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Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood
2002;100:3457e69.
Klinger M, Brandl C, Zugmaier G, Hijazi Y, Bargou RC, Topp MS, et al. Immunopharmacologic response of patients
with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE
antibody blinatumomab. Blood 2012;119:6226e33.
Kroll MH, Rojas-Hernandez C, Yee C. Hematologic complications of immune checkpoint inhibitors. Blood
2022;139:3594e604.
Kunzi MS, Pitha PM. Interferon targeted genes in host defense. Autoimmunity 2003;36:457e61.
Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, et al. Engineered antibody Fc variants with enhanced effector
function. Proc Natl Acad Sci U S A 2006;103:4005e10.
Leach MW, Halpern WG, Johnson CW, Rojko JL, MacLachlan TK, Chan CM, et al. Use of tissue cross-reactivity
studies in the development of antibody-based biopharmaceuticals: history, experience, methodology, and future
directions. Toxicol Pathol 2010 Dec;38(7):1138e66. https://doi.org/10.1177/0192623310382559. Epub 2010 Oct 6.
PMID: 20926828.
Lebrec H, Narayanan P, Nims R. Overview of the nonclinical quality and toxicology testing for recombinant bio-
pharmaceuticals produced in mammalian cells. J Appl Toxicol 2010;30:387e96.
Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, et al. Effects of single-dose interleukin-12
exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 1997;90:2541e8.
Lupușoru G, Ailinc
ai I, Fr
at
¸il
a G, Ungureanu O, Andronesi A, Lupușoru M, et al. Tumor lysis syndrome: an endless
challenge in onco-nephrology. Biomedicines 2022 Apr 28;10(5):1012. https://doi.org/10.3390/biomedicines
10051012. PMID: 35625753; PMCID: PMC9138780.
Luster MI, Portier C, Pait DG, Rosenthal GJ, Germolec DR, Corsini E, et al. Risk assessment in immunotoxicology. II.
Relationships between immune and host resistance tests. Fund Appl Toxicol 1993;21:71e82.
Martin PL, Bugelski PJ. Concordance of nonclinical and clinical pharmacology and toxicology of mAbs and fusion
proteins: soluble targets. Br J Pharmacol 2012;166:806e22.
McFarlane A. The behavior of I 131-labeled plasma proteins in vivo. Ann N Y Acad Sci 1957;70:19e25.
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011;480:480e9.
Menter A. The status of biologic therapies in the treatment of moderate to severe psoriasis. Cutis 2009;84:14e24.
Meyer T, Robles-Carrillo L, Robson T, Langer F, Desai H, Davila M, et al. Bevacizumab immune complexes activate
platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemostasis 2009;7:171e81.
Millward TA, Heitzmann M, Bill K, Langle U, Schumacher P, Forrer K. Effect of constant and variable domain glyco-
sylation on pharmacokinetics of therapeutic antibodies in mice. Biologicals 2008;36:41e7.
Monjazeb AM, Hsiao HH, Sckisel GD, Murphy WJ. The role of antigen-specific and non-specific immunotherapy in
the treatment of cancer. J Immunotoxicol 2012;9(3):248e58.
Moore GL, Chen H, Karki S, Lazar GA. Engineered Fc variant antibodies with enhanced ability to recruit complement
and mediate effector functions. mAbs 2010;2:181e9.
Musnier A, Bourquard T, Vallet A, Mathias L, Bruneau G, Ayoub MA, et al. A new in silico antibody similarity mea-
sure both identifies large sets of epitope binders with distinct CDRs and accurately predicts off-target reactivity. Int
J Mol Sci 2022 Aug 28;23(17):9765. https://doi.org/10.3390/ijms23179765. PMID: 36077163; PMCID: PMC9456297.
Martin PL, Fisher D, Glass W, O’Neil K, Das A, Martin EC, et al. Nonclinical safety and pharmacology of an anti-
human interleukin-13 mAb in normal macaques and in macaques with allergic asthma. Int J Toxicol 2008;27:351e8.
Narayanan PK, Ragheb K, Lawler G, Robinson JP. Defects in intracellular oxidative metabolism of neutrophils un-
dergoing apoptosis. J Leukoc Biol 1997;61:481e8.
