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      Factors Affecting the Pharmacology of Antibody–Drug Conjugates

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          Abstract

          Major advances in therapeutic proteins, including antibody–drug conjugates (ADCs), have created revolutionary drug delivery systems in cancer over the past decade. While these immunoconjugate agents provide several advantages compared to their small-molecule counterparts, their clinical use is still in its infancy. The considerations in their development and clinical use are complex, and consist of multiple components and variables that can affect the pharmacologic characteristics. It is critical to understand the mechanisms employed by ADCs in navigating biological barriers and how these factors affect their biodistribution, delivery to tumors, efficacy, and toxicity. Thus, future studies are warranted to better understand the complex pharmacology and interaction between ADC carriers and biological systems, such as the mononuclear phagocyte system (MPS) and tumor microenvironment. This review provides an overview of factors that affect the pharmacologic profiles of ADC therapies that are currently in clinical use and development.

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          Most cited references145

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          Properties of mouse and human IgG receptors and their contribution to disease models.

          Pierre Bruhns (2012)
          Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcγRIII and FcγRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcγRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock.
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            The function of Fcγ receptors in dendritic cells and macrophages.

            Martin Guilliams, Pierre Bruhns, Yvan Saeys … (2014)
            Dendritic cells (DCs) and macrophages use various receptors to recognize foreign antigens and to receive feedback control from adaptive immune cells. Although it was long believed that all immunoglobulin Fc receptors are universally expressed by phagocytes, recent findings indicate that only monocyte-derived DCs and macrophages express high levels of activating Fc receptors for IgG (FcγRs), whereas conventional and plasmacytoid DCs express the inhibitory FcγR. In this Review, we discuss how the uptake, processing and presentation of antigens by DCs and macrophages is influenced by FcγR recognition of immunoglobulins and immune complexes in the steady state and during inflammation.
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              Fcgamma receptors: old friends and new family members.

              Falk Nimmerjahn, Jeffrey V. Ravetch (2006)
              Although cellular receptors for immunoglobulins were first identified nearly 40 years ago, their central role in the immune response was discovered only in the last decade. They are key players in both the afferent and efferent phase of an immune response, setting thresholds for B cell activation, regulating the maturation of dendritic cells, and coupling the exquisite specificity of the antibody response to innate effector pathways, such as phagocytosis, antibody-dependent cellular cytotoxicity, and the recruitment and activation of inflammatory cells. Moreover, because of their general presence as receptor pairs consisting of activating and inhibitory molecules on the same cell, they have become a paradigm for studying the balance of positive and negative signals that ultimately determine the outcome of an immune response. This review will summarize recent results in Fc-receptor biology with an emphasis on data obtained in in vivo model systems.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antibodies (Basel)
                Journal ID (iso-abbrev): Antibodies (Basel)
                Journal ID (publisher-id): antibodies
                Title: Antibodies
                Publisher: MDPI
                ISSN (Electronic): 2073-4468
                Publication date (Electronic): 07 February 2018
                Publication date Collection: March 2018
                Volume: 7
                Issue: 1
                Electronic Location Identifier: 10
                Affiliations
                [1 ]Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; andrew_lucas@ 123456unc.edu (A.T.L.); lslprice@ 123456email.unc.edu (L.S.L.P.); aschorz@ 123456email.unc.edu (A.N.S.)
                [2 ]UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; mastorrie@ 123456gmail.com (M.S.); joseph_piscitelli@ 123456unc.edu (J.A.P.); juanrazo@ 123456email.unc.edu (J.R.)
                [3 ]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
                Author notes
                [* ]Correspondence: zamboni@ 123456email.unc.edu ; Tel.: +1-919-843-6665; Fax: +1-919-966-5863
                Article
                Publisher ID: antibodies-07-00010
                DOI: 10.3390/antib7010010
                PMC ID: 6698819
                PubMed ID: 31544862
                SO-VID: cc30b234-3e9a-47bf-8671-5eb91981c9a6
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 14 December 2017
                Date accepted : 01 February 2018
                Categories
                Subject: Review

                Keywords: antibody–drug conjugates,mononuclear phagocyte system,pharmacokinetics,pharmacology,therapeutic proteins
                Data availability:
                Keywords: antibody–drug conjugates, mononuclear phagocyte system, pharmacokinetics, pharmacology, therapeutic proteins

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