs. Overall, this study has identified the combination of Alum and MPL as the most effective adjuvant for ZIKV EDIII subunit vaccines, and it has important implications for subunit vaccines against other enveloped viruses, including non-ZIKV flaviviruses.Vaccines 2019, 7, 161 2 of 16 with microcephaly, fetal demise, and other congenital disorders [4][5][6]. Thus, ZIKV has emerged as a global health threat and there is an urgent requirement for an effective vaccine to combat ZIKV-associated diseases.The ZIKV genome encodes a single polyprotein, which is processed into three structural proteins (capsid (C), precursor of membrane/membrane (prM/M), and envelope (E)) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [7][8][9]. The E protein has important roles in infection and pathogenesis, is involved in virus binding to target cells and membrane fusion, and also serves as an important vaccine target [7,8]. The E protein is a transmembrane protein and consists of three domains termed I, II, and III (DI-DIII), a fusion loop (FL), and a stalk region (S) [8]. The DI-DII region of ZIKV E protein is a target for cross-reactive antibodies with other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), whereas the DIII domain induces ZIKV-specific antibodies [10][11][12], and therefore, is a key target for ZIKV vaccine development. ZIKV vaccine candidates under development include inactivated virus, live attenuated virus, DNA, mRNA, viral vectors, virus-like particles (VLPs), and viral proteins (or subunit vaccines) [13][14][15][16]. Although ma...

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“…The most successful class of antibody‐fusion proteins are comprised of bioactive proteins fused to the Fc‐domain of IgG (Beck & Reichert, ; Jafari, Zolbanin, Rafatpanah, Majidi, & Kazemi, ). Among the 11 FDA‐approved Fc‐fusion therapeutics, two are indicated for cancer treatment.…”

Section: Antibody Conjugates and Fusionsmentioning

confidence: 99%

Antibody and antibody derivatives as cancer therapeutics

Arlotta

Owen

2019

WIREs Nanomed Nanobiotechnol

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Antibodies are an important class of therapeutic for treating a wide range of diseases. These versatile macromolecules can be engineered to target many different antigens and to utilize several mechanisms of action to produce a pharmacological effect. The most common antibody platform used for therapeutics is immunoglobulin G (IgG). Advances in protein-display and genetic engineering have enabled the construction and manipulation of IgG to enhance desired activity such as increasing antigen affinity, modulating pharmacokinetics, and enhancing effector functions.IgGs can also be altered to suppress undesired effects, such as immunogenicity. The main approaches to control IgG behavior include engineering the protein sequence and glycosylation of intact IgG; constructing IgG-based derivatives, including bispecific and multivalent binders; and fusing small-drug molecules or proteins to IgG-derived scaffolds. Often, a single modification applied to a given IgG can alter more than one property. The desired effects of an antibody therapeutic should be carefully tailored to the physiology and characteristics of each disease condition.

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Fc-fusion Proteins in Therapy: An Updated View

Cited by 69 publications

References 0 publications

Considerations for the Design of Antibody-Based Therapeutics

Considerations for the Design of Antibody-Based Therapeutics

Effects of Adjuvants on the Immunogenicity and Efficacy of a Zika Virus Envelope Domain III Subunit Vaccine

Antibody and antibody derivatives as cancer therapeutics

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