Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues
The decision to pursue a monoclonal antibody (mAb) as a therapeutic for disease intervention requires the assessment of many factors, such as target-biology, including the total target burden and its accessibility at the intended site of action, as well as mAb-specific properties like binding affini...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1746520 |
| _version_ | 1817987895395352576 |
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| author | Kip P. Conner Cinthia V. Pastuskovas Marcus Soto Veena A. Thomas Mylo Wagner Dan A. Rock |
| author_facet | Kip P. Conner Cinthia V. Pastuskovas Marcus Soto Veena A. Thomas Mylo Wagner Dan A. Rock |
| author_sort | Kip P. Conner |
| collection | DOAJ |
| description | The decision to pursue a monoclonal antibody (mAb) as a therapeutic for disease intervention requires the assessment of many factors, such as target-biology, including the total target burden and its accessibility at the intended site of action, as well as mAb-specific properties like binding affinity and the pharmacokinetics in serum and tissue. Interleukin-36 receptor (IL-36 R) is a member of the IL-1 family cytokine receptors and an attractive target to treat numerous epithelial-mediated inflammatory conditions, including psoriatic and rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease. However, information concerning the expression profile of IL-36 R at the protein level is minimal, so the feasibility of developing a therapeutic mAb against this target is uncertain. Here, we present a characterization of the properties associated with absorption, distribution, metabolism, and excretion of a high-affinity IL-36 R-targeted surrogate rat (IgG2a) mAb antagonist in preclinical mouse models. The presence of IL-36 R in the periphery was confirmed unequivocally as the driver of non-linear pharmacokinetics in blood/serum, although a predominant site of tissue accumulation was not observed based upon the kinetics of radiotracer. Additionally, the contribution of IL-36 R-mediated catabolism of mAb in kidney was tested in a 5/6 nephrectomized mouse model where minimal effects on serum pharmacokinetics were observed, although analysis of functional mAb in urine suggests that target can influence the amount of mAb excreted. Our data highlight an interesting case of target-mediated drug disposition (TMDD) where low, yet broadly expressed levels of membrane-bound target result in a cumulative effect to drive TMDD behavior typical of a large, saturable target sink. The potential differences between our mouse model and IL-36 R target profile in humans are also presented. |
| first_indexed | 2024-04-14T00:27:09Z |
| format | Article |
| id | doaj.art-243a6b7f7dbe4e909e8a123c532462bf |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-14T00:27:09Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-243a6b7f7dbe4e909e8a123c532462bf2022-12-22T02:22:40ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2020.1746520Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissuesKip P. Conner0Cinthia V. Pastuskovas1Marcus Soto2Veena A. Thomas3Mylo Wagner4Dan A. Rock5Department Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA, USADepartment Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA, USADepartment Pharmacokinetics and Drug Metabolism, Amgen, Thousand Oaks, CA, USADepartment Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA, USADepartment Pharmacokinetics and Drug Metabolism, Amgen, Thousand Oaks, CA, USADepartment Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA, USAThe decision to pursue a monoclonal antibody (mAb) as a therapeutic for disease intervention requires the assessment of many factors, such as target-biology, including the total target burden and its accessibility at the intended site of action, as well as mAb-specific properties like binding affinity and the pharmacokinetics in serum and tissue. Interleukin-36 receptor (IL-36 R) is a member of the IL-1 family cytokine receptors and an attractive target to treat numerous epithelial-mediated inflammatory conditions, including psoriatic and rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease. However, information concerning the expression profile of IL-36 R at the protein level is minimal, so the feasibility of developing a therapeutic mAb against this target is uncertain. Here, we present a characterization of the properties associated with absorption, distribution, metabolism, and excretion of a high-affinity IL-36 R-targeted surrogate rat (IgG2a) mAb antagonist in preclinical mouse models. The presence of IL-36 R in the periphery was confirmed unequivocally as the driver of non-linear pharmacokinetics in blood/serum, although a predominant site of tissue accumulation was not observed based upon the kinetics of radiotracer. Additionally, the contribution of IL-36 R-mediated catabolism of mAb in kidney was tested in a 5/6 nephrectomized mouse model where minimal effects on serum pharmacokinetics were observed, although analysis of functional mAb in urine suggests that target can influence the amount of mAb excreted. Our data highlight an interesting case of target-mediated drug disposition (TMDD) where low, yet broadly expressed levels of membrane-bound target result in a cumulative effect to drive TMDD behavior typical of a large, saturable target sink. The potential differences between our mouse model and IL-36 R target profile in humans are also presented.https://www.tandfonline.com/doi/10.1080/19420862.2020.1746520CytokineIL-36RIL-1Rrp2TMDDmonoclonal antibodybiodistribution |
| spellingShingle | Kip P. Conner Cinthia V. Pastuskovas Marcus Soto Veena A. Thomas Mylo Wagner Dan A. Rock Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues mAbs Cytokine IL-36R IL-1Rrp2 TMDD monoclonal antibody biodistribution |
| title | Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues |
| title_full | Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues |
| title_fullStr | Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues |
| title_full_unstemmed | Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues |
| title_short | Preclinical characterization of the ADME properties of a surrogate anti-IL-36R monoclonal antibody antagonist in mouse serum and tissues |
| title_sort | preclinical characterization of the adme properties of a surrogate anti il 36r monoclonal antibody antagonist in mouse serum and tissues |
| topic | Cytokine IL-36R IL-1Rrp2 TMDD monoclonal antibody biodistribution |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1746520 |
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