Antibody and antibody derivatives as cancer therapeutics

Abstract

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.

Protein-Protein Interactions, Clustering, and Rheology for Bovine IgG up to High Concentrations Characterized by Small Angle X-Ray Scattering and Molecular Dynamics Simulations

“…Antibody (Ab)-based drugs are one of the fastest growing classes of therapeutics, with more complex formulations such as shortchain variable fragments, bispecific antibodies, antibody-drug conjugates, and fixed-dose combinations becoming more prevalent. [1][2][3] High concentrations of these solutions are desirable both for processing efficiency and for subcutaneous drug delivery. However, owing to interparticle distances at high concentration of only~1 nm, short-range anisotropic (i.e., charge-charge, charge-dipole, dipole-dipole, hydrogen bonding, and hydrophobic) proteinprotein interactions (PPIs) may promote formation of reversible oligomers, which can lead to viscosities above the practical threshold of~20 cp and irreversible aggregates upon storage.…”

Targeting Glycosylation: A New Road for Cancer Drug Discovery

“…Additionally, cancer-associated glycans present at Box 1. Selective Therapies: Specific Inhibitors and mAbs Antibodies are now an established option in cancer treatment, with more than 30 antibodies or antibody derivatives currently approved by the FDA and European Medicines Agency and hundreds more in clinical trials [48]. Anticancer mAbs target a broad range of antigens, including soluble proteins, cancer cell surfaces, and effector cell receptors.…”

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

“…The most common oligosaccharides found in current antibody therapeutics are shown in Fig. 1 B [ 28 ]. The glycosylation of mAbs is closely related to the genetic engineering, expression system (yeast, mammalian, and plant) and the incubation condition.…”

“…Controlling glycosylation can bias the effect of the Fc-related functions of therapeutic antibodies [ 29 , 30 ], so glycol-engineering technologies are also being developed to control glycoforms ( Fig. 1 B, right) [ 28 , 31 ]. Very recently, Weiss’s group [ 32 ] engineered Chinese hamster ovary (CHO) cells with synthetic genetic circuits to rationally tune N -glycosylation of a stably expressed IgG under small-molecule inducible promoters.…”

“…The most common oligosaccharides found in current therapeutic antibody products are shown (left). Several engineered oligosaccharides and the resulting impact on functions are shown (right) [ 28 ]. The figures were reproduced with permission from Refs.…”