Therapeutic Antibodies: Current State and Future Trends – Is a Paradigm Change Coming Soon?

Abstract

Antibody-based therapeutics currently enjoy unprecedented success, growth in research and revenues, and recognition of their potential. It appears that the promise of the “magic bullet” has largely been realized. There are currently 22 monoclonal antibodies (mAbs) approved by the United States Food and Drug Administration (FDA) for clinical use and hundreds are in clinical trials for treatment of various diseases including cancers, immune disorders, and infections. The revenues from the top five therapeutic antibodies (Rituxan, Remicade, Herceptin, Humira, and Avastin) nearly doubled from $6.4 billion in 2004 to $11.7 billion in 2006. During the last several years major pharmaceutical companies raced to acquire antibody companies, with a recent example of MedImmune being purchased for $15.6 billion by AstraZeneca. These therapeutic and business successes reflect the major advances in antibody engineering which have resulted in the generation of safe, specific, high-affinity, and non-immunogenic antibodies during the last three decades. Currently, second and third generations of antibodies are under development, mostly to improve already existing antibody specificities. However, although the refinement of already known methodologies is certainly of great importance for potential clinical use, there are no conceptually new developments in the last decade comparable, for example, to the development of antibody libraries, phage display, domain antibodies (dAbs), and antibody humanization to name a few. A fundamental question is then whether there will be another change in the paradigm of research as happened 1–2 decades ago or the current trend of gradual improvement of already developed methodologies and therapeutic antibodies will continue. Although any prediction could prove incorrect, it appears that conceptually new methodologies are needed to overcome the fundamental problems of drug (antibody) resistance due to genetic or/and epigenetic alterations in cancer and chronic infections, as well as problems related to access to targets and complexity of biological systems. If new methodologies are not developed, it is likely that gradual saturation will occur in the pipeline of conceptually new antibody therapeutics. In this scenario we will witness an increase in combination of targets and antibodies, and further attempts to personalize targeted treatments by using appropriate biomarkers as well as to develop novel scaffolds with properties that are superior to those of the antibodies now in clinical use.

Monoclonal antibody N-glycosylation profiling using capillary electrophoresis – Mass spectrometry: Assessment and method validation

“…Glycosylation is a post-transcriptional modification (PTM) that occurs naturally during excretion of antibodies from the expression system to the extracellular medium. It only represents 2-5% of the total mass of the protein but it is subjected to extensive studies due to its significant influence on effector functions of mAbs, especially antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [5][6][7][8]. As a consequence, the mAbs glycosylation profile is considered as a critical quality attribute (CQA) and must be thoroughly analyzed [9][10][11][12][13].…”

Comparison of methods for the analysis of therapeutic immunoglobulin G Fc-glycosylation profiles—Part 1: Separation-based methods

“…1,2 The use of mammalian expression systems results in a remarkable heterogeneity of mAb products, generally due to post-translational modifications, such as N-and C-terminal modifications, deamidation, isomerization and glycosylation. Glycosylation is a critical post-translational modification because it may affect mAbs characteristics such as solubility, stability, pharmacokinetic and pharmacodynamics properties, as well as in vivo efficacy.…”

Soluble Monomeric IgG1 Fc

“…Therapeutic monoclonal antibodies have been improved gradually during the past two decades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Most of the mAbs approved for clinical use are full-size (7,9,10).…”

“…Most of the mAbs approved for clinical use are full-size (7,9,10). However, fullsize antibodies exhibit poor penetration into tissues, especially solid tumors, and also poor or absent binding to regions of some antigens that are occluded and can only be accessed by molecules of smaller size (11)(12)(13).…”