The development of therapeutic antibodies

This modern era of therapeutic antibodies originated with the invention of hybridoma technology to generate mouse monoclona1 antibodies in 1975. Major limitations of mouse antibodies as therapeutic agents, such as immunogenicity, lack of effector functions and short serum half-life, were subsequently identified and largely overcome by the advent of chimeric antibodies and, later, humanization technologies in the mid- 1980s. Many antibody drugs are chimeric or humanized versions of rodent antibodies.

The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety.

Mechanism of antibody therapy

The basic unit of an antibody is a symmetric structure consisting of four peptide chains, including two identical heavy chains and two identical light chains. The heavy and light chains are composed of a variable region and a constant region, respectively.

The complementarity determining regions (CDRs) in the variable regions are directly related to the diversity of antibody and antigen binding, while the structure of the constant regions is related to the biological activity of the antibody.

In a few cases, the antibody binds to the antigen and can directly protect the body, such as neutralizing the toxicity of the toxin with the antibody, but in most cases it is necessary to inactivate or eliminate the foreign antigen through the effector function.
There are two types of antibody effector functions, one is through activation of complement, which produces a variety of biological effects, such as cell lysis, immune adhesion and opsonization, to promote inflammatory response; the other is through the Fc segment and cell surface in antibody molecules.

The interaction of the Fc receptor mediates opsonization or antibody-dependent cellular cytotoxicity(ADCC) via the Fc segment, respectively. Furthermore, the effect and mechanism of action of a therapeutic antibody is directly dependent on the antigenic determinant it recognizes. For example, anti-CD20 antibodies that treat non-Hodgkin's B cell lymphoma can affect the function of ion channels on the cell membrane, thereby modulating B cell differentiation, proliferation and apoptosis.

Current characteristics of antibody drugs

Several approved antibody drugs and an increasing proportion of antibodies entering clinical trials are of human origin. These humanized antibodies are typically derived from large phage display libraries expressing humanized antibody fragments or transgenic mice engineered with human immunoglobulin genes human antibodies from transgenic mice are commonly developed as therapeutic agents without prior optimization.

By contrast, phage-derived antibodies may require improvements in binding affinity for antigen or biological potency that are routinely obtained by additional selection for desired phenotypes from phage display library technologies, including yeast, ribosome, mRNA, mammalian and Escherichia coli display libraries, as well as the direct cloning of human antibodies from human blood or bone marrow-derived cells, which might also contribute to future therapeutic antibodies. Beyond improved generation and optimization technologies, the development of antibody drugs has benefited from better choices and matching of target, antibody and patients, as well as advances in the industrialization of recombinant antibody production and purification processes.

Future therapeutic antibody development

In recent years, both the scientific community and the pharmaceutical industry have shown increasing interest in the study of therapeutic antibodies.

The emergence of humanized antibodies and human antibodies has brought new hope for the widespread use of therapeutic antibodies.

However, whether human antibodies can solve all the problems in the clinical application of murine antibodies remains to be tested in a large number of clinical trials.

There are many factors affecting the immunogenicity of antibodies, such as antigen presentation, secondary signaling systems, and individual differences in donors. The humanization of antibodies can only solve one problem.

Similarly, antibody derivatives may face inherent problems such as immunogenicity and toxic side effects, so the feasible development direction is to advance the research of therapeutic small molecule antibody derivatives while perfecting human antibody technology.
According to the clinical design of flexible treatment programs, humanized antibodies and antibody derivatives complement each other to achieve the best therapeutic effect.

Current therapeutic antibodies provide much experience to guide future antibody drug development -- -strengths on which to build, limitations to overcome and new opportunities to seize. The quest for better therapeutic antibodies has gained great momentum in recent years, motivated by a convergence of clinical, scientific, technological and commercial factors.

First, there is a strong desire to improve on the clinical benefits for patients that were achieved by first-generation therapeutic antibodies. Second, there is a growing understanding of the mechanisms of action of antibody-based drugs and, in some cases, their limitations, including mechanisms of resistance. Third, technological advances are available to optimize and overcome existing biophysical, functional and immunogenic limitations of antibodies, as well as to confer antibodies with new activities. Fourth, the major commercial success of antibodies fuelled strong competition between companies that will probably intensify as many approved and developing drugs target the same antigen and/or diseases. Together, these major factors of target biology modulated by antibody properties can greatly affect the degree of clinical efficacy achieved and the ultimate successful adoption and use of a drug.

Author's Bio: 

Creative Biolabs is a pioneer and undisputed global leader in the rapidly emerging market for therapeutic antibodies. We offer a full range of therapeutic antibodies currently available for research of a wide variety of diseases. We guarantee generated endotoxin free antibodies are fully functional and ready to use in animal-based assays.