Nelson AL, Reichert JM. Development trends for therapeutic antibody fragments. Nat Biotechnol 2009;27:331e7.
Nelson AL, Dhimolea E, Reichert JM. Development trends for human mAb therapeutics. Nat Rev Drug Discov
2010;9:767e74.
Neumeister P, Eibl M, Zinke-Cerwenka W, Scarpatetti M, Sill H, Linkesch W. Hepatic veno-occlusive disease in two
patients with relapsed acute myeloid leukemia treated with anti-CD33 calicheamicin (CMA-676) immunoconju-
gate. Ann Hematol 2001;80:119e20.
Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol 2007;96:179e204.
Notkins AL. Polyreactivity of antibody molecules. Trends Immunol 2004;25:174e9.
Omalizumab. Omalizumab: anti-IgE mAb E25, E25, humanised anti-IgE MAb, IGE 025, mAb E25, Olizumab, Xolair,
rhuMAb-E25. BioDrugs 2002;16(5):380e6.
4. Early de-risking strategy for biotherapeutics126
I. Development of biopharmaceuticals
Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. Induction of regular cytolytic T cell synapses by bispecific
single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol 2006;43:763e71.
Ostensen M, Forre O. Modulation of human natural killer cell function by cytokines and rheumatic disease. Scand J
Rheumatol Suppl 1988;76:183e8.
Otte L, Knaute T, Schneider-Mergener J, Kramer A. Molecular basis for the binding polyspecificity of an anti-cholera
toxin peptide 3 mAb. J Mol Recogn 2006;19:49e59.
Polson AG, Fuji RN. The successes and limitations of nonclinical studies in predicting the pharmacodynamics and
safety of cell-surface-targeted biological agents in patients. Br J Pharmacol 2012;166:1600e2.
Ponce R. Adverse consequences of immunostimulation. J Immunotoxicol 2008;5:33e41.
Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J, et al. Immunogenicity of biologically-derived ther-
apeutics: assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol 2009;54:164e82.
Rudmann DG, Page TJ, Vahle JL, Chouinard L, Haile S, Poitout F, et al. Rat-specific decreases in platelet count caused
by a humanized mAb against sclerostin. Toxicol Sci 2012;125:586e94.
Reed DM, Paschalaki KE, Starke RD, Mohamed NA, Sharp G, Fox B, et al. An autologous endothelial cell:peripheral
blood mononuclear cell assay that detects cytokine storm responses to biologics. Faseb J 2015 Jun;29(6):2595e602.
https://doi.org/10.1096/fj.14-268144. Epub 2015 Mar 6. PMID: 25746794.
Repp R, Kellner C, Muskulus A, Staudinger M, Nodehi SM, Glorius P, et al. Combined Fc-protein- and Fc-glyco-en-
gineering of scFv-Fc fusion proteins synergistically enhances CD16a binding but does not further enhance NK-cell
mediated ADCC. J Immunol Methods 2011;373:67e78.
Reusch U, Duell J, Ellwanger K, Herbrecht C, Knackmuss SH, Fucek I, et al. A tetravalent bispecific TandAb (CD19/
CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(þ) tumor cells. mAbs 2015;7(3):584e604.
https://doi.org/10.1080/19420862.2015.1029216. PMID: 25875246; PMCID: PMC4622993.
Robak T, Robak E. New anti-CD20 mAbs for the treatment of B-cell lymphoid malignancies. BioDrugs 2011;25:13e25.
Rodewald R. pH-dependent binding of immunoglobulins to intestinal cells of the neonatal rat. J Cell Biol
1976;71:666e9.
Romer PS, Berr S, Avota E, Na SY, Battaglia M, ten Berge I, et al. Preculture of PBMCs at high cell density increases
sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412. Blood 2011;118:
6772e82.
Rommer PS, Stuve O, Goertsches R, Mix E, Zettl UK. Monoclonal antibodies in the therapy of multiple sclerosis: an
overview. J Neurol 2008;255(Suppl 6):28e35.
Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J 2006;8:E501e7.
Rosewicz S, Detjen K, Scholz A, von Marschall Z. Interferon-alpha: regulatory effects on cell cycle and angiogenesis.
