Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

Vexler, Vladimir; Yu, Li; Pamulapati, Chandrasena; Garrido, Rosario; Grimm, Hans Peter; Sriraman, Priya; Bohini, Sandhya; Schraeml, Michael; Singh, Usha Rani; Brandt, Michael R.; Ries, Stefan; Ma, Han; Klumpp, Klaus; Ji, Changhua

doi:10.4161/mabs.25642

Cited by 12 publications

(10 citation statements)

References 35 publications

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“…39 The antibody-ASGPR complex is internalized with a half-life of approximately 5 days; consistent with previous reports in the literature. 40 This suggests that the rate-limiting step in the ASGPR-driven uptake is the internalization of the antibody-ASGPR complex. Therefore, overall the parameters and estimates from the TMDD model show good agreement with literature findings and in-vitro measured affinity (Kd).…”

Section: Discussionmentioning

confidence: 99%

Capacity limits of asialoglycoprotein receptor-mediated liver targeting

Bon

Höfer

Bousquet‐mélou

et al. 2017

mAbs

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The abundant cell surface asialoglycoprotein receptor (ASGPR) is a highly selective receptor found on hepatocytes that potentially can be exploited as a selective shuttle for delivery. Various nucleic acid therapeutics that bind ASGPR are already in clinical development, but this receptor-mediated delivery mechanism can be saturated, which will likely result in reduced selectivity for the liver and therefore increase the likelihood for systemic adverse effects. Therefore, when aiming to utilize this mechanism, it is important to optimize both the administration protocol and the molecular properties. We here present a study using a novel ASGPR-targeted antibody to estimate ASGPR expression, turnover and internalization rates in vivo in mice. Using pharmacokinetic data (intravenous and subcutaneous dosing) and an in-silico target-mediated drug disposition (TMDD) model, we estimate an ASGPR expression level of 1.8 million molecules per hepatocyte. The half-life of the degradation of the receptor was found to be equal to 15 hours and the formed ligand-receptor complex is internalized with a half-life of 5 days. A biodistribution study was performed and confirmed the accuracy of the TMDD model predictions. The kinetics of the ASGPR shows that saturation of the shuttle at therapeutic concentrations is possible; however, simulation allows the dosing schedule to be optimized. The developed TMDD model can be used to support the development of therapies that use the ASGPR as a shuttle into hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Capacity limits of asialoglycoprotein receptor-mediated liver targeting

Bon

Höfer

Bousquet‐mélou

et al. 2017

mAbs

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“…CD151 is known to be a promoter of metastasis and several antibodies targeting this tetraspanin have been reported to inhibit tumour spread, motility and invasion in vitro and in vivo [ 38 ]. With the exception of platelets CD81 is ubiquitously expressed and is not considered a therapeutic target, nevertheless a recent study demonstrated that intravenous administration of an anti-CD81 mAb in cynomolgus monkeys leads to a defined accumulation in the liver [ 39 ]. Although our studies have identified a role for CD81 in hepatoma cell migration and invasion, anti-CD81 mAbs failed to modulate these processes suggesting limited therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

A Role for CD81 and Hepatitis C Virus in Hepatoma Mobility

Brimacombe

Wilson

Hübscher

et al. 2014

Viruses

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Tetraspanins are a family of small proteins that interact with themselves, host transmembrane and cytosolic proteins to form tetraspanin enriched microdomains (TEMs) that regulate important cellular functions. Several tetraspanin family members are linked to tumorigenesis. Hepatocellular carcinoma (HCC) is an increasing global health burden, in part due to the increasing prevalence of hepatitis C virus (HCV) associated HCC. The tetraspanin CD81 is an essential receptor for HCV, however, its role in hepatoma biology is uncertain. We demonstrate that antibody engagement of CD81 promotes hepatoma spread, which is limited by HCV infection, in an actin-dependent manner and identify an essential role for the C-terminal interaction with Ezrin-Radixin-Moesin (ERM) proteins in this process. We show enhanced hepatoma migration and invasion following expression of CD81 and a reduction in invasive potential upon CD81 silencing. In addition, we reveal poorly differentiated HCC express significantly higher levels of CD81 compared to adjacent non-tumor tissue. In summary, these data support a role for CD81 in regulating hepatoma mobility and propose CD81 as a tumour promoter.

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“…Antibodies targeting CD81, a receptor required by hepatitis C virus (HCV) to infect human hepatocytes, were recently described by Vexler et al 25 and Ji et al 26 Two of these high affinity anti-CD81 mAbs, CD81K04 and CD81K13, showed potent and broad spectrum antiviral activity in various in vitro assays and were humanized. The anti-CD81 mAb CD81K04 could completely block HCV infection and spread in vivo, indicating that CD81 is essential for HCV-mediated pathology in the liver.…”

Section: Introductionmentioning

confidence: 99%

VH-VL orientation prediction for antibody humanization candidate selection: A case study

Bujotzek¹,

Lipsmeier²,

Harris³

et al. 2015

mAbs

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Antibody humanization describes the procedure of grafting a non-human antibody's complementaritydetermining regions, i.e., the variable loop regions that mediate specific interactions with the antigen, onto a b-sheet framework that is representative of the human variable region germline repertoire, thus reducing the number of potentially antigenic epitopes that might trigger an anti-antibody response. The selection criterion for the so-called acceptor frameworks (one for the heavy and one for the light chain variable region) is traditionally based on sequence similarity. Here, we propose a novel approach that selects acceptor frameworks such that the relative orientation of the 2 variable domains in 3D space, and thereby the geometry of the antigen-binding site, is conserved throughout the process of humanization. The methodology relies on a machine learning-based predictor of antibody variable domain orientation that has recently been shown to improve the quality of antibody homology models. Using data from 3 humanization campaigns, we demonstrate that preselecting humanization variants based on the predicted difference in variable domain orientation with regard to the original antibody leads to subsets of variants with a significant improvement in binding affinity.

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Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

Cited by 12 publications

References 35 publications

Capacity limits of asialoglycoprotein receptor-mediated liver targeting

Capacity limits of asialoglycoprotein receptor-mediated liver targeting

A Role for CD81 and Hepatitis C Virus in Hepatoma Mobility

VH-VL orientation prediction for antibody humanization candidate selection: A case study

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