Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for <scp>CNTO</scp> 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

Nnane, Ivo P.; Xu, Zhenhua; Zhou, Honghui; Davis, Hugh M.

doi:10.1111/bcpt.12391

Cited by 13 publications

(10 citation statements)

References 34 publications

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“…Anrukinzumab (IMA‐638) is an anti‐IL‐13 with an analogous mode of action to lebrikizumab. In contrast, similar to tralokinumab, RPC4046 (ABT‐308) and CNTO 5825 block the binding of IL‐13 to both IL‐13Rα1 and IL‐13Rα2.…”

Section: Ppimsmentioning

confidence: 99%

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis

Bieber¹

2019

Allergy

240

273

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Atopic dermatitis (AD) is a common inflammatory skin condition that has traditionally been considered a paradigmatic type 2 immunity (T2)-driven disease. Interleukin (IL)-4 and IL-13 are both pivotal cytokines involved in the generation of allergic diseases. Currently, besides dupilumab, which blocks the binding of both cytokines to their receptors, a number of new pharmacologic entities have been designed to target both T2 cytokines and/or their receptors and/or receptor-associated signal transduction machinery such as Janus kinases. Recently, IL-13 has been suggested to be the key T2 cytokine driving inflammation in the periphery, while IL-4 may merely have a central effect. There is increasing evidence that this concept holds true for the inflammatory reaction underlying AD, where IL-13 is overexpressed locally and has a significant impact on skin biology, including the recruitment of inflammatory cells, the alteration of the skin microbiome, and the decrease in the epidermal barrier function. This review provides an update on the role of IL-13 in AD and discusses the different strategies aimed at interfering with its biologic activity as well as their potential in a precision medicine approach in the management of AD.

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Section: Ppimsmentioning

confidence: 99%

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis

Bieber¹

2019

Allergy

240

273

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“…Other PK parameters, such as clearance and volume of distribution were in the range of previously reported therapeutic antibodies. [44][45][46] The IgG dA antibody exhibited the highest clearance rate and a lower area under the curve despite having a half-life of 11.8 days, yet clearance was similar to that of pertuzumab, which was also measured in rats at the same dose regimen. 44 A lower C max is also to be taken into account.…”

Section: Avidity Purification Of Heterodimeric Iggs Via a Single Pa Omentioning

confidence: 87%

Single-step Protein A and Protein G avidity purification methods to support bispecific antibody discovery and development

Ollier¹,

Wassmann²,

Monney³

et al. 2019

mAbs

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Heavy chain (Hc) heterodimers represent a majority of bispecific antibodies (bsAbs) under clinical development. Although recent technologies achieve high levels of Hc heterodimerization (HD), traces of homodimer contaminants are often present, and as a consequence robust purification techniques for generating highly pure heterodimers in a single step are needed. Here, we describe two different purification methods that exploit differences in Protein A (PA) or Protein G (PG) avidity between homo- and heterodimers. Differential elution between species was enabled by removing PA or PG binding in one of the Hcs of the bsAb. The PA method allowed the avidity purification of heterodimers based on the VH3 subclass, which naturally binds PA and interferes with separation, by using a combination of IgG3 Fc and a single amino acid change in VH3, N82aS. The PG method relied on a combination of three mutations that completely disrupts PG binding, M428G/N434A in IgG1 Fc and K213V in IgG1 CH1. Both methods achieved a high level of heterodimer purity as single-step techniques without Hc HD (93–98%). Since PA and PG have overlapping binding sites with the neonatal Fc receptor (FcRn), we investigated the effects of our engineering both in vitro and in vivo. Mild to moderate differences in FcRn binding and Fc thermal stability were observed, but these did not significantly change the serum half-lives of engineered control antibodies and heterodimers. The methods are conceptually compatible with various Hc HD platforms such as BEAT® (Bispecific Engagement by Antibodies based on the T cell receptor), in which the PA method has already been successfully implemented.

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“…The terminal half‐life of CNTO 8212 in cynomolgus monkeys was approximately twofold to threefold longer than that of other IgG1 mAbs. Humanized IgG monoclonal antibody targeting soluble ligands generally exhibit terminal half‐life of approximately 2–3 weeks in human beings . Although several factors including physicochemical and physiological factors may impact CNTO 8212 clearance and terminal half‐life, it appears that selective modification of the Fc region on CNTO 8212 to increase the binding affinity of its Fc region to FcRn resulted to the slow clearance and prolonged terminal half‐life .…”

Section: Discussionmentioning

confidence: 99%

“…Prediction of human pharmacokinetics. Simple allometry and/or a time-invariant method (elementary Dedrick plot) have been shown to predict human PK clearance (with optimal exponents estimated to be 0.85 or 0.90) from cynomolgus monkey data for mAbs targeting soluble receptors or membrane-bound receptors with limited tissue distribution with similar accuracy [22,23]. In this investigation, the species time-invariant method (with fixed allometric exponent of 0.9) was used to predict the human PK profile of CNTO 1119 and CNTO 8212 after IV and SC administration in cynomolgus monkeys [14][15][16][17][18][19][20][21][22][23].…”

Section: Methodsmentioning

confidence: 99%

“…As part of the lead candidate selection process for an IgG1 anti-OSM mAb, it was necessary to assess the potential of LS(Xtend) mutation to generate IgG1 anti-OSM mAb with extended half-life in cynomolgus monkeys [5][6][7][8][9][14][15][16][17]. The cynomolgus monkey is the most relevant species for evaluation of PK properties of mAbs and prediction of human PK to guide dose selection before first-inhuman (FIH) studies of mAbs are initiated [18][19][20][21][22][23].…”

mentioning

confidence: 99%

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Modification of the Fc Region of a Human Anti‐oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half‐life in Cynomolgus Monkeys

Nnane

Han

Jiao

et al. 2017

Basic Clin Pharma Tox

Self Cite

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The purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T ), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two-compartment population PK model with first-order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V ) = 31.3 mL/kg, volume of distribution of peripheral compartment (V ) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V = 39.8 mL/kg, V = 32.6 mL/kg, F = 0.75 and T = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V +V ) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T of CNTO 8212 was significantly (p < 0.05) longer by about 2.7-fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti-OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half-life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1-20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half-life in human beings and may likely allow less frequent dosing in the clinical setting.

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Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

Cited by 13 publications

References 34 publications

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis

Single-step Protein A and Protein G avidity purification methods to support bispecific antibody discovery and development

Modification of the Fc Region of a Human Anti‐oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half‐life in Cynomolgus Monkeys

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