Neuroendocrinology 2004;80(Suppl 1):85e93.
Sandilands GP, Wilson M, Huser C, Jolly L, Sands WA, McSharry C. Were monocytes responsible for initiating the
cytokine storm in the TGN1412 clinical trial tragedy? Clin Exp Immunol 2010;162:516e27.
Santostefano MJ, Kirchner J, Vissinga C, Fort M, Lear S, Pan WJ, et al. Off-target platelet activation in macaques
unique to a therapeutic mAb. Toxicol Pathol 2012;40:899e917.
Schlaeth M, Berger S, Derer S, Klausz K, Lohse S, Dechant M, et al. Fc-engineered EGF-R antibodies mediate
improved antibody-dependent cellular cytotoxicity (ADCC) against KRAS-mutated tumor cells. Cancer Sci
2010;101:1080e8.
Scheerer P, Kramer A, Otte L, Seifert M, Wessner H, Scholz C, et al. Structure of an anti-cholera toxin antibody Fab in
complex with an epitope-derived D-peptide: a case of polyspecific recognition. J Mol Recogn 2007;20:263e74.
Schlereth B, Quadt C, Dreier T, Kufer P, Lorenczewski G, Prang N, et al. T-cell activation and B-cell depletion in chim-
panzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol Immun-
other 2006;55:503e14.
Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, et al. High resolution mapping of the binding site on
human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with
improved binding to the Fc gamma R. J Biol Chem 2001;276:6591e604.
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release
syndrome. J Immunother Cancer 2018 Jun 15;6(1):56. https://doi.org/10.1186/s40425-018-0343-9. PMID:
29907163; PMCID: PMC6003181.
Smith PL, Lombardi G, Foster GR. Type I interferons and the innate immune responsedmore than just antiviral cy-
tokines. Mol Immunol 2005;42:869e77.
References 127
I. Development of biopharmaceuticals
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial
of the anti-CD28 mAb TGN1412. N Engl J Med 2006;355:1018e28.
St Clair EW. Novel targeted therapies for autoimmunity. Curr Opin Immunol 2009;21:648e57.
Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, et al. “Cytokine storm” in the phase I trial of mAb
TGN1412: better understanding the causes to improve nonclinical testing of immunotherapeutics. J Immunol
2007;179:3325e31.
Stopeck AT, Gessner A, Miller TP, Hersh EM, Johnson CS, Cui H, et al. Loss of B7.2 (CD86) and intracellular adhesion
molecule 1 (CD54) expression is associated with decreased tumor-infiltrating T lymphocytes in diffuse B-cell
large-cell lymphoma. Clin Cancer Res 2000;6:3904e9.
Szebeni J. Hemocompatibility testing for nanomedicines and biologicals: predictive assays for complement mediated
infusion reactions. Eur J Nanomed 2012;1:33e53.
Tacke M, Hanke G, Hanke T, Hunig T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo
without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol
1997;27:239e47.
Tian Z, Liu M, Zhang Y, Wang X. Bispecific T cell engagers: an emerging therapy for management of hematologic
malignancies. J Hematol Oncol 2021 May 3;14(1):75. https://doi.org/10.1186/s13045-021-01084-4. PMID:
33941237; PMCID: PMC8091790.
Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging
antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic
leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol
2011;29:2493e8.
Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP. Triggering of OX40 (CD134) on CD4(þ)
CD25þ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR.
Blood 2005;105:2845e51.
Vessillier S, Eastwood D, Fox B, Sathish J, Sethu S, Dougall T, et al. Cytokine release assays for the prediction of ther-
apeutic mAb safety in first-in man trialsdwhole blood cytokine release assays are poorly predictive for TGN1412
cytokine storm. J Immunol Methods 2015 Sep;424:43e52. https://doi.org/10.1016/j.jim.2015.04.020. Epub 2015
May 7. PMID: 25960173; PMCID: PMC4768082.
Vessillier S, Fort M, O’Donnell L, Hinton H, Nadwodny K, Piccotti J, et al., Participants of the study. Development of
the first reference antibody panel for qualification and validation of cytokine release assay platforms - Report of an
international collaborative study. Cytokine X 2020 Dec;2(4):100042. https://doi.org/10.1016/j.cytox.2020.100042.
