Tutorial on Monoclonal Antibody Pharmacokinetics and Early Development PDF

Citation: Clin Transl Sci (2018) 11, 540–552; doi:10.1111/cts.12567  C 2018 ASCPT. All rights reserved TUTORIAL Tutorial on Monoclonal Antibody Pharm...

Citation: Clin Transl Sci (2018) 11, 540–552; doi:10.1111/cts.12567  C 2018 ASCPT. All rights reserved TUTORIAL Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development Meric Ovacik1 and Kedan Lin2,∗ The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug devel- opment. Topics covered include an overview of antibody development, PK characteristics, and the application of antibody PK/pharmacodynamics (PD) in research and development decision-making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies. Clin Transl Sci (2018) 11, 540–552; doi:10.1111/cts.12567; published online on 07 Aug 2018. BRIEF HISTORY OF ANTIBODY DEVELOPMENT by antagonistic antibodies against the TNF family (e.g., infliximab)11 and receptor blockade and/or receptor modu- Endogenous antibodies are mainly produced by differenti- lation, as shown by antibodies against programmed death ated plasma B-cells. They function to neutralize pathogens 1 (PD-1) receptor (e.g., pembrolizumab).12 The stem region such as bacteria and viruses. As the largest class of bio- of the Y constitutes the so called fragment crystallizable pharmaceuticals, therapeutic antibodies have been devel- region (Fc) and is composed of only the heavy chains. This oped for the treatment of a broad range of diseases including region is responsible for mAb binding to Fc receptors for cancer, immunological disorders, and infectious diseases.1,2 IgG and proteins of complement system, i.e., Fc gamma Over 60 antibodies have been marketed in the United States, receptors (Fcγ Rs), complement (C1q) protein, and neona- and 350 new antibody entities are in active clinical tal FcR (FcRn).13 The main therapeutic functions of IgG are development.3 Of the five antibody immunoglobulin (Ig) sub- dictated by their interactions with several classes of binding types (IgA, IgD, IgE, IgG, and IgM), the IgGs are the most partners: antigen, complement, Fc receptor for IgG (Fcγ Rs), abundant and most frequently explored as therapeutics.4 and the neonatal FcR (FcRn). Among them, the selective Development of monoclonal antibodies (mAbs) as thera- binding of antibody to antigen through variable domains peutics was initiated by the introduction of mouse hybridoma serves crucial pharmacological functions, such as blockage technology 40 years ago.5 However, the use of mouse of cytokines and growth factors, as shown by antagonis- mAbs as therapeutics was handicapped by their ubiqui- tic antibodies against the TNF family (e.g., infliximab)12 and tous induction of antidrug antibodies (ADA), their short half- receptor blockade and/or receptor modulation, as shown life, and the lack of an effector function.6 Efforts to reduce by antibodies against programmed death 1 (PD-1) receptor immunogenicity led to the development of chimeric and (e.g., pembrolizumab).13 Other functions of IgG are depen- humanized antibodies, which constitute the majority of mar- dent on the interaction of the Fc region with other proteins. keted antibodies today.7 Moreover, phage-display technol- Binding of mAb Fc to Fcγ Rs and complement protein leads ogy, which utilizes bacteriophage expressing recombinant to cellular depletion through both Fcγ -mediated antibody- human antigen-binding fragments for high-affinity binder dependent cytotoxicity (ADCC) and C1q-mediated comple- selection, led to the development of fully human antibod- ment protein-dependent cytotoxicity (CDC), as exemplified ies with enhanced diversity and potency.8 Human antibod- by anti-CD20 antibodies14 and binding to FcRn leads to long ies can also be generated from transgenic mice engineered half-life of mAb in circulation. Similar to its biological func- with human immunoglobulin genes, human hybridomas, and tions, the pharmacokinetic (PK) characteristics of antibody patient-derived lymphocytes.9 are also driven by interactions with their binding partners IgGs are Y-shaped 150 kDa immunoglobulins consisting (antigen, Fcγ Rs, and FcRn). of two pairs of identical heavy and light chains linked by disulphide bonds10 (Figure 1). The two arms of the Y con- mAb PHARMACOKINETICS stitute the antigen-binding region (Fab) and are formed by the variable