What are Chimeric Antibodies?

The chimerization of monoclonal antibodies results in a chimeric antibody that retains variable domains from its original species, such as a mouse, and constant domains that have been incorporated into the antibody from another species, such as humans.

Chimeric antigen receptor therapy

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Purpose of chimeric antibodies

As compared to their parent antibodies, chimeric antibodies differ in their constant domains, which are typically obtained from a different species. Although chimeric antibodies will often retain the parent antibody’s original antigen-binding variable domains, this change in their constant domains will reduce their immunogenicity when used therapeutically.

One example of a common chimeric antibody structure will therefore consist of four rodent variable domains and eight human constant domains, which will create a final chimeric antibody that is approximately 67% human.

Chimerization is an important step in the preclinical process of developing therapeutic antibodies, as it reduces the risk that human patients will experience an adverse reaction to the foreign protein.

Without chimerization, the continued use of a rodent antibody treatment could induce a process known as the human anti-mouse antibody (HAMA) response, which causes the formation of immune complexes, thus rendering the treatment ineffective as a result of subsequent immunological complications.

Generation of chimeric antibodies

One method of producing chimeric antibodies can involve the use of the traditional mouse hybridoma model combined with genetic engineering. To this end, the genes coding for both the immunoglobulin (Ig) variable regions of a selected mouse hybridoma, as well as those that code for the human Ig constant regions, are isolated and amplified by polymerase chain reaction (PCR).

Both the human and murine genes are then inserted into a plasmid and transfected into bacteria cells which are ultimately lysed. The lysis of these cells causes inclusion bodies to be released, which are ultimately purified to form the final chimeric antibody product.

Applications of chimeric antibodies

Chimeric antibodies are used in a wide range of both in vivo and in vitro biomedical applications. For both flow cytometry and immunohistochemistry (IHC) applications, chimeric antibodies have successfully reduced non-specific binding that can occur between secondary antibodies and antigens present within the cell or tissue sample.

Furthermore, immunofluorescence (IF) applications have also benefited from the use of chimeric antibodies, as these antibodies have significantly improved the specificity of co-labeling studies.

Another in vitro application of chimeric antibodies can be found in the serum calibrators of certain serological immunoassays. Serum calibrators, which are often referred to as standard or positive controls, are crucial in immunoassays, as they allow researchers to both generate a standard curve and/or confirm that the assay is performing correctly. When compared to serum-based calibrators, chimeric antibodies are considered to be more reliable, as they produce more consistent results.

For in vivo studies, chimeric antibodies that have originated from a mouse hybridoma cell line, for example, can effectively be used in mouse models without the concern that an anti-species immune response will arise.

In fact, several preclinical studies have successfully used chimeric antibodies in various animal models to effectively treat several different diseases. The positive data produced from these studies have even supported the transition of some chimeric antibodies into clinical use in human patients, which have also supported their therapeutic efficacy.

Chimeric antibodies used therapeutically

In the United States, several different chimeric antibodies have already been approved for clinical use by the Food and Drug Administration (FDA). Some of the most notable chimeric antibodies that are currently approved by the FDA include infliximab, abciximab, basiliximab, cetuximab, and rituximab.

Infliximab, for example, is a chimeric antibody that specifically targets tumor necrosis factor-alpha (TNF) to reduce inflammation in rheumatoid arthritis (RA) patients. Comparatively, abciximab, which is a chimeric human mAb, binds to the glycoprotein receptor of human platelets to prevent the aggregation of platelets that could otherwise cause cardiac ischemic complications in certain patient populations.

Basiliximab is another type of chimeric monoclonal antibody that contains both human and murine regions and is currently approved for use in the United States. Basiliximab, which functions as an interleukin-2 (IL-2) antagonist, is used as an immunosuppressive agent in both children and adult patients who have recently undergone a kidney transplant.

Within the field of anti-cancer therapeutics, cetuximab is a targeted recombinant chimeric antibody that competitively binds to epidermal growth factor receptor (EGFR) to prevent the binding of epidermal growth factor (EGF). The overexpression of EGFR has been implicated in several different types of cancers; therefore, cetuximab is currently approved for use alongside chemotherapeutic agents in the treatment of head and neck cancer, as well as metastatic KRAS wild-type colorectal cancer.

Another type of chimeric antibody that has been approved for use in treating certain types of cancers is rituximab. Rituximab is a chimeric anti-CD20 mAb that is currently approved for use in the treatment of B-cell malignancies such as diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia (CLL). In fact, in 1997, rituximab was the first therapeutic chimeric antibody to be approved for use in cancer patients in the United States.

Limitations

The production of chimeric antibodies is considered to be much cheaper as compared to that which is required for the generation of fully humanized antibodies. While chimeric antibodies are effective, both in terms of their therapeutic applications and from a financial point of view, these antibodies are associated with certain limitations.

For example, the chimerization process required to produce these antibodies involves multiple steps, including time-consuming genetic manipulation processes that must be performed for each selected antigen-specific clone.

In addition to lengthy production times, the chimerization of antibodies can also result in a loss in the expression and/or specificity of the monoclonal antibody (mAb). In the event that this loss of function occurs, the selection process for potentially compatible candidate clones must restart, which can further extend the time required to produce the ideal chimeric antibody.

Finally, even though all of the constant regions of the rodent antibody are replaced with human regions, a HAMA response can still arise and limit the therapeutic use of chimeric antibody treatment.

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Further Reading

Last Updated: Apr 9, 2021

Benedette Cuffari

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Benedette Cuffari

After completing her Bachelor of Science in Toxicology with two minors in Spanish and Chemistry in 2016, Benedette continued her studies to complete her Master of Science in Toxicology in May of 2018. During graduate school, Benedette investigated the dermatotoxicity of mechlorethamine and bendamustine; two nitrogen mustard alkylating agents that are used in anticancer therapy.

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