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Monoclonal Antibodies: Past, Present and Future

by Scientific Writing Team 

Monoclonal antibodies (mAbs) are antigen-recognizing glycoproteins that are made by identical immune cells, all of which are clones of a unique parent cell. Since 2014, FDA has approved at least five monoclonal antibodies per year, and this trend shows no signs of slowing. These therapies encompass a number of indications such as autoimmune disorders, infectious diseases, and oncology, among others.

Due to their exquisite specificity, monoclonal antibodies embody the promise of precision medicine, which is to develop therapies that are specifically tailored to a particular target. The advantage of such a strategy is clear: for example, instead of treating a patient with conventional chemotherapy, which is toxic not only to tumor cells but to normal cells as well, a monoclonal antibody therapy can selectively target the cancer via recognition of specific surface antigens that are over-expressed on tumor cells and not expressed (or at least to the same degree) on normal cells.

Despite their promise, monoclonal antibodies have not had a smooth road to approval. Over the years, even seemingly well-designed monoclonal antibodies have often resulted in unacceptable adverse reactions, more times than not sending researchers back to the drawing board to devise new ways to make the technology viable. The big breakthrough that pushed monoclonal antibodies from a good idea to a clinically useful tool came about with the advent of antibody humanization. To understand antibody humanization, it is helpful to review a brief history of monoclonal antibodies.

The Origin of Monoclonal Antibodies

In 1986, Orthoclone OKT3® (muromonab-CD3) became the first monoclonal antibody approved by the FDA. Its production was based on the Nobel-winning work of Kohler and Milstein on murine hybridoma technology. This technology, part of which is still used in the generation of some modern monoclonal antibodies, had several steps. The first step involved generating a specific immune response in mice by injecting them with a particular antigen. In the case of muromonab, the antigen was the T-cell co-receptor CD3. This resulted in the mouse’s immune system producing antibodies against CD3. Antibody-producing cells, however, are typically short-lived, and thus not great candidates for the mass production of a therapeutic antibody. To get around this limitation, the second step of the process involved isolating the antibody-producing mouse cells and fusing them with immortalized myeloma tumor cells. This step resulted in the creation of hybrid cells that could produce antibodies but also had the replicative properties of tumor cells.

The problem with using monoclonal antibodies secreted directly from these hybrid cells, however, became apparent almost immediately. The human immune system is trained to attack anything it sees as foreign. Since muromonab was a mouse protein and thus foreign to the human immune system, patients treated with the drug generated anti-mouse antibodies, limiting the effectiveness of the drug and creating serious side effects. The story of monoclonal antibody therapeutics might have ended with muromonab had it not been for advances in genetic engineering made in the late 1980s and early 1990s.

Introduction of Chimeric Monoclonal Antibodies

The ability to manipulate and recombine genes ushered in a second generation of therapeutic monoclonal antibodies known as chimeras. Production of chimeric monoclonal antibodies, such as ReoPro® (abciximab, approved in 1994), used the same murine hybridoma process to generate antigen-specific mouse antibodies, but then replaced the constant region (the domains of the antibody that do not confer antigen specificity) of the mouse antibody with equivalent regions from a human antibody. This had the effect of preserving antigen specificity while limiting the number of foreign epitopes introduced to the patient. This strategy had mixed clinical results, with some chimeric monoclonal antibodies having a very low incidence of anti-drug antibodies (ADAs), while others showed little improvement over their fully mouse counterparts.

The Rise of Humanized Monoclonal Antibodies

Humanized monoclonal antibodies, such as Zenapax® (daclizumab, approved in 1997) are an extension of the chimera strategy in which all regions of the mouse antibody are replaced with human counterparts except for the complementarity-determining regions (CDRs, i.e., the amino acids that make direct contact with the antigen). In general, humanized monoclonal antibodies generate lower levels of ADAs compared to chimeric monoclonal antibodies, although the incidence of ADAs is not eliminated. Additionally, humanization of monoclonal antibodies often has the unintended consequence of altering monoclonal antibody specificity. Current thinking suggests that when alterations are made to the regions surrounding the CDRs, structural changes result that decrease the ability of the antibody to interact with its antigen.

Humanized Monoclonal Antibodies Today

The newest generation of therapeutic antibodies includes what are referred to as fully human monoclonal antibodies. Fully human monoclonal antibodies are produced by one of two very different routes. The first route, used to make Vectibix® (panitumumab, approved in 2006), is very similar to the murine hybridoma process. The major difference is that the mice used to produce fully human monoclonal antibodies have been genetically altered to carry human antibody genes rather than mouse antibody genes. Thus, no part of the eventual therapeutic monoclonal antibody is mouse-derived. The second route, used to make Humira® (adalimumab, approved in 2002), uses a technology called phage display to identify optimal CDRs. Phage display involves inserting a genetic library of CDRs into a type of virus that infects bacteria (bacteriophages). The phages then express the CDRs, allowing for easy screening of the CDRs exhibiting the strongest antigen binding. Once the best CDRs are identified, they are then grafted onto a human antibody scaffold. Fully human monoclonal antibodies generally show a lower incidence of ADAs than their humanized counterparts, but immune responses to fully human monoclonal antibodies still persist and vary widely by product and indication.

The Future of Monoclonal Antibodies

It is difficult to predict what the future of antibody humanization will look like. Over time, the humanization process of mouse-derived antibodies has become much more sophisticated, with several companies now performing in silico optimization of CDRs for T-cell epitope avoidance to reduce immunogenicity. Yeast display is a new technology that in theory avoids some of the disadvantages of the phage display process for monoclonal antibody generation. Newer transgenic mice that have a fuller complement of human antibody genes are also being used to develop a new generation of fully human monoclonal antibodies.

Regardless of the exact path that gives rise to the next generation of monoclonal antibody therapies, one thing is for certain: therapeutic antibodies can do things that few small molecules can, and as such will remain firmly a part of the drug development landscape for years to come.


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