Review
Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering

https://doi.org/10.1016/j.dmpk.2018.10.003Get rights and content

Abstract

Monoclonal antibodies (mAbs) have become an important therapeutic option for several diseases. Since several mAbs have shown promising efficacy in clinic, the competition to develop mAbs has become severe. In efforts to gain a competitive advantage over other mAbs and provide significant benefits to patients, innovations in antibody engineering have aimed at improving the pharmacokinetic properties of mAbs. Because engineering can provide therapeutics that are more convenient, safer, and more efficacious for patients in several disease areas, it is an attractive approach to provide significant benefits to patients. Further advances in engineering mAbs to modulate their pharmacokinetics were driven by the increase of total soluble target antigen concentration that is often observed after injecting a mAb, which then requires a high dosage to antagonize. To decrease the required dosage, several antibody engineering techniques have been invented that reduce the total concentration of soluble target antigen. Here, we review the various ways that antibody engineering can improve the pharmacokinetic properties of mAbs.

Introduction

Monoclonal antibodies (mAbs) have been tested in clinical trials and approved for the treatment of several diseases. The major advantages of a mAb are its long plasma/serum half-life and low clearance from the body. Generally, small molecule drugs have a plasma/serum half-life of a few hours in human [1], [2] because they are highly metabolized by cytochrome P450 and eliminated by several transporters and renal filtration. Thus, 1–3 oral doses daily are required to show and maintain the efficacy. In contrast, many of the mAbs show a plasma/serum half-life of 5–25 days in human [3]. Due to this long plasma/serum half-life, mAbs can be used to treat several diseases by intravenous or subcutaneous injections given weekly or less frequently. This long plasma/serum half-life of mAbs is the result of two important factors. The first factor is its large molecular weight. Because most mAbs have a whole immunoglobulin (IgG) structure, their molecular weight is approximately 150 kDa. As renal filtration is reported to eliminate proteins with a molecular weight of up to 50 kDa [4], the contribution of renal filtration to the elimination of mAbs would be negligible [5], [6], [7], and their plasma/serum half-life is consequently longer. In fact, non-IgG proteins, such as immunoglobulin E (IgE) [8], thrombomodulin [9], or mannan-binding lectin [10], also have a molecular weight of over 50 kDa and negligible renal clearance but show a plasma/serum half-life of only a few days in human. Although the plasma/serum half-life of these proteins is longer than that of small molecule drugs, it is still shorter than that of mAbs. This difference is caused by the second factor that contributes to the longer plasma/serum half-life of mAbs: their pH-dependent binding property to neonatal Fc receptor (FcRn). IgG has been reported to bind FcRn strongly at acidic pH, but weakly at neutral pH [11]. This property allows IgG to be rescued from lysosomal degradation (Fig. 1A). FcRn is internalized from the cell membrane into the endosome and then recycled back from the endosome to the cell membrane. Thus, after endocytosis, if IgG binds to FcRn in the endosome, the IgG–FcRn complex can be recycled back to the cell membrane. Since IgG has very weak binding affinity to FcRn at neutral pH, IgG is then released from FcRn at the cell membrane. In FcRn-knockout mice, mAbs have shown a plasma/serum half-life of only a few days, which demonstrates the importance of FcRn in their pharmacokinetics [12], [13]. Another important factor that needs to be considered in the pharmacokinetics of mAbs is the inter-species difference in FcRn-IgG binding between animals and human. This difference is described in detail in Section 2.2.

Recent developments in antibody engineering of therapeutic antibodies have sought to maximize the potency of mAbs. For example, afucosylated Fc [14], symmetric engineered Fc [15], and asymmetric engineered Fc [16], [17] have been reported to enhance antibody-dependent cellular cytotoxicity (ADCC) activity. Also, Fc engineering to promote the hexamerization of mAbs has enhanced the complement-dependent cytotoxicity (CDC) activity [18] and receptor agonistic activity [19]. These techniques have been applied in several mAbs, mainly those targeting cancer. Also recently, bispecific antibody has shown promising clinical efficacy in cancer patients by redirecting T cells to cancer cells [20], [21] and in hemophilia A patients by mimicking the function of coagulation factor VIII [22]. In all, antibody engineering has become an important approach for generating superior mAbs with properties that cannot be achieved by conventional mAbs. This review focuses on how an antibody can be engineered to improve the pharmacokinetic properties by improving the half-life and clearance (Section 2) and by suppressing the total concentration of soluble target antigens (Section 3).

Section snippets

Improving the plasma/serum half-life and clearance of mAbs

Since mAbs can be rescued from lysosomal degradation by FcRn recycling (as described in Section 1), mAbs show a long plasma/serum half-life and low clearance in the body. However, mAbs that are used for the treatment of chronic diseases or for prophylactic usage for some diseases require even longer half-life and/or lower clearance and less dosing frequency to improve their convenience. Therefore, antibody engineering that further improves the half-life and clearance could be valuable for

Enhancing the elimination of a soluble target antigen

As described so far, mAbs have a long half-life and low clearance in the body. On the other hand, for many reasons—the contribution of renal clearance, the absence of FcRn recycling, instability in blood, and so on—some soluble target antigens have a much shorter half-life and higher clearance. However, once a mAb binds to the soluble target antigen, the clearance of the complex that they form is dramatically reduced compared with that of the soluble target antigen alone, because the large

Future perspective

In this review, we discussed several antibody engineering techniques that can improve the pharmacokinetic properties of mAbs. Three major processes determine the pharmacokinetics of mAbs, and four different techniques can modulate these processes. The first major process is non-specific endocytosis, which can be modulated by pI/charge engineering (Section 2.1). The second major process is FcRn-mediated recycling from endosome to plasma, which can be modulated by increased FcRn binding at acidic

Financial disclosures

All authors are employees of Chugai Pharmaceutical Co., Ltd. and hold financial interest in Chugai Pharmaceutical Co., Ltd.

Conflicts of interest

The authors declare that they have no conflict of interest.

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