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Journal Article•DOI•

Pharmacokinetics of Monoclonal Antibodies

Josiah T. Ryman1, Bernd Meibohm2•
University of Tennessee Health Science Center1, University of Tennessee2
01 Sep 2017-Vol. 6, Iss: 9, pp 576-588
TL;DR: This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product‐specific and patient‐specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy.
Abstract: Monoclonal antibodies (mAbs) have developed in the last two decades into the backbone of pharmacotherapeutic interventions in a variety of indications, with currently more than 40 mAbs approved by the US Food and Drug Administration, and several dozens more in clinical development. This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product-specific and patient-specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy.
Citations
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Journal Article•DOI•
The evolution of commercial drug delivery technologies.

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Ava M. Vargason1, Aaron C. Anselmo1, Samir Mitragotri2, Samir Mitragotri3•
University of North Carolina at Chapel Hill1, Wyss Institute for Biologically Inspired Engineering2, Harvard University3
01 Apr 2021-Nature Biomedical Engineering
TL;DR: In this article, the authors discuss seminal approaches that led to the development of successful therapeutic products involving small molecules and macromolecules, identify three drug delivery paradigms that form the basis of contemporary drug delivery and discuss how they have aided the initial clinical successes of each class of therapeutic.
Abstract: Drug delivery technologies have enabled the development of many pharmaceutical products that improve patient health by enhancing the delivery of a therapeutic to its target site, minimizing off-target accumulation and facilitating patient compliance. As therapeutic modalities expanded beyond small molecules to include nucleic acids, peptides, proteins and antibodies, drug delivery technologies were adapted to address the challenges that emerged. In this Review Article, we discuss seminal approaches that led to the development of successful therapeutic products involving small molecules and macromolecules, identify three drug delivery paradigms that form the basis of contemporary drug delivery and discuss how they have aided the initial clinical successes of each class of therapeutic. We also outline how the paradigms will contribute to the delivery of live-cell therapies. This Review Article discusses how delivery challenges associated with small molecules, nucleic acids, peptides, proteins and cells led to the development of commercial products and are now informing the delivery of live-cell therapeutics.

313 citations

Journal Article•DOI•
Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors

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Maddalena Centanni1, Dirk Jan A.R. Moes2, Iñaki F. Trocóniz3, Joseph Ciccolini4, J. G. Coen van Hasselt1 •
Leiden University1, Leiden University Medical Center2, University of Navarra3, Aix-Marseille University4
01 Jul 2019-Clinical Pharmacokinectics
TL;DR: An overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance, and important issues related to the efficacy and safety, the pharmacodynamics, of ICIs are addressed, including exposure–response relationships related to clinical outcome.
Abstract: Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20-40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure-response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure-response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.

197 citations

Journal Article•DOI•
Bispecific antibodies in cancer immunotherapy.

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Eva Dahlén, Niina Veitonmäki, Per Norlén
28 Mar 2018
TL;DR: Following the clinical success of immune checkpoint antibodies targeting CTLA-4, PD-1 or PD-L1 in cancer treatment, bispecific antibodies are now emerging as a growing class of immunotherapies with potential to further improve clinical efficacy and safety.
Abstract: Following the clinical success of immune checkpoint antibodies targeting CTLA-4, PD-1 or PD-L1 in cancer treatment, bispecific antibodies are now emerging as a growing class of immunotherapies with potential to further improve clinical efficacy and safety. We describe three classes of immunotherapeutic bispecific antibodies: (a) cytotoxic effector cell redirectors; (b) tumor-targeted immunomodulators; and (c) dual immunomodulators. Cytotoxic effector cell redirectors are dominated by T-cell redirecting compounds, bispecific compounds engaging a tumor-associated antigen and the T-cell receptor/CD3 complex, thereby redirecting T-cell cytotoxicity to malignant cells. This is the most established class of bispecific immunotherapies, with two compounds having reached the market and numerous compounds in clinical development. Tumor-targeted immunomodulators are bispecific compounds binding to a tumor-associated antigen and an immunomodulating receptor, such as CD40 or 4-1BB. Such compounds are usually designed to be inactive until binding the tumor antigen, thereby localizing immune stimulation to the tumor environment, while minimizing immune activation elsewhere. This is expected to induce powerful activation of tumor-specific T cells with reduced risk of immune-related adverse events. Finally, dual immunomodulators are bispecific compounds that bind two distinct immunomodulating targets, often combining targeting of PD-1 or PD-L1 with that of LAG-3 or TIM-3. The rationale is to induce superior tumor immunity compared to monospecific antibodies to the same targets. In this review, we describe each of these classes of bispecific antibodies, and present examples of compounds in development.

155 citations

Journal Article•DOI•
Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance

[...]