PMID: 33458650; PMCID: PMC7789043.
Vidal JM, Kawabata TT, Thorpe R, Silva-Lima B, Cederbrant K, Poole S, et al. In vitro cytokine release assays for pre-
dicting cytokine release syndrome: the current state-of-the-science. Report of a European Medicines Agency
Workshop. Cytokine 2010;51:213e5.
Vilcek J. Fifty years of interferon research: aiming at a moving target. Immunity 2006;25:343e8.
Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy 1969;13:1e110.
Wani MA, Haynes LD, Kim J, Bronson CL, Chaudhury C, Mohanty S, et al. Familial hypercatabolic hypoproteinemia
caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad
Sci U S A 2006;103:5084e9.
Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immuno-
therapy. Front Immunol 2022 Oct 28;13:1035276. https://doi.org/10.3389/
fimmu.2022.1035276. PMID: 36389699;
PMCID: PMC9650279.
Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to
rituximab in patients with follicular lymphoma. J Clin Oncol 2003;21:3940e7.
Wing M. Monoclonal antibody first dose cytokine release syndromes-mechanisms and prediction. J Immunotoxicol
2008;5:11e5.
Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecific antibody constructs with unique anti-tumor
activity. Drug Discov Today 2005;10:1237e44.
Wolf B, Morgan H, Krieg J, Gani Z, Milicov A, Warncke M, et al. A whole blood in vitro cytokine release assay with
aqueous mAb presentation for the prediction of therapeutic protein induced cytokine release syndrome in
humans. Cytokine 2012;60:828e37.
4. Early de-risking strategy for biotherapeutics128
I. Development of biopharmaceuticals
Wu H, Pfarr DS, Johnson S, Brewah YA, Woods RM, Patel NK, et al. Development of motavizumab, an ultra-potent
antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. J Mol
Biol 2007;368:652e65.
Yang B, Lu XC, Yu RL, Chi XH, Zhang WY, Zhu HL, et al. Diagnosis and treatment of rituximab-induced acute tumor
lysis syndrome in patients with diffuse large B-cell lymphoma. Am J Med Sci 2012;343:337e41.
Yu M, Brown D, Reed C, Chung S, Lutman J, Stefanich E, et al. Production, characterization, and pharmacokinetic
properties of antibodies with N-linked Mannose-5 glycans. mAbs 2012;4:475e87.
Zareba KM. Eculizumab: a novel therapy for paroxysmal nocturnal hemoglobinuria. Drugs Today 2007;43:539e46.
Further reading
Assessment, O. P. Orencia European public assessment report; scientific discussion, EMA.
Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res 2009;69:4941e4.
Further reading 129
I. Development of biopharmaceuticals
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5
Novel biopharmaceuticals:
Pharmacokinetics,
pharmacodynamics, and bioanalytics
Sieto Bosgra
1
and Manish Gupta
2
1
Clinical Pharmacology & Quantitative Science, Genmab, Utrecht, the Netherlands;
2
Translational & Quantitative Sciences, Genmab, Princeton, NJ, United States
OUTLINE
Introduction 132
Absorption, distribution and elimination
of biopharmaceuticals 132
Absorption 133
Distribution and elimination: Nonspecific
processes 134
mAbs, mAb fragments, and mAb
constructs 134
Therapeutic proteins and peptides 136
Distribution and elimination: Target-
mediated processes 139
Monoclonal antibodies 139
Therapeutic proteins and peptides 140
Modifications and impact on PK and
biodistribution 140
“Metabolism” and biodistribution for
biopharmaceuticals 144
Immunogenicity and impact on PK and
biodistribution 145
Pharmacokinetics and
pharmacodynamics 146
PK methods 147
Representative PK for molecule
types 148
Pharmacodynamics, PK/PD methods
and examples 149
Model types and examples 149
Nonclinical to clinical translation 150
Human PK projections 151
CHAPTER
131
Nonclinical Development of Biologics, Vaccines and
Specialty Biologics, Second Edition
https://doi.org/10.1016/B978-0-443-13344-2.00013-4
© 2025 Elsevier Inc. All rights are reserved, including those for text
and data mining, AI training, and similar technologies.
