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WIREs Nanomed Nanobiotechnol
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Antibody and antibody derivatives as cancer therapeutics

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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. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Peptide‐Based Structures
Immunoglobulin G (IgG) is the most common antibody format used for therapeutics. A cartoon representation is shown on the left with the crystal structure (PDB entry 1HZH) shown on the right. Each IgG is composed of two heavy chains (gray) and two light chains (blue) which are linked together through disulfide bonds. The two fragments of a standard IgG are the crystallizable, constant fragment (Fc) (orange box) and the antigen‐binding fragment (Fab) (blue box). The Fc region is comprised of constant portions of the heavy chains as well as a conserved glycosylation (purple). The Fc is important for effector functions, including antibody‐dependent cellular cytotoxicity, opsonization, and complement activation. The Fab region includes constant portions of the heavy and light chains and the variable fragment (Fv) (green box) that contain the complementarity determining regions where sequence variability imparts antigen‐binding specificity
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Antibody‐drug conjugates (ADCs) consist of a monoclonal antibody scaffold that is chemically attached to a therapeutic payload through a linker. Several methods have been developed to incorporate linkers at various sites using a range of conjugation chemistries. The linker portion of an ADC can function as both a spacer to improve stability, as well as a cleavable moiety to increase effective drug release. Current ADCs employ extremely toxic payloads with the majority blocking tubulin formation or DNA replication
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Multivalent antibody formats are being developed to enhance potency by introducing avidity and multifunctional activity. These formats can be multivalent and further engineered multispecific by combining different binding domains. (a) Bivalent and bispecific antibody formats are created from single domain (sdAb) fused in tandem, two single chain Fv (scFv) fused in tandem, or similar derivatives. (b) Trivalent formats expand on the modular sdAb scaffold to create longer tandem chains or series of scFv. Trivalent antibody formats can also be built on the more standard IgG format, using constant heavy chains to bridge various domains. (c) Tetravalent are constructed by extension and combination of bi‐ and tri‐valent formats, such as the double diabody. (Reprinted with permission from Nunez‐Prado et al. (). Copyright 2015 Elsevier)
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Immunoglobulin G (IgG) fragments and derivatives. Fragments, such as single chain variable fragments (scFv) or single‐arm Fabs can be used to alter soluble and cell surface antigens by direct interaction. Other derivatives are engineered to include constant domains essential for Fc‐related activity
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Therapeutic antibodies are glycosylated through the ubiquitous asparagine residue (N297) found in the Fc region. The most common oligosaccharides found in current therapeutic antibody products are shown (left), with N‐acetylglucosamine (GlcNAc) terminated the most prevalent. The glycosylation type and distribution is a result of expression system (mammalian, yeast, plant) and genetic engineering. Controlling glycosylation can bias the effect of the Fc‐related functions of therapeutic antibodies. Several engineered oligosaccharides and the resulting impact on function are shown (right)
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Biology-Inspired Nanomaterials > Lipid-Based Structures
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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