Recombinant Antibodies as Therapeutic Agents

Abstract

Hybridoma fusion technology, proposed by Köhler and Milstein in 1975, started major developments in the field of monoclonal antibodies (mAbs). During the following 2 decades, their high potential as laboratory tools was rapidly exploited for biotechnology and biomedical applications. Today, mAbs represent over 30% of all biological proteins undergoing clinical trials and are the second largest class of biodrugs after vaccines. With the help of antibody engineering, mAbs have been reduced in size, rebuilt into multivalent molecules, and conjugated with drugs, toxins, or radioisotopes for the treatment of cancer, autoimmune disorders, graft rejection, and infectious diseases. Additionally, in the past few years, important advances have been made in the design, selection, and production of these new types of engineered antibodies. The present review focuses on the structural and functional characteristics of mAbs and their fragments, and also provides a walk through the most important methods used in antibody selection. In addition, the recent trends in antibody engineering for improving antibody clinical efficacy are also reviewed.

Structure of the LINGO-1–Anti-LINGO-1 Li81 Antibody Complex Provides Insights into the Biology of LINGO-1 and the Mechanism of Action of the Antibody Therapy

“…Of these, antibodies were preferred because of their potency, selectivity, and duration of treatment effects due to long serum half-life (Aires da Silva et al, 2008;Kontermann, 2009;Pepinsky et al, 2011). The anti-LINGO-1 antibody Li81 was isolated using Fab phage display technology and engineered into a human IgG1 aglycosyl framework (Hoet et al, 2005;Pepinsky et al, 2011).…”

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

“…Antibodies are a common platform for biopharmaceuticals, and with more than 20 antibodies approved and several hundred others in clinical trials they account for approximately 30% of biological proteins in clinical trials (Aires da Silva et al, 2008;Labrijn et al, 2008). Most target diseases with an immunological basis or cancer.…”

Improving the solubility of anti‐LINGO‐1 monoclonal antibody Li33 by isotype switching and targeted mutagenesis

“…Humans have four IgG isotypes: IgG1, IgG2, IgG3, and IgG4. 1,2 All are heterotetrameric with two identical heavy (HC) and light chains (LC) linked by intrachain disulfides. IgGs contain two identical Fabs and an Fc connected by a flexible hinge region.…”

“…[3][4][5] Enormous strides have been made in the development and optimization of therapeutic antibodies with the IgG1, IgG2, and IgG4 frameworks being successfully exploited for drug development. 1,2 Targeted molecular designs that either eliminate the Fc glycosylation sites to reduce effector function or that stabilize the IgG4 hinge to prevent conversion of IgG4 antibodies into functionally monovalent forms in vivo are two examples of the many engineering achievements. 1,3,[6][7][8][9] Perhaps the most common and challenging issue encountered in developing protein biopharmaceuticals is aggregation, which can be exacerbated by the need to develop high protein concentration formulations to support systemic administration.…”

“…1,2 Targeted molecular designs that either eliminate the Fc glycosylation sites to reduce effector function or that stabilize the IgG4 hinge to prevent conversion of IgG4 antibodies into functionally monovalent forms in vivo are two examples of the many engineering achievements. 1,3,[6][7][8][9] Perhaps the most common and challenging issue encountered in developing protein biopharmaceuticals is aggregation, which can be exacerbated by the need to develop high protein concentration formulations to support systemic administration. 10 The size and complexity of proteins makes aggregation a difficult issue to address.…”