Elimination mechanisms of therapeutic monoclonal antibodies

Tabrizi, Mohammad; Tseng, Chih-Ming L.; Roskos, Lorin

doi:10.1016/s1359-6446(05)03638-x

Cited by 438 publications

(351 citation statements)

References 46 publications

Supporting

Mentioning

333

Contrasting

Unclassified

Order By: Relevance

“…It has been reported that trastuzumab is taken up by HER2-expressing cells via HER2-mediated endocytosis (39,40). Rituximab, a chimeric Ab directed against CD20, is also internalized in an Ag-mediated manner (41). Because the ligand-dependent internalization is followed by degradation of Abs, this property seems to be an important reason for the short half-life of trastuzumab and rituximab.…”

Section: Discussionmentioning

confidence: 99%

“…Because the ligand-dependent internalization is followed by degradation of Abs, this property seems to be an important reason for the short half-life of trastuzumab and rituximab. It has been reported that, in general, the half-life of monoclonal IgG Abs increases depending on the degree of humanization in the order of murine , chimeric , humanized , human (6,41,42). Because infliximab and rituximab are chimeric Abs, the involvement of common factors influencing the half-life of chimeric Abs such as the presence of human antichimeric Ab would be another reason for the shorter half-life.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR

Suzuki

Ishii‐Watabe

Tada

et al. 2010

The Journal of Immunology

316

239

View full text Add to dashboard Cite

The neonatal FcR (FcRn) binds to the Fc domain of IgG at acidic pH in the endosome and protects IgG from degradation, thereby contributing to the long serum half-life of IgG. To date, more than 20 mAb products and 5 Fc-fusion protein products have received marketing authorization approval in the United States, the European Union, or Japan. Many of these therapeutic proteins have the Fc domain of human IgG1; however, the serum half-lives differ in each protein. To elucidate the role of FcRn in the pharmacokinetics of Fc domain-containing therapeutic proteins, we evaluated the affinity of the clinically used human, humanized, chimeric, or mouse mAbs and Fc-fusion proteins to recombinant human FcRn by surface plasmon resonance analysis. The affinities of these therapeutic proteins to FcRn were found to be closely correlated with the serum half-lives reported from clinical studies, suggesting the important role of FcRn in regulating their serum half-lives. The relatively short serum half-life of Fc-fusion proteins was thought to arise from the low affinity to FcRn. The existence of some mAbs having high affinity to FcRn and a short serum half-life, however, suggested the involvement of other critical factor(s) in determining the serum half-life of such Abs. We further investigated the reason for the relatively low affinity of Fc-fusion proteins to FcRn and suggested the possibility that the receptor domain of Fc-fusion protein influences the structural environment of the FcRn binding region but not of the FcγRI binding region of the Fc domain.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR

Suzuki

Ishii‐Watabe

Tada

et al. 2010

The Journal of Immunology

316

239

View full text Add to dashboard Cite

show abstract

“…For novel biotherapeutics to be effective, it is important to understand the factors that affect their pharmacokinetics. In contrast to small-molecule drugs, mAbs generally have more complex pharmacokinetic properties and are often associated with nonlinear distribution and elimination largely determined by interaction with the target Ag (19,20). If the Ab binds to a membrane Ag that is internalized or forms an immune complex with secreted Ag that is removed from the circulation, the Ag may act as a "drain" for the administered Ab.…”

Section: Therapeutic Antibody Targeting Of Cd97 In Experimentalmentioning

confidence: 99%

“…If the Ab binds to a membrane Ag that is internalized or forms an immune complex with secreted Ag that is removed from the circulation, the Ag may act as a "drain" for the administered Ab. As a result, at mAb doses that do not saturate the Ag the clearance rate is faster than that of endogenous IgG, whereas in the case of excess levels of mAb, clearance will be similar to endogenous IgG, largely determined by the reticuloendothelial system (20).…”

Section: Therapeutic Antibody Targeting Of Cd97 In Experimentalmentioning

confidence: 99%

Therapeutic Antibody Targeting of CD97 in Experimental Arthritis: the Role of Antigen Expression, Shedding, and Internalization on the Pharmacokinetics of Anti-CD97 Monoclonal Antibody 1B2

Groot¹,

Vogel²,

Dulos³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

CD97 is a member of the EGF-TM7 family of adhesion class receptors, with a proposed role in inflammatory cell recruitment. Neutralization of murine CD97 with the anti-mCD97 mAb 1B2 was efficacious in prevention of murine collagen-induced arthritis, a model with features resembling rheumatoid arthritis. Here, the therapeutic potential of neutralizing CD97 in arthritis was studied with emphasis on the 1B2 pharmacokinetics. Mice with established arthritis were treated with anti-mCD97 or anti-TNF-α serum. Ab pharmacokinetics and biodistribution were studied in diseased and nondiseased mice using labeled 1B2. The impact of CD97 expression on Ab pharmacokinetics was studied using CD97 knockout mice. Treatment with 1B2 showed an efficacy comparable to anti-TNF-α treatment. Pharmacokinetic analysis of 1B2 in wild-type and CD97 knockout mice indicated a dose-dependent Ab clearance, due to specific interaction with CD97. Biodistribution studies showed accumulation of 1B2 in spleen and lung. In vitro studies using murine splenocytes revealed that CD97 when bound to Ab was internalized. Moreover, soluble CD97 was detected in the supernatant, suggesting Ag shedding. Finally, in arthritic mice, higher levels of soluble CD97 were found and 1B2 treatment led to specific targeting of inflamed paws, resulting in a higher clearance rate of 1B2 in arthritic mice than in wild-type mice. In conclusion, our data support a therapeutic value of CD97 neutralization in experimental arthritis. The pharmacokinetic profile of the 1B2 Ab illustrates the complexity of Ab elimination from an organism and stresses the importance of understanding Ag-Ab interactions when developing therapeutic mAbs.

show abstract

“…The primary elimination route for mAbs is cellular uptake followed by proteolytic degradation. There are two distinct catabolic pathways for mAbs 3 . The first is a non-specific, linear (first-order) clearance (CL) pathway mediated by fluid phase pinocytosis or unspecific fluid phase endocytosis 2 .…”

Section: Introductionmentioning

confidence: 99%

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

Betts

Keunecke²,

Steeg³

et al. 2018

mAbs

View full text Add to dashboard Cite

The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of ‘typical’ popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

show abstract

Elimination mechanisms of therapeutic monoclonal antibodies

Cited by 438 publications

References 46 publications

Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR

Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR

Therapeutic Antibody Targeting of CD97 in Experimental Arthritis: the Role of Antigen Expression, Shedding, and Internalization on the Pharmacokinetics of Anti-CD97 Monoclonal Antibody 1B2

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

Contact Info

Product

Resources

About