Exposure response: Determining
minimum and maximum targets for
FIH dosing 151
Bioanalytics 152
Method development guidances and
regulations 154
Methods and platforms 154
Immunoassays 154
LC-MS 159
Assays 161
Drug exposure 161
Biomarkers: Target engagement 163
Immunogenicity assessment 164
Summary 166
Acknowledgment 166
References 166
Introduction
Quantitative evaluation of in vivo drug exposure (pharmacokinetics, PK) and effect (phar-
macodynamics, PD) is a fundamental step in preclinical development. Biopharmaceuticals
(peptides, therapeutic proteins, and monoclonal antibodies) present unique challenges in
defining drug exposure, including the requirement for highly sensitive, specific assays that
can identify and quantitate the biopharmaceutical swimming in a biological sea of similar
molecules. PK/PD and metabolism methods and tools are also needed to integrate and
unravel often complicated interactions between the biopharmaceutical and physiologic
processes.
In the past decade, research and development in PK/PD, metabolism, and bioanalytics for
biopharmaceuticals continued to be dominated by monoclonal antibodies (mAbs) with more
limited development of new methods for therapeutic proteins and peptides (Brown and
Wobst, 2021; Martins et al., 2022; Walsh and Walsh, 2022). As a consequence, the contents
of this chapter will reflect the more extensive information generally available for mAbs.
Absorption, distribution and elimination of biopharmaceuticals
The observed behavior of biopharmaceuticals in vivo is a consequence of both nonspecific
protein processes and target-mediated processes. If the biopharmaceuticals are essentially
copies of endogenous molecules, they will traffic through existing nonspecific absorptio n,
distribution, and elimination processes. However, target-mediated processes are common
with biopharmaceuticals, and may dominate absorption, distribution, or elimination for
the molecu le. Biopharmaceuticals, such as endogenous proteins, are typically catabolized
to their amino acid constituents upon cellular uptake. Metabolism is therefore usually not
extensively studied during therapeutic protein development (see Sec tion “Metabolism”
and Biodistribution for Biopharmaceuticals).
5. Novel biopharmaceuticals: Pharmacokinetics, pharmacodynamics, and bioanalytics132
I. Development of biopharmaceuticals
Absorption
Proteins, in general, have poor oral bioavailability due to high proteolytic enzyme activity
and poor mucosal permeability in the gastrointestinal tract. Most biopharmaceuticals are
administered parenterally with intravenous (IV), subcutaneous (SC), or intramuscular (IM)
being the common routes used for administration. IV administration is often used with
less frequent dosing intervals (weekly to monthly) or when large dose volumes are required.
SC or IM administration may be preferred for frequent administration (daily to weekly) and
for home usage. Approved biopharmaceuticals also use ocular (Lucentis, Eylea) and pulmo-
nary administration (Exubera, DNase). Other routes (nasal, buccal, rectal, vaginal, trans-
dermal) have also been investigated, primarily for therapeutic proteins and peptides, but
these routes have produced generally poor bioavailability and high variability in exposure
(Meibohm and Braeckman, 2008). The success of mRNA-based vaccines in response to the
COVID-19 pandemic (Focosi et al., 2022) has spiked an interest in mRNA as a means of deliv-
ering biopharmaceuticals in general. However, application beyond vaccines is still in its in-
fancy and several hurdles need to be overcome for mRNA therapeutics to come to fruition
(Rohner et al., 2022).