domains from both the heavy and light chains Typically, systemically administered mAbs exhibit bipha- (Fv). The selective binding of antibody to antigen through sic PK profiles in circulation, i.e., a relatively fast dis- variable domains serves crucial pharmacological functions, tribution phase followed by a slower elimination phase. such as blockage of cytokines and growth factors, as shown Other mAb-specific PK characteristics include their confined 1 Department of Preclinical and Translational Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA; 2 Clinical Pharmacology, NGM Biopharmaceuti- cals, Inc., South San Francisco, California, USA. ∗ Correspondence: Kedan Lin ([email protected]) Received 28 November 2017; accepted 11 May 2018; published online on: 07 Aug 2018. doi:10.1111/cts.12567  Tutorial on Monoclonal Antibody Pharmacokinetics Ovacik and Lin 541 lating concentrations and/or variable bioavailability of mAbs can be attributed to: 1) physiological factors such as blood flow and skin morphology, etc. At the site of injection, 2) bio- logical interactions (target expression, binding, degradation at the site of injection, etc.),20 and 3) molecule and product specific characteristics (molecule charge, glycosylation, for- mulation, and volume of the injection, etc.). Non-human primate (NHP) models are often used for early assessment of bioavailability for their physiological and bio- chemical proximity to humans.21 Rodents and mini pig have also been explored to further understand the mechanism and variables in mAbs absorption.22 Despite efforts in predicting mAbs bioavailability in humans using preclinical models, the translatability remains uncertain.20 DISTRIBUTION MECHANISMS OF mAbs At steady state, mAbs generally exhibit a low volume of distribution of 3–8 L (Table 3), reflecting their confined distri- bution to the vascular and interstitial spaces because of their Figure 1 Schematic structure of IgG antibody: A simplified repre- size and polarity.23 The primary mechanism of antibody dif- sentation of IgG structure. VL = variable light chain; VH = variable fusion in tissues is through the convective transport through heavy chain; CH 1 = constant heavy chain domain 1; CH 2 = con- paracellular pores in vascular endothelial cell membranes.19 stant heavy chain domain 2; CH 3 = constant heavy chain domain 3; CDR = complementary determining region (responsible for spe- Additional factors influencing mAbs distribution to individual cific antigen binding); Fab = fragment antigen-binding (Fab); Fc = organs or tissues include: drug-specific features such as fragment crystallizable region; Fv = fragment variable. their binding affinity to specific target antigens, targets internalization rate,24 mAb hydrophilicity, charge,25 and tissue-specific features such as membrane structure and distribution in vasculature and interstitial space because blood flow.26 Optimizing these determinants to improve the of their size and polarity, long half-lives (11–30 days in distribution to relevant organs or tissues is currently being humans, Table 3) from FcRn-mediated recycling, and non- explored. For example, Rudnick et al. showed that when tar- linear PK due to target-mediated clearance. A summary of geting high-density and rapidly internalized antigens such as the key features of mAb-specific concepts and important PK HER2, a lower-affinity antibody could penetrate tumors more parameters is presented in Table 1. While this tutorial focuses effectively, while an ultrahigh-affinity antibody could limit the on mAb PK and its key determinants, a high-level com- distribution of the antibody to tumor as a result of “binding parison of PK characteristics between small molecules and site barrier.”27 Another effective utility of target-specific mAbs are shown in Table 2. A list of recently approved mAbs binding is to deliver antibodies to “off-limit” sites such as with their indications, dosing regimens, important PK param- the central nervous system (CNS), which is discussed in a eters, and immunogenicity rates are presented in Table 3. later section (see “Next-generation antibody”). It is worth noting that insights on mAbs distribu- ABSORPTION AND ROUTES OF mAb ADMINISTRATION tion are often revealed through physiologically based PK modeling28,29 integrated analytical tools including enzyme- mAbs have limited oral bioavailability (typically