Pharmacokinetics and Toxicology of Therapeutic Proteins: Advances and Challenges

Overview

Journal World J Biol Chem

Publisher Baishideng Publishing Group

Specialty Biochemistry

Date 2012 May 5

PMID 22558487

Citations 84

Authors

Yulia Vugmeyster

Xin Xu

Frank-Peter Theil

Leslie A Khawli

Michael W Leach

Affiliations

Soon will be listed here.

Abstract

Significant progress has been made in understanding pharmacokinetics (PK), pharmacodynamics (PD), as well as toxicity profiles of therapeutic proteins in animals and humans, which have been in commercial development for more than three decades. However, in the PK arena, many fundamental questions remain to be resolved. Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans, and from in vitro assays to in vivo readouts, which would ultimately lead to a higher success rate in drug development. In toxicology, it is known, in general, what studies are needed to safely develop therapeutic proteins, and what studies do not provide relevant information. One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity. In this review, we will highlight the emerging science and technology, as well as the challenges around the pharmacokinetic- and safety-related issues in drug development of mAbs and other therapeutic proteins.

Citing Articles

Nanotherapeutics in Kidney Disease: Innovations, Challenges, and Future Directions.

Roointan A, Xu R, Corrie S, Hagemeyer C, Alt K J Am Soc Nephrol. 2024; 36(3):500-518.

PMID: 39705082 PMC: 11888965. DOI: 10.1681/ASN.0000000608.

Bioinspired synthetic peptide-based biomaterials regenerate bone through biomimicking of extracellular matrix.

Azadi S, Yazdanpanah M, Afshari A, Alahdad N, Chegeni S, Angaji A J Tissue Eng. 2024; 15:20417314241303818.

PMID: 39670180 PMC: 11635874. DOI: 10.1177/20417314241303818.

Functional Scaffolds for Bone Tissue Regeneration: A Comprehensive Review of Materials, Methods, and Future Directions.

Todd E, Mirsky N, Silva B, Shinde A, Arakelians A, Nayak V J Funct Biomater. 2024; 15(10).

PMID: 39452579 PMC: 11509029. DOI: 10.3390/jfb15100280.

Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies.

Choi S, Lee J, Ko S, Hong S, Jin H Biomol Ther (Seoul). 2024; 32(6):708-722.

PMID: 39448393 PMC: 11535297. DOI: 10.4062/biomolther.2024.146.

Innovative Formulation Platform: Paving the Way for Superior Protein Therapeutics with Enhanced Efficacy and Broadened Applications.

Cao Z, Liu C, Wen J, Lu Y Adv Mater. 2024; 36(41):e2403116.

PMID: 38819929 PMC: 11571700. DOI: 10.1002/adma.202403116.

References

Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C . Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel. 2010; 23(5):385-92. DOI: 10.1093/protein/gzq009. View

Kaneko E, Niwa R . Optimizing therapeutic antibody function: progress with Fc domain engineering. BioDrugs. 2010; 25(1):1-11. DOI: 10.2165/11537830-000000000-00000. View

Lichtenstein G, Panaccione R, Mallarkey G . Efficacy and safety of adalimumab in Crohn's disease. Therap Adv Gastroenterol. 2010; 1(1):43-50. PMC: 3002485. DOI: 10.1177/1756283X08092548. View

Oldham R, Dillman R . Monoclonal antibodies in cancer therapy: 25 years of progress. J Clin Oncol. 2008; 26(11):1774-7. DOI: 10.1200/JCO.2007.15.7438. View

Cappon G, Bailey G, Buschmann J, Feuston M, Fisher J, Hew K . Juvenile animal toxicity study designs to support pediatric drug development. Birth Defects Res B Dev Reprod Toxicol. 2009; 86(6):463-9. DOI: 10.1002/bdrb.20220. View

Tao M, Morrison S . Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region. J Immunol. 1989; 143(8):2595-601. View

Roopenian D, Sun V . Clinical ramifications of the MHC family Fc receptor FcRn. J Clin Immunol. 2010; 30(6):790-7. PMC: 3069705. DOI: 10.1007/s10875-010-9458-6. View

Garg A, Balthasar J . Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. 2007; 34(5):687-709. DOI: 10.1007/s10928-007-9065-1. View

Raghavan M, Bjorkman P . Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol. 1996; 12:181-220. DOI: 10.1146/annurev.cellbio.12.1.181. View

10.

Eastwood D, Findlay L, Poole S, Bird C, Wadhwa M, Moore M . Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br J Pharmacol. 2010; 161(3):512-26. PMC: 2990151. DOI: 10.1111/j.1476-5381.2010.00922.x. View

11.

Mould D, Green B . Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010; 24(1):23-39. DOI: 10.2165/11530560-000000000-00000. View

12.

Sasseville V, Mansfield K . Overview of known non-human primate pathogens with potential to affect colonies used for toxicity testing. J Immunotoxicol. 2009; 7(2):79-92. DOI: 10.3109/15476910903213521. View

13.

Gorovits B . Antidrug antibody assay validation: industry survey results. AAPS J. 2009; 11(1):133-8. PMC: 2664891. DOI: 10.1208/s12248-009-9091-6. View

14.

Datta-Mannan A, Witcher D, Tang Y, Watkins J, Wroblewski V . Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor. J Biol Chem. 2006; 282(3):1709-17. DOI: 10.1074/jbc.M607161200. View

15.

Geary R . Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol. 2009; 5(4):381-91. DOI: 10.1517/17425250902877680. View

16.

Meier W, Gill A, Rogge M, Dabora R, Majeau G, Oleson F . Immunomodulation by LFA3TIP, an LFA-3/IgG1 fusion protein: cell line dependent glycosylation effects on pharmacokinetics and pharmacodynamic markers. Ther Immunol. 1995; 2(3):159-71. View

17.

Stewart J . Developmental toxicity testing of monoclonal antibodies: an enhanced pre- and postnatal study design option. Reprod Toxicol. 2009; 28(2):220-5. DOI: 10.1016/j.reprotox.2009.04.002. View

18.

Stebbings R, Poole S, Thorpe R . Safety of biologics, lessons learnt from TGN1412. Curr Opin Biotechnol. 2009; 20(6):673-7. DOI: 10.1016/j.copbio.2009.10.002. View

19.

Charman S, Segrave A, Edwards G, Porter C . Systemic availability and lymphatic transport of human growth hormone administered by subcutaneous injection. J Pharm Sci. 2000; 89(2):168-77. DOI: 10.1002/(SICI)1520-6017(200002)89:2<168::AID-JPS4>3.0.CO;2-Q. View

20.

Lin J . Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies. Curr Drug Metab. 2009; 10(7):661-91. DOI: 10.2174/138920009789895499. View