Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Zheng, Yanan; Tesar, Devin; Benincosa, Lisa J.; Birnböck, Herbert; Boswell, C. Andrew; Bumbaca, Daniela; Cowan, Kyra J.; Danilenko, Dimitry M.; Daugherty, Ann L.; Fielder, Paul J.; Grimm, Hans Peter; Joshi, Amita; Justies, Nicole; Kolaitis, Gerry; Lewin‐Koh, Nicholas; Li, Jing; McVay, Sami; O'Mahony, Jennifer; Otteneder, Michael B.; Pantze, Michael; Putnam, Wendy S.; Qiu, Zhihua; Ruppel, Jane; Singer, Thomas P.; Stauch, Oliver B.; Theil, Frank‐Peter; Visich, Jennifer; Yang, Jihong; Ying, Yun; Khawli, Leslie A.; Richter, Wolfgang

doi:10.4161/mabs.4.2.19387

Cited by 123 publications

(121 citation statements)

References 56 publications

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“…To deliver several hundred milligrams of the active drug in a small volume (∼1 mL) into the s.c. space, a liquid formulation containing high concentrations of mAb is required (1,2). Therefore it is essential that the lead clinical mAb candidate meets the following criteria: (i) an injectable solution of low viscosity (higher viscosity solutions are difficult to manufacture and administer, and could be painful to inject) (2); (ii) minimal chemical/physical degradation in solution such that the efficacy and safety is maintained; and (iii) a normal in vivo clearance profile to avoid multiple injections and/or more frequent dosing (3,4).…”

mentioning

confidence: 99%

In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability

Sharma

Patapoff

Kabakoff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

212

276

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Significance mAbs are increasingly being used for treatment of chronic diseases wherein the subcutaneous delivery route is preferred to enable self-administration and at-home use. To deliver high doses (several hundred milligrams) through a small volume (∼1 mL) into the subcutaneous space, mAb solutions need to have low viscosity. Concomitantly, acceptable chemical stability is required for adequate shelf life, and normal in vivo clearance is needed for less frequent dosing. We propose in silico tools that provide rapid assessment of atypical behavior of mAbs (high viscosity, chemical degradation, and fast plasma clearance), which are simply predicted from sequence and/or structure-derived parameters. Such analysis will greatly improve the probability of success to move mAb-based therapeutics efficiently into clinical development and ultimately benefit patients.

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mentioning

confidence: 99%

In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability

Sharma

Patapoff

Kabakoff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

212

276

View full text Add to dashboard Cite

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“…A few empirical approaches for comparison of absorption rates in animals and man have been published (78,79). The reasons for the reported species differences are not known.…”

Section: Knowledge Gapsmentioning

confidence: 99%

Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration

Richter

Bhansali

Morris

2012

AAPS J

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288

280

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Abstract. The subcutaneous (SC) route is of growing interest for the administration of biotherapeutics. Key products on the biotherapeutic market such as insulins, but also several immunoglobulins or Fcfusion proteins, are administered SC. Despite the importance of the SC route, the available knowledge about the processes involved in the SC absorption of biotherapeutics is limited. This review summarizes available information on the physiology of the SC tissue and on the pharmacokinetic processes after SC administration including "first pass catabolism" at the administration site as well as transport in the extracellular matrix of the SC tissue, followed by absorption into the blood circulation or the lymphatic system. Both monoclonal antibodies and other biotherapeutics are discussed. Determinants of absorption after SC administration are summarized including compound properties such as charge or molecular weight. Scale-up of animal data to humans is discussed, including the current shortcomings of empirical scaling approaches and the lack of suitable mechanistic approaches.

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“…It has been observed that a neutral charge modification that decreased an antibody's pI by more than 1 unit can exhibit faster blood clearance compared to its unmodified counterpart with less activity in normal tissues and improved localization in the target (27). More recently, a study has shown that antibodies with higher pI values also tended to exhibit faster systemic clearance rates and lower subcutaneous bioavailabilities in both human and minipig than antibodies with lower pI values (28).…”

Section: Charge and Isoelectric Point (Pi)mentioning

confidence: 99%

Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics

Bumbaca¹,

Boswell²,

Fielder³

et al. 2012

AAPS J

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110

107

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Abstract. Monoclonal antibodies are increasingly being developed to treat multiple disease areas, including those related to oncology, immunology, neurology, and ophthalmology. There are multiple factors, such as charge, size, neonatal Fc receptor (FcRn) binding affinity, target affinity and biology, immunoglobulin G (IgG) subclass, degree and type of glycosylation, injection route, and injection site, that could affect the pharmacokinetics (PK) of these large macromolecular therapeutics, which in turn could have ramifications on their efficacy and safety. This minireview examines how characteristics of the antibodies could be altered to change their PK profiles. For example, it was observed that a net charge modification of at least a 1-unit shift in isoelectric point altered antibody clearance. Antibodies with enhanced affinity for FcRn at pH 6.0 display longer serum half-lives and slower clearances than wild type. Antibody fragments have different clearance rates and tissue distribution profiles than full length antibodies. Fc glycosylation is perceived to have a minimal effect on PK while that of terminal high mannose remains unclear. More investigation is warranted to determine if injection route and/or site impacts PK. Nonetheless, a better understanding of the effects of all these variations may allow for the better design of antibody therapeutics.

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Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Abstract: (2012) Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration, mAbs, 4:2, 243-255,

Cited by 123 publications

References 56 publications

In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability

In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability

Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration

Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics

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