Systemic absorption of proteins from injection sites occurs via direct diffusion into blood
capillaries and/or convective transport through the lymph system and then into the blood
(Meibohm and Braeckman, 2008; McDonald et al., 2010; Porter and Charman, 2001). Molecule
size and charge, as well as capillary pore size, influence the contribution of direct diffusion
versus lymph system transport. In general, molecules that are larger than w20 kDa or nega-
tively charged are preferentially transported via the lymph system in large animals (Super-
saxo et al., 1990; Wang et al., 2012). Uptake of biopharmaceuticals by the lymphatics in
small animals (rats, rabbits) is more variable and not consistently related to size or charge
(McDonald et al., 2010; Wang et al., 2012). The ultimate bioavailability of the protein depends
upon the rates and efficiency of the diffusion or lymph transport processes and the extent of
degradation and absorption either at the injection site or within the lymph system (presyste-
mic catabolism) (McDonald et al., 2010; Mrsny, 2009; Wang et al., 2008). Absolute bioavail-
ability is generally high for mAbs (w50% to 100%) but varies widely for therapeutic
proteins and peptides, reflecting more complicated injection site or lymph system interac-
tions. Therapeutic proteins and peptides such as vascular endothelial growth factor
(VEGF) and transforming growth factor beta (TGF-b) can attract cells involved in tissue
remodeling and vessel formation, which can alter the protease/peptidase environment
(Mrsny, 2009). Therapeutic proteins and peptides can also bind to extracellular matrix com-
ponents (VEGF: heparin, heparin-like molecules; epidermal growth factor (EGF), basic fibro-
blast growth factor (bFGF), insulin-like growth factor I (IGF-I): vitronectin) causing delayed
release from SC sites and increased risk of local metabolism (Mrsny, 2009). Systemic absorp-
tion is slow for mAbs with maximal plasma or serum concentrations (Cmax) achieved typi-
cally 1e8 days post dose (time of maximum observed concentrations, T
max
)(Lobo et al., 2004;
Wang et al., 2008). The rate of absorption is highly variable for therapeutic proteins and pep-
tides, depending somewhat on particular formulations, but generally occurs much more
rapidly than for mAbs, with T
max
values of typically minutes to hours post dose (Tang
et al., 2004; Foote, 2008; Ryff et al., 2008; Beals et al., 2008 ; Marian and Oeswein, 2008;
Modi, 2008; Lazarus and Wagener, 2008; Sam, 2008). The dose range achievable by SC
Absorption, distribution and elimination of biopharmaceuticals 133
I. Development of biopharmaceuticals
delivery was traditionally limited by the formulated protein concentration and an injection
volume between 1 and 2 mL. However, current technologies allow formulation of bio-
therapeutics as high-concentration injectables and considerable increase of injection volume
by coformulation with recombinant human hyaluronidase (Bookbinder et al., 2006; Locke
et al., 2019; Badkar et al., 2021). Examples of biotherapeutics for which high dose SC formu-
lations were successfully developed include rituximab (Davies et al., 2014), trastuzumab
(Ismael et al., 2012) and daratumumab (Mateos et al., 2020). SC dosing of proteins may pro-
vide an opportunity to reduce the risk of acute adverse reactions including cytokine release
syndrome and infusion related reactions. On the other hand, between-patient variability in
absorption rate and bioavailability may not favor extravascular routes for biotherapeutics
with narrow therapeutic index (Bittner et al., 2018).
Distribution and elimination: Nonspecific processes
mAbs, mAb fragments, and mAb constructs
Once in the bloodstream, mAbs extravasate from blood into interstitial fluids and tissues
(Lobo et al., 2004; Ternant and Paintaud, 2005; Wang et al., 2008; Tabrizi et al., 2009a). Diffu-
sion across vascular endothelium for large, charged molecules such as mAbs is minimal, and
convection is assumed to be the primary mechanism for transport from blood to interstitial
fluid. The rate of convective transport or “solvent drag” (Wang et al., 2008) is determined
by the rates of fluid flow from blood to tissue, the morphology of the capillary pores, and
the size, shape, and charge of the molecu le. Initial distribution of mAbs to highly perfused
tissues (spleen, liver, bone marrow) may be aided by the presence of vascular endothelium,
which is fenestrated and “leaky.” Model simulations suggested typical antibody concentra-
tions in tissues at equilibrium to be between 5% and 15% of plasma concentrations, with
some more extreme values (0.35% for brain to 67.5% for thyroid) (Shah and Betts, 2013).
Elimination of mAbs occurs via generic protein processes (fluid-phase endocytosis) or via
receptor-mediated endocytosis (RME) (Table 5.1)(Lobo et al., 2004; Tabrizi et al., 2006). Once
endocytosed, mAbs can traffic to lysosomes where they are catabolized to amino acids. These
amino acids are then recycled into new protein and peptide molecules (Meibohm and Braeck-
man, 2008). In the absence of significant renal or liver disease, there is little or no excretion of
intact peptides or protein in urine or bile.
