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mAb Post-Translational Modifications (PTMs)

The final process in completion of the functional structure of any protein often requires a degree of alteration (via covalent addition / alteration or enzymatic action) in the form of post-translational modifications (PTMs). Correct PTMs are critical for correct protein function and defining cellular location. Alternatively a modification can be added to prepare a protein for degradation.

The occurrence of PTMs is particularly important in mAb development; the effectiveness and immunogenicity (ability of a substance to provoke an immune response) of an antibody is highly dependent on having the correct PTMs. They can have both beneficial and detrimental effects on the stability, therapeutic efficacy, and safety of the biopharmaceutical agent. PTMs essential for the therapeutic use of the mAb, such as glycosylation, must be accurately replicated in all instances of production to ensure effective treatment. The wrong mAb structure, due to incorrect PTMs, will consequently affect the ability of the antibody to form the necessary complexes to activate the effector mechanisms and initiate an immune response. It may also lead to instability and aggregation of the mAbs, which could result in the patient mounting an immune response to the biopharmaceutical agent. Biopharmaceutical aggregates have also been reported to cause anaphylactic reactions and renal failure.  The monitoring of PTMs during development and manufacture is, therefore, critical and forms part of the Critical Quality Attributes (CQA) of the mAb which are measured using chromatographic and mass spectrometric techniques.

Incorrect or extended storage, or inconsistencies in the manufacturing process, can all contribute to unwanted or incorrect PTMs. As can the use of non-human mammalian cell lines; most therapeutic mAbs are produced using Chinese hamster ovary (CHO) cell lines, or one of two murine (mouse) cell lines (NS0 or SP2/0), occasionally this results in PTMs added to the antibodies that would not usually be present on a human protein which can have negative consequences for the biopharmaceutical.
Examples of common unwanted PTMs include methionine oxidation and asparagine/glutamine deamidation or isomerization, all of which can have an effect on mAb structure and so may have a negative impact on the overall efficacy of the mAb.

Monoclonal Antibody Post Translational Modifications Trastuzuma
Figure1: Monoclonal antibody post-translational modifications Herceptin
 

 

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