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      Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action

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          Abstract

          Eculizumab, a monoclonal antibody (mAb) directed against complement protein C5, is considered to be the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. This study describes the generation and preclinical attributes of ALXN1210, a new long-acting anti-C5 mAb, obtained through select modifications to eculizumab to both largely abolish target-mediated drug disposition (TMDD) and increase recycling efficiency via the neonatal Fc receptor (FcRn). To attenuate the effect of TMDD on plasma terminal half-life (t 1/2), histidine substitutions were engineered into the complementarity-determining regions of eculizumab to enhance the dissociation rate of the mAb:C5 complex in the acidic early endosome relative to the slightly basic pH of blood. Antibody variants with optimal pH-dependent binding to C5 exhibited little to no TMDD in mice in the presence of human C5. To further enhance the efficiency of FcRn-mediated recycling of the antibody, two additional substitutions were introduced to increase affinity for human FcRn. These substitutions yielded an additional doubling of the t ½ of surrogate anti-mouse C5 antibodies with reduced TMDD in transgenic mice expressing the human FcRn. In conclusion, ALXN1210 is a promising new therapeutic candidate currently in clinical development for treatment of patients with PNH and atypical hemolytic uremic syndrome.

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          Most cited references18

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          Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR.

          Minoru Tada, Takuo Suzuki, Akiko Ishii-Watabe … (2010)
          The neonatal FcR (FcRn) binds to the Fc domain of IgG at acidic pH in the endosome and protects IgG from degradation, thereby contributing to the long serum half-life of IgG. To date, more than 20 mAb products and 5 Fc-fusion protein products have received marketing authorization approval in the United States, the European Union, or Japan. Many of these therapeutic proteins have the Fc domain of human IgG1; however, the serum half-lives differ in each protein. To elucidate the role of FcRn in the pharmacokinetics of Fc domain-containing therapeutic proteins, we evaluated the affinity of the clinically used human, humanized, chimeric, or mouse mAbs and Fc-fusion proteins to recombinant human FcRn by surface plasmon resonance analysis. The affinities of these therapeutic proteins to FcRn were found to be closely correlated with the serum half-lives reported from clinical studies, suggesting the important role of FcRn in regulating their serum half-lives. The relatively short serum half-life of Fc-fusion proteins was thought to arise from the low affinity to FcRn. The existence of some mAbs having high affinity to FcRn and a short serum half-life, however, suggested the involvement of other critical factor(s) in determining the serum half-life of such Abs. We further investigated the reason for the relatively low affinity of Fc-fusion proteins to FcRn and suggested the possibility that the receptor domain of Fc-fusion protein influences the structural environment of the FcRn binding region but not of the FcgammaRI binding region of the Fc domain.
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            A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration.

            S Franchini, D Mastellos, J Papadimitriou … (2001)
            Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl(4)-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl(4.) In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2'-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.
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              Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

              Y Wang, J Madri, S Rollins … (1995)
              Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors C5a and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.
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                Author and article information

                Contributors
                Douglas Sheridan:
                ORCID: http://orcid.org/0000-0001-9505-1668
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Zhao-Xue Yu: Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Yuchun Zhang: Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Rekha Patel: Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Fang Sun: Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Melissa A. Lasaro: Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Keith Bouchard: Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Bruce Andrien: Role: ConceptualizationRole: Formal analysisRole: Writing – review & editing
                Andre Marozsan: Role: Formal analysisRole: Writing – review & editing
                Yi Wang: Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing – review & editing
                Paul Tamburini: Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Stanislaw Stepkowski: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 12 April 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 4
                Electronic Location Identifier: e0195909
                Affiliations
                [1 ] Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
                [2 ] Product Characterization, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
                [3 ] Early Assay Development, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
                University of Toledo, UNITED STATES
                Author notes

                Competing Interests: All authors were employees and shareholders of Alexion Pharmaceuticals, Inc., at the time the study was performed. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0001-9505-1668
                Article
                Publisher ID: PONE-D-17-44736
                DOI: 10.1371/journal.pone.0195909
                PMC ID: 5897016
                PubMed ID: 29649283
                SO-VID: 5fe117b6-c9df-4a0a-8d37-f3da8a0f3c3e
                Copyright © © 2018 Sheridan et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 22 December 2017
                Date accepted : 2 April 2018
                Page count
                Figures: 4, Tables: 3, Pages: 15
                Funding
                This study was funded by Alexion Pharmaceuticals, Inc. ( http://www.alexion.com/). Alexion Pharmaceuticals, Inc., was involved with study design, data collection and analysis, decision to publish, and preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Model Organisms
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Animal Models
                Subject: Mouse Models
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Organic Compounds
                Subject: Amino Acids
                Subject: Basic Amino Acids
                Subject: Histidine
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Organic Chemistry
                Subject: Organic Compounds
                Subject: Amino Acids
                Subject: Basic Amino Acids
                Subject: Histidine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Amino Acids
                Subject: Basic Amino Acids
                Subject: Histidine
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Complement Inhibitors
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Antibodies
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Antibodies
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Antibodies
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Antibodies
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Immune System Proteins
                Subject: Antibodies
                Subject: Biology and Life Sciences
                Subject: Physiology
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                Subject: Complement System
                Subject: Complement Activation
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Complement System
                Subject: Complement Activation
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Complement System
                Subject: Complement Activation
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Complement System
                Subject: Complement Activation
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Complement Activation
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Complement Activation
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Complement Activation
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Complement System
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Complement System
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Complement System
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Complement System
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Immune System Proteins
                Subject: Complement System
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Structures and Organelles
                Subject: Vesicles
                Subject: Endosomes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
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