Antibodies also have a unique mechanism to escape catabolism within endothelial cells.
Antibodies may escape catabolism if they bind a neonatal Fc (FcRn) receptor during early en-
dosome formation (Ward and Ober, 2009). Antibody: FcRn complexes are then returned to
the cell membrane, where the antibody dissociates and is released back into intracellular fluid
(recycling). The same FcRn-mediated process also moves antibodies within or across a wide
variety of cell types (transcytosis) (Ward and Ober, 2009). FcRn has been identified as the pri-
mary receptor controlling IgG homeostasis and is a major determinant in the sustained expo-
sure seen with mAbs. FcRn is ubiquitously expressed on vascular endoth elium and
hematopoietic cells. As a consequence, FcRn-me diated mAb elimination is a diffuse process
not localized to a specific target organ, and not saturable within the typical mAb therapeutic
dose range. Antibodies may also be cleared via interactions with the Fcg family of receptors,
but it is likely this pathway is more important for antibody complexes containing multiple
5. Novel biopharmaceuticals: Pharmacokinetics, pharmacodynamics, and bioanalytics134
I. Development of biopharmaceuticals
antibody molecules, than for monomeric antibodies (Ward and Ober, 2009; Alvares et al.,
2012).
The limited role of FcgR in normal clearance of mAbs is further supported by observations
that various antibodies with Fc doma ins engineered for reduced or enhanced FcgR binding
displayed unaltered PK compared with their isotype controls (Leabman et al., 2013). Phys-
ical/chemical factors that can influence nonspecific distribution and elimination of mAbs
include affinity for the Fc receptors, especially FcRn, Ig subclass, glycosylation, molecule
size and charge (Table 4.1). FcRn-me diated antibody recycling is pH dependent and mAbs
with tighter binding to FcRn at acidic pH (pH 6.0), while maintaining negligible binding at
neutral pH (pH 7.4), show slower clearance and better absorption (Wang et al., 2008;
Ward and Ober, 2009). Human IgG1 and IgG2 isotypes are more stable than IgG4 or IgG3
isotypes (Correia, 2010). IgG1 and IgG2 also have somewhat better binding to FcRn than
IgG3 or IgG4 and likewise show slower clearance (Correia, 2010). The impact of glycosylation
on antibody clearance is not clear and publications show conflicting results (Tao and Morri-
son, 1989; Harris, 2005). Molecules with an overall positive molecule charge, as measured by
pI, usually show slower systemic clearance than molecules with negative charges (Boswell
et al., 2010; Khawli et al., 2010; Igaw a et al., 2010). Impact of charge on both clearance and
bioavailability is somewhat less clear following extravascular administration, and may indi-
cate more complicated interactions with charged molecules at the injection sites.
Antibody fragments clear faster than full-length antibodies (Fig. 5.1, Table 5.2), but clear-
ance depends upon fragment size and whether the Fc portion of the antibody is retained
(Covell et al., 1986; Bazin-Redu reau et al., 1997; Kim et al., 1995). Fragments that have a
TABLE 5.1 Overview of nonspecific clearance mechanisms for peptides, therapeutic proteins, and mono-
clonal antibodies.
Molecule type
Molecular
weight (kDa)
Clearance
tissue/ organ Mechanisms Factors impacting clearance
Peptides 0.5e1 Liver Carrier-mediated
uptake; passive
lipoid diffusion
Structure, lipophilicity
Peptides, therapeutic
proteins, Fab fragments
1e60 Kidney Glomerular filtration Hydrodynamic size
Fc fragments 55 Endothelium RME FcRn
Therapeutic proteins 60e200 Kidney, liver RME Carbohydrates, charge; a2
macroglobulin; other specific
binding proteins
mAbs; mAb complexes 150e400 Endothelium,
liver, spleen,
lung
RME, opsonization FcRn; FcgR (complexes)
mAb complexes;
aggregates
>400 Liver, spleens Phagocytosis Particle aggregation
RME, receptor-mediated endocytosis.
Adapted from Meibohm and Braeckman (2008).
Absorption, distribution and elimination of biopharmaceuticals 135
I. Development of biopharmaceuticals
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