David C. Turner1, Anna Georgieva Kondic1, Keaven M. Anderson1, Andrew G. Robinson2, Edward B. Garon3, Jonathan W. Riess4, Lokesh Jain1, Kapil Mayawala1, Jiannan Kang1, Scot Ebbinghaus1, Vikram Sinha1, Dinesh P. de Alwis1, Julie A. Stone1 •
Merck & Co.1, Kingston General Hospital2, University of California, Los Angeles3, University of California, Davis4
01 Dec 2018-Clinical Cancer Research
TL;DR: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg, and suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.
Abstract: Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 subgroups. Results: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR = 0.98; 95% CI, 0.95–1.01); however, a strong CL0–OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72–3.80 and NSCLC HR = 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL0–OS association (multivariate-adjusted CL0 HR = 1.64; 95% CI, 1.06–2.52 for melanoma and HR = 1.88; 95% CI, 1.22–2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs. See related commentary by Coss et al., p. 5787

141 citations

Cites background from "Pharmacokinetics of Monoclonal Anti..."

  • ...(42, 43) Their shared metabolic pathways and the well-established link of anorexia/cachexia-related metabolic wasting and patient outcome thus present a credible explanation that should be further explored....

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Journal Article•DOI•
The pharmacology and therapeutic applications of monoclonal antibodies.

[...]

María Sofía Castelli1, Paul McGonigle1, Pamela J. Hornby2, Pamela J. Hornby1•
Drexel University1, Janssen Pharmaceutica2
01 Dec 2019-Pharmacology Research & Perspectives
TL;DR: Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability.
Abstract: Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane-bound receptors and have increased circulating half-life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off-target effects and drug-drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off-target adverse effects, fewer drug-drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.

117 citations

References
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Journal Article•DOI•
Continuous cultures of fused cells secreting antibody of predefined specificity

[...]

G Köhler1, C. Milstein1•
Laboratory of Molecular Biology1
07 Aug 1975-Nature
TL;DR: The derivation of a number of tissue culture cell lines which secrete anti-sheep red blood cell (SRBC) antibodies is described here, made by fusion of a mouse myeloma and mouse spleen cells from an immunised donor.
Abstract: THE manufacture of predefined specific antibodies by means of permanent tissue culture cell lines is of general interest. There are at present a considerable number of permanent cultures of myeloma cells1,2 and screening procedures have been used to reveal antibody activity in some of them. This, however, is not a satisfactory source of monoclonal antibodies of predefined specificity. We describe here the derivation of a number of tissue culture cell lines which secrete anti-sheep red blood cell (SRBC) antibodies. The cell lines are made by fusion of a mouse myeloma and mouse spleen cells from an immunised donor. To understand the expression and interactions of the Ig chains from the parental lines, fusion experiments between two known mouse myeloma lines were carried out.

19,053 citations

Journal Article•DOI•
Fcγ receptors as regulators of immune responses

[...]

Falk Nimmerjahn1, Jeffrey V. Ravetch2•
University of Erlangen-Nuremberg1, Rockefeller University2
01 Jan 2008-Nature Reviews Immunology
TL;DR: Recent studies addressing the multifaceted roles of FcRs for IgG (FcγRs) in the immune system are discussed and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases are discussed.
Abstract: In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

2,390 citations

Journal Article•DOI•
FcRn: the neonatal Fc receptor comes of age

[...]

Derry C. Roopenian, Shreeram Akilesh1•
Washington University in St. Louis1
17 Aug 2007-Nature Reviews Immunology
TL;DR: The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus and throughout life, FcRm protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum.
Abstract: The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. This Review summarizes these two areas of FcRn biology.

1,998 citations

Journal Article•DOI•
IgG subclasses and allotypes: from structure to effector functions.

[...]

Gestur Vidarsson1, Gillian Dekkers1, Theo Rispens1•
University of Amsterdam1
20 Oct 2014-Frontiers in Immunology
TL;DR: IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.
Abstract: Of the five immunoglobulin isotypes, Immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3 and IgG4 which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptor (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or Antibody-dependent cell-mediated cytotoxicity (ADCC), and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc-receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function, will be the focus of the current review.

1,834 citations

Additional excerpts

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Journal Article•DOI•
Anti-Inflammatory Activity of Immunoglobulin G Resulting from Fc Sialylation

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Yoshikatsu Kaneko1, Falk Nimmerjahn1, Jeffrey V. Ravetch1•
Rockefeller University1
04 Aug 2006-Science
TL;DR: It is shown that IgG acquires anti-inflammatory properties upon Fc sialylation, which is reduced upon the induction of an antigen-specific immune response, and may provide a switch from innate anti- inflammatory activity in the steady state to generating adaptive pro-inflammatory effects upon antigenic challenge.
Abstract: Immunoglobulin G (IgG) mediates pro- and anti-inflammatory activities through the engagement of its Fc fragment (Fc) with distinct Fcg receptors (FcgRs) One class of Fc-FcgR interactions generates pro-inflammatory effects of immune complexes and cytotoxic antibodies In contrast, therapeutic intravenous gamma globulin and its Fc fragments are anti-inflammatory We show here that these distinct properties of the IgG Fc result from differential sialylation of the Fc core polysaccharide IgG acquires anti-inflammatory properties upon Fc sialylation, which is reduced upon the induction of an antigen-specific immune response This differential sialylation may provide a switch from innate anti-inflammatory activity in the steady state to generating adaptive pro-inflammatory effects upon antigenic challenge

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