Why are the isoelectric points of monoclonal antibodies 8-9?

An important feature of monoclonal antibodies (mAbs) is their isoelectric point (PI), which is essentially the pH value of the antibody without net charge, which depends on the charged amino acids contained in the antibody. If the pH value of the surrounding environment is lower than the Pi of the antibody, the molecule will have a net positive charge, while when the pH value is higher than PI, the antibody will have a net negative charge.

When evaluating the pharmacokinetic (PK) characteristics of therapeutic antibodies, both target mediated drug disposal (TMDD) and non target related mechanisms will affect the overall PK behavior, and PI is an important factor of the latter. Since most cell surfaces are negatively charged and antibodies need to be positively charged for effective liquid-phase endocytosis (pinocytosis), the environmental pH value needs to be lower than the Pi of antibodies. Since the physiological pH value is 7.4, the therapeutic antibody with pI value in the range of 8-9 will be fully absorbed after administration. However, the pI value of some antibodies exceeds this range or has been ionized, resulting in the increase or decrease of PI value.
The increase of antibody net positive charge will increase the blood clearance rate and tissue retention rate, and shorten the half-life; The antibody tissue with lower PI has lower uptake time and longer half-life of 1-3.
Even subtle operations, such as molecular surface remodeling to destroy the positive plaque area, will affect PK characteristics 4. In conclusion, the Pi of mAb has a significant effect on PK behavior, which is independent of Fc receptor FcRn mediated recycling. However, in the conventional manufacturing process of mAb charge variants, small changes in PI generally do not lead to large changes, and a large amount of analysis may not be required 5. In addition, since selecting the best candidate drugs in the early clinical stage of product development can greatly reduce the development time and cost, it is very important to consider risk reduction strategies and tools in the process of drug discovery and development, including antibody variable region charge and antibody PI analysis 6-8.

References:

1. Boswell et al, Bioconjug Chem. 2010 Dec 15;21(12):2153-63.
2. Igawa et al, Protein Eng Des Sel. 2010 May;23(5):385-92.
3. Li et al, MAbs. 2014;6(5):1255-64.
4. Datta-Mannan et al, MAbs. 2015;7(3):483-93.
5. Khawli et al, mAbs, 2010;(2)6:613-624.
6. Bumbaca Yadav et al, J Biol Chem. 2015 Dec 11;290(50):29732-41.
7. Dostalek et al, MAbs. 2017 May 2:1-11.
8. Jarasch et al, J Pharm Sci. 2015 Jun;104(6):1